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TITLE: Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU)
ABSTRACT.AIM:
To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n ≥ 228) or placebo (n = 114) with glimepiride (2–4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes.
ABSTRACT.METHODS:
In total, 1041 adults (mean ± sd), age 56 ± 10 years, weight 82 ± 17 kg and glycated haemoglobin (HbA1c) 8.4 ± 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study.
ABSTRACT.RESULTS:
Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA1c from baseline, (−1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (−0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (−0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (−1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (−0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (−0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%).
ABSTRACT.CONCLUSIONS:
Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.
BODY.INTRODUCTION:
Most drugs that target Type 2 diabetes (T2D) also cause weight gain or hypoglycaemia, or both, with the risk increasing with combination therapy. Glucagon-like peptide-1 (GLP-1)-based therapies stimulate insulin secretion and reduce glucagon secretion only during hyperglycaemia. GLP-1 also slows gastric emptying and reduces appetite [1]. Although American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines recommend lifestyle and metformin as initial therapy for T2D [2], sulphonylureas are used widely, particularly when metformin or thiazolidinediones are not tolerated. Glycaemic control eventually deteriorates with sulphonylureas while hypoglycaemia and weight gain are common [3]. Incretin therapy improves glycaemic control with low hypoglycaemic risk, while delayed gastric emptying and reduced appetite can reduce weight [1,4]. Liraglutide is a once-daily human GLP-1 analogue with 97% linear amino-acid sequence homology to human GLP-1 [5] and half-life of 13 h after subcutaneous administration that produces 24-h blood glucose control [6]. Liraglutide monotherapy for 14 weeks reduced glycated haemoglobin (HbA1c) by 1.7% and fasting plasma glucose (FPG) by 3.4 mmol/l without causing hypoglycaemia, along with weight loss (∼3 kg) compared with placebo [7]. Improvements in pancreatic B-cell function [7–9] and blood pressure [7], along with decreased glucagon secretion [7,10], also occurred. As part of the phase 3 programme [the Liraglutide Effect and Action in Diabetes (LEAD) programme] with liraglutide in > 4000 subjects with T2D as monotherapy or in combination therapy, this 26-week trial examined liraglutide plus glimepiride compared with either placebo or rosiglitazone added to glimepiride on glycaemic control and body weight.
BODY.SUBJECTS AND METHODS.STUDY PARTICIPANTS:
Inclusion criteria: T2D treated with oral glucose-lowering agents (OGLAs) for ≥ 3 months; 18–80 years of age; HbA1c 7.0–11.0% (previous OGLA monotherapy) or 7.0–10.0% (previous OGLA combination therapy); body mass index (BMI) ≤ 45.0 kg/m2. Exclusion criteria: used insulin within 3 months, impaired liver or renal function, uncontrolled hypertension (≥ 180/100 mmHg), cancer or used any drugs apart from OGLAs likely to affect glucose concentrations. Subjects provided written informed consent. The study was conducted in accordance with good clinical practice guidelines and approved by independent ethics committees.
BODY.SUBJECTS AND METHODS.STUDY DESIGN:
The study was a 26-week, double-blind, double-dummy, randomized, active-control, five-armed parallel (116 sites in 21 countries, primarily Europe and Asia) trial enrolling 1041 subjects (1–37 subjects per centre), all receiving glimepiride (2–4 mg/day) in combination with (Fig. 1): FIGURE 1Overview of trial design and treatment arms. one of three liraglutide doses [0.6, 1.2 or 1.8 mg, injected subcutaneously (Novo Nordisk, Bagsvaerd, Denmark) and rosiglitazone placebo];liraglutide placebo and rosiglitazone placebo;liraglutide placebo and rosiglitazone 4 mg/day (rosiglitazone; AvandiaTM; GlaxoSmithKline, London, UK). The doses of rosiglitazone and glimepiride used were determined by the highest doses approved in all participating counties. After discontinuing previous OGLAs except glimepiride, separate 2-week titration and maintenance periods with glimepiride (open-label) preceded randomization (Fig. 1). Subjects were stratified according to previous treatment (monotherapy or combination therapy). After randomization, 2-week treatment titration and 24-week treatment (maintenance) phases (Fig. 1) were completed. Liraglutide was up-titrated weekly in 0.6-mg increments until allocated doses were reached. Glimepiride could be adjusted between 2 and 4 mg/day in case of hypoglycaemia or other adverse events (AEs), while other drug doses were fixed. Liraglutide (active and placebo) was supplied in 3-ml pre-filled pens with 31G needles (Novo Nordisk). Subjects were encouraged to inject liraglutide into the upper arm, thigh or abdomen at the same time each day. Rosiglitazone and glimepiride were taken in the morning or with the first meal.
BODY.SUBJECTS AND METHODS.STUDY MEASUREMENTS.EFFICACY:
The primary endpoint was change from baseline HbA1c after 26 weeks of treatment. Secondary endpoints included: percentages of subjects reaching HbA1c (< 7.0%, ≤ 6.5%), FPG (5.0 to ≤ 7.2 mmol/l) and postprandial plasma glucose (PPG; 10.0 mmol/l) targets [11–13]; changes in body weight, FPG, mean PPG, indices of pancreatic B-cell function [pro-insulin : insulin ratio and homeostasis model assessment (HOMA)-B], HOMA-insulin resistance (HOMA-IR) and blood pressure (BP). HbA1c was measured centrally (MDS Pharma Services, King of Prussia, PA, USA) by high performance liquid chromatography while plasma glucose (PG) was self-measured using MediSense® glucose meters (Abbott Diagnostics Inc., Abbott Park, IL, USA). Insulin and C-peptide were measured by chemiluminescence, proinsulin by ELISA, while glucagon was measured in aprotinin-treated plasma by radioimmunoassay. The proinsulin : insulin ratio was calculated from fasting insulin and fasting proinsulin. HOMA-B and HOMA-IR were both calculated from FPG and fasting insulin. Samples measured centrally were collected and transported according to detailed procedures in the MDS Pharma Services manual. Samples stored at ambient temperature were shipped by courier to the central laboratory on the same day as collection, while frozen samples were shipped every 3 weeks.
BODY.SUBJECTS AND METHODS.STUDY MEASUREMENTS.SAFETY:
Safety variables included hypoglycaemic episodes based on PG levels (< 3.1 mmol/l), liraglutide antibodies including cross-reacting and neutralizing antibodies, tolerability (gastrointestinal complaints) and pulse. AEs, vital signs, electrocardiogram (ECG), biochemical and haematology measures including calcitonin were also monitored. Self-treated hypoglycaemic episodes were classified as minor, while those requiring third-party assistance were considered major. Serum antibodies against liraglutide were measured by radioimmunoprecipitation assay.
BODY.SUBJECTS AND METHODS.STATISTICAL ANALYSES:
All efficacy and safety analyses were based on intent-to-treat criteria, defined as subjects who were exposed to ≥ 1 dose of trial product(s). Efficacy endpoints were analysed by ancova with treatment, country and previous glucose-lowering treatment as fixed effects and baseline values as covariates. Missing data were imputed by last observation carried forward (LOCF). Sample size calculations were based on predicted HbA1c and body weight after trial completion. As the three liraglutide + glimepiride groups were to be compared with both rosiglitazone + glimepiride and glimepiride monotherapy, two calculations were performed. These sample size calculations assumed a standard deviation of 1.2% of HbA1c, the non-inferiority/superiority margin vs. active control was set to 0.4% and the difference to detect (superiority vs. placebo) was set to 0.5%. For body weight, a coefficient of variation of 3% (based on phase 2a trials for liraglutide) and a difference to detect of 3% were assumed. A combined power (calculated as the product of the marginal powers for HbA1c and body weight) of at least 85% was required. These calculations indicated that at least 168 and 81 patients completing the study would be needed for the combination and glimepiride monotherapy groups, respectively. Assuming a drop-out rate of 25%, targets for randomization were 228 in each of the combination therapy groups and 114 in the placebo group (total n = 1026). To protect against Type 1 errors, HbA1c was analysed using hierarchical testing for descending doses of liraglutide. First, superiority of liraglutide 1.8 mg to placebo was tested and, only if superior to placebo, non-inferiority to rosiglitazone was tested. If non-inferiority was obtained, superiority to rosiglitazone for liraglutide 1.8 mg was tested and superiority to placebo for liraglutide 1.2 mg was tested. If superiority was confirmed, non-inferiority to rosiglitazone would be tested and so on (i.e. testing sequence was stopped when hypotheses could not be rejected). Superiority was concluded when upper limits of two-sided 95% confidence intervals (CIs) for treatment differences were below 0%; non-inferiority was concluded if these values were < 0.4%; for secondary endpoints, Type 1 errors were controlled by estimating simultaneous CIs using Dunnett's method. Proportions of subjects achieving HbA1c (HbA1c < 7.0%, and ≤ 6.5%) and FPG (5.0 ≤ FPG ≤ 7.2 mmol/l) targets [13] were compared between treatments using logistic regression with allocated treatment and baseline values as covariates. Chi-square analyses assessed differences in treatments for percentages of subjects achieving no, one, two or three PPG values < 10 mmol/l [13]. Hypoglycaemic episodes were analysed under the assumption that number per subject were negatively binomially distributed using a generalized linear model, including treatment and country as fixed effects. Other safety data were compared by descriptive statistics. Values for descriptive statistics are expressed as means ± sd, while ancova results are expressed as least square means ± SEM or with 95% CI unless otherwise noted. Significance levels were set to 5% for two-sided tests and 2.5% for one-sided tests.
BODY.RESULTS.DISPOSITION AND DEMOGRAPHICS:
The treatment groups were well balanced (Table 1). Of 1712 subjects screened, 1041 were randomized and 1040 were exposed to trial drugs; 147 subjects (14.1%) withdrew (Fig. 2). Withdrawals were higher with placebo (27%) and rosiglitazone treatment (16%) compared with liraglutide 0.6 mg (11%), liraglutide 1.2 mg (14%) and liraglutide 1.8 mg (9%) treatment. Thirty-eight subjects (3.7%) withdrew as a result of AEs (Fig. 2). Table 1 Demographic characteristics of study participants Liraglutide 0.6 mg ( n = 233) Liraglutide 1.2 mg ( n = 228) Liraglutide 1.8 mg ( n = 234) Placebo ( n = 114) Rosiglitazone ( n = 232) Male : female (%) 54 : 46 45 : 55 53 : 47 47 : 53 47 : 53 Age (years) 55.7 ± 9.9 57.7 ± 9.0 55.6 ± 10.0 54.7 ± 10.0 56.0 ± 9.8 Duration of diabetes (years) 6.5 (4.0,10.2) 6.7 (4.0,10.7) 6.5 (3.7,10.5) 6.5 (4.5,10.6) 6.6 (4.3,10.7) Previous on mono : combi (%) 30 : 70 31 : 69 27 : 73 32 : 68 32 : 68 FPG (mmol/l) 10.0 ± 2.4 9.8 ± 2.7 9.7 ± 2.4 9.5 ± 2.0 9.9 ± 2.5 HbA 1c (%) 8.4 ± 1.0 8.5 ± 1.1 8.5 ± 0.9 8.4 ± 1.0 8.4 ± 1.0 Diabetic retinopathy (%) 17.2 14.9 12.0 13.2 16.4 Hypertension (%) 69.1 68.0 69.7 64.9 66.8 BMI (kg/m 2 ) 30.0 ± 5.0 29.8 ± 5.1 30.0 ± 5.1 30.3 ± 5.4 29.4 ± 4.8 Weight (kg) 82.6 ± 17.7 80.0 ± 17.1 83.0 ± 18.1 81.9 ± 17.1 80.6 ± 17.0 Systolic blood pressure (mmHg) 131 ± 16 133 ± 15 132 ± 16 131 ± 15.3 133 ± 15 Data are mean ± sd and percentages, except for duration of diabetes, where data are median, 25th and 75th percentile. BMI, body mass index; FPG, fasting plasma glucose; HbA 1c , glycated haemoglobin; mono : combi, previous treatment with either monotherapy or combination therapy; sd , standard deviation. FIGURE 2Flow of patients through the study.
BODY.RESULTS.EFFICACY.HBA:
HbA1c decreased rapidly with all doses of liraglutide when added to glimepiride compared with either rosiglitazone or placebo (i.e. glimepiride monotherapy), irrespective of previous therapy. The greatest decreases occurred with liraglutide 1.2 and 1.8 mg (Fig. 3a–c). After 26 weeks, HbA1c decreased by 1.1% from baseline (primary endpoint) with either liraglutide 1.2 or 1.8 mg, respectively, compared with either placebo (+0.2%) or rosiglitazone (−0.4%) (Fig. 3d). Estimated treatment differences and 95% CIs to placebo were: liraglutide 1.8 mg: −1.4% (1.6, −1.1); liraglutide 1.2 mg: −1.3% (1.5, −1.1); liraglutide 0.6 mg: −0.8% (−1.1, −0.6); rosiglitazone: −0.7% (−0.9, −0.4). All liraglutide doses were superior to placebo (P < 0.0001), while the two higher liraglutide doses were superior to rosiglitazone (P < 0.0001). Liraglutide 0.6 mg was non-inferior to rosiglitazone. Rosiglitazone also was superior to placebo (P < 0.0001). FIGURE 3Mean glycated haemoglobin (HbA1c) by treatment and week (intent-to-treat population with last observation carried forward): (a) overall population; (b) previously on monotherapy; or (c) previously on combination therapy; (d) mean changes in HbA1c from baseline after 26 weeks of treatment. Keys: (a–c) liraglutide 0.6 mg: grey dotted line with squares; liraglutide 1.2 mg: black solid line with triangles; liraglutide 1.8 mg: black dotted line with squares; rosiglitazone: grey solid line with circles; placebo: black solid line with circles. (d) liraglutide 0.6 mg: black stripes on white; liraglutide 1.2 mg: white stripes on black, liraglutide 1.8 mg: grey tint; rosiglitazone: white; placebo: black. ****P < 0.0001 compared with placebo; ††††P < 0.0001 compared with rosiglitazone. HbA1c decreases were greater for subjects who entered from monotherapy compared with combination therapy (Fig. 3d). However, because the increase with placebo was higher for individuals entering on combination therapy (0.7 vs. 0.23%), the differences between treatment groups in favour of liraglutide were similar irrespective of whether subjects were treated previously with monotherapy or combination therapy. Neither age, gender nor BMI affected these trends.
BODY.RESULTS.EFFICACY.PERCENTAGE REACHING AN HBA:
The percentage of subjects reaching ADA [2] and International Diabetes Federation (IDF)/American Association of Clinical Endocrinologists (AACE) [11,12] treatment HbA1c goals with liraglutide was dose dependent (Fig. 4). At week 26, 42% and 21% of subjects treated with liraglutide 1.8 mg reached an HbA1c < 7.0% and ≤ 6.5%, respectively, compared with 8% and 4% for placebo (Fig. 4). The estimated proportion of subjects treated with either liraglutide 1.2 or 1.8 mg reaching ADA/EASD and IDF/AACE HbA1c targets was substantially greater compared with either placebo (P < 0.0001) or rosiglitazone (Fig. 4; P ≤ 0.0003), with more patients reaching < 7.0% with liraglutide 1.8 mg compared with 1.2 mg (P = 0.018). FIGURE 4Subjects achieving specified glycated haemoglobin (HbA1c) levels: (a) percentage reaching HbA1c < 7.0% (American Diabetes Association/European Association for the Study of Diabetes target); (b) percentage reaching HbA1c < 6.5% (International Diabetes Federation/American Association of Clinical Endocrinologists targets); (c) cumulative distribution of HbA1c at 26 weeks for the intent-to-treat (ITT) population; and (d) for the ITT last observation carried forward (LOCF) population. Keys: (a, b) liraglutide 0.6 mg: black stripes on white; liraglutide 1.2 mg: white stripes on black, liraglutide 1.8 mg: grey tint; rosiglitazone: white; placebo: black. (c, d) liraglutide 0.6 mg: pale grey solid line; liraglutide 1.2 mg: grey solid line, liraglutide 1.8 mg: black solid line; rosiglitazone: dotted black line; placebo: dotted grey line; baseline visit: long dashed black line. ****P < 0.0001 or **P < 0.01 compared with placebo; ††††P < 0.0001 or †††P = 0.0005 compared with rosiglitazone.
BODY.RESULTS.EFFICACY.FASTING PLASMA GLUCOSE:
By week 2, subjects treated with liraglutide had rapid and larger decreases in FPG vs. comparator treatment. At week 26, all doses of liraglutide decreased FPG more than did placebo (Fig. 5; P < 0.0001), while only liraglutide 1.2 or 1.8 mg produced greater reductions than rosiglitazone. FPG treatment differences to placebo were 1.7 mmol/l for liraglutide 0.6 mg and 2.6 mmol/l for both liraglutide 1.2 and 1.8 mg. An 0.7-mmol/l greater reduction in FPG was achieved with either liraglutide 1.2 or 1.8 mg compared with rosiglitazone (P ≤ 0.006) after 26 weeks. FIGURE 5Mean changes from baseline in fasting plasma glucose after 26 weeks of treatment. ****P < 0.0001 compared with placebo; ††P < 0.01 compared with rosiglitazone. The percentage of subjects achieving FPG values between 5.0 mmol/l and ≤ 7.2 mmol/l (ADA target) after 26 weeks was higher with liraglutide: 0.6 mg (19%; P = 0.002); 1.2 mg (37%; P < 0.001); and 1.8 mg (38%;P < 0.001) compared with placebo (7%). The liraglutide 1.2 and 1.8 mg treatment groups also had more subjects achieving the same FPG target at end of treatment compared with rosiglitazone (26%) (P = 0.007 and P = 0.01, respectively).
BODY.RESULTS.EFFICACY.POSTPRANDIAL PLASMA GLUCOSE:
PPG was reduced similarly after each meal. The greatest reductions in mean PPG values from baseline (average of values obtained 90 min after breakfast, lunch and evening meal) occurred with liraglutide 1.2 mg (2.5 mmol/l) and liraglutide 1.8 mg (2.7 mmol/l). By comparison, the reduction from baseline in mean PPG values was 1.8 mmol/l for rosiglitazone and liraglutide 0.6 mg and 0.4 mmol/l for placebo. Treatment differences for PPG were greater with all doses of liraglutide compared with placebo (1.5–2.4 mmol/l; P < 0.0001) and greater with liraglutide 1.2 mg (0.64 mmol/l; P = 0.043) and 1.8 mg (0.87 mmol/l;P = 0.0022) compared with rosiglitazone.
BODY.RESULTS.EFFICACY.PPG MEASUREMENTS < 10.0 MMOL/L:
The percentage of subjects with one, two or three PPG measurements < 10.0 mmol/l (ADA target) were greater for all doses of liraglutide compared with placebo (P < 0.05) but not rosiglitazone.
BODY.RESULTS.BODY WEIGHT:
Mean weight at baseline was 81.6 kg. Mean reductions in weight from baseline to end of treatment were 0.2 kg with liraglutide 1.8 mg and 0.1 kg with placebo treatment, while increases occurred with either liraglutide 0.6 mg (0.7 kg), liraglutide 1.2 mg (0.3 kg) or rosiglitazone (2.1 kg) (Fig. 6). Unlike rosiglitazone, weight did not increase substantially with liraglutide and the differences between rosiglitazone and liraglutide were statistically significant (−2.3 to −1.4 kg; P < 0.0001), although there were no significant differences compared with placebo. Gender appeared to have no influence on the results, as indicated when added as a fixed effect in the ancova model. FIGURE 6Mean changes in body weight from baseline after 26 weeks of treatment. *P < 0.05 compared with placebo; ††††P < 0.0001 compared with rosiglitazone.
BODY.RESULTS.INDICES OF PANCREATIC B-CELL FUNCTION AND INSULIN RESISTANCE:
Reductions in the proinsulin : insulin ratio were greater with both liraglutide 1.2 and 1.8 mg compared with either rosiglitazone or placebo (Table 2; P ≤ 0.02). HOMA-B increased with liraglutide (1.8 or 1.2 mg) compared with rosiglitazone (P < 0.05), while this increase was only different to placebo with liraglutide 1.2 mg (P = 0.01) and not liraglutide 1.8 mg (P = 0.051). There were no significant differences between treatments for HOMA-IR. Table 2 Selected indices of pancreatic B-cell function Variable Treatment Baseline Week 26 (LOCF) Least square difference from placebo (95% CI) Least square difference from rosiglitazone (95% CI) Proinsulin : insulin ratio Liraglutide 0.6 mg 0.42 ± 0.22 0.38 ± 0.24 −0.05 (−0.11; 0.00) −0.02 (−0.06; 0.03) Liraglutide 1.2 mg 0.45 ± 0.31 0.33 ± 0.20 −0.10 (−0.16; −0.05) † −0.07 (−0.11; −0.02) * Liraglutide 1.8 mg 0.48 ± 0.33 0.36 ± 0.20 −0.09 (−0.15; −0.03) * −0.05 (−0.10; −0.01) * Placebo 0.44 ± 0.27 0.46 ± 0.29 Rosiglitazone 0.45 ± 0.29 0.40 ± 0.20 HOMA-B (%) Liraglutide 0.6 mg 51 ± 43.3 70 ± 88.6 15 (−19.10; 49.0) 11 (−16.7; 39.0) Liraglutide 1.2 mg 71 ± 254.3 99 ± 184.3 43 (8.10; 76.9) * 39 (10.3; 67.0) * Liraglutide 1.8 mg 56 ± 84.6 91 ± 108.2 34 (−0.23; 68.5) 30 (2.00; 58.6) * Placebo 56 ± 103.3 52 ± 107.3 Rosiglitazone 46 ± 36.2 59 ± 63.3 * P ≤ 0.05; † P < 0.0001. CI, confidence interval; HOMA, homeostatis model assessment; LOCF, last observation carried forward.
BODY.RESULTS.BLOOD PRESSURE AND PULSE:
Although decreases in systolic blood pressure occurred with either liraglutide 1.2 or 1.8 mg (2.6–2.8 mmHg), they were not significantly different from placebo or rosiglitazone (0.9–2.3 mmHg). Reductions in diastolic blood pressure also occurred with all treatments (0.7–1.4 mmHg), with no significant differences between treatments. Pulse increases above baseline ranged from 2 to 4 beats/min with the three doses of liraglutide and 1 beat/min with rosiglitazone, while pulse decreased by 1 beat/min with placebo. Changes in pulse for all doses of liraglutide were significant vs. placebo (P ≤ 0.002). This also was true with either liraglutide 1.8 or 1.2 mg compared with rosiglitazone (P < 0.01).
BODY.RESULTS.SAFETY:
The most common treatment-emergent AEs that were considered by investigators to be either possibly or probably related to liraglutide were gastrointestinal (diarrhoea, nausea, dyspepsia and constipation) and nervous system disorders (headache and dizziness), particularly during the first 4 weeks. Nausea was highest with liraglutide 1.2 mg (10.5%) and lowest with placebo (1.8%). Vomiting (4.4%) and diarrhoea (7.9%) were also higher with liraglutide 1.2 mg. Withdrawals because of nausea ranged from 0.9–2.2%, vomiting 0.4–0.9% and diarrhoea 0–1.3%. Nausea was more common with liraglutide compared with placebo and rosiglitazone, particularly during the first 4 weeks (Fig. 7). Frequency of nausea was less in the liraglutide 0.6 mg treatment group compared with the higher doses of liraglutide. Generally, the occurrence of nausea dissipated from 4 to 26 weeks of treatment in all groups using liraglutide (Fig. 7). FIGURE 7Percentage of subjects experiencing nausea over the course of the study. Key: liraglutide 0.6 mg with glimepiride: black line with filled circles; liraglutide 1.2 mg with glimepiride: black line with filled triangles; liraglutide 1.8 mg with glimepiride: grey line with hollow circles; glimepiride grey lines with filled squares; rosiglitazone and glimepiride: grey line with hollow triangles. The incidence of serious AEs ranged between 3 and 5%: placebo (3%), rosiglitazone (3%), liraglutide 0.6 mg (3%), liraglutide 1.2 mg (4%) and liraglutide 1.8 mg (5%). Most treatment-emergent serious AEs were judged by investigators to be unlikely to be related to trial products. No deaths were reported during the trial. One subject developed chronic pancreatitis whilst taking liraglutide 0.6 mg; the person had no reported previous history of pancreatitis. The subject continued on liraglutide therapy and completed the trial. At screening, five patients had been previously diagnosed with pancreatitis. As pancreatitis was not an exclusion criterion, these patients were randomized as follows: one to liraglutide 0.6 mg, one to liraglutide 1.2 mg, two to liraglutide 1.8 mg and one to rosiglitazone + glimepiride. All five patients completed the trial without reporting pancreatitis as an adverse event. Hypoglycaemia was infrequent with all treatments. One major hypoglycaemic episode (self-measured blood glucose = 3.0 mmol/l) occurred 9 days after treatment started in a subject receiving liraglutide 1.8 mg in combination with glimepiride. Although medical assistance was not needed, the subject required third-party assistance. The investigator judged the episode as likely to be related to glimepiride and reduced the dose from 4 to 3 mg after the incident. Minor hypoglycaemia occurred in < 10% of subjects for any treatment. The proportion of subjects experiencing minor hypoglycaemia during the trial was lowest with placebo (i.e. glimepiride monotherapy 2.6%; 0.17 events/subject-year), comparable with liraglutide 0.6 mg (5.2%, 0.17 events/subject-year) and rosiglitazone (4.3%, 0.12 events/subject-year) groups and similar between the liraglutide 1.2 mg (9.2%, 0.51 events/subject-year) and liraglutide 1.8 mg (8.1%, 0.47 events/subject-year) treatment groups. Incidence was higher with liraglutide 1.2 mg (P = 0.0024) and 1.8 mg (P = 0.0065) compared with rosiglitazone and liraglutide 1.2 mg compared with placebo (P = 0.048), occurring in the setting of lower mean HbA1c values. Antibodies to liraglutide were found in 9–13% of subjects treated with liraglutide. No significant effects of these antibodies on HbA1c were found in pooled analyses of four trials including the current study. There were no clinically relevant changes in ophthalmoscopy, biochemistry, urinalysis, haematology or ECG assessments. No significant differences in calcitonin were found between the three groups treated with liraglutide when compared with either placebo or rosiglitazone at the end of the trial at week 26.
BODY.DISCUSSION:
Treatment with liraglutide plus glimepiride was superior to glimepiride monotherapy at all doses of liraglutide and superior to rosiglitazone plus glimepiride for the two higher liraglutide doses for improving HbA1c. Similar findings for reductions in FPG and PPG highlight improved 24-h glucose control with once-daily liraglutide, with substantially more subjects reaching glycaemic targets, particularly with liraglutide 1.8 mg. Improvements in pancreatic B-cell function were larger with liraglutide 1.2 and 1.8 mg compared with rosiglitazone. Liraglutide was well tolerated and occurrence of gastrointestinal AEs was low overall, particularly after week 4. Although rates of hypoglycaemia were low in all treatment groups (< 10%), minor hypoglycaemic events occurred more often in patients treated with glimepiride plus liraglutide 1.2 or 1.8 mg than with glimepiride alone. It should be noted, however, that patients treated with liraglutide 1.2 or 1.8 mg achieved a lower HbA1c than those receiving glimepiride monotherapy. At lower HbA1c levels, sulphonylureas are known to elicit hypoglycaemia more readily than at higher levels. In clinical practice it may be possible to reduce the dose of sulphonylurea (when used with liraglutide) to minimize risk of hypoglycaemia and maintain HbA1cimprovements. Although weight effects were modest, liraglutide produced more favourable weight effects compared with rosiglitazone, which produced substantial weight gain. In other studies with liraglutide, subjects adding a 1.8-mg dose to metformin lost 2.8 kg [14], while those adding both metformin and glimepiride lost 1.8 kg compared with placebo [15] (both over 26 weeks) and those on liraglutide monotherapy (1.8 mg) lost 2.45 kg over 52 weeks [16]. In our study, because sulphonylureas usually cause weight gain, inclusion or optimization of glimepiride but not metformin may have mitigated the weight benefits typically associated with liraglutide. Lack of weight effects could be secondary to lower baseline body weight, withdrawal of previous metformin treatment or defensive snacking to minimize risk of hypoglycaemia. It might have been expected that the greater weight gain with rosiglitazone compared with liraglutide 1.8 mg would be associated with a concurrent increase in insulin resistance with rosiglitazone. The absence of this effect could reflect the insulin-sensitizing nature of rosiglitazone. Improvements in pancreatic B-cell function associated with liraglutide are consistent with other studies [7–9]. Study strengths include inclusion of both placebo and active (rosiglitazone) comparators and that OGLAs were optimized (not maximized) before randomization to minimize risk of hypoglycaemia. Limitations of the study include short duration of the trial and restriction on glimepiride and rosiglitazone in some countries that precluded maximal dosing. The impact of using other GLP-1-based treatments [such as exenatide, or the dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin] with sulphonylureas in subjects with T2D has been studied. In a 30-week American trial where exenatide twice a day was added to sulphonylureas, HbA1c was reduced by 0.46% from baseline with 5 μg and 0.86% with 10 μg [17] compared with 1.1% with liraglutide 1.8 or 1.2 mg. This reduction in HbA1c with liraglutide is consistent with other LEAD trials investigating liraglutide as monotherapy or in combination with various OGLA drugs. In these trials, HbA1c was reduced by 1–1.5%[14,16,18–20]. Reductions in FPG with exenatide were 0.3 and 0.6 mmol/l from baseline with 5 μg and 10 μg, respectively, compared with 1.4 mmol/l with liraglutide 1.8 mg; weight loss of 1.6 kg occurred with exenatide 10 μg compared with 0.2 kg for liraglutide 1.8 mg [17]. Differences in weight effects may be as a result of lower baseline weight in this trial (82 kg) compared with exenatide (96 kg) and discontinuation of previous metformin therapy, unlike the exenatide trial where exenatide was added to previous sulphonylurea monotherapy [17]. Other large-scale trials with liraglutide in combination with sulphonylureas have demonstrated weight loss of 2–3 kg [18,20]. Withdrawals from exenatide trials ranged from 24–30% compared with 9–14% with liraglutide in this study. Nausea with exenatide ranged from 39% with 5 μg to 51% with 10 μg [17] compared with 10.5% for liraglutide. Furthermore, 41% were positive for anti-exenatide antibodies compared with 9–13% with anti-liraglutide antibodies. With sitagliptin 100 mg once daily for 24 weeks, HbA1c decreased by 0.3% from baseline in subjects receiving glimepiride, with 11% achieving an HbA1c < 7.0%[21]. Reductions in FPG and PPG from baseline were 0.05 and 1.4 mmol/l, respectively, while weight increased by 0.8 kg and the prevalence of nausea was < 1%. Although head-to-head trials are required to test true differences between these agents, the marked effects of liraglutide on FPG may be as a result of consistent blood levels of liraglutide maintained over 24 h compared with exenatide which has to be administered 60 min before breakfast and dinner and has a half-life of 1.5–3.6 h [22]. In a recent 26-week head-to-head trial comparing liraglutide with exenatide, liraglutide produced a 0.3% greater decrease on HbA1c (P < 0.0001) [20]. Because DPP-4 inhibitors inhibit the degradation of GLP-1, the efficacy of sitagliptin is dependent on levels of endogenous GLP-1 which is physiologically low compared with the much higher pharmacological levels of liraglutide. Pharmacological levels may be needed to induce satiety, weight loss and possibly larger HbA1c reductions. Liraglutide is an effective and well-tolerated once-daily human GLP-1 analogue that improves overall glycaemic control and indices of pancreatic B-cell function with minimal weight gain and risk of hypoglycaemia when used in combination with a sulphonylurea for T2D.
BODY.COMPETING INTERESTS:
The study was funded by Novo Nordisk, the manufacturer of liraglutide. In collaboration with the investigators, Novo Nordisk was responsible for the study design, protocol, statistical analysis plans, oversight, analysis and reporting of the results. Data were recorded at the clinical centres and maintained by the sponsor. The LEAD-1 SU study group had full access to the data. Final responsibility for the decision to submit the manuscript for publication was the authors. MM has received lecture fees from Novo Nordisk, Servier, MSD; JS has received honoraria, grants and lecture fees from Novo Nordisk; MB, WMWB and NAK have no conflicts to declare; JS has received lecture fees from Novo Nordisk; MZ is employed by, and holds stock in, Novo Nordisk; TLT is employed by Novo Nordisk; SC is a member of the international advisory board on liraglutide for Novo Nordisk and has received lecture fees from Novo Nordisk. | 2,871,176 | {
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"Although decreases in systolic blood pressure occurred with either liraglutide 1.2 or 1.8 mg (2.6–2.8 mmHg), they were not significantly different from placebo ",
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"Incidence was higher with liraglutide 1.2 mg (P = 0.0024) and 1.8 mg (P = 0.0065) compared with rosiglitazone and liraglutide 1.2 mg compared with placebo (P = 0.048), occurring in the setting of lower mean HbA1c values.",
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"Incidence was higher with liraglutide 1.2 mg (P = 0.0024) and 1.8 mg (P = 0.0065) compared with rosiglitazone and liraglutide 1.2 mg compared with placebo (P = 0.048), occurring in the setting of lower mean HbA1c values."
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"The estimated proportion of subjects treated with either liraglutide 1.2 or 1.8 mg reaching ADA/EASD and IDF/AACE HbA1c targets was substantially greater compared with either placebo (P < 0.0001) or rosiglitazone (Fig. 4; P ≤ 0.0003), with more patients reaching < 7.0% with liraglutide 1.8 mg compared with 1.2 mg (P = 0.018). ",
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"The percentage of subjects with one, two or three PPG measurements < 10.0 mmol/l (ADA target) were greater for all doses of liraglutide compared with placebo (P < 0.05) but not rosiglitazone.",
"The percentage of subjects with one, two or three PPG measurements < 10.0 mmol/l (ADA target) were greater for all doses of liraglutide compared with placebo (P < 0.05) but not rosiglitazone."
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"Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (−1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). "
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"At week 26, all doses of liraglutide decreased FPG more than did placebo (Fig. 5; P < 0.0001),",
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"HOMA-B increased with liraglutide (1.8 or 1.2 mg) compared with rosiglitazone (P < 0.05),",
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"Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (−1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). ",
"Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) ",
"Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (−1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). "
],
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"HOMA-B increased with liraglutide (1.8 or 1.2 mg) compared with rosiglitazone (P < 0.05),",
"HOMA-B increased with liraglutide (1.8 or 1.2 mg) compared with rosiglitazone (P < 0.05), while this increase was only different to placebo with liraglutide 1.2 mg (P = 0.01) and not liraglutide 1.8 mg (P = 0.051)"
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20728
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"Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l).",
"At week 26, all doses of liraglutide decreased FPG more than did placebo (Fig. 5; P < 0.0001)",
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"Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA1c from baseline, (−1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%)",
"After 26 weeks, HbA1c decreased by 1.1% from baseline (primary endpoint) with either liraglutide 1.2 or 1.8 mg, respectively, compared with either placebo (+0.2%) or rosiglitazone (−0.4%) (Fig. 3d). ",
"Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA1c from baseline, (−1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) ",
"After 26 weeks, HbA1c decreased by 1.1% from baseline (primary endpoint) with either liraglutide 1.2 or 1.8 mg, respectively, compared with either placebo (+0.2%) or rosiglitazone (−0.4%) (Fig. 3d). Estimated treatment differences and 95% CIs to placebo were: liraglutide 1.8 mg: −1.4% (1.6, −1.1); liraglutide 1.2 mg: −1.3% (1.5, −1.1); liraglutide 0.6 mg: −0.8% (−1.1, −0.6); rosiglitazone: −0.7% (−0.9, −0.4). All liraglutide doses were superior to placebo (P < 0.0001), while the two higher liraglutide doses were superior to rosiglitazone (P < 0.0001)"
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TITLE: Anti-TNF-α treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial
ABSTRACT.BACKGROUND:
Endometriosis is associated with an inflammatory response. Hence infliximab, an anti-TNF-α monoclonal antibody, might relieve pain.
ABSTRACT.METHODS:
A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule of at least 1 cm. After 1 month of observation, three infusions of infliximab (5 mg/kg) or placebo were given. Surgery was performed 3 months later and follow-up continued for 6 months. The primary end-point was pain (dysmenorrhea, deep dyspareunia and non-menstrual pain) rated at each visit by the clinician and on a daily basis by the patient who in addition scored pain by visual analog pain scale and analgesia intake. Secondary end-points included the volume of the endometriotic nodule, pelvic tenderness and the visual appearance of endometriotic lesions at laparoscopy.
ABSTRACT.RESULTS:
Pain severity decreased during the treatment by 30% in both the placebo (P < 0.001) and infliximab groups (P < 0.001). However, no effect of infliximab was observed for any of the outcome measures. After surgery, pain scores decreased in both groups to less than 20% of the initial value.
ABSTRACT.CONCLUSIONS:
Infliximab appears not to affect pain associated with deep endometriosis. Treatment is associated with an important placebo effect. After surgery, pain decreases to less than 20%. Trials registration number ClinicalTrials.gov: NCT00604864.
BODY.INTRODUCTION:
Endometriosis is associated with pelvic pain, especially if deep and/or ovarian cystic lesions are present (Koninckx et al., 1991b, 1994). Whether subtle lesions cause pain is not yet substantiated. The association of pain and typical endometriosis was derived from observational studies in which women with pelvic pain have a higher incidence of endometriosis (range: 40–80%) than women with infertility without pain (20–50%) or control groups (5–20%) (Koninckx et al., 1991b). Surgical ablation of typical endometriosis has been reported to decrease pain in several observational studies and in a randomized controlled trial (Sutton et al., 1994, 1997; Jacobson et al., 2001). The strong association between cystic ovarian and deep endometriosis with severe pelvic pain was invariably noted in observational studies, and logistic regression showed deep and cystic endometriosis to be the strongest predictors of pelvic pain (Koninckx and Martin, 1994; Vercellini et al., 1996). Following the surgical excision, pain invariably decreased by some 80% (Donnez et al., 1995; Koninckx and Martin, 1997; Brouwer and Woods, 2007; Darai et al., 2007; Kristensen and Kjer, 2007). The pathophysiology of the association between endometriosis and pain is poorly understood. Several hypotheses have been put forward. First, as endometriosis is a hormonally responsive tissue similar to endometrium, it is reasonable to assume that mini-menstrual bleedings (Brosens, 1997) cause pain because of pelvic irritation by blood, by an inflammatory reaction or by the tension in the micro cysts of the lesions. This hypothesis is supported by a series of observations. During menstruation pain typically worsens and deep lesions feel tender (Koninckx et al., 1996a). At laparoscopy, endometriotic lesions were observed to bleed during menstruation (personal observation). Natural menopause and all medical treatments, which inactivate the endometrium (Vercellini et al., 1997, 2007a), prevent menstruation or decrease menstrual blood loss, including GnRH agonists (Shaw, 1991) and oral contraceptives decrease pain. Inflammatory reaction and neo angiogenesis (Oosterlynck et al., 1993) around endometriotic lesions have been observed during laparoscopy and by pathology. Secondly, in deep lesions, the observed endometriotic invasion of nerve fibers and the association with mast cells (Anaf et al., 2000, 2002, 2004, 2006) might explain the severe pain. Finally, especially deep endometriosis can cause sclerotic compression of ureters and of nerve fibers, as demonstrated by the excision of endometriosis surrounding the sciatic nerve (Batt et al., 2004; Possover and Chiantera, 2007) or the pudendal nerve in cases of menstrual sciatalgia or Alcock syndrome (Robert et al., 1998; Possover and Chiantera, 2007). TNF-α, a pro-inflammatory cytokine, has been implicated in the pathophysiology of endometriosis (Agic et al., 2006). TNF-α levels are increased in peritoneal fluid of women with endometriosis (Bedaiwy et al., 2002), and the levels correlate with severity of disease (Richter et al., 2005). Peritoneal fluid TNF-α is produced locally by activated peritoneal macrophages (Koninckx et al., 1999). TNF-α induces IL-8 secretion by peritoneal mesothelial cells (Arici, 2002). The peritoneal fluid concentrations of TNF-α and IL-8 correlate with the size and the number of active peritoneal lesions (Bullimore, 2003). Serum TNF-α levels are increased, and monocytes from patients with endometriosis release more TNF-α in vitro compared with monocytes from controls (Braun et al., 1996). Peritoneal fluid levels of MCP-1 are increased in patients with endometriosis. TNF-α, IL-8 and MCP-1 drive an inflammatory Th-1 type response in the peritoneal fluid of patients with endometriosis (Akoum et al., 1995). The anti-inflammatory effect of blocking TNF-α by monoclonal antibodies (e.g. infliximab) or by soluble TNF-α receptors (e.g. etanercept) has been demonstrated in vivo in animal models and also in the human. The clinical effectiveness of blocking TNF-α has been demonstrated in inflammation driven conditions including Crohn's disease and rheumatoid arthritis but not in severe endometriosis (Shakiba and Falcone, 2006). In baboons with laparoscopically confirmed endometriosis, TNF-α blockade with p55 soluble TNF-α receptors results in inhibition of the development and growth of endometriotic implants (D'Hooghe et al., 2006). The size of peritoneal red lesions was decreased in comparison with a control group (Barrier et al., 2004), but there was no increase in pregnancy rates (Falconer et al., 2007). In rats with ectopically transplanted endometrial tissue, the administration of recombinant human TNF-α binding protein-1 (r-hTBP-1) resulted in defective development of implants compared with controls (D'Antonio et al., 2000). TNF-α mediated inflammation may be a causal factor in the pain associated with endometriosis and blocking TNF-α appears to inhibit the development of the disease in animal models. We evaluated the effect of infliximab on pain in women with rectovaginal endometriosis at a dose proven to be effective in inflammatory bowel disease and rheumatoid arthritis.
BODY.MATERIALS AND METHODS.PATIENTS:
All patients (aged 18–50 years) were recruited from a single, tertiary referral hospital at Leuven University, Belgium. All women suffered from pelvic pain and were scheduled for surgical excision of a rectovaginal endometriotic nodule of at least 1 cm in diameter with or without cystic ovarian endometriosis. None of the women had previously been operated for deep endometriosis. All women had a regular cycle (25–40 days) and moderate to severe pelvic pain as defined by their score on the Biberoglu–Behrman scale. If previously treated with hormonal medication, including progestagens, GnRH analogs, Danazol or oral contraceptives, at least 3 months had elapsed and they had at least two menstrual cycles since stopping treatment. The study was reviewed and approved by the institutional review board of KULeuven. Written informed consent was obtained from each subject. If not sterilized the patient had to agree to use a double-barrier method of contraception for the duration of the study, and up to 6 months after receiving the last infusion with infliximab. In view of infliximab's known side-effect profile, the following were exclusion criteria: (i) old or currently active TB; (ii) evidence of serious infections in the previous 3 months; (iii) documented HIV infection, active hepatitis-B or C, or an opportunistic infection (e.g. herpes zoster, cytomegalovirus, pneumocystis carinii, aspergillosis, histoplasmosis or mycobacteria other than TB) in the previous 6 months; (iv) previous transplant surgery, a lymphoproliferative disorder or other malignancy; (v) positive cervical cytology in the previous 6 months; (vi) previous treatment with infliximab or, any drug known to affect TNF-α levels, e.g. pentoxifylline, thalidomide and etanercept, or any human/murine recombinant products; (vii) known allergy to murine products; (viii) recent use of other investigational drugs within 1 month of recruitment or within five half-lives of the investigational agent, whichever was longer and (ix) any hematological or biochemical abnormalities on routine screening. Subjects were also excluded if there was pelvic pathology on transvaginal ultrasound (TVU) scan other than small uterine fibroids (<4 cm in diameter) or an ovarian endometrioma or endometriotic nodule.
BODY.MATERIALS AND METHODS.STUDY DESIGN:
This study was a single center, randomized, double-blind, placebo-controlled pilot study in 21 women with deep endometriosis-associated pain in whom excisional surgery was planned as therapy. Randomization was performed in a 2–1 ratio for active and placebo treatments, respectively, 14 women thus receiving active treatment and seven receiving placebo. In one patient of the infliximab group, with a deep nodule diagnosed by TVU only, no deep endometriotic nodule was found during surgery. Both groups were similar for age, weight, height, blood pressure, heart rate, days of bleeding, age of menarche, number of pregnancies and spontaneous abortions, leucocyte and blood cell count and liver function tests. Patients receiving placebo (n = 7) and infliximab (n = 13) were 30.7 ± 5.5 and 28.4 ± 4.5 years old with a weight of 52.7 + 5.4 and 62.5 ± 7.4 kg (P = 0.002), a height of 161 + 5 and 162 + 5 cm, a cycle length of 29 + 2 and 32 + 5 days, a systolic blood pressure of 127 ± 15 and 120 ± 12 mm of mercury, a diastolic blood pressure of 78 ± 11 and 78 ± 7 mm of mercury and a heart rate of 79 ± 14 and 83 ± 12, respectively. The study period consisted of 40 weeks, i.e. at least 4 weeks pre-treatment evaluation, a 12 week treatment period followed by surgery and 24 weeks follow-up period. Visits were scheduled at least 4 weeks before the start of treatment (Visit 1, Week 4), at the start of treatment (Visit 2, Week 0), then 2 (Visit 3), 4 (Visit 4), 8 (Visit 5) and 12 (Visit 6) weeks after the start of treatment and 6 (Visit 7) and 12 (Visit 8) weeks after surgery. Infliximab or placebo was administered as a slow infusion of 250 ml at the beginning of the cycle (Week 0 or Visit 2) and repeated after 2 (Visit 3) and 6 weeks (Visit 4) reflecting the typical induction treatment scheme of 0, 2 and 6 weeks given in other inflammatory pathologies, such as Crohn's disease and rheumatoid arthritis. Women were monitored for adverse effects for 1 h post-infusion. A pregnancy test was performed prior to the infusion and on Week 8. At each visit and during the follow-up period, safety was monitored through standard blood tests, vital signs and breast examination. Adverse events were reviewed by a Safety Monitoring Committee every 3 months. The primary end-point was the effect of infliximab treatment upon pelvic pain including the intake of pain killers. Secondary end-points included the volume of endometriotic nodules assessed clinically and on TVU, the macroscopical appearance of endometriotic lesions during surgery and the extend of endometriosis. The revised American Fertility (rAFS) classification system was not used to score endometriosis since the severity of deep endometriosis is poorly reflected in the rAFS score.
BODY.MATERIALS AND METHODS.CLINICAL EVALUATIONS OF ENDOMETRIOSIS AND PAIN ASSESSMENT:
Pain was assessed by one gynecologist (PK) at each visit using a modified Biberoglu–Behrman scale, scoring from 0 (no pain) to 3 (severe pain) dysmenorrhea, deep dyspareunia, chronic pelvic pain, pelvic tenderness and pelvic induration. In addition the patients independently recorded daily dyspareunia, dysmenorrhea and pelvic pain and the intake of Ibuprofen 100 mg tablets. In addition, they recorded weekly by visual analog pain scale (VAS), the average maximum tolerated pain (i.e. before intake of a pain killer) over the last 7 days. Ibuprofen was taken as required up to a maximum of 2.4 g/day; additional pain medication was permitted with documentation. A TVU was performed during the screening period and at Visits 2, 3, 5 and 6 to measure deep endometriosis volume and endometrial thickness (Timmerman et al., 2002). Patients recorded daily the amount of vaginal blood loss.
BODY.MATERIALS AND METHODS.TREATMENTS, RANDOMIZATION AND BLINDING:
Infliximab an IgG monoclonal anti-TNF antibody was supplied by Centocor as a lyophilized solid containing 100 mg of infliximab IgG, 0.5 g of sucrose, 6.1 mg of dibasic sodium phosphate dihydrate, 2.2 mg of monobasic sodium phosphate monohydrate and 0.5 mg of polysorbate 80 in a 20 ml vial for reconstitution in 10 ml of sterile water for injection. The placebo was supplied as a lyophilized solid containing 0.5 g of sucrose, 6.1 mg of dibasic sodium phosphate dihydrate, 2.2 mg of monobasic sodium phosphate monohydrate and 0.5 mg of polysorbate 80 in a 20 ml vial for reconstitution in 10 ml of sterile water. The vials of infliximab/placebo were supplied by Centocor, stored at 2–8°C and reconstituted immediately before each administration. All investigators, research nurses and patients were blinded throughout the study. Randomization (prepared by Centocor Paris) was performed by consecutive sealed envelopes opened by the pharmacist prior to the preparation of medication. Randomization code was broken only after the database had been locked.
BODY.MATERIALS AND METHODS.SURGERY AND OTHER PROCEDURES:
Surgery for endometriosis was performed as reported (Koninckx and Barlow, 1999) 4–6 weeks after the last infliximab dose. A follow-up visit was planned 4–9 weeks after surgery (Visit 7) and a final visit to assess safety was performed between 26 and 29 weeks (Visit 8). During surgery, an endometrial biopsy was taken and subsequently processed for routine pathology.
BODY.MATERIALS AND METHODS.STATISTICS:
This study was an exploratory trial, and thus not powered to detect small differences. An important decrease of pain would have been detected, since with a SD of 2, a difference in BB score of 3 would have been detected with a power of 90%. To detect small differences, e.g. of one point with a power of 80% a RCT of 120 women would have been necessary. Statistical analysis was performed with the SAS system (SAS/STAT users guide, 1988). Wilcoxon Rank sum test was used to evaluate differences of means at each visit for each variable. Since in this study obviously two possible effects were present simultaneously, i.e. the effect of Infliximab treatment and the effect of placebo or surgery, a two-way analysis of variance (proc GLM, general linear methods) was performed, analysing simultaneously for each end-point the effect of treatment (control or anti-TNF-α) and the placebo or surgery effect (the difference between two treatment periods). Baseline was defined as the mean of Visits 1 and 2, the early treatment period as the mean of Visits 3 and 4 and the late treatment period as mean of Visits 5 and 6. For the effect of surgery, baseline, early and late treatment periods were compared with the post-operative period (mean of Visits 7 and 8). Since pain was exacerbated during menstruation, the menstrual period, defined as the first 4 days of the cycle was analysed separately. A menstrual cycle was defined as starting with the first day of bleeding and lasting for 28 days. The effect upon pain was evaluated from the 5 BB entries made by the physician, and the 3 BB entries, the VAS scale and the intake of ibuprofen and other painkillers recorded by the patients. Analysis of pain killer intake was done twice: a first analysis was done considering only the ibuprofen intake (the number of tablets of ibuprofen taken); in a second analysis other painkiller intake was taken into account: if other painkillers had been taken the number of tablets taken was added to the number of ibuprofen tablets taken; if other strong pain killers had been injected, e.g. a morphine product, these injections were arbitrarily scored as six tablets in order to obtain the total score. In addition, the effect of treatment upon two calculated total pain scores combining the individual BB entries and pain killer intake was calculated. A first total pain score consisted of the sum of dysmenorrhea, deep dyspareunia and pelvic pain (both as assessed by the clinician and by the patients). In order to take also the ibuprofen intake into account, a second total pain score was calculated by multiplying the total daily pain score with the number +1 (in order to avoid to multiply by zero) of ibuprofen tablets taken during that day. Both an intention to treat analysis, considering all 21 patients included, and an analysis of the 20 women with endometriosis was performed. Since results were identical only the latter will be given in the manuscript. Means and SE are given unless indicated otherwise. For the safety analysis, obviously all 14 women treated with Infliximab were included. Results are presented as mean + SE. Spearman correlation was used for correlation analysis.
BODY.RESULTS:
These women with endometriosis had very severe pain before treatment with a total BB score of 12.2 on a scale of 15 (Figs 1 and 2). The baseline BB scorings by the clinician were calculated as 2.7 + 0.09 for dysmenorrhea, 2.3 + 0.19 for deep dyspareunia, 2.2 + 0.12 for chronic pain, 2.2 + 0.14 for pelvic tenderness, 2.8 + 0.07 for pelvic induration, with a sum of the pain scores of 7.1 + 0.24 and a total BB score of 12.2 + 0.28. Figure 1:Dysmenorrhea, deep dyspareunia and chronic pelvic pain, as assessed by the clinician (upper graphs) and by the patient in her diary, before treatment, during the 12 week treatment period (shaded area) and after surgery.Baseline versus early treatment: NS, baseline versus late treatment: >0.003 for all. Baseline and late treatment versus post-surgery: P < 0.001 for all. Infliximab: NS for all. Figure 2:Induration, pelvic tenderness and total Biberoglu–Behrman score together with VAS scales as recorded at each visit and weekly by the patient in her diary, before treatment, during the 12 week treatment period (shaded area) and after surgery.Baseline versus early treatment, NS; baseline versus late treatment, >0.003 for all except NS for VAS dysmenorrhea. Baseline and late treatment versus post-surgery: P < 0.001 for all. Infliximab: NS for all. As shown in Figs 1, 2 and 3, during the 12 week treatment period a similar exponential decrease in pain of some 25–30% was observed in both the control and the infliximab group, compatible with a placebo effect. No statistically significant differences between placebo and infliximab treatment could be identified. The strong and significant placebo effect and the absence of an infliximab effect were consistently found for all pain estimations in this study, i.e. the five scorings by the clinician and the calculated total scores (i.e. dysmenorrhea, deep dyspareunia, chronic pain, pelvic tenderness, the sum of the 3 BB pain scores and the total BB score) and the pain recorded in the dairy by the patients (i.e. the 3 BB scores, the visual analog scales, the pain killer intake and both calculated total scores, i.e. with or without taking pain killer intake into account). The placebo effect was not significant for the early treatment period (Visits 3 and 4) but highly significant for the late treatment period (Visits 5 and 6) both by two way analysis of variance (P < 0.003 to 0.001 for all) and when the placebo (Wilcoxon, P < 0.001) and the infliximab group (Wilcoxon, P < 0.001) were analysed separately. No effect of treatment was found upon the mean diameters of the nodules as measured by TVU. For the placebo group (n = 7) and the infliximab group (n = 13), the diameters were 15.2 ± 4.6 and 13.6 ± 3.2 mm, during Visit 3, 15.1 ± 5.12 and 14.25 ± 3.5 mm, during Visit 5, 13.5 ± 4.9 and 15.6 ± 3.5 mm and during Visit 6, 13.2 + 3.4 and 15.1 + 2.38 mm. Endometrial thickness was not affected by treatment, being at baseline and at the end of the treatment period for the infliximab group 5.2 (range 1.3–18) and 7.8 (1.9–11) mm and for the placebo group 7.7 (1.8–23) and 8.2 (3–15) mm, respectively. During surgery, no obvious differences were observed in the extend of the disease, the macroscopic aspect of endometriosis (vascularization and sclerosis), the duration of surgery and bleeding estimates. Routine pathology (FC) also showed no obvious differences between the two groups. After surgery, all pain estimates decreased to less than 10% of the baseline in both groups (Figs 1 and 2), and no differences were found between the placebo and the infliximab group (two-way analysis of variance). This decrease of pain after surgery was highly significant (P < 0.001) for all pain estimates at all visits. During treatment all side-effects were reviewed by the safety committee. One patient had 2 days after the second infliximab infusion an acute tonsillitis, which resolved quickly by antibiotic treatment. One patient had a mild (infliximab) infusion reaction during the 3rd infusion. One patient developed an acute leukemia 4 months after the last infliximab infusion. Two infliximab patients, who failed to use contraception, became pregnant 6 and 10 weeks after surgery, respectively; one miscarried spontaneously at 10 weeks and the other delivered a healthy baby at term. One infliximab patient had myalgia for a few days after the second infusion and another infliximab patient had a bad taste in the mouth for a few days; both events were considered unrelated to the drug by the safety review committee. There were no AEs reported in the placebo patients. Figure 3:Ibuprofen intake and total pain calculated from the patient dairy. A Spearman correlation between all entries of the whole dataset was performed. We realize that this crude analysis is strictly incorrect since all entries were used as independent variables, and that this blind analysis carries the risk of spurious correlations. Since correlations were so strong, some seem worth mentioning. There was a strong intercorrelation (P < 0.001 for all) between all pain estimates by the physician (dysmenorrhea, deep dyspareunea and chronic pain) and by the patients (dysmenorrhea, deep dyspareunea, chronic pain, VAS scales and ibuprofen intake), suggesting that pain estimates are not entirely independent. Over the whole observation period, the infliximab group had a slightly higher intake of pain killers (P < 0.01), and higher dysmenorrhea scores (P < 0.001 for physician assessment, for patient VAS scales and for patient diary). The volume of the nodule assessed by TVU correlated with the pelvic induration assessed by the physician (P = 0.04) but surprisingly not with any of the pain estimates nor with ibuprofen intake. Unexpected correlations were found between weight and temperature (P < 0.001), between temperature and dysmenorrhea (P < 0.001) and deep dyspareunea (P < 0.001), and between pulse rate and pain estimates (P < 0.001).
BODY.DISCUSSION:
To the best of our knowledge, this is the first randomized, placebo-controlled trial to assess the effect of an anti-TNF-α drug in the treatment of deep endometriosis-associated pain. Women with deep lesions were chosen as the study group for two reasons. First, these lesions were diagnosed on clinical examination rather than at laparoscopy and the women participated in the study while awaiting definitive surgical treatment. Second, for deep endometriosis the association between pain and endometriosis is much stronger than for other disease types (Koninckx et al., 1991a; Vercellini et al., 2007b). Women with deep endometriosis have severe pain close to the maximum on a BB painscale, the painful nodules can be confirmed by clinical exam and less than 5% is pain free (Koninckx et al., 1996b). A study of women with typical lesions only would carry a much higher risk of including women in whom pain is not caused by the endometriosis. In typical endometriosis pain is highly variable, is rarely very severe and 30–50% of women are pain free. Women with deep endometriosis may thus be a preferred group to evaluate drug effects on endometriosis-associated pain. The observed placebo effect was unexpectedly high in these women, and is consistent with previous reports albeit in women with less severe pain (Sutton et al., 1994, 1997). Placebo effect was observed for all pain measures, including tenderness on pelvic examination. The absence of effect upon pelvic induration, indirectly confirms that the effect on pain was a placebo effect and that the clinician remained objective. The strong placebo effect can be explained by the patient perception of the importance of an intravenous infusion followed by the close observation in hospital for 1 h. In addition, the enthusiasm of the researchers who became convinced of the efficacy of infliximab could have been conveyed to the patients. Indeed, two-thirds of the patients reported a greater than 50% decrease in pain, with little effect in the remaining third. Understanding the mechanisms involved in this important decrease of pain by more than 50% (Fuente-Fernandez et al., 2006; Pacheco-Lopez et al., 2006; Beauregard, 2007; Benedetti, 2007; Koshi and Short, 2007; Lidstone and Stoessl, 2007; Olshansky, 2007) could lead to clinical effective treatments of endometriosis related pain (Rostkowska-Nadolska, 2007). The lack of efficacy for infliximab as a treatment for deep endometriosis-associated pain was unexpected because of the widely held belief that inflammation is a major cause of pain in endometriosis (Vercellini et al., 2007a). However, the pathophysiology of the severe pain associated with deep endometriosis may be different from that caused by typical lesions, i.e. inflammation might be more important in superficial peritoneal endometriosis whereas nerve invasion or compression is more important in deep lesions (Anaf et al., 2000, 2002, 2004, 2006). This absence of effect upon pain is consistent with the absence of effect during surgery or after examination by routine pathology. Whether another treatment protocol or a higher dose would be effective cannot be excluded. We have scrutinized the literature on the medical treatment of endometriosis-associated pain. The evidence of efficacy may be weak as the blinding in most studies appears inadequate. Researchers and patients were able to guess whether individuals were randomized to placebo or active treatment if menstruation was prevented or if there were major side-effects such as hot flushes, or recognizable physical signs such as vaginal atrophy. In addition, conclusions are usually based upon a reduction in the total pain score and all drugs that abolish menstruation will thus by definition be effective in reducing dysmenorrhea. Given the strong correlation between pain symptoms it remains uncertain whether these treatments are effective for all pain symptoms associated with endometriosis or simply dysmenorrhea alone. The correlations found should be regarded cautiously since the study is small, and since some might be spurious. It was surprising not to find a correlation between the size of the nodules measured by TVU and the pain estimates. Second, that dysmenorrhea correlated negatively with age and age of menarche is an intriguing observation as are the systematic correlations of pain estimates with temperature, blood pressure and pulse rate. That anticipation of a clinical exam could have increased blood pressure and pulse rate more in women with more severe pain remains speculative. When designing this study, we were concerned about the theoretical possibility of increasing post-operative complication rates as a result of infliximab's effect on the immune system. The existing evidence was reassuring, i.e. there were no differences in length of hospital stay or surgical complications between patients with Crohn's disease who received infliximab 2 months before surgery (n = 22) or 1 month after surgery (n = 13) compared with matched controls (Parsi et al., 2002). Since then, two retrospective studies in patients with Crohn's disease have similarly concluded that the use of infliximab, as well as steroids or immunomodulators, before abdominal surgery does not increase the risk for post-operative complications (Colombel et al., 2004; Marchal et al., 2004). In our study, there were no differences in post-operative complication rates between the groups. Given that we only recruited women with deep endometriosis, we accept the possibility that anti-TNF-α treatment might have an effect on other types of endometriosis, e.g. minimal disease with a marked inflammatory component. However, we urge caution about conducting a study to evaluate the effect of anti-TNF-α drugs in such patients. We are not convinced that the potential benefits outweigh the risk of serious side-effects, the high cost of anti-TNF-α drugs and the ethical problems associated with not treating minimal disease surgically at the time of diagnosis. This study confirmed the effectiveness of surgical excision of deep endometriosis upon pain (Koninckx and Martin, 1994; Redwine and Wright, 2001; Wright and Redwine, 2002; Donnez et al., 2004; Garry, 2004). We do not know to what extend a placebo effect contributes to the surgical outcome. In conclusion, infliximab appears to have no important beneficial effect upon pain associated with deep endometriosis. We observed an overall placebo effect of 25%, which reached over 50% in two-thirds of the women, emphasizing the need for well conducted, double-blind, randomized, placebo-controlled studies when evaluating novel treatments for pain. The efficacy of surgical excision upon pain was confirmed, as was the safety of infliximab treatment in the pre-operative period.
BODY.FUNDING:
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TITLE: Routine resite of peripheral intravenous devices every 3 days did not reduce complications compared with clinically indicated resite: a randomised controlled trial
ABSTRACT.BACKGROUND:
Peripheral intravenous device (IVD) complications were traditionally thought to be reduced by limiting dwell time. Current recommendations are to resite IVDs by 96 hours with the exception of children and patients with poor veins. Recent evidence suggests routine resite is unnecessary, at least if devices are inserted by a specialised IV team. The aim of this study was to compare the impact of peripheral IVD 'routine resite' with 'removal on clinical indication' on IVD complications in a general hospital without an IV team.
ABSTRACT.METHODS:
A randomised, controlled trial was conducted in a regional teaching hospital. After ethics approval, 362 patients (603 IVDs) were randomised to have IVDs replaced on clinical indication (185 patients) or routine change every 3 days (177 patients). IVDs were inserted and managed by the general hospital medical and nursing staff; there was no IV team. The primary endpoint was a composite of IVD complications: phlebitis, infiltration, occlusion, accidental removal, local infection, and device-related bloodstream infection.
ABSTRACT.RESULTS:
IVD complication rates were 68 per 1,000 IVD days (clinically indicated) and 66 per 1,000 IVD days (routine replacement) (P = 0.86; HR 1.03; 95% CI, 0.74-1.43). Time to first complication per patient did not differ between groups (KM with log rank, P = 0.53). There were no local infections or IVD-related bloodstream infections in either group. IV therapy duration did not differ between groups (P = 0.22), but more (P = 0.004) IVDs were placed per patient in the routine replacement (mean, 1.8) than the clinical indication group (mean, 1.5), with significantly higher hospital costs per patient (P < 0.001).
ABSTRACT.CONCLUSIONS:
Resite on clinical indication would allow one in two patients to have a single cannula per course of IV treatment, as opposed to one in five patients managed with routine resite; overall complication rates appear similar. Clinically indicated resite would achieve savings in equipment, staff time and patient discomfort. There is growing evidence to support the extended use of peripheral IVDs with removal only on clinical indication.
ABSTRACT.REGISTRATION NUMBER:
Australian New Zealand Clinical Trials Registry (ANZCTR) Number ACTRN12608000421336.
BODY.BACKGROUND:
Peripheral intravenous device (IVD) insertion is the most commonly performed invasive procedure in hospitalised patients, with an estimated 150 million peripheral intravenous devices placed each year in North America alone [1]. IVDs are vital for delivery of hydration, medicines and nutrition but are not without complications. Serious adverse outcomes are fortunately rare, with IVD-related bloodstream infection reported in a recent meta-analysis of 110 studies to occur in 0.1% of devices and 0.5 per 1,000 device days [2]. IVD treatment is more frequently interrupted by phlebitis, an irritation of the vein characterised by pain, tenderness on palpation, erythema, warmth, swelling, induration or palpable cord (thrombosis) of the cannulated vein; diagnostic algorithms usually require two or more of these conditions [3-5]. Phlebitis is in almost all cases a biochemical reaction to the mechanical irritation by the presence of the IVD and associated infusate [3], although phlebitis symptoms such as erythema may be misperceived as indicative of an infection. In fact, there is not a high correlation between phlebitis and device infection, and the Centers for Disease Control (CDC) states that infection is rarely associated with peripheral, as opposed to central, venous devices [3,6,7]. Fluid infiltration or 'tissuing' of devices is another common IVD complication which may also reflect the inflammatory (phlebitic) response of the vein, rather than simple misplacement of the device tip [8]. Early cohort studies noted an association between increased device time in situ and phlebitis [9,10]. This association was responded to with policies for routine device removal. Recommended timelines for routine resite have been extended over the past three decades from 24, to 48, then to 72 hours. Currently, 72- to 96-hour resite is recommended to reduce phlebitis by the CDC's 2002 Guidelines for the Prevention of Intravascular Device Infection, with the exemption that this is not required in children or those with poor veins [7]. Such policies cause increased workload in hospitals, where the task of removing and replacing well-functioning IVDs generally falls to busy nursing and junior medical staff. In addition, few patients welcome the prospect of additional venipuncture. Despite the general clinical acceptance of routine IVD replacement as a phlebitis and infection prevention measure, it has not been supported by recent data. It may be that the risk of complications during the entire IVD treatment episode is similar, regardless of whether multiple short-dwell or fewer longer-dwell IVDs are used over this time. Three small (n = 47-60) randomised, controlled trials (RCTs) suggested routine replacement at 12, 24 or 48 hours may reduce phlebitis compared to resite on clinical indication, although a systematic review for the Swedish Council on Technology Assessment in Healthcare assessed these as low- to medium-quality studies providing 'limited scientific evidence' [11-14]. More recently, two well-conducted RCTs found no evidence of effect when comparing IVD replacement every 3 days with replacement only on clinical indication for medical and surgical inpatients [15,16]. The largest of these studies reported findings from 755 general medical and surgical patients with 1,428 IVDs and found a 5% difference in combined phlebitis and infiltration rates per patient (38% clinically indicated resite, 33% routine resite), suggesting a potential small clinical benefit of 3-day resite [15]. However, this difference was not statistically significant (RR 1.15; 95% CI, 0.95-1.40) and disappeared when overall cannulation time was considered (59.8/1,000 IVD days clinically indicated resite, 60.9/1,000 IVD days routine resite; RR 0.98; 95% CI 0.78-1.24) [15]. In addition, no clinically important or statistically significant differences were observed in the secondary endpoints of phlebitis, infiltration, occlusion, local infection or suspected bloodstream infection rates between study groups [15]. Another recent RCT in the 'hospital in the home' community setting also found no important clinical or statistically significant difference in phlebitis, occlusion or bloodstream infection rates in 316 patients when resite every 3 days was compared with clinically indicated resite [17]. A 2010 Cochrane Collaboration review concluded there was 'no conclusive evidence of benefit' of routine IVD resite and suggested organisations could consider adopting a resite on clinical indication policy [18]. There is growing evidence that routine IVD replacement may be ineffective, although caution has been urged in light of the large number (74% in both groups in the largest study to date) of reported devices inserted by a specialised IV team, a factor known to reduce complications [19]. Device insertion (and reinsertion) is unpleasant for patients, requires skilled and available clinical staff, and has associated costs for the health sector. If replacement only on clinical indication is safe and effective, this would have important benefits for patients and the health system. We report a RCT of 3-day routine IVD resite versus clinically indicated replacement in a medical-surgical hospital where IVDs were inserted by the general medical and nursing staff; the insitution did not have a specialised IV service.
BODY.METHODS.AIM:
The aim of the study was to compare the impact of 3-day routine resite, with clinically indicated resite, on peripheral IVD complications.
BODY.METHODS.DESIGN:
Open (nonblinded), parallel group RCT.
BODY.METHODS.ETHICS:
The study was approved by the Tasmanian State Human Research Ethics Committee. Written informed consent was obtained prospectively from all participants.
BODY.METHODS.SETTING AND SAMPLE:
The study was undertaken at a large regional teaching hospital in Australia which functions as the tertiary referral centre for the northern half of the State of Tasmania. The hospital has more than 32,000 separations per annum, with a spectrum of medical and surgical specialties. Eligible patients were at least 18 years of age and scheduled or expected to have a peripheral IVD indwelling for at least 4 days, and they gave written informed consent. Exclusion criteria were immunosuppression, current bloodstream infection or an IVD already in situ for >48 hours. IVDs were inserted and cared for by the general nursing and medical staff; there was no special IV team or service.
BODY.METHODS.SAMPLE SIZE:
Sample size calculations were performed using PASS 2008 (Version 8.0.8; Kaysville, UT) to detect a change in rates by 30% (from 36% to 25%, two-tailed α = 0.05, 90% power) on the basis of the complication rates of routinely resited IVs in a previous study [16]. Although this indicated that n = 378 per group (total 756) were required, the study was ceased early (total n = 606 IVs) because all investigators left the employment of the institution. Consequently, study power was reduced, but remained over 80% (required minimum n = 282 per group).
BODY.METHODS.RECRUITMENT:
All adult patients admitted to the inpatient acute medical and surgical wards of the study hospital were screened by a full-time research nurse. This excluded paediatric, day-surgery, mental health, obstetric, critical care and dialysis units.
BODY.METHODS.STUDY PROCEDURES:
Patients were randomly assigned (computer generated) in a 1:1 allocation ratio to either the 'routine replacement' (control) or 'clinically indicated replacement' (intervention) group. Assignment was concealed until randomisation by use of a telephone service. A tag was placed on the insertion site indicating the study group. All devices for the patient were managed as per randomised group. The intervention group did not have their IVD resited unless clinically indicated. This decision was made by the treating clinician (not the investigators), who ordered IVD resite if the device failed or phlebitis occurred and ongoing IV treatment was required. The control group had a new device relocated to a different site by the general medical or nursing staff every 3 days. Control devices could also be removed at any stage by the clinical staff if they were not required or if complications occurred. Clinical nursing and medical staff undertook insertion and follow-up care of all IVDs as per the CDC Guidelines [7]. Laboratory staff undertaking microbiological culture assessments were blinded to the study group. Due to the nature of the intervention, patients, research, and clinical staff were unable to be blinded. However, the investigators had no involvement in assessing or documenting complications. IVDs were assessed by the clinical nursing staff on each nursing shift for complications as part of standard clinical practice in the hospital. Times and dates of device insertion and removal were recorded along with the reason for device removal and any protocol deviations. A full-time research nurse collected data from the hospital chart and sought clarification from patients and clinical staff if necessary. Microbiological investigations (device tip, blood cultures and site cultures) were performed by the clinical staff on clinical suspicion of infection by the treating clinician. Demographic and clinical data were collected on age, sex, diagnosis at hospital admission, phlebitis risk based on Tagar et al.'s classification (low/medium/high risk) [20], past history of phlebitis, any comorbidities requiring active medical treatment (e.g., type 2 diabetes or congestive heart failure), haemoglobin, concurrent infection at other sites, antibiotic therapy, type of surgery, type of infusate and any additives (and their level of irritability), vein and skin quality assessment, size of device, insertion site, health professional inserting the device, and setting for insertion, presence of other vascular devices, wound drains and urinary catheters. Vein quality was assessed as good (vein easy to visualise and easy to palpate with tourniquet on), fair (not easily visible but can palpate with tourniquet), or poor (veins small, scarred or difficult to palpate with tourniquet; may require heat pack to aid vasodilation). Skin quality was assessed as good (healthy, well hydrated, elastic), fair (mildly dehydrated, reduced elasticity), or poor (papery, dehydrated, or reduced elasticity).
BODY.METHODS.ANALYTIC APPROACH:
The primary outcome was a composite measure of any complication causing unplanned cannula removal prior to completion of IV treatment. The composite included phlebitis, infiltration, occlusion, accidental removal, local infection, and IV device-related bloodstream infection (IVD-BSI). These were also analysed individually as secondary endpoints. A composite measure was chosen due to the low rates of these conditions individually and to the assumption that they are comparable measures of 'infusion failure'; that is, the device can no longer be used to deliver treatment. This approach has been used in previous studies on the topic [15-17]. Phlebitis was defined as two or more of pain, erythema, purulence, streak formation, or a palpable venous cord [3]. Local infection IVD-BSI (bacteremia/fungemia with at least one positive blood culture obtained from a peripheral vein, clinical manifestations of infection, and no apparent source for the bloodstream infection (BSI) except the device with or without positive tip or entry site swab culture) were defined using CDC criteria [7]. Other secondary outcomes were time in situ (hours of catheterisation from insertion to removal, both per patient and per device) [7]; IVDs per patient (number of peripheral devices inserted to complete the course of treatment) [7]; costs (calculations based on 20 minutes nursing or medical insertion time at relevant rates [15], plus the cost of the required equipment (cannula, insertion pack including dressing and solution, gloves, saline, syringe, extension tubing and starter pack for all plus fluid bag, tubing and secondary tubing for medication administration for those patients requiring this) for insertions, nursing time and equipment to routinely remove IVDs that were otherwise functional, and the costs of treating any complications that occurred (e.g., IVD-BSI). Cost calculations were undertaken from the viewpoint of the hospital using negotiated wage costs and purchasing agreements for government hospitals in the State of Tasmania. Costs would be similar for other Australian hospitals. All randomised patients were analysed by intention to treat. Each patient was randomised once and could have multiple IVDs, with subsequent IVD resites managed as per the randomised group. Relative incidence complication rates per 1,000 IVD days and 95% confidence intervals were calculated to summarise the impact of clinically indicated replacement relative to 3-day replacement. Kaplan-Meier survival curves were drawn to compare time to first IVD complication between patients in the two study groups. To assess for any potential impact of protocol violations, a per protocol analysis was also undertaken. All clinical and demographic variables were subjected to univariate testing against the primary endpoint to guide selection of possible covariates for the multivariable model. Cox proportional hazards regression modelling was used to examine the impact of age, gender, oncology status, number of comorbidities (nil, one, two, or more than two), IV gauge, site, vein quality, skin quality, oral antibiotics, IV antibiotics, wound drain, inserter occupation, initial versus subsequent IVDs, phlebitis in a preceeding IVD, haemoglobin level, parenteral nutrition, continuous versus intermittent infusion, patient risk category and study group on the outcome of time to complication events using an additive model [3,5,7,20-25]. In addition, to adjust for any inherent correlations or codependencies in the failure times of IVDs (i.e., same patient multiple failure-time data) within the Cox model, we also used the Prentice-Williams-Peterson conditional risk-set method [26]. The Mann-Whitney test was used to compare various secondary outcomes between study groups. Cost differences were calculated using arithmetic means and the t-test [27]. P values <0.05 were considered significant. All statistical data were entered and analysed using SPSS (Version 15.0; Chicago, IL) and Stata (Version 8.2; College Station, TX).
BODY.RESULTS.SAMPLE:
Over a 10-month period, 1,954 patients were screened for eligibility. Of these, 788 were eligible, with 362 (46%) recruited into the study. The most frequent exclusion criterion was altered mental state that precluded consideration of consent as assessed by the research nurse. Altered mental state was generally related to older medical patients and the immediate postoperative phase for surgical patients. Reasons for exclusion are shown in Figure 1. The 362 patients were randomised into either the routine change group (n = 177 participants, 323 devices) or the clinically indicated replacement group (n = 185 participants, 280 devices). In total 50,173 IVD hours were studied (routine change group 23,288 hours, clinically indicated group 26,885 hours). More patients in the routine change group had an active infection (53% vs. 44%) and were receiving IV antibiotics (73% vs. 64%). However, as shown in Tables 1 and 2, the two groups were generally comparable at baseline for patient- and cannula-related factors. Figure 1Participant flowchart. Table 1 Baseline characteristics of study participants Variable 3-Day Routine Change Group (n = 177) Clinically Indicated Change Group (n = 185) Sex - Male, n (%) 96 (54%) 103 (56%) Age, mean (SD) 65.1 (17.3) 62.7 (15.4) Reason for admission, n (%) • Gastrointestinal 46 (26%) 52 (28%) • Respiratory 37 (21%) 34 (18%) • Oncology 21 (12%) 21 (11%) • Orthopaedic 16 (9%) 22 (12%) • Cardiac 10 (6%) 10 (5%) • Neurological 9 (5%) 10 (5%) • Vascular 7 (4%) 7 (4%) • Renal 16 (9%) 9 (5%) • Other 15 (8%) 20 (11%) Number of comorbidities, n (%) • None 6 (3.4%) 10 (5.4%) • 1 22 (12.4%) 21 (11.4%) • 2 44 (24.9%) 54 (29.2%) • >2 105 (59.3%) 100 (54.1%) Type of surgery, n (%) • Nil 124 (70%) 132 (71%) • Gastrointestinal 22 (12%) 22 (12%) • Orthopaedic 8 (5%) 15 (8%) • Other 23 (13%) 16 (9%) Most recent Hb - Mean (SD) 124.8 (23.2) 126.2 (21.9) Table 2 Baseline infusion-related characteristics of study devices Variable 3-Day Routine Change Group (n = 323) , n (%) Clinically Indicated Change Group (n = 280) , n (%) IV cannula gauge • 22 43 (13%) 46 (16%) • 20 241 (75%) 201 (72%) • 18 27 (12%) 30 (11%) • Other 2 (1%) 3 (1%) Vein assessment • Good 143 (44.3%) 107 (38.2%) • Fair 160 (49.5%) 144 (51.4%) • Poor 20 (6.2%) 29 (10.4%) Skin integrity • Good 138 (43%) 104 (37%) • Fair 178 (55%) 164 (59%) • Poor 7 (2%) 12 (4%) Past history of phlebitis 2 (0.6%) 4 (1.4%) Insertion site • Hand 206 (64%) 187 (67%) • Forearm 59 (18%) 49 (18%) • Cubital fossa 51 (16%) 38 (14%) • Other 7 (2%) 6 (2%) Receiving infusate 241 (75%) 215 (77%) pH of infusate - Mean (SD) 6.0 (0.5) 6.0 (0.4) Receiving oral antibiotics 24 (7%) 24 (9%) Receiving IV antibiotics 236 (73%) 176 (63%) pH of IV antibiotics - Mean (SD) 6.9 (1.1) 6.9 (1.3) Receiving other IV meds 190 (59%) 179 (64%) pH of other IV meds - Mean (SD) 5.6 (2.6) 6.0 (2.8) Wound drain 50 (16%) 40 (14%) Urinary catheter 55 (17%) 41 (15%) Other vascular device 26 (8%) 24 (9%) Inserted by • Junior doctor 232 (72%) 207 (74%) • Registered Nurse 67 (21%) 57 (20%) • Senior doctor 24 (7%) 16 (6%) Where inserted • Ward 216 (67%) 188 (67%) • Emergency department 74 (23%) 70 (25%) • Other 33 (10%) 22 (8%) Current infection (site) • Respiratory 97 (30%) 49 (18%) • Urinary 24 (7%) 19 (7%) • Wound 16 (5%) 15 (5%) • Other 29 (9%) 37 (13%) • >1 site 5 (2%) 4 (1%) N/A (none) 152 (47%) 156 (56%) Risk of phlebitis (Tagar scale) • Low 174 (54%) 144 (51%) • Medium 149 (46%) 136 (49%) • High 0 0
BODY.RESULTS.EFFECT OF INTERVENTION ON PRIMARY OUTCOME:
Outcome data were available for all patients. Table 3 shows the rates of primary and secondary outcomes. Differences in complication rates between groups were not significantly different (routine replacement 66.0 per 1,000 IVD days; clinical replacement 67.8 per 1,000 IVD days; HR 1.03; 95% CI, 0.74-1.43; P = 0.86). As shown in Figure 2, the time to first complication per patient was also not significantly different between groups (Kaplan Meier [KM] with log rank P = 0.53). On crude rate per IVD, the catheters replaced on clinical indication had higher complication rates (110/280 or 39% vs. 91/323 or 28%; P = 0.004). However, total complication rates per patient (to deliver the course of IV therapy) were not significantly different (P = 0.39) between clinically indicated (76/185, 41%) and routine resite patients (64/177, 36%). Table 3 Effect of intervention on primary and secondary endpoints Outcomes 3-Day Routine Change Group (n = 177) Clinically Indicated Change Group (n = 185) RR (95% CI) , P Value Primary: IVD complications per patient, n (%) 64 (36%) 76 (41%) RR 1.14 (0.88, 1.47), p = 0.39 IVD complications per 1000 IVD days 66.0 (95% CI 49.8, 82.1) 67.8 (95% CI 52.6, 83.1) HR 1.03 (0.74, 1.43), p = 0.86 Secondary: Phlebitis, n (%) 12 (7%) 18 (10%) RR 1.44 (0.71, 2.89), p = 0.34 Infiltration, n (%) 53 (30%) 61 (33%) RR 1.10 (0.81, 1.49), p = 0.57 Occlusion, n (%) 5 (3%) 4 (2%) RR 0.77 (0.21, 2.80), p = 0.75 Accidental removal, n (%) 11 (6%) 16 (9%) RR 1.39 (0.66, 2.92), p = 0.43 Local infection 0 0 - IVD-related BSI, n (%) 0 0 - IVD costs per patient, AUD$ mean (SD) $55.42 ($35.26) $43.35 ($26.78) Mean difference $12.07 (95%CI $5.57, $18.56), p < 0.001 Figure 2Kaplan-Meier survival curve of time to first intravenous device complication per patient (log rank, P = 0.53). Patient- and device-related variables considered in the multivariable model were older age, number of comorbidities (nil, one, two or more than two), smaller cannula size, poor skin or vein integrity, IV antibiotics, insertion by medical staff and study group. None of these were found to be statistically significant. The final Cox proportional hazards model after adjusting for time found study group was not a significant factor (HR 1.02; 95% CI, 0.77-1.36; P = 0.89). Variance-adjustment testing for potential multiple-failures per patient (cannula data) found no inconsistency in significant results compared to the main Cox model.
BODY.RESULTS.PROTOCOL COMPLIANCE:
Compliance with the study intervention was achieved in 78% (251 of 323) of routinely replaced IVDs removed at Day 3 and 100% (280 of 280) of IVDs resited on clinical indication. Noncompliance in the routine resite group was generally related to high staff workloads on that day or to staff's perception that the patient was soon to be discharged or have therapy completed, and so the IVD remained in situ beyond Day 3. A per protocol analysis was performed including only those patients in the routine replacement group whose IVDs were all actually removed by 96 hours (n = 251). This found no significant difference (KM with log rank P = 0.16) in the rate of complications between groups (routine replacement 92 per 1,000 IVD days vs. clinically indicated 68 per 1,000 IVD days).
BODY.RESULTS.EFFECT OF INTERVENTION ON SECONDARY OUTCOMES:
There was no statistically significant difference in group outcomes for any phlebitis (P = 0.34), infiltration (P = 0.57), occlusion (P = 0.75), or accidental removal (P = 0.43). No cases of local infection or IVD-related bloodstream infection occurred in either group. For overall IVD therapy (total cannulation time per patient for all devices), clinically indicated devices had a median therapy of 120 hours (quartiles 86.5 and 172.5 hours), and those replaced routinely had median therapy of 113 hours (quartiles 72 and 172 hours) (P = 0.21). For individual IVD dwell times, the clinically indicated group devices had a median dwell time of 85 hours (quartiles 51 and 121 hours), and those replaced routinely had a median dwell time of 71 hours (quartiles 48 and 90 hours) (P < 0.001). The maximum IVD dwell time was 1,023 hours (43 days) in the clinical replacement group, and this cannula was still working well on removal for completion of therapy. The overall number of IVDs per patient was significantly less (P = 0.004) for those replaced on clinical indication (mean 1.5, SD 0.8, median 1, quartiles 1 and 2) than for those routinely replaced (mean 1.8, SD 1.1, median 1, quartiles 1 and 2). A total of 22% of patients in the routinely replaced group had three or more IVDs compared with 9% in the clinical indication group. A total of 82 (28%) IVDs in the routine replacement group were resited after 3 days despite functioning well and ongoing treatment being required. (The remainder removed at this time were no longer required and so not resited, or infusion failure had already occurred.) Mean hospital costs per patient for the course of IV therapy were significantly higher (P < 0.001) for those managed with routine resite (mean $55.42, SD $35.26) compared with resite on clinical indication (mean $43.35, SD $26.78).
BODY.DISCUSSION:
The finding that 3-day routine resite was not an effective intervention was consistent across the intention-to-treat primary analysis and the per protocol analysis. There remained no effect when events were expressed per patient or per 1,000 IVD days. Neither composite nor individual complication rates differed between groups, and there were no cases of local or device-related bloodstream infection. It appears safe and practical to leave IVDs in situ as long as they are functioning well and are still needed for clinical treatments. All IVDs will fail eventually, but this study shows that artificially shortening the lifespan of individual catheters does not reduce the overall complication rates over the course of therapy. Our results indicate that the average duration of IV therapy is 5-6 days and that many catheters can remain complication-free for this period. If catheters are not routinely resited, the median dwell time would remain within the 72-96 hours recommended by the CDC, but about 10% would remain in situ for longer (in this study up to 43 days with no complications). Our data show that a policy of resite on clinical indication would mean that one of every two patients would need a single cannula to receive treatment, whereas a 3-day change policy would result in only one in five patients having this scenario, with the rest requiring multiple cannulations and therefore additional pain and inconvenience. The results are consistent with the findings of recent RCTs in both hospitals and the community that have found no benefit in routinely resiting IVDs every 3 days [15-17]. In these studies, many cannulae were inserted by an expert IVD team [15-17], which may have minimised complications in both groups [19]. Our study confirms and extends these findings into the general medical/surgical setting without an IV team where IVDs were inserted by a variety of nursing and medical staff. Data from this study were included in a 2010 Cochrane Collaboration systematic review and meta-analysis on the topic [18]. This review included six trials (n = 3,455) and reported no clinically important or statistically significant difference in catheter-related bloodstream infection or phlebitis between IVDs that were routinely resited (at 48-96 hours) or resited on clinical indication, yet there were significantly lower costs in the group resited on clinical indication [18]. The belief that routine resite of IVDs will prevent complications appears to stem from early observational studies that noted longer-dwelling IVDs had more complications than shorter-dwelling IVDs [9,10]. This is intuitively true, given, for example, that an IVD in situ for 6 days has twice the time exposure of risk than an IVD in situ for 3 days. However, this does not prove that two sequentially inserted IVDs (in the same patient), both used for 3 days, have a combined lower risk over time than the 6-day dwell device. Indeed, this and other recent trials strongly suggest that the risk for the patient over the 6-day period is similar. Well-designed cohort studies with modern catheter materials suggest that the daily risk of phlebitis is relatively stable after the first 24 or 48 hours [3,21,28-31]. The peak in phlebitis between 24 and 48 hours is likely associated with the time taken by the body to mount a biological response after the instigation of therapy; those most likely to develop phlebitis will do so at this time. The results support the extension of the use of peripheral IVDs beyond the 72-96 hours currently recommended by the CDC [7]. There is incongruity in the CDC recommendations; they recommend not to routinely resite IVDs in children or in those with limited venous access. If it is safe in these populations, it is unclear why it would be necessary to routinely resite adults or those with better veins. Higher-risk cannulae such as central venous devices are no longer recommended by the CDC for routine replacement, because trials showed this was not of benefit [7]. Our study also confirms that the CDC guidelines are not always complied with; one fifth of IVDs in the routine change group were not replaced by this time. However, the per protocol analysis showed that the intervention remained ineffective even for those who truly had their IVDs resited every 3 days. Limitations of the study included a 9% higher frequency of IV antibiotics and concurrent infection in the routine resite group. This may have put the group at higher risk due to vein irritation, or conversely it protected against bacterial entry. Neither variable was significant in the multivariable model. The unblinded study design was unavoidable, but also a limitation. Our use of clear outcome measures, a full-time research nurse and laboratory staff blinded to culture assessments should have reduced the risk for potential bias. Resource constraints prematurely ended recruitment, thus reducing the anticipated power of the study from 90% to 80%. Routine IVD resite involves pain for patients, staff procedural time, equipment costs and environmental waste. Contemporary evidence suggests the current policy for routine resite by 72-96 hours is ineffective and should be replaced with a 'resite on clinical indication' policy. It remains imperative that clinical staff monitor IVDs closely and that a daily review of the need for continuing therapy be made, with cessation as soon as possible; the only no-risk IVD is no IVD. Of the 4.3 million acute hospital admissions in Australia each year (excluding day cases), over half have IV treatment [15,32]. Conservatively, if even 2 million courses of IV therapy were managed with clinically indicated rather than routine resite, this would save the unnecessary insertion of approximately 660,000 IVDs and free 280,000 hours of staff insertion time. Assuming our costs are similar to those in other Australian hospitals, a change to resite on clinical indication would save approximately AUD$24 million nationally each year.
BODY.CONCLUSIONS:
Although larger, multisite trials are required, evidence to date suggests that routine resite of peripheral IVDs increases patient discomfort and healthcare costs, but does not reduce IVD complications as has traditionally been thought.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
CMR designed the study, applied for funding and drafted the manuscript. DM participated in study design and manuscript preparation, and managed the study. JM recruited patients, ensured protocol integrity and collected data. MRM undertook statistical analyses and assisted with drafting the manuscript. All authors read and approved the final manuscript.
BODY.AUTHORS' INFORMATION:
CMR, PhD is Professor, Research Centre for Clinical and Community Practice Innovation, Griffith University, Australia. DM holds a Masters by Research and is Senior Lecturer, University of Tasmania, Australia. JM is an RN and Nurse Unit Manager, Calvary Tasmania, Australia. MRM is a PhD qualified Biostatistician, Gippsland Medical School, Monash University, Australia.
BODY.PRE-PUBLICATION HISTORY:
The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1741-7015/8/53/prepub | 2,944,158 | {
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TITLE: Pilot study of Lokomat versus manual-assisted treadmill training for locomotor recovery post-stroke
ABSTRACT.BACKGROUND:
While manually-assisted body-weight supported treadmill training (BWSTT) has revealed improved locomotor function in persons with post-stroke hemiparesis, outcomes are inconsistent and it is very labor intensive. Thus an alternate treatment approach is desirable. Objectives of this pilot study were to: 1) compare the efficacy of body-weight supported treadmill training (BWSTT) combined with the Lokomat robotic gait orthosis versus manually-assisted BWSTT for locomotor training post-stroke, and 2) assess effects of fast versus slow treadmill training speed.
ABSTRACT.METHODS:
Sixteen volunteers with chronic hemiparetic gait (0.62 ± 0.30 m/s) post-stroke were randomly allocated to Lokomat (n = 8) or manual-BWSTT (n = 8) 3×/wk for 4 weeks. Groups were also stratified by fast (mean 0.92 ± 0.15 m/s) or slow (0.58 ± 0.12 m/s) training speeds. The primary outcomes were self-selected overground walking speed and paretic step length ratio. Secondary outcomes included: fast overground walking speed, 6-minute walk test, and a battery of clinical measures.
ABSTRACT.RESULTS:
No significant differences in primary outcomes were revealed between Lokomat and manual groups as a result of training. However, within the Lokomat group, self-selected walk speed, paretic step length ratio, and four of the six secondary measures improved (p = 0.04–0.05, effect sizes = 0.19–0.60). Within the manual group, only balance scores improved (p = 0.02, effect size = 0.57). Group differences between fast and slow training groups were not revealed (p ≥ 0.28).
ABSTRACT.CONCLUSION:
Results suggest that Lokomat training may have advantages over manual-BWSTT following a modest intervention dose in chronic hemiparetic persons and further, that our training speeds produce similar gait improvements. Suggestions for a larger randomized controlled trial with optimal study parameters are provided.
BODY.BACKGROUND:
Stroke is the leading cause of serious, chronic disability in the United States and Canada. While two-thirds of people who suffer a stroke regain ambulatory function, the resulting gait pattern is typically asymmetrical, slow, and metabolically inefficient [1,2]. These characteristics are associated with difficulty advancing and bearing weight through the more affected limb, leading to instability and an increased risk of falls [3]. Secondary impairments, including muscle disuse and reduced cardiorespiratory capacity, often contribute to further functional declines in gait. Hence, improved walking is one of the most frequently articulated goals of rehabilitation and interventions that effectively enhance locomotor function are essential to improve quality of life for many stroke survivors and their families [4,5]. Nevertheless, the effectiveness of locomotor training still remains unclear and the need to conduct randomized controlled trials to definitively answer this question is paramount. To best determine the key parameters of such a large-scale study, preliminary data must first be collected in the form of a pilot study. Manually-assisted body-weight supported treadmill training (BWSTT) is a contemporary approach to gait rehabilitation wherein an individual walks on a treadmill with body-weight partially supported by an overhead harness. One to three therapists/trainers manually facilitate hemiparetic limb and trunk control in an effort to normalize upright, reciprocal stepping and dynamic postural control. Advantages of this approach are that little to no ambulatory function is required to initiate locomotion and early post-stroke training effects are transferred to improvements in overground gait including: symmetry, speed, and endurance as well as motor impairment and balance scores [6,7]. These positive outcomes can be maintained even at 6 months post-locomotor training [8]. However, because locomotor training involves repetition of hundreds of steps within one session, facilitation of a symmetrical, patterned gait can be very labor intensive for both therapist(s) and participant and further, presents a non-trivial risk of injury to the trainers. Moreover, the repetition of kinematically consistent stepping patterns is hindered by inconsistencies in motor performance of the therapists assisting movement. Conflicting evidence within 15 randomized controlled trials comparing BWSTT and traditional gait training (i.e. overground gait training, motor relearning) in persons post-stroke highlight the difficulty in interpreting the effectiveness of manually applied cues during repetitive stepping [9]. In response to the challenges presented in administering manual-BWSTT, robotic devices, such as the Lokomat® (Hocoma, Inc., Zurich, Switzerland), have recently emerged as a means to automate locomotor training in neurorehabilitation. Using robotic assistance, an exoskeleton facilitates a bilaterally symmetrical gait pattern as the individual actively attempts to advance each limb while walking on the treadmill. The preprogrammed walking pattern corresponds with normal gait kinematics including: gait cycle timing (i.e. stance vs. swing phase), inter-limb and inter-joint coordination, appropriate limb loading, and afferent signaling [10]. Animal models have demonstrated that afferent signals derived from limb movement and loading converge at the level of the spinal cord to trigger and control locomotor pattern generators (LPGs) [11,12]. Previous work in persons with spinal cord injuries underscores the importance of the accuracy of relevant timed peripheral inputs to induce changes in locomotor function [13]. Accordingly, the rhythmic and repetitive stepping pattern provided by robotic assistance, combined with active limb loading and kinematic consistency has been shown to promote plasticity of LPGs at the spinal cord level [14] as well as supraspinal structures [15]. Still, despite recent interest in automated locomotor training, there remains very little evidence to support the superiority of this technique over traditional gait training. Previous comparisons between robotic-BWSTT and manual-BWSTT, overground gait training, and traditional approaches result in equivocal findings based, in part, on differences in outcome measures, subject characteristics, and gait training protocols [16-20]. However, separation of the general effects of locomotor training from true automated training effects requires standardization of BWSTT parameters, i.e. BWS percentage and stiffness, treadmill speed, and use of handrails [21], and a comparison between the application of manual or robotic limb guidance with the intent of approximating normal gait kinematics in a well-defined subject population. In controlling these variables, we hypothesize that Lokomat training will produce greater improvements in gait speed and symmetry than manual training. Extending the notion of task-specificity underlying both Lokomat and manual-BWSTT, one particular variable of interest is training speed. If the therapeutic goal is increased overground walking speed, then training must occur at speeds that exceed habitual overground walking speed for a person with hemiparesis. The majority of the current models of the Lokomat robotic orthosis offer treadmill belt speeds up to 0.83 m/s (3 km/h), thus it is yet unknown whether training at higher Lokomat speeds produces similar positive gait changes as revealed in earlier studies [8,22]. Here, we hypothesize that the addition of external timing cues and kinesthetic input induced by Lokomat training and manual BWSTT at training speeds of up to 1.4 m/s (5 km/h) will produce greater improvements in spatio-temporal gait parameters, postural control, and clinical outcomes than groups trained at slower speeds. Objectives of this pilot study were to: 1) compare the efficacy of Lokomat versus manual assisted-BWSTT in persons with chronic locomotor deficits post-stroke and 2) probe the effect of locomotor training at speeds corresponding with overground gait in non-disabled individuals to habitual self-selected walking speed in persons post-stroke. Since self-selected overground gait speed and step length symmetry are important indicators of locomotor performance, and further, are related to function and quality of life following stroke [23,24], these variables were selected as our primary variables of interest. Secondary outcomes included fast overground walking speed, a battery of clinical and functional measures, and a quality of life indicator.
BODY.METHODS.PARTICIPANTS:
Sixteen persons with hemiparesis resulting from a single cortical or subcortical stroke (confirmed by CT or MRI) greater than 6 months prior to the study, who were categorized as at least unlimited household ambulators (e.g. > 0.3 m/s) [4] participated. Exclusion criteria included: 1) unstable cardiovascular, orthopedic, or neurological conditions, 2) uncontrolled diabetes that would preclude exercise of moderate intensity, or 3) significant cognitive impairment affecting the ability to follow directions. Participants were recruited from local hospitals, rehabilitation centers, and stroke associations. All procedures were approved by the Stanford University Institutional Review Board and all participants provided written, informed consent prior to study involvement.
BODY.METHODS.ALLOCATION PROCEDURES:
In an effort to achieve our primary research goal, participants were randomized into either a Lokomat (n = 8) or manual (n = 8) group using a computer-generated random order. To reach our secondary goal, an equal number of participants within each group were randomly assigned to either a fast (n = 8) or slow (n = 8) training group. The randomization list was overseen by one of the investigators (CP) who had no contact with participants until group assignment was revealed. Further, group assignment was not revealed to study personnel until the participant was consented and baseline testing was complete.
BODY.METHODS.INTERVENTION:
Both groups received 12 sessions (3×/wk over 4 weeks) involving 30 min of stepping per session. At least one 2–3 minute break was provided after 15 min. Total set-up and treatment time never exceeded 1 hr. Training speeds were maintained below 0.69 m/s (2.5 km/h) in the slow groups and above 0.83 m/s (3 km/h) in the fast groups. Within the fast groups, locomotor training was either started at 0.83 m/s or progressed to this speed as early as possible (e.g. by Session 3) while maintaining gait quality, i.e. symmetrical, foot clearance, without knee buckling. Treadmill speed was progressed in 0.2 km/hr increments approximately every 5 min as long as the above-mentioned gait quality was observed by the therapists. If a new high speed could not be maintained for an extended period, training would ensue in 2–3 minute intervals at the higher speed followed by 2–3 minutes at a lower speed. BWS was initiated at 35%. The Lokomat system used for this study includes the Lokolift, a compliant, electromechanical body-weight support system that monitors and adjusts unweighting in real time to maintain BWS at the prescribed level. This BWS system contrasts with the stiff, counterweighted support system used in the original Lokomat models. A compliant system adjusts to the participant's center of gravity throughout the gait cycle, enabling vertical pelvic movement similar to overground gait, supporting symmetrical movement and producing kinetics similar to overground walking [21,25]. If the maximal treadmill speed, 0.69 m/s (2.5 km/h) in the slow group or 1.4 m/s (5 km/h) in the fast group, was reached, BWS was reduced in increments of 5% as long as gait quality was maintained. Our goal during training was to improve gait kinematics. To achieve this objective, all participants trained without an ankle-foot orthosis, assistance was reduced once safety was no longer a concern, and rest periods were provided if gait quality was noted to deteriorate. In addition, handrail use has been shown to significantly alter the gait pattern and thus was strongly discouraged [25]. Participants assigned to the Lokomat group trained in a robotic orthosis. Thigh and leg straps secured the Lokomat exoskeleton to the participant; motors on each robotic leg facilitated movement of the hip and knee joints with trajectories programmed by the manufacturer based on a single, healthy individual's gait pattern. Only when necessary to maintain foot clearance, the ankle was maintained in neutral dorsiflexion by means of an elastic foot strap. Force sensors within the Lokomat hip and knee joints provided output on a visual display that was monitored by the treating physical therapist. In an effort to maintain consistency in training parameters, Lokomat assistance was provided at 100% bilateral guidance force for all participants throughout all training sessions. Participants were provided verbal encouragement to actively step in conjunction with the movement presented by the Lokomat. Participants in the manual-BWSTT group were treated by 1–2 skilled physical therapists/trainers who provided manual guidance of the more affected limb, trunk stabilization/alignment, and verbal and visual cues to normalize stepping kinematics. Our intent in using this number of therapists was to mimic clinic feasibility and training in previous reports [20]. The target gait pattern included: adequate trunk alignment, weight shift, acceptance to and from the paretic limb and temporal symmetry between limbs. The treating therapist individualized treatment to facilitate trunk and limb control throughout the gait cycle. Common cues included coaching to: increase plantarflexion propulsion and/or hip flexion at swing initiation, increase dorsiflexion and knee extension at heel strike, and maintain neutral knee alignment (i.e. avoid hyperextension) at midstance. A second trainer provided pelvic stabilization and assistance with weight shift/acceptance as needed. Participants in both groups were provided visual feedback via a full-length mirror placed at the front of the treadmill.
BODY.METHODS.MEASUREMENT:
Participants were assessed before and after the 4-week intervention. Self-selected overground walking speed and fast overground walking speed were recorded using a 4.3 m GaitRite mat (CIR Systems, Havertown, Pennsylvania, USA). Participants walked an additional 0.5 m on both ends of the walkway to allow for acceleration and deceleration and were instructed to walk either: "as if taking a comfortable walk in the park" for self-selected walking speed or "as if they were in the middle of the intersection and the light had just changed to red" for fast walking speed. The mean of 3 trials was calculated. Step length of the paretic (P) and nonparetic (NP) limb was also recorded and later used to calculate absolute (ABS) step length asymmetry during self-selected walking speed as follows: This calculation is a modification of the paretic step length ratio (SLR) [26] and can range from 0 to 1, with an index of 0 reflecting perfect symmetry. The 6-minute walk test was recorded as a measure of gait endurance. Participants were instructed to cover as much distance as possible within a 6-minute period while walking safely. This test was completed along a level carpeted corridor with one turn-around point every 39 meters. For all overground gait assessments, ambulation without an assistive device or lower extremity orthoses was encouraged. However, use of these assistive devices was allowed if deemed necessary for safety. Device usage was consistent between pre- and post-testing. Secondary outcomes were selected to target impairment, activity, and participation according to the World Health Organization classifications. Motor impairment was evaluated with the lower extremity Fugl-Meyer assessment, which is a valid and reliable measure in persons post-stroke [27,28]. Activities were assessed with the short physical performance battery and the Berg Balance Scale. The short physical performance battery produces a summary score (range 0–12) reflecting scores on 3 timed tasks: walking 8-ft, rising from a chair 5 times, and maintaining a static posture (feet together, semi-tandem, tandem) [29]. Good to excellent reliability and predictive validity have been demonstrated for these tests [30,31]. The Berg Balance Scale is comprised of 14 static and dynamic balance tasks with a maximum score of 56. This measure demonstrates good reliability and validity in a population post-stroke [32,33]. Participation in life events was assessed using the Late Life Function and Disability Instrument (LLFDI) [34], which is composed of a disability section assessing limitation and frequency of performance and a function section measuring difficulty in performing certain physical tasks. Good reliability and validity has also been demonstrated for this measure in a population with a range of functional limitations [35,36].
BODY.METHODS.DATA ANALYSIS:
Statistical analyses were conducted using SPSSv15.0 (SPSS, Inc., Chicago, Illinois, USA). Given the small sample size, non-parametric statistics were used. Baseline characteristics between groups were compared using the Mann-Whitney U test for continuous and ordinal variables and the Fisher's exact test for categorical variables. Between group comparisons (Lokomat vs. Manual groups and Fast vs. Slow Training groups) were assessed with the Mann-Whitney U-test using pre-post change scores in ordinal variables. Within group comparisons (Pre vs. Post training) were assessed using the Wilcoxon Signed Ranks Test. Statistical significance was established at α < 0.05. To determine whether a statistically significant difference is of practical concern, effect sizes and percent change were calculated. Effect sizes were calculated as the difference between the means of the two groups (Lokomat and manual) or between the mean pre-test and post-test values of the same group divided by the common standard deviation (SD) at pre-test. Results were interpreted following standards established by Cohen [37] where 0.2 is indicative of a small effect, 0.5 a medium, and 0.8 a large effect size.
BODY.RESULTS:
All sixteen participants completed the study and the twelve training sessions were well tolerated with two exceptions. First, following the eleventh session, one participant in the manual group complained of ankle pain on the hemiparetic side and failed to complete the final training session. Second, despite using a regular rotation of two treating therapists, one therapist suffered a repetitive strain injury of the rotator cuff while training the third manual group participant. Participant characteristics are enumerated in Table 1. Group equivalency (i.e. Lokomat vs. manual and fast vs. slow) was established with no significant baseline differences, p ≥ 0.13. In the Lokomat group removal of the foot strap was possible in 3 participants. One participant advanced to walking without the foot strap for approximately 54% of sessions, while two additional participants advanced to no foot strap for 25% of sessions. Table 1 Baseline characteristics and training parameters Lokomat (n = 8) Manual (n = 8) p value Age, mean (SD), y 58.6 (16.9) 55.1 (13.6) 0.72 a Women, n (%) 2 (25) 1 (12.5) 1.0 b Time since stroke, mean (SD), mo 43.8 (26.8) 36.8 (20.3) 0.72 a Stroke location, n MCA territory (multiple locations) 3 4 1.0 b Frontal lobe 0 1 1.0 b Temporoparietal lobe 1 0 1.0 b Parietal lobe 1 1 1.0 b Basal Ganglia 3 1 1.0 b Thalamus 0 1 1.0 b Pons 0 1 1.0 b Type of Stroke, n Ischemic 3 5 1.0 b Hemorrhagic 5 3 1.0 b Left sided hemiparesis, n 4 5 1.0 b LE Fugl-Meyer total score, mean (SD) 83.3 (7.3) 80.6 (6.3) 0.13 a Self-selected walking speed, mean (SD), m/s 0.62(0.31) 0.62 (0.28) 0.80 a Training speed, mean (SD), m/s 0.82 (0.2) 0.67 (0.2) 0.16 a Training BWS, mean (SD) 29.4 (5.9) 31 (9.1) 0.28 a a Mann-Whitney U test; b Fisher's exact test Our first aim of this pilot study was to compare the effectiveness of Lokomat versus manual-assisted BWSTT on gait-related outcomes. Overall results revealed no significant differences between Lokomat and manual training group improvements on self selected walk speed, p = 0.72, absolute paretic step length ratio, p = 0.28, or secondary variables, p = 0.54–0.96. However, within the Lokomat group, a greater number of variables demonstrated significant pre- vs. post-test differences compared with the manual group (Table 2). Table 2 Group Comparisons of selected outcomes Variable Lokomat Group (n = 8) Manual Group (n = 8) Pre-Test Post-Test Pre-Test Post-Test SSWS (m/s) 0.62 ± 0.31 (0.26–1.04) 0.72 ± 0.38* (0.3–1.38) 0.62 ± 0.28 (0.24–0.91) 0.65 ± 0.29 (0.30–1.02) FWS (m/s) 0.87 ± 0.55 (0.32–1.85) 0.96 ± 0.66* (0.33–2.28) 0.72 ± 0.37 (0.26 ± 1.2) 0.70 ± 0.33 (0.35–1.13) 6 MWT (m) 267.3 ± 187.2 (71–625.5) 278.1 ± 176.5 (89.3–638.0) 234.3 ± 141.2 (66.4–452.7) 212.4 ± 113.5 (86.5–362.9) SLR abs 0.53 ± 0.58 (0.03–1.87) 0.37 ± 0.46 * (0.06–1.46) 0.39 ± 0.37 (0.05–1.10) 0.34 ± 0.35 (0.02–1.04) LE FM (/35) 23.0 ± 4.3 (15–28) 25.6 ± 5.0 * (19–34) 21.4 ± 5.1 (14–29) 22.4 ± 5.2 (14–29) SPPB (/12) 6.9 ± 3.4 (2–12) 7.9 ± 3.2 * (4–12) 7.8 ± 3.0 (4–12) 8.5 ± 3.1 (4–12) BBS (/56) 46.9 ± 7.5 (38–56) 48.3 ± 6.8 * (41–56) 47.0–7.0 (38–55) 51.0–5.4 † (40–56) LLFDI Disability Frequency (/100) 52.6 ± 8.1 (41.4–65.1) 52.8 ± 7.9 (41.4–62.3) 49.7 ± 11.4 (29.2–70.6) 53.5 ± 10.2 (35.2–66.7) Limitation (/100) 59.4 ± 7.0 (49.2–69.2) 62.3 ± 8.5 (49.9–71.3) 61.6 ± 9.1 (46.4–75.6) 66.4 ± 10.2 (47.9–77.6) Function 51.3 ± 7.7 52.0 ± 8.6 48.6 ± 6.0 54.1 ± 4.8 (/100) (43.1–64.0) (42.5–66.8) (41.9–58.7) (46.1–61.6) Note: values are mean ± SD (range) * Pre-post difference within Lokomat group, p < 0.05; † difference within manual group, p < 0.05 Abbreviations: SSWS = self selected walking speed; FWS = Fast walking speed; 6 MWT = 6 minute walk test; SLR abs = Absolute step length ratio; LE FM = Lower extremity Fugl-Meyer; SPPB, short physical performance battery; BBS = Berg Balance Scale; LLFDI = late life function and disability instrument. Although an equal number of participants (n = 7) produced a training related increase in self-selected overground walking speed in each group, a significant difference, p = 0.04, was revealed only in the Lokomat group with a pre-post intervention difference of 0.10 m/s and an effect size of 0.32 which contrasted with a 0.03 m/s difference and 0.11 effect size in the manual group (Figure 1A; Table 2). Figure 1Medians and lower and upper quartiles for pre-post differences in the manual and Lokomat group. A. Self-selected walk speed. B. Absolute step length ratio (negative change scores represent a shift towards symmetrical step lengths). Extreme values are greater than 3 times the interquartile distance.* Significant difference only within the Lokomat group (p < 0.05). Absolute paretic step length ratio (SLRabs) during self-selected overground walking speed was also significantly reduced (i.e. closer to an SLRabs of 0) from pre- to post-test in the Lokomat group, p = 0.05, effect size 0.26, reflecting improved symmetry in 6 of 8 Lokomat group participants (Figure 1B; Table 2). With the exception of the 6-minute walk test and LLFDI, p ≥ 0.16, all secondary measures revealed significant improvements within the Lokomat group, yet only one improvement was noted in the manual group (Table 2). Fast overground walk speed improved from pre- to post-training in 6 of 8 Lokomat participants, p = 0.05, with a small effect size of 0.15 (Figure 2A). Lower extremity Fugl-Meyer score improvements were also noted, p = 0.04, with an effect size of 0.60 and higher scores in 5 of 8 Lokomat group participants (Figure 2B). Similarly, short physical performance battery scores were improved in the Lokomat group, p = 0.04, with an effect size of 0.29 and improvements in 5 of 8 participants. Berg Balance Scale scores significantly improved in both the Lokomat group, p = 0.04, effect size 0.19 (5 participants improved), and manual group, p = 0.02, effect size 0.57 (7 participants improved) (Figure 2C). Figure 2Medians and lower and upper quartiles for pre-post differences in the manual and Lokomat group. A. Fast Walk speed. B. Lower Extremity Fugl-Meyer scores (higher scores represent improved sensorimotor recovery). C. Berg Balance Scale (higher scores represent improved balance). D. Six minute walk test (distance covered). * Significant difference within Lokomat group between pre- and post-test (p < 0.05). † Significant difference within manual group between pre- and post-test (p < 0.05). Participation in life events, as measured by the LLFDI, also demonstrated improvements, but statistical differences were attained only as a main effect of visit (i.e. pre vs. post) and were not specific to either the Lokomat or manual-BWSTT group. The disability component reflects two dimensions: limitation and frequency. Our data revealed that participants felt less limited in their participation in activities at home and in the community, p = 0.02, with an effect size of 0.49. Interestingly, the frequency of self-reported participation in these tasks remained unchanged from pre-test to post-test, p ≥ 0.11. Participants also perceived less difficulty in terms of the performance of certain functional tasks including: dressing, walking a mile, and climbing stairs, p = 0.004, with an effect size of 0.47. In an effort to differentiate changes in motor control from aerobic conditioning effects, we conducted two post-hoc correlations: 1) self-selected overground walking speed and 6-minute walk test, and 2) Berg Balance Scale and 6-minute walk test. Due to the influence of gait speed and balance in a chronic population (mean 5.5 years post-stroke), previous work has cautioned against interpreting the 6-minute walk test as an indicator of aerobic capacity [38]. However, in our study of participants who averaged 3.3 years post-stroke, no significant relationship was identified between either changes in 6-minute walk test and self selected gait speed, r = 0.14, p = 0.61, or changes in 6-minute walk test and balance (Berg Balance Scale), r = 0.27, p = 0.32. Therefore, improvements in gait speed and balance detected in the present study could be attributed to enhanced locomotor control and were not likely due to changes in endurance as measured using the 6-minute walk test. Our second aim was to assess locomotor-training effects at faster vs. slower treadmill speeds. As anticipated, independent of whether training occurred in the Lokomat or manual-BWSTT mode, average weekly training speeds within the fast and slow groups were similar, p ≥ 0.29 (Table 3). Therefore, data from both Lokomat and manual groups were collapsed to isolate the effects of training speed. On average, participants in the fast group trained at speeds that were 50% above their baseline overground walking speed, while the training speed in the slow group was similar to their baseline overground walking speed. Despite these differences in absolute and relative between-group training speeds, no group differences were noted on primary or secondary outcome measures, p ≥ 0.28. Table 3 Treadmill training speeds and self-selected walking speeds of fast and slow training groups Treadmill training speed (m/s) Final overground SSWS (m/s) Group Initial overground SSWS (m/s) Week 1 Week 2 Week 3 Week 4 Mean Fast 0.6 ± 0.2 (0.2–1.0) 0.8 ± 0.1 (0.5–1.1) 0.9 ± 0.1 (0.7–1.2) 0.94 ± 0.0 (0.7–1.2) 1.0 ± 0.1 (0.8–1.3) 0.9 ± 0.2 (0.7–1.2) 0.7 ± 0.4 (0.3–1.4) Robot 0.6 ± 0.3 (0.3–1.0) 0.9 ± 0.1 (0.8–1.1) 1.0 ± 0.1 (0.9–1.2) 1.0 ± 0.1 (0.9–1.2) 1.1 ± 0.2 (0.9–1.3) 1.0 ± 0.1 (0.9 ± 1.2) 0.7 ± 0.5 (0.4–1.4) Manual 0.6 ± 0.3 (0.2–0.9) 0.7 ± 0.2 (0.5–0.8 0.8 ± 0.1 (0.7–0.9) 0.9 ± 0.11 (0.7–1.0) 1.0 ± 0.1 (0.8–1.1) 0.8 ± 0.1 (0.7 ± 0.9) 0.7 ± 0.3 (0.3–0.9) Slow 0.6 ± 0.3 (0.3–0.9) 0.5 ± 0.1 (0.3–0.7) 0.6 ± 0.1 (0.3–0.7) 0.6 ± 0.1 (0.3–0.7) 0.6 ± 0.1 (0.4–0.7) 0.6 ± 0.1 (0.3–0.7) 0.7 ± 0.3 (0.3–1.0) Robot 0.7 ± 0.3 (0.3–0.9) 0.6 ± 0.1 (0.6–0.7) 0.7 ± 0.1 (0.6–0.7) 0.7 ± 0.0 (0.6–0.7) 0.7 ± 0.0 (0.7–0.7) 0.7 ± 0.0 (0.7 ± 0.7) 0.8 ± 0.3 (0.3–1.0) Manual 0.6 ± 0.3 (0.3–0.9) 0.5 ± 0.1 (0.3–0.6) 0.5 ± 0.1 (0.3–0.6) 0.5 ± 0.2 (0.3–0.7) 0.6 ± 0.1 (0.4–0.7) 0.5 ± 0.1 (0.3 ± 0.6) 0.7 ± 0.4 (0.3–1.0) Note: values are mean ± SD (range) Abbreviations: SSWS = self selected walking speed
BODY.DISCUSSION:
The primary purpose of this pilot study was to compare the efficacy of locomotor training implemented using a Lokomat robotic gait orthosis versus manual-BWSTT in a sample with chronic locomotor deficits post-stroke. In conducting this study, we sought to determine the key parameters and reveal challenges in future randomized controlled trials with larger cohorts. Although statistically significant differences were not apparent between Lokomat and manual groups in this small, pilot trial, our data revealed significantly greater training-related improvements within the Lokomat, but not the manual group. Differential treatment effects produced include: 1) Lokomat group improvements in: self-selected overground walking speed, gait symmetry (SLRabs), fast overground walking speed, lower extremity motor impairment (Fugl-Meyer), function (short physical performance battery), and balance (Berg Balance Scale), and 2) manual group improvements solely in balance outcomes (Berg Balance Scale).
BODY.DISCUSSION.CHANGES IN SELF-SELECTED WALKING SPEED:
Modest improvements in self-selected overground walking speed were not unexpected considering that participants were in the chronic post-stroke phase in which recovery is expected to be minimal. The minimal detectable change (MDC) necessary to conclude clinically significant change in gait speed has occurred ranges from 0.07–0.36 m/s in a post-stroke population [39]. Therefore, the 0.1 m/s increase from the mean baseline value revealed in the Lokomat group was not only statistically significant, but also clinically important with an effect size of 0.32. This modest, but significant, effect is especially notable considering the small treatment dose in this preliminary work. Despite the statistically non-significant between-group difference, it is also notable that participants in the Lokomat group increased overground gait speed by 16% over baseline, whereas those in the manual group advanced by only 4.8%. The magnitude of this difference suggests a potential clinical advantage of Lokomat training. While the overall outcome of this pilot study provides further evidence for the efficacy of locomotor training, the lack of statistical evidence supporting superiority of either Lokomat or manual form of locomotor training highlights inconsistencies between previous studies. Our results agree with investigations during the acute and subacute post-stroke stages using the Lokomat [18] and a robotic gait trainer [17] in which differences were noted within groups, but no differences were identified in the extent of improvement between robot and manual groups. However, in their recent publication, Hornby et al. [20] studied a sample of hemiparetic individuals of greater chronicity (i.e. 4–6 yrs post-stoke) and with lower baseline function (i.e. 0.4 m/s preferred gait speed) than our participant pool and reported greater increases in overground gait speed in a manual-BWSTT group compared with a Lokomat trained group. While speculative at this point, a secondary reduction in cardiorespiratory capacity of chronic stroke survivors [38] suggests that participants with long-term functional deficits may benefit from the aerobic training induced by the higher metabolic cost required for manual-BWSTT [40]. Results of the 6-minute walk test highlight this potential effect. A statistically significant improvement of 34 m, indicative of an aerobic conditioning effect, was found in the manually-trained group of Hornby et al., while a statistically non-significant reduction of 24 m was found in our manually-trained group. Further, a lack of correlation between change scores on the 6 minute walk test and self-selected walking speed suggests that increases in gait speed revealed in the present study are more likely to have resulted from factors other than increased physical capacity, including enhanced neural control, and reflect a change in the underlying locomotor pattern. Moreover, our decision to remove the AFO from all participants during locomotor training appears to have proven effective in improving gait symmetry. In contrast, Hornby and co-workers elected not to focus on improving kinematics, performed locomotor training with AFOs in place, and failed to detect changes in gait symmetry. Future investigations comparing Lokomat versus manual training with a common goal of improved kinematics at different stages of chronicity, may provide more definitive insight into an approximate timeline of beneficial use of one approach over the other.
BODY.DISCUSSION.CHANGES IN GAIT SYMMETRY:
Our intent throughout locomotor training, whether delivered using the Lokomat or manually, was to normalize gait kinematics during stepping, while simultaneously controlling for variables of BWS and stiffness and treadmill speed. Consistency of training variables in both groups enabled us to discern important differences between motor learning induced by Lokomat and manual-BWSTT. Kinematic improvements in paretic step length symmetry were noted only in the Lokomat group, suggesting greater benefits of consistent, normalized kinesthetic input delivered automatically at a constant guidance force to both lower extremities during gait. In contrast, the inconsistency in both kinematic stepping patterns and manual cues to the hemiparetic leg with therapist-determined level of assistance appears to be a limitation to improvements in gait symmetry, thereby supporting previous research [20]. Further improvements in gait symmetry within the Lokomat group may have arisen from the safe removal of the foot straps in 3 participants. Foot straps are included as part of the standard Lokomat package and are meant to passively set the ankle in neutral and enable foot clearance. Generation of paretic leg propulsive forces is correlated with gait speed, effective step length symmetry [26] and plantarflexion activity during late stance [41]. For these reasons, we strongly encouraged active plantarflexion/push-off and provided verbal and tactile cues in an effort to induce motor learning and voluntary execution of plantarflexion. Examining individual subject changes in gait speed and symmetry, we noted that two of the three participants who were able to train without foot straps demonstrated the most remarkable improvements in step length symmetry. Though we searched for other commonalities between these participants, including sensorimotor impairment scores, initial functional level, location and type of lesion, time since stroke, and age, the one similarity was the removal of the foot strap during training. From a biomechanical perspective, the automated symmetrical step length of the Lokomat would have forced the propulsive forces of the ankle plantarflexors to be initiated posterior to the subject's center of mass (COM) at preswing. A strong relationship between step length symmetry and propulsive force symmetry in addition to the importance of the plantarflexors to propulsive force supports this premise [26,42]. However, further investigations conducted without the use of the foot straps in a larger cohort are necessary to address this issue definitively. At this point we are only able to speculate that a more significant training effect was induced by the opportunity to experience active ankle movement and a normal range of ankle motion while in the Lokomat.
BODY.DISCUSSION.CHANGES IN BALANCE:
Results also revealed significantly improved balance scores producing small to moderate effect sizes on the BBS in both groups. Scores fell within the range in which each 1-pt increase translates to a 6–8% decrease in fall risk. Therefore, the 1.4-pt improvement following Lokomat training and the 4-pt improvement following manual training equates to an 8–14% and 24–32% reduction in fall risk, respectively [43]. These results are not surprising given that treadmill training with or without the Lokomat exposes the central nervous system to several sources of conflicting sensory information, thereby constantly challenging sensory re-weighting processes. Throughout training, proprioceptive inputs from the lower extremity mimic an appropriate stepping pattern on a moving support surface while vestibular and visual cues remain relatively stable. Sensory integration training in such challenging situations may have also translated to improved balance scores in our subject sample. Moreover, the importance of active lateral stabilization to the control of static and dynamic posture and prevention of falls is well established. In this respect, the manual group had a particular advantage in inducing balance improvements with increased lateral freedom compared to the constraints imposed by the Lokomat.
BODY.DISCUSSION.COMPARISON OF GAIT TRAINING SPEEDS:
The second purpose of this study was to assess effects of training at speeds comparable to preferred walking speeds of non-disabled individuals versus speeds comparable to persons post-stroke. Against our hypothesis, our data revealed no differences attributable to training speed on primary or secondary variables. Our hypothesis was based, in part, on a related study by Sullivan et al. [8], who found that training at speeds approaching normal walking speed (0.89 m/s) improved preferred overground gait speed compared with a considerably slower training speed (0.22 m/s). It is possible that since the mean training speed in our slow group at 0.58 m/s was higher, yet more functional, than the slow group in Sullivan et al., the difference between fast and slow groups was not sufficient to reveal training-related differences. Nevertheless, the slow speed in the current study was representative of the pre-intervention comfortable over ground walking speed of the participants, while the fast speed corresponded to a normal (e.g. non-disabled) gait speed of 1.3 m/s [44]. In this view, the two studies are complementary with results supporting training at or above participants' comfortable over ground walking speed rather than non-functional speeds that are below mean overground gait speed of individuals with stroke.
BODY.DISCUSSION.STUDY LIMITATIONS AND IMPLICATIONS:
It may be argued that the automaticity of the Lokomat may have afforded the opportunity to take more steps and, in turn, receive quantitatively more gait training. However, since the mean training speed did not differ between groups, the difference in the number of steps taken would likely be minimal. Moreover, our goal was to evaluate the effectiveness of the Lokomat compared to manual training within a 30 min time frame typically allotted in clinical settings. As with most pilot studies, the small sample size and resultant low statistical power limit interpretation of this study. However, given that participants demonstrated significant improvements after only 12 treatment sessions in the chronic post-stroke stage, the small to moderate effect sizes are promising. Our results support the original intent of the present pilot study, which was to determine if a larger clinical trial was plausible and should be conducted. This study was different from previous studies because we controlled for many factors such as handrail use, orthotic use, the amount of body weight support, and we placed emphasis on normalizing kinematics during training in order to isolate the specific effects of automated vs. manually-assisted treadmill training. Thus, we were able to show that subjects benefited from training with the Lokomat for a number of performance metrics. One product of our pilot study is tangible results from which to project requisite sample size(s) for future randomized controlled trials designed to definitively evaluate the efficacy of Lokomat compared to manual training. Our primary outcome, self-selected overground walking speed, revealed a between group effect size of 0.59 favoring Lokomat vs. manual training with a probability of 0.6. From this we determined that 51 subjects per group are necessary to detect significant between-group differences. For paretic step length ratio, the demonstrated between-group effect size was 0.73 favoring Lokomat vs. manual training with a probability of 0.70 which translates to a projected sample size of 34 subjects per group. Finally, for fast walking speed, our data revealed a between-group effect size of 0.70 favoring Lokomat vs. manual training at a probability of 0.69 which projects to a sample size of 37 subjects per group to detect between group differences. All sample sizes were projected assuming 80% power at a 5% level of significance.
BODY.DISCUSSION.RECOMMENDATIONS:
While these early, positive findings are encouraging, taken together with the disparate findings reported in the current literature [18-20,45,46], there is a clear need to pursue both the questions regarding efficacy of locomotor training, in general, and robotic-driven locomotor training specifically. We recommend a follow-up study based on our sample size calculations to: probe whether these findings will be reproduced in a larger sample, determine additional differential effects that may not have been revealed in this short pilot trial and test for retention of training effects over an extended period of weeks to months post-training. Further, the advantages and disadvantages of each approach to locomotor training should be weighed in terms of cost-effectiveness, ease of application, and consistency of treatment before definitive conclusions regarding Lokomat use in stroke rehabilitation settings may be drawn. Early evidence favoring locomotor training [9] as an effective intervention post-stroke is tempered by the personnel costs involved (2–4 therapists/trainers), which are unrealistic for the majority of clinical settings. Indeed, many clinics and laboratories that deliver locomotor training depend on considerable volunteer and/or student manpower to simply conduct locomotor training [47] let alone achieve financial feasibility [48]. Equally important is the considerable risk of injury to the trainers representing a significant liability for health care administrators. In this light, equivalent functional outcomes achieved between Lokomat and manual locomotor training represent an favorable result in which Lokomat training may be used in place of manual training to benefit a larger proportion of affected individuals. Further, as demonstrated in the present study, when administered carefully and systematically, robotic-driven motor learning appears to promote adaptation at the level of the locomotor pattern rather than simply offering aerobic conditioning or non-specific changes that contribute to increased gait speed. Long-term retention of these locomotor adaptations is desired and the target of future investigation beyond this initial pilot study. Further research is required to identify the ideal population (i.e. hemiparetic chronicity, severity) for locomotor training, especially robotic-driven approaches to locomotor training, and to elaborate the critical parameters of effective locomotor training, including the ideal amount of variability in kinematic guidance and the most effective schedule for adjusting and ultimately withdrawing kinematic guidance.
BODY.CONCLUSION:
While this pilot study revealed no between-group differences in efficacy of Lokomat versus manual locomotor training, significant within-group effects reveal positive effects of locomotor training and suggest that Lokomat training may offer a potential advantage of this mode over manual BWSTT. A modest dose of Lokomat training is effective for improving overground walking speed and gait symmetry, and other lower extremity impairments and physical function in persons with chronic hemiparesis post-stroke. Consequently, larger, randomized controlled trials are warranted.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
KPW assisted in experimental design, conducted the experiments and data collection, analyzed the data, and was responsible for the initial drafting of the manuscript. CP conceived the study and experimental design, assisted with the experiments and data collection, and helped draft the manuscript. Both authors read and approved the final manuscript. | 2,708,184 | {
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TITLE: Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial
ABSTRACT.BACKGROUND:
Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.
ABSTRACT.METHODS:
Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Δ = 5% difference in proportion of failures).
ABSTRACT.RESULTS:
Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.
ABSTRACT.CONCLUSIONS:
Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.
ABSTRACT.TRIAL REGISTRATION:
The trial was registered at ClinicalTrials.gov under identifier NCT00682578.
BODY.BACKGROUND:
Plasmodium vivax is associated with less mortality than Plasmodium falciparum, but still exerts a considerable burden of disease globally [1] and is a major cause of morbidity in Asia [2]. In endemic areas it is a particular problem of children and pregnant women in whom it is associated with poor outcomes, notably anaemia and low birth weight [3]. Control measures are confounded by the persistence of dormant hypnozoite stages in the liver, which cause relapses of the infection if radical therapy is not administered. Chloroquine remains the treatment of choice for treatment for the erythrocytic stage of P. vivax infection, but chloroquine resistance is spreading [4]. High level resistance is still confined mainly to Oceania [5] and Indonesia [6], but lower level resistance has been reported in other areas across Asia and South America [4]. Chloroquine was used for more than 50 years as the first-line drug for all forms of malaria in Afghanistan. Chloroquine continues to be first-line drug treatment as a mono-therapy for slide-confirmed P. vivax malaria and is also used in combination with sulphadoxine-pyrimethamine for presumptive treatment of clinical malaria episodes when accurate laboratory diagnosis is unavailable. Radical treatment with primaquine is not currently recommended because of the risk of oxidant haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as testing for G6PD deficiency is not available. Limited access to prompt diagnosis and treatment, self-medication with low quality medicines [7] and non-adherence to the national treatment policy are all potential contributors to drug resistance in Afghanistan. To date, anti-malarial therapeutic monitoring in Afghanistan has largely been conducted at the Malaria Reference Centre, Jalalabad (Nangarhar province) in the eastern region of the country near the border with Pakistan. In this area, chloroquine resistance is established in P. falciparum [8] but appears not to be a major problem for P. vivax [9,10]. Relatively little data exists for the rest of the country; sulphadoxine-pyrimethamine has been shown to have good efficacy against P. falciparum in Kunduz province [11] and molecular studies indicate that P. vivax resistance to sulphadoxine-pyrimethamine is present at a relatively early stage in Nangarhar and Herat provinces[12]. Since 2004, artemisinin combination therapy (ACT) in the form of artesunate/sulphadoxine-pyrimethamine has been the recommended first-line treatment for P. falciparum infections in Afghanistan. As the correct malaria parasite species may not be identified in patients presenting with fever, P. vivax infections in Afghanistan will inevitably be treated with ACT [9]. For operational reasons, there may an argument for treating both vivax and falciparum malaria with the same drug regimen. The fixed-dose combination of dihydroartemisinin co-formulated with the bisquinoline piperaquine represents a promising alternative to chloroquine. Piperaquine is related to 4-aminoquinolines but it retains activity against chloroquine-resistant P. falciparum [13] and several studies from Indonesia and Papua New Guinea have indicated that dihydroartemisinin-piperaquine is also safe and effective for the treatment of chloroquine-resistant vivax malaria, with more long-lasting post-treatment prophylactic effects than other forms of ACT [5,14,15]. Dihydroartemisinin-piperaquine is relatively expensive (1-2 US$ per treatment course) but has a simple dosing schedule (daily doses for three days). For the purpose of evidence-based decision making, and to obtain better information on the effectiveness of available anti-malarial drugs against vivax malaria in Afghanistan, the relative therapeutic efficacy of chloroquine and dihydroartemisinin-piperaquine in the treatment of vivax malaria was assessed at three sites in Afghanistan.
BODY.METHODS.STUDY AREA AND PARTICIPANTS:
The study was conducted from July 2007 to February 2009 at three provincial malaria control centres, one in the east and two in the north of the country. The epidemiology of malaria in Afghanistan is determined by the physical geography of the country, malaria being confined to lower lying areas with sufficient rainfall for mosquito survival consisting of the northern plains (bordering Turkmenistan, Uzbekistan and Tajikistan) [16], the Jalalabad basin to the east (bordering Pakistan) and river valleys that fringe the central mountains to the west and south [17]. The central area of Afghanistan, occupied by the western end of the Hindu Kush mountain range, is relatively free of malaria [18,19]. In Afghanistan, P. vivax remains endemic and accounts for more than 90% of all malaria cases [20]. Cases begin to present in the spring months (May onwards) consistent with periodic relapse from long latency hypnozoites, reach a peak in July and August, and few cases are seen after November. Jalalabad, capital of Nangarhar province, is a referral centre for the whole eastern region and lies adjacent to the Pakistani border where population movement in both directions takes place. The population is multi-ethnic with Pashtoon being the dominant group. The province as a whole (altitudes below 2,000 meters) is generally semiarid but where possible rice is cultivated. Taloqan is the capital of the north-east province of Takhar with a population that is mainly Tajik with significant proportions of Uzbek and Pashtoon. Rice is cultivated on the plain and malaria is a well-known health problem [21]. Maimana is the capital city of the north-west province of Faryab bordering Turkmenistan, with which there is no open border. The population is mainly Uzbek and Turkmen and the region is semi-arid.
BODY.METHODS.ENROLMENT:
This was a prospective, open label, randomized controlled trial conducted in patients with microscopically confirmed symptomatic vivax malaria who were aged three months and older. All febrile patients over three months of age presenting to the sites were screened and enrolled according to preset criteria. A standard data sheet was used to record demographic information, details of symptoms and their duration, and previous anti-malarial medications. Clinical examination findings and vital signs were documented, including axillary temperature measured with a digital thermometer. Venous blood samples were obtained for haemoglobin measurement (Hemocue) and white cell count using the counting chamber method. Giemsa-staining of thick and thin blood films was performed to confirm parasite species and parasitaemia by a standard approximation method (40 × number of parasites per 200 white blood cells on the thick film). 10% of slides were cross-checked in the MORU (Bangkok) parasitology laboratory. Approximately 20 μl capillary blood was collected on filter papers for subsequent confirmation of species by PCR and future molecular studies. Slide examination results were considered to be negative after examination of 30 high-power fields of the thick film. The inclusion criteria were slide-confirmed infection with asexual stages of P. vivax, written informed consent by the patient or attending parent/guardian, and a negative urine pregnancy test in women of childbearing age. Exclusion criteria were any clinical or laboratory feature of severe malaria [22], haemoglobin concentration of less than 7 g/dl, concomitant disease that would mask treatment responses, known allergy to any of the study drugs, anti-malarial treatment in the previous month, mixed species Plasmodium infection, pregnancy (or unwillingness to undergo pregnancy testing), lactation, and anticipated inability or unwillingness to complete the 56 day follow-up.
BODY.METHODS.RANDOMIZATION:
Patients were allocated to the two treatment arms based on a pre-generated randomization list made in blocks of 20 that was produced and held independently of the field teams by a statistician. The individual allocations were kept in sealed, opaque envelopes and opened only after enrolment by the field team. Patients and clinical field workers were, therefore, not blinded to the treatment arm after allocation. Microscopists were blinded to treatment allocation at follow-up examinations.
BODY.METHODS.DRUGS:
Patients received either quality-controlled chloroquine (IDA, Netherlands) aiming for a target total dose of 25 mg base/kg in divided doses over three days, or dihydroartemisinin-piperaquine (Artekin®, each tablet containing 40 mg dihydroartemisinin and 320 mg piperaquine; Holleypharm, China) aiming for a target total dose of 6/48 mg/kg in divided doses over three days. According to the body weight, individual doses were either rounded to the nearest half or quarter tablet or, if necessary, tablets were crushed, mixed with 5 ml water and the appropriate volume was given. All doses were taken under supervision at the malaria treatment centre and patients were observed for 60 minutes after drug administration. Patients vomiting within this time received the same dose again. Patients who vomited the medication twice were withdrawn from the study.
BODY.METHODS.FOLLOW-UP:
The subjects were seen on days 0 to 3 inclusive and weekly to 56 days, so that late recrudescence and relapses could be detected [23,24]. Patients were also requested to attend if they felt unwell on any other day during the 56 days of follow-up. At each follow up visit a clinical assessment was undertaken and the patient was asked about adverse events by the use of a standard symptom questionnaire. Thick and thin blood slides were examined and haemoglobin was measured. Other tests such as peripheral white blood cell count and urine examination were undertaken as indicated to rule out other conditions and investigate possible adverse effects of drugs. Patients showing parasitological failure with recurrence of P. vivax had capillary blood collected on filter paper for PCR analysis and were treated with chloroquine (25 mg base/kg over 3 days) and followed up by standard protocols. Patients with mixed P. falciparum/P. vivax infection were also classified as treatment failures but treated with artesunate/sulphadoxine-pyrimethamine. Patients were censored from the analysis if there was stated withdrawal of consent at any stage, persistent vomiting during the acute phase (necessitating parenteral treatment) or occurrence during the follow-up of concomitant disease that would interfere with a clear classification of the treatment outcome (including mono-infection with P. falciparum). Patients failing to attend follow-up visits received a visit at home and were asked to reattend the centre for assessment. Transportation was provided for all follow-up visits for all subjects. All enrolled patients were given one long-lasting insecticide treated bed net.
BODY.METHODS.OUTCOMES:
The primary outcome was the difference in the proportion of patients with parasitologically-confirmed recurrence of P. vivax infection at or before day 56 between the two arms. Secondary outcomes were parasite and fever clearance times, recurrence at earlier time points, gametocytaemia at day 28 and 56, haemoglobin recovery, and safety and tolerability of the treatments.
BODY.METHODS.SAMPLE SIZE:
Given the relatively high predicted efficacy of chloroquine, a non-inferiority design was used [23] with the aim of testing whether dihydroartemisinin-piperaquine was non-inferior to (i.e. equivalent or better than) chloroquine in terms of the proportion of patients with parasitological failure at 56 days; the non-inferiority margin (Δ) was set at 5%. The sample size was 550 patients (275 per arm), calculated assuming a 95% cure rate with chloroquine, a one-sided alpha of 0.05 and 80% power.
BODY.METHODS.STATISTICAL ANALYSIS:
Data were double entered into Microsoft Access. All analyses were conducted using STATA version 9.0. The Student's t-test, Mann-Whitney U and chi-squared (or Fisher's exact) tests were used for comparison of baseline variables, as appropriate. Parasitological failure rates were assessed by survival analysis using the Kaplan-Meier method and Wilson confidence intervals for the difference in efficacy proportions were calculated using the effective sample size [25]. Dihydroartemisinin-piperaquine was considered non-inferior to chloroquine if the lower bound of the confidence interval of the difference was greater than 0.05 (the non-inferiority margin). Differences between treatment groups were estimated using the log-rank test. A sensitivity analysis, in which losses to follow-up were considered failures, was also undertaken [26]; patients who did not complete treatment were excluded. Cox regression including age (years), gender, recruitment site, treatment arm, admission haemoglobin level (g/dl), presence of gametocytes and parasitaemia as independent variables was performed to identify possible independent predictors of recurrence, using a stepwise elimination method.
BODY.METHODS.SPECIES CONFIRMATION BY PCR:
DNA was extracted from filter-paper blood spots and nested PCR performed to detect P. vivax and P. falciparum as described previously [27].
BODY.METHODS.ETHICAL APPROVAL:
The study was approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, Thailand, the Oxford Tropical Research Ethics Committee, Oxford University, UK and the Institutional Review Board of the Afghan Public Health Institute, Ministry of Public Health, Afghanistan. The trial was registered with the clinical trials website http://www.clinicaltrials.gov/ct as NCT00682578. This description of the trial describes recruitment of patients with uncomplicated infection with either P. falciparum or P. vivax, with treatments depending on the species detected. Recruitment of P. falciparum cases proved much slower than for P. vivax and the ongoing P. falciparum study will be presented elsewhere.
BODY.RESULTS.RECRUITMENT:
From July 2007 to February 2009, 536 patients were enrolled in the study with 268 receiving chloroquine and 268 dihydroartemisinin-piperaquine (Figure 1). The main reasons for not being enrolled in the study were lack of consent (n = 608; 37%), history of taking anti-malarial drugs in the past month (n = 394; 24%), home too far away for follow-up (n = 337; 20%), concomitant disease (n = 228; 14%), pregnancy or lactation (n = 113; 7%), mixed infection with P. falciparum (n = 44) and severe malaria (n = 12). The majority of patients (314/536 (58.6%)) were recruited in Jalalabad; 119 (22.2%) patients were recruited in Taloqan and 103 (19.2%) in Maimana. 73 (13.6%) patients were less than five years of age, 258 (48.1%) were 5-14 years of age and 205 (38.2%) were 15 or older. Figure 1Trial flow. At the reference laboratory 94% of baseline slides were confirmed as P. vivax monoinfection; the remaining slides were classed as Plasmodium infection of undetermined species because of slide quality. PCR confirmation was undertaken on an independent, randomly selected subset of paired blood samples from 10 patients with parasitological failure. All 10 baseline samples and 9 of 10 samples taken at recurrence contained P. vivax by this method. P. falciparum was not detected in any sample by either microscopic or molecular methods.
BODY.RESULTS.BASELINE CHARACTERISTICS:
Patient characteristics at baseline were broadly similar between the two treatment groups (Table 1) except that the median white blood cell count was lower in the chloroquine group compared with dihydroartemisinin-piperaquine (median 6.0 vs. 6.6 × 109/l respectively, p = 0.02). Table 1 Baseline characteristics of enrolled patients. Characteristic Treatment arm Number of patients randomized CQ (n = 268) DP (n = 268) P Gender: Male/Female (ratio) 126/142 (0.89) 132/136 (0.97) 0.60 Age, median years (range) 11 (0.25 -71) 12 (1 - 70) 0.38 Age Groups: 0.18 <5 years 43 (16.0) 30 (11.2) 5 -14 years 130 (48.5) 128 (47.8) >14 years 95 (35.5) 110 (41.0) Location: 0.61 Jalalabad 154 (57.5) 160 (59.7) Taloqan 58 (21.6) 61 (22.8) Maimana 56 (20.9) 47 (17.5) Weight, median kg (range) 30 (5-93) 33 (7-89) 0.69 Geometric mean parasitaemia/μL (95% CI) 3339 (3000-3716) 3236 (2940 -3560) 0.67 Number with gametocytes 218 (81.3) 203 (75.2) 0.12 Haemoglobin concentration, mean g/dl (SD) 10.9 (1.46) 10.9 (1.42) 0.99 Anaemia (haemoglobin concentration < 10 g/dl) 49 (18.4) 44 (16.5) 0.35 Median white blood cells ×10 9 /ml, median (range) 6.0 (3.6-54) 6.6 (3.0-12.4) 0.02 Body temperature °C, mean (95% CI) 37.3 (37.2-37.4) 37.3 (37.2-37.4) 0.77 Median systolic blood pressure, mmHg (range) 100 (80-160) 100 (80-170) 0.43 Median diastolic blood pressure, mmHg (range) 70 (50-100) 70 (50-100) 0.38 Median pulse rate, beat/min (range) 88 (60-140) 88 (60-140) 0.53 Jaundice 30 (11.3) 32 (12.1) 0.79 History of convulsions in last 24 hours 1 (0.37) 1 (0.37) Data for chloroquine (CQ) and dihydroartemisinin-piperaquine (DP) are number (%) unless otherwise indicated.
BODY.RESULTS.RESPONSE TO TREATMENT AND FOLLOW-UP:
Patients in the chloroquine group who completed treatment received a median total dose of 25.9 mg/kg base (IQR 25.0 - 27.3 mg/kg); for the dihydroartemisinin-piperaquine group the median total dihydroartemisinin dose was 6.0 mg/kg (IQR 5.45 - 6.67 mg/kg). Both treatments were generally well tolerated. Repeated vomiting of the study medication was not reported within 60 minutes of drug administration in any patient. No patient deteriorated or developed signs of severity. Five patients who received the first dose withdrew consent before completing treatment and were censored from analysis. Of the 531 individuals who completed treatment, 38 (7.2%) cases were lost to follow-up before day 56; 13 in the chloroquine arm and 25 in dihydroartemisinin-piperaquine arm (p = 0.04) (Figure 1).
BODY.RESULTS.PARASITOLOGICAL FAILURES:
By the end of the 56-day follow-up period, there were 23 recurrences (parasitological failures) in the chloroquine group and 7 in the dihydroartemisinin-piperaquine group, giving a day 56 failure rate of 8.9% (95% CI 6.0 - 13.1%) in the chloroquine group and 2.8% (1.4 - 5.8%) in the dihydroartemisinin-piperaquine group (Figure 2). The difference in day 56 parasitological failure rates between chloroquine and dihydroartemisinin-piperaquine was 6.1% (2-sided 90% CI +2.6 to +9.7%). The lower bound of this confidence interval was not only higher than the prespecified non-inferiority margin (i.e. -5%), but also did not include zero, indicating that dihydroartemisinin-piperaquine was superior to chloroquine in terms of outcome (Figure 3) [26]. The superiority of dihydroartemisinin-piperaquine was confirmed by the log rank test (p = 0.003). Figure 2Survival curves. The proportion of subjects free from recurrence of P. vivax is displayed according to treatment arm; dihydroartemisinin-piperaquine (DP) and chloroquine (CQ). A sensitivity analysis (in which all losses to follow-up were classed as failures) yielded a difference in cumulative parasitological failure rate between chloroquine and dihydroartemisinin-piperaquine of 1.5% (2-sided 90% CI -3.3 to +6.3%); as predicted there was a wider 90% confidence interval than that based on survival analysis but also a lower point estimate for the difference in failure rate between the chloroquine and dihydroartemisinin-piperaquine groups caused by the greater number of losses to follow-up in the dihydroartemisinin-piperaquine group. The lower bound of the 90% confidence interval was still higher than the prespecified non-inferiority margin (5%), but included zero, indicating that dihydroartemisinin-piperaquine was not inferior to chloroquine even in this considerably more conservative analysis [26] (Figure 3). Figure 3Analysis of primary outcome (cumulative failure rate at day 56). Non-inferiority analysis refers to the pre-specified survival analysis.
BODY.RESULTS.SECONDARY OUTCOMES:
Initial parasitological responses were faster with dihydroartemisinin-piperaquine (Figure 4); in the dihydroartemisinin-piperaquine group 241/264 (91.3%) of patients cleared their parasitaemia at day 1 compared to 209/265 (78.9%) in the chloroquine group (p < 0.001, relative risk of clearance in chloroquine group = 0.87, 95% CI 0.81-0.93). At day 2, the groups were no longer significantly different with 259/265 (97.8%) of the dihydroartemisinin-piperaquine group and 257/265 (97.0%) in the chloroquine group having cleared their parasitaemia (p = 0.59). Two patients in the chloroquine arm remained parasitaemic at day 3. Figure 4Proportion with clearance of parasites (a) and fever (b) at day 1-3 after treatment. In terms of resolution of fever (defined as axillary temperature >37.0°C) dihydroartemisinin-piperaquine was again superior (Figure 4), with 29/266 (10.9%) of the dihydroartemisinin-piperaquine group febrile on day 1 compared to 45/268 (16.8%) in the chloroquine group (p = 0.049). By day 2 there was no longer a significant difference in the proportion with fever (3/265 (1.1%) for dihydroartemisinin-piperaquine, 9/264 (3.4%) for chloroquine, p = 0.08). At day 1, headache was less frequent in the dihydroartemisinin-piperaquine arm (105/265 (39.6%)) compared to the chloroquine arm (145/266 (54.5%), p = 0.001). The day 28 cure rate was 100% in both arms with the first recurrences observed at day 35 in the chloroquine group and day 42 in the dihydroartemisinin-piperaquine group. Twenty-one of 30 (70%) recurrent parasitaemias were associated with gametocytaemia, with no significant difference between treatment arms in terms of proportion of recurrent patients with gametocytaemia (16/23 and 5/7 for chloroquine and dihydroartemisinin-piperaquine respectively, p = 1.0).
BODY.RESULTS.ADVERSE EVENTS:
There were no serious adverse events recorded during the trial and no patient required hospitalization. Both study drugs appeared to be well tolerated. There was a significant increase in the proportion of patients with pruritus in the chloroquine arm compared to dihydroartemisinin-piperaquine on days 1, 2 and 3; on day 1, 15/268 subjects in the chloroquine arm had pruritus compared to 2/266 in the dihydroartemisinin-piperaquine arm (p = 0.002, relative risk 7.44, 95% CI 1.71-32.3), consistent with the known side-effects of chloroquine. None of the other signs or symptoms documented in the first three days of treatment were found to be significantly different between the groups. There were no significant differences between the two arms in haemoglobin concentration or occurrence of anaemia (haemoglobin < 10 g/dl) at any stage during follow-up (all p > 0.5).
BODY.RESULTS.PREDICTORS OF TREATMENT FAILURE:
A univariate analysis undertaken to identify variables associated with failure showed that treatment allocation (chloroquine rather than dihydroartemisinin-piperaquine), study site (recruitment in Maimana compared to Jalalabad), younger age and lower haemoglobin concentration at baseline were all significantly associated with recurrent infection. Admission parasitaemia, presence of gametocytes at admission and gender had no effect in this model (Table 2). Table 2 Univariate analysis of risk factors for treatment failure Univariate analysis Factor Hazard Ratio p value Chloroquine treatment 3.28 (1.41-7.63) 0.006 Female 0.93 (0.46-1.91) 0.85 Age (years) 0.96 (0.92-1.00) 0.03 Recruitment site (Jalalabad as reference) Taloqan 0.79 (0.26-2.43) 0.68 Maimana 3.06 (1.42-6.61) 0.004 Parasitaemia 0.86 (0.32-2.29) 0.76 Presence of gametocytes 1.13 (0.46-2.77) 0.784 Haemoglobin at admission (g/dl) 0.49 (0.37-0.65) <0.001 Multivariate analysis of the same seven variables entered into the univariate analysis indicated that treatment with chloroquine and lower haemoglobin concentration at baseline were the only two significant independent predictors of recurrent infection (Adjusted Hazard Ratio (AHR) 3.66, 95% CI 1.48-9.02, p < 0.001 for treatment allocation and AHR 0.50, 95% CI 0.37-0.66, p = 0.005 for haemoglobin concentration).
BODY.DISCUSSION:
This trial in three separate malaria areas of Afghanistan confirmed that both chloroquine and dihydroartemisinin-piperaquine are well-tolerated and broadly efficacious treatments for vivax malaria. Initial parasite clearance was significantly faster after dihydroartemisinin-piperaquine, consistent with the pharmacodynamic properties of artemisinin-containing therapies observed in P. falciparum [28] and P. vivax [9,24]. Nevertheless 97% of patients in the chloroquine arm were parasite free and afebrile by day 2, and there were no recurrences in either arm before day 28, suggesting that P. vivax remains sensitive to chloroquine in the study area, which included locations both north and south of the Hindu Kush divide of central Afghanistan. These data extend the geographic range of efficacy monitoring beyond Eastern Afghanistan where chloroquine has been shown previously to be efficacious in clearing P. vivax parasitaemia [9,10]. These findings stand in marked contrast to data from Indonesia where P. vivax chloroquine-resistance manifests as frequent failure to clear parasites by day 4 [6,29-31] and recurrence rates by day 28 approximate 50% [29-31] or higher [6]. Over the 56-day follow-up period dihydroartemisinin-piperaquine proved superior to chloroquine in terms of the prespecified survival analysis of recurrence rates. Approximately 9% of cases had recurrent P. vivax infections in the chloroquine arm, compared to 3% in the dihydroartemisinin-piperaquine arm, with all failures occurring on or after day 35. Recurrences of P. vivax may consist of a mixture of relapses from liver hypnozoites, recrudescences of the erythrocytic infection (due to inadequate drug levels or resistance), and reinfections acquired from additional innoculations. It is not possible with current methodologies to distinguish reliably between these possibilities [32,33]. However, in studies undertaken in a neighbouring region of Pakistan, radical treatment with primaquine following chloroquine prevented the majority of recurrent infections over the course of 9-12 months, indicating that most recurrences following chloroquine monotherapy are likely to be relapses from liver hypnozoites [34-36]. In this study, primaquine was not given, and none of the treatments administered has activity against P. vivax hypnozoites. The rapid clearance of parasites in the chloroquine group, and the fact that failures were not seen before day 28, suggest that recrudescences associated with chloroquine-resistance did not contribute significantly to the number of recurrences. For these reasons, the majority of recurrences observed in this study are likely to have been relapses. The pattern of recurrences is consistent with the known properties of the drugs under study. Chloroquine is effective in preventing early relapses (<28 days) of vivax malaria in chloroquine-sensitive vivax malaria [4,9,10,36-39]. This is because chloroquine is eliminated very slowly (terminal half-life one to two months), and provides post-treatment prophylaxis against relapse for 3-4 weeks after treatment [39]. Piperaquine also has a very long terminal elimination half- [40]. In an area where chloroquine-resistant P. vivax is prevalent DHA-PPQ has been shown in several comparative trials to prevent recurrences of P. vivax over a six-week period more effectively than ACT containing partner drugs with shorter half-lives [5,14,15]. In these studies, the recurrence rate (typically measured over 42 days) can be correlated with the half-life of the partner drug; for example, recurrences are fewer in patients treated with dihydroartemisinin-piperaquine compared to artemether-lumefantrine [5,14] and artesunate-amodiaquine [15], presumably because the lumefantrine and amodiaquine components have shorter terminal elimination half-lives (approximately 10 and 18 days respectively) than piperaquine. In the only previous trial directly comparing dihydroartemisinin-piperaquine to chloroquine (combined with sulfadoxine-pyrimethamine, CQ-SP) for P. vivax infection in Papua New Guinea, high levels of chloroquine-resistance were present, as evidenced by prolonged parasite clearance times in the CQ-SP arm. There was an 87% rate of recurrence in the first 42 days after CQ-SP compared to 30.6% in the dihydroartemisinin-piperaquine arm [5], a difference that is likely to reflect both failure to clear initial parasitaemia (leading to recrudescence) as well as failure to suppress relapse. This study provides the first comparison of chloroquine and dihydroartemisinin-piperaquine in chloroquine-sensitive P. vivax, and confirms the longer lasting post-treatment prophylactic effect of dihydroartemisinin-piperaquine compared to chloroquine in this setting. The observed proportion of chloroquine-treated patients with recurrence over 56 days is less than in a study undertaken in the Jalalabad Malaria Reference Centre in 2004 [9] (where more than 40% of patients treated with chloroquine had recurrence from days 28-42 after treatment), for reasons that are unclear. Ancillary studies would help to shed further light on these issues, including pharmacological assessment of chloroquine and piperaquine levels in blood during the follow-up period. This would also allow the question of chloroquine resistance to be excluded more definitively. This study was not powered to undertake detailed assessments of factors associated with recurrence. In the univariate analysis (although not the multivariate), younger age was found to be a risk factor for recurrence, a finding consistent with previous studies examining this effect over longer follow-up periods [35,37]. Possible explanations for this include pharmacokinetic effects [39,41], reduced immunity compared to adults and higher burdens of hypnozoites. Patients recruited in Maimana had a significantly higher rate of failure than those from Jalalabad in the univariate analysis although the effect disappeared in the multivariate analysis, suggesting that other factors may have contributed to this finding. The data do not provide substantive support for the existence of chloroquine resistance at Maimana or any of the study sites. The finding of a strong association between lower baseline haemoglobin and recurrence of P. vivax infection was not anticipated and requires further investigation. It is possible that the action of dihydroartemisinin-piperaquine is simply to delay relapses of vivax malaria rather than prevent them; in other words the survival curves for recurrence with dihydroartemisinin-piperaquine and chloroquine will eventually merge. Studies with longer-term follow-up would be needed to determine if this is the case and if dihydroartemisinin-piperaquine offers tangible benefits in terms of long-term health of the individual (preventing relapse and associated anaemia) and possibly the community (by reducing transmission). Any health benefits have to be balanced against the relative cost of each treatment course, which is currently in favour of chloroquine use. These issues also have to be considered in the context of the challenges of treating patients with radical therapy in this region [35,36].
BODY.CONCLUSION:
Both dihydroartemisinin-piperaquine and chloroquine are efficacious treatments for P. vivax malaria across three regions of Afghanistan. Consistent with the known pharmacological properties of the drugs, dihydroartemisinin-piperaquine provides a longer period of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
GRA, SP, MI, AMD, SJL, NPJD, PS, NJW and FK were involved in the conception and design of the study. GRA and FK were responsible for supervising patient recruitment and follow-up. MI undertook species confirmation by PCR. GRA, SP, CJW and SJL participated in the statistical analysis. GRA, SP, CJW, SJL and NJW drafted and critically revised the manuscript. All authors read and approved the final manuscript. | 2,864,284 | {
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TITLE: Is the operative delivery rate in low-risk women dependent on the level of birth care? A randomised controlled trial
ABSTRACT.OBJECTIVE:
To investigate possible differences in operative delivery rate among low-risk women, randomised to an alongside midwifery-led unit or to standard obstetric units within the same hospital.
ABSTRACT.DESIGN:
Randomised controlled trial.
ABSTRACT.SETTING:
Department of Obstetrics and Gynaecology, Østfold Hospital Trust, Tromsø, Norway.
ABSTRACT.POPULATION:
A total of 1111 women assessed to be at low risk at onset of spontaneous labour.
ABSTRACT.METHODS:
Randomisation into one of three birth units: the special unit; the normal unit; or the midwife-led unit.
ABSTRACT.MAIN OUTCOME MEASURES:
Total operative delivery rate, augmentation, pain relief, postpartum haemorrhage, sphincter injuries and intrapartum transfer, Apgar score <7 at 5 minutes, metabolic acidosis and transfer to neonatal intensive care unit.
ABSTRACT.RESULTS:
There were no significant differences in total operative deliveries between the three units: 16.3% in the midwife-led unit; 18.0% in the normal unit; and 18.8% in the special unit. There were no significant differences in postpartum haemorrhage, sphincter injuries or in neonatal outcomes. There were statistically significant differences in augmentation (midwife-led unit versus normal unit RR 0.73, 95% CI 0.59–0.89; midwife-led unit versus special unit RR 0.69, 95% CI 0.56–0.86), in epidural analgesia (midwife-led unit versus normal unit RR 0.68, 95% CI 0.52–0.90; midwife-led unit versus special unit RR 0.64, 95% CI 0.47–0.86) and in acupuncture (midwife-led unit versus normal unit RR 1.45, 95% CI 1.25–1.69; midwife-led unit versus special unit RR 1.45, 95% CI 1.22–1.73).
ABSTRACT.CONCLUSIONS:
The level of birth care does not significantly affect the rate of operative deliveries in low-risk women without any expressed preference for level of birth care.
BODY.INTRODUCTION:
Over the last few decades there has been an increasing trend towards the centralisation of childbirth in larger clinics in developed countries. As the level of available obstetric technology increases, the use of this technology increases as well, leaving researchers to suggest that low-risk women may receive excess interventions.1–4 Intervention rates for low-risk births might be higher than necessary, and there are large variations in inter-unit comparisons.5 In their intrapartum care guidelines, the UK's National Institute for Health and Clinical Excellence concluded that if a low-risk woman plans to give birth in a midwife-led unit she will have a higher likelihood of a normal birth with less intervention.6 As a counterbalance towards the trend of increased perinatal intervention, low-risk birth units or birth centres have been established. Low-risk birth units can either be freestanding, i.e. localised away from a hospital, or sit alongside, i.e. integrated within a hospital. These units are most often midwife led. Transfer from a low-risk birth unit to a standard care birth unit or hospital is required if medical services are necessary. Freestanding birth centres have been studied in different settings, concluding that birth centres are a safe alternative to hospital for low-risk women.7 It is also shown that general practitioners and midwives can identify a low-risk population that can deliver safely at maternity homes, with a low rate of operative deliveries and transfers.8 Freestanding, midwife-led birth centres report higher rates of normal births and lower rates of caesarean sections and episiotomies.9 Alongside birth units have also been studied widely. The Stockholm birth centre trial concludes that birth centre care is associated with less medical interventions, without statistically significant differences in health outcome.10 A Cochrane review on the topic concludes that an alternative birth setting versus conventional institutional birth setting is associated with reduced rates of medical interventions and increased maternal satisfaction, but states that there might be an increased risk for perinatal mortality.11 According to Gottvall et al.,12 there is no statistically significant difference in perinatal mortality between birth centres and standard care. A systematic review on low-risk units concludes that birth centres can offer the possibility of accessible, appropriate and personal maternity care for women and their families, but points to a strong need for randomised trials.13 Hatem et al.14 conclude in a Cochrane review that women who had midwife-led care were less likely to experience operative delivery, with no statistically significant differences in fetal or neonatal death overall. Studies reporting results from low-risk units often include participants early in pregnancy.10,15–18 This implies that a certain number of women included do not fulfil the selection criteria for midwife-led units at onset of labour, and therefore do not attend these units at all in labour. Following the important principle of intention to treat, the participants are still analysed according to the group they were originally allocated to.Waldenstrøm and Nilsson10 state that among women randomised to the midwife-led unit, 34% were transferred antepartum and 16% were transferred intrapartum. In this trial we wanted to study the effect of birth unit on birth outcome for low-risk women, and inclusion was therefore conducted at the onset of spontaneous labour. When searching for similar trials including women at onset of labour conducted in the last 20 years, only two randomised controlled trials were found: one from the USA and one from Hong Kong.19,20 Earlier data from several standard care obstetric departments in Norway show an operative delivery rate (caesareans, vacuum extractions and forceps deliveries) amongst low-risk women of ≥10%.21 At freestanding midwife-led units the operative delivery rate for the same group is approximately 5%.22 The aim of the present randomised controlled trial was to investigate if there were differences in operative delivery rates in low-risk women giving birth in an alongside, midwifery-led unit, compared with obstetric units. We hypothesised that it was possible to reduce the need for operative deliveries, with the same or better results for mother and child, if low-risk women were delivered in a separate low-risk unit.
BODY.METHODS:
In 1999 the Norwegian Parliament decided to organise national birth care into three levels. Departments of obstetric and gynaecology with more than 1500 births per year, providing all birth care services with obstetricians, paediatricians and anaesthesiologists on duty at all times, and with a neonatal intensive care unit.Smaller obstetrical departments with 400–1500 births per year, providing low-risk birth care with obstetricians and anaesthesiologist on call.Midwife-led maternity homes with 40–400 births per year, providing birth care for healthy women with expected normal births. The Norwegian Parliament also advised obstetric departments to have low-risk units within hospitals.23 Therefore, the Department of Obstetrics and Gynaecology at Østfold Hospital Trust, with approximately 3000 births per year, was divided into three separate units, placed on separate floors, in 2004: The midwife-led unit (MU), the normal unit (NU) and the special unit (SU). The MU is organised for low-risk women with expected normal births who want as little intervention as possible. Restrictive selection criteria must be fulfilled to attend this unit. No epidural is offered nor augmentation, unless required for the second phase of the second stage. If extended surveillance is needed or if the birth needs to be taken over by an obstetrician, the woman will be transferred to either the NU or the SU. Obstetricians are not present at the unit unless called on for a specific reason. The NU is organised for women with expected normal births. The unit has access to extended surveillance, epidural and operative vaginal delivery. It also provides room for women with elective caesareans and inductions after spontaneous rupture of membranes. If extended surveillance is necessary throughout the birth at the NU, a transfer to the SU is not required. The SU is organised for women who are in need of extended surveillance in the antenatal period, during labour and after birth. Women expecting normal births may give birth at any of the three units, but at the MU only low-risk women are accepted. The MU has approximately 600 births annually, and the other two units have approximately 1200 births each. Each unit has its own separate staff, and midwives are responsible for all normal deliveries. All units provide both birth and postpartum care. To explore our hypothesis a randomised trial was carried out. The primary outcome was operative delivery rates. Secondary outcomes were: augmentation of labour, pain relief, and postpartum haemorrhage, and neonatal outcomes measured by an Apgar score <7 at 5 minutes, metabolic acidosis defined as an umbilical artery pH <7.05 and BE (Base Excess) <−12 mmol/l,24 and transfers to the neonatal intensive care unit (NICU). Information about the trial was sent to all women planning to give birth at Østfold Hospital Trust when being called for a routine ultrasound examination. At the routine ultrasound examination at 18–20 weeks of gestation, all women roughly suited for the trial received additional written and verbal information about the trial. If eligible for the trial and willing to participate, she was recruited for the trial. If she fulfilled the inclusion criteria at the onset of spontaneous labour, she was randomised to one of the three units. The inclusion criteria for this study were similar to the selection criteria at the MU. Healthy, low-risk women without any disease known to influence the pregnancy, one fetus in cephalic presentation, a pre-pregnant body mass index (BMI) ≤32, not smoking more than ten cigarettes per day, no prior operation on the uterus, no prior complicated deliveries, and spontaneous onset of labour between 36+1 and 41+6 weeks of gestation. Written informed consent was obtained from all study participants. All 10 902 women who gave birth at the Østfold Hospital Trust during the study period were given written information on the trial when invited to ultrasound screening at 18 weeks of gestation. As the trial includes only healthy women, a certain number were excluded according to the inclusion criteria. Of the 2884 possible candidates assessed as being both eligible and willing to participate, 1773 did not meet the inclusion criteria by the time of onset of spontaneous labour for the following reasons: no longer considered to be at low risk because of pre-eclampsia, placenta praevia, intrauterine growth retardation, breech presentation, haemorrhage in third trimester, and pre- and post-term pregnancies and inductions (n = 697); changed their minds about participating (n = 300); the study was paused during summer and Christmas vacations because the MU was closed (n = 254); and for other reasons (n = 522). This led to a number of 1111 participants (Figure 1). Figure 1Flowchart of recruiting and inclusion process. The randomisation process was performed through a digital randomisation database developed by the Clinical Research Unit at the University Hospital of North Norway. The midwife who administered the randomisation entered the women's name and checked for eligibility before receiving the randomisation number and unit from the database. Allocation was concealed and the randomisation stratified between primiparous (para 0) and multiparous (para 1+) women (Table 1). As the SU serves women with extended needs, their capacity to receive low-risk women is limited. Because of this, randomisation was pre-specified to allocate 37.5, 37.5 and 25.0% to the NU, MU and SU, respectively. Table 1 Some basic characteristics of the participants Variable Midwife-led unit n = 282 (%) Normal unit n = 417 (%) Special unit n = 412 (%) Parity Nulliparous(P0) 278 (67.5) 285 (68.3) 184 (65.2) Multiparous(P+) 134 (32.5) 132 (31.7) 98 (35.4) Education Primary school 20 (4.9) 25 (6.0) 23 (8.2) High school 182 (44.2) 168 (40.3 112 (39.7) College/university 202 (49.0) 218 (52.3) 139 (49.3) Unknown 8 (1.9) 6 (1.4) 8 (2.8) Age <25 years 103 (25.0) 100 (24.0) 64 (22.7) 25–35 years 263 (63.8) 270 (64.7) 181 (64.2) >35 years 46 (11.2) 47 (11.3) 37 (13.1) Social status Married 155 (37.6) 165 (39.6) 120 (42.6) Cohabiting 236 (57.3) 229 (54.9) 152 (53.9) Single 19 (4.6) 20 (4.8) 9 (3.2) Unknown 2 (0.5) 3 (0.7) 1 (0.4)
BODY.METHODS.DOCUMENTATION PROCESS:
All data were registered by the midwife in charge in the electronic journal system of the department, partus (Clinsoft®), as is routine for all births. A midwife at each unit monitored the entries and was responsible for the documentation in connection with the trial. As a third and last documentation control, all the participants' data were checked by a midwife not working at any of the three units.
BODY.METHODS.STATISTICAL ANALYSIS:
To detect a statistically significant reduction in operative delivery rate for low-risk women, from an estimated >10% in standard care units to approximately 5%, which is closer to the estimated rate in freestanding birth units, a power calculation was conducted. With a power of 80% and a probability of P < 0.05, one would have to include 1642 low-risk women. The inclusion process proceeded slower than expected, and unfortunately the funding was running out. Hence the inclusion stopped the first week of March 2010, including just 1111 participants in the trial. All data were analysed by the principle of 'intention to treat'. Analyses presenting differences between the three units were performed by chi-squared tests, and Pearson's two-sided asymptomatic significance level P values were calculated. The MU was set as the reference unit, and all primary and secondary outcomes of this unit were compared with the outcomes of the NU and SU. The statistician who performed the statistical analysis was blinded to the participants' affiliation to the groups. Each result is presented with a risk ratio (RR) and a 95% confidence interval (95% CI). The analysis was conducted in statistical product and service solutions (SPSS) 17.
BODY.RESULTS:
Of the 1111 participants in this trial, 67.2% were primiparous and 32.8% were multiparous. Table 1 shows the baseline characteristics of the participants.
BODY.RESULTS.MODE OF DELIVERY:
There was no statistically significant difference in mode of delivery between the three birth-care units (Table 2). At the MU, the total operative delivery rate was 16.3%, with 23.4% for primiparas. At the NU these figures were 18.0 and 25.6%, respectively, and at the SU the rates were 18.8 and 27.7% (Table 3). Table 2 Relative risk (RR) assessments, with the MU set as the reference Variable MU vs NU RR (95% CI) MU vs SU RR (95% CI) Operative delivery 0.90 (0.67–1.22) 0.87 (0.62–1.20) Operative vaginal delivery 0.85 (0.58–1.25) 0.98 (0.65–1.52) caesarean section 1.01 (0.58–1.75) 0.71 (0.41–1.24) Dystocia * 0.79 (0.65–0.96) 0.72 (0.59–0.89) Oxytocin augmentation 0.71 (0.58–0.87) 0.69 (0.55–0.86) Epidural 0.68 (0.51–0.90) 0.64 (0.47–0.86) N 2 O 0.99 (0.90–1.09) 0.92 (0.83–1.02) Acupuncture for pain relief 1.45 (1.25–1.69) 1.45 (1.22–1.73) Postpartum haemorrhage >1000 0.79 (0.30–2.09 0.59 (0.20–1.41) Episiotomy of all vaginal 0.85 (0.66–1.09) 0.78 (0.60–1.02) Third-or fourth-degree tear of all vaginal deliveries 0.56 (0.19–1.66) 0.67 (0.20–2.28) Apgar score <7 at 5 minutes 0.68 (0.19–2.37) 2.74 (0.31–24.37) Metabolic acidocis ** 0.78 (0.25–2.42) 1.10 (0.30–4.0) Transfers to NICU *** 1.25 (0.76–2.05) 1.15 (0.67–1.99) * Midwife or doctor recorded labour dystocia, according to the hospital criteria. ** Metabolic acidosis: sample taken from umbilical cord showing arterial pH <7.05 and BE <−12 mmol/l. *** Transfer of newborn to NICU within the first 2 hours postpartum. Table 3 Birth outcome within the first 2 hours postpartum at all three birth care units Variable MU n = 412 (%) NU n = 417 (%) SU n = 282 (%) P Mode of delivery Total number of spontaneous deliveries 345 (84.0) 342 (82.0) 229 (81.0) ns Total number of operative deliveries 67 (16.0) 75 (18.0) 53 (18.8) ns Number of operative deliveries (P0) 65/278 (23.4) 73/285 (25.6) 51/184 (27.7) ns Number of operative deliveries (P+) 2/134 (1.5) 2/132 (1.5) 2/98 (2.0) ns Indication for operative delivery Labour dystocia 39 (58.2) 31 (41.3) 32 (60.4) ns Fetal distress 19 (28.4) 26 (34.7) 13 (24.5) ns Total number of operative vaginal deliveries 43 (10.0) 51 (12.0) 30 (11.0) ns Number of operative vaginal deliveries (P0) 42/278 (15.1) 49/285 (17.2) 29/184 (15.8) ns Number of operative vaginal deliveries (P+) 1/134 (0.7) 2/132 (0.7) 1/98 (1.0) ns Indication for operative vaginal delivery Labour dystocia 26 (60.5) 23 (45.0) 21 (70.0) ns Fetal distress 14 (32.6) 20 (39.2) 9 (30.0) ns Total number of caesarean sections 24 (6.0) 24 (6.0) 23 (8.0) ns Number of caesarean sections (P0) 23/278 (8.3) 24/285 (8.4) 22/184 (12.0) ns Number of caesarean sections (P+) 1/134 (0.7) 0/132 (0.0) 1/98 (1.0) ns Indication for caesarean section Labour dystocia 13 (54.2) 8 (33.3) 11 (47.8) ns Fetal distress 5 (20.8) 6 (25.0) 4 (17.4) ns Labour * 120 (29.0) 154 (37.0) 114 (40.0) <0.01 Oxytocin augmentation 108 (26.2) 153 (36.7) 107 (38.0) <0.01 Epidural 65 (16.0) 97 (23.0) 70 (25.0) <0.01 N 2 O 270 (66.0) 275 (66.0) 201 (71.0) ns Acupuncture for pain relief 227 (55.0) 158 (38.0) 107 (38.0) <0.001 Postpartum haemhorrage >1000 ml 7 (1.7) 9 (2.2) 9 (3.2) ns 500–999 ml 33 (8.0) 38 (9.0) 36 (13.0) ns 1000–1500 ml 4 (1.0) 6 (1.0) 3 (3.0) ns >1500 ml 3 (1.0) 3 (1.0) 6 (2.0) ns Episiotomy, of all vaginal deliveries 88/388 (23.0) 105/393 (27.0) 75/259 (29.0) ns Third- or fourth-degree tear, all vaginal deliveries 5 (1.0) 9 (2.0) 5 (2.0) ns Intrapartum transfer ** 117 (28.0) Apgar score <7 at 5 minutes 4 (1.0) 6 (1.0) 1 (0.5) ns Metabolic acidocis *** 5 (2.0) 7 (3.0) 4 (2.0) ns Transfers to NICU **** 32 (8.0) 26 (6.0) 19 (7.0) ns * Midwife or doctor recorded labour dystocia, according to the hospitals criteria. ** Intrapartum transfer from the MU. *** Metabolic acidosis: sample from umbilical cord showing arterial pH <7.05 and BE (Base Excess) <−12 mmol/l. **** Transfer of newborn to NICU within the first 2 hours postpartum. ns, not significant; P0, primiparous; P+, multiparous. Of all 24 women delivered by caesarean section at the MU, 23 were primiparous. The main reason for the intervention was dystocia (54.2%). At the NU there were 24 caesarean sections, all of them among nulliparous women. Dystocia was the reason for 33.3% of the operations at this unit. At the SU, one multiparous and 22 nulliparous women were delivered by caesarean section, and the main reason given for this intervention was dystocia (47.8%) (Table 3). Regarding operative vaginal delivery at the MU, 42 out of 43 deliveries were for primiparous women, and the main indication was dystocia. Of the women having an operative vaginal delivery at the NU, only two out of the 49 were multiparous, and the main reason for intervention was dystocia. At the SU, one of the 30 women who had an operative vaginal delivery was multiparous, and dystocia was the main indication for the interventions (Table 3).
BODY.RESULTS.MODE OF DELIVERY.PERINEAL OUTCOME:
There was no significant difference between the three groups concerning the number of episiotomies or the incidence of sphincter injuries (Table 2). An episiotomy was performed on 22.7, 26.7 and 29.0% of the women in the MU, NU and SU, respectively (Table 3). A sphincter injury occurred in 1.3, 2.3 and 1.9% of the vaginal deliveries at the MU, NU and SU, respectively (Table 3). Of the five women with a sphincter injury at the MU, none had an episiotomy, one had an operative vaginal delivery and four had spontaneous delivery. Of the nine women with sphincter injuries at the NU, four had both an episiotomy and operative vaginal delivery, one had spontaneous delivery with episiotomy and four had spontaneous delivery with no episiotomy. At the SU, five women had sphincter injuries: three had an operative vaginal delivery and episiotomy, one had an episiotomy and spontaneous delivery, and one had spontaneous delivery and no episiotomy.
BODY.RESULTS.MODE OF DELIVERY.LABOUR DYSTOCIA:
Labour dystocia was evaluated and recorded by the midwives or the doctors. According to the hospital guidelines, dystocia is defined as progression of <1 cm dilatation of the cervix per hour in the active phase of the first stage (defined as 3–4 cm dilatation of the cervix and regular contractions until a cervix dilatation of 10 cm). Dystocia in the second stage is recorded if the expulsion phase lasts more than 60 minutes for both nulliparous and multiparous women. Dystocia in the second stage is also recorded if the second stage lasts longer than 2 hours for nulliparous women without epidural or multiparous women with epidural, or more than 3 hours for nulliparous women with epidural or more than 60 minutes for multiparous women without epidural. In the MU dystocia was recorded in 29.1% of the cases, which is a significantly lower rate than 36.9% in the NU (RR 0.79, 95% CI 0.65–0.96) and 40.4% in the SU (RR 0.72, 95% CI 0.59–0.89) (Table 2). Of all women allocated to the MU, 26.2% were given oxytocin infusion for augmentation of labour, which was significantly lower than 36.7% in the NU (RR 0.73, 95% CI 0.59–0.89) and 38.0% in the SU (RR 0.69, 95% CI 0.56–0.86) (Table 2). Labour dystocia was the main reason for all operative deliveries (Table 3). The mean time for the active phase of the first stage was 4.9, 4.6 and 4.8 hours in the MU, NU and SU, respectively. The mean time for the expulsion phase of all vaginal deliveries was 40.4, 39.2 and 40.1 minutes in the MU, NU and SU, respectively.
BODY.RESULTS.MODE OF DELIVERY.PAIN RELIEF:
Of all women randomised to the MU, 15.8% had an epidural, which is a significantly lower rate than 23.3% in the NU (RR 1.47, 95% CI 1.11–1.96) and 24.8% in the SU (RR 1.57, 95% CI 1.16–2.13). The women randomised to the MU had acupuncture in 55.1% of the cases, a significantly higher rate compared with those randomised to the NU (37.9%; RR 1.45, 95% CI 1.25–1.69) and SU (37.9%; RR 1.45, 95% CI 1.22–1.73) (Table 2).
BODY.RESULTS.MODE OF DELIVERY.HAEMORRHAGE:
There was no statistically significant difference in the rate of postpartum haemorrhage between the three units (Table 2). The vast majority of all participants had normal postpartum haemorrhage of 500 ml or less (MU 90.3%, NU 88.7% and SU 84.0%; Table 3). Of the 25 women with a haemorrhage of 1000 ml or more, 17 were caused by atonic postpartum haemorrhage (five operative vaginal deliveries, 11 spontaneous deliveries and one caesarean section), three were caused by a retained placenta (two operative vaginal deliveries and one spontaneous delivery) and for five women no indication was stated.
BODY.RESULTS.MODE OF DELIVERY.NEONATAL OUTCOMES:
Neonatal outcomes were evaluated by Apgar score <7 at 5 minutes, metabolic acidosis and transfer to NICU within 2 hours of birth. An Apgar score <7 at 5 minutes was observed in 1.0, 1.4 and 0.4% of cases in the MU, NU and SU, respectively. An umbilical cord pH test was taken in 57.7, 68.8 and 77.3% of the cases in the MU, NU and SU, respectively. Metabolic acidosis was stated in 2.2, 2.8 and 2.0% in the MU, NU and SU, respectively. Transfers to the NICU were conducted in 7.8, 6.2 and 6.7% of the cases in the MU, NU and SU, respectively (Table 3). None of these outcomes showed a statistically significant difference between the units (Table 2).
BODY.RESULTS.MODE OF DELIVERY.INTRAPARTUM TRANSFER:
Of the 412 women randomised to the MU, 117 (28.4%) were transferred intrapartum to a higher level of care, either to the NU or SU (Table 3). The reasons for transfer were need for pain relief (39.3%), stained amniotic fluid (18.8%), fetal distress (9.4%), labour dystocia (23.9%) and other reasons (8.5%). Mean dilatation of the cervix was 6.4 cm at the time of transfer; 51% were transferred with a cervix dilatation of <7 cm. Of all women transferred intrapartum, 61 (52.0%) had an operative delivery, and among these, 39.3% were delivered by caesarean section and 60.7% were delivered by operative vaginal delivery. Of those transferred for labour dystocia, 60.8% had an operative delivery and 39.2% had a spontaneous delivery.
BODY.DISCUSSION:
In this randomised controlled trial three birth units within the same hospital were compared concerning birth care for low-risk women. The results when including 1111 participants showed no statistically significant differences in the total operative delivery rate, nor did it show differences in postpartum haemorrhage or neonatal outcomes between the three units. Operative delivery rate is often used as a measure of the quality of birth care,7–11,14,16,19,20,22,25,26 but it is a subtle way of measuring quality, as it predicts poor quality if the operative delivery rate is low but gives a negative outcome, or if the rate is high without improving the outcome or even increasing the complications for the mother or newborn, yet it predicts good quality if performed when needed. Finding the right level or percentage of operative delivery will always be a challenge. Operative delivery rates differ between countries and institutions. Data from the Medical Birth Registry of Norway (MBRN) from 2008 show an average total operative delivery rate for low-risk women of approximately 13.8%, but varies between institutions. It is worth noting that the birth population in Norway 2006–2009 consisted of 42.2% primiparous and 57.9% multiparous women.21 During the study period the Department of Obstetrics and Gynaecology at Østfold Hospital Trust had a high overall operative delivery rate (29.2%) compared with most hospitals in Norway.21 This fact is reflected in the high numbers of caesarean deliveries in this study in all three birth units. The overall high risk of having an operative delivery for low-risk nulliparas with no expressed preferences for level of birth care, leave birth attendants with the challenge of focusing on low-risk primiparous women, guiding them safely through their first labour. Statistically significant differences were found for dystocia and augmentation of labour by oxytocin, and the use of epidural and acupuncture as pain relief. Moen et al.27 studied augmentation for all low-risk women in a retrospective study conducted at a large hospital in Norway. They found that low-risk women were given oxytocin in 39% of the cases (62% of the primiparous and 24% of the multiparous women), many of them without any documented indication. In a debate article in the BMJ in 2002, the authors state that medical interventions have become routine in normal childbirth, without evidence of effectiveness.4 This view is supported by others.2 A strength of this trial is the time for randomisation when comparing intrapartum birth care and birth outcome in low-risk birth units and standard care units. All participants were defined as low risk when entering the trial at onset of spontaneous labour, making sure that only those fulfilling the selection criteria were included. As far as we know no similar trial has been conducted in Europe during the last two decades. A possible limitation of this trial is the fact that the number of women included was less than estimated by the power calculations, based on the primary outcome: operative delivery. This also might be the reason for the wide confidence interval for the primary outcome. However, the differences between the three units were so small that even if the total number of participants were included, it is considered unlikely that the differences would be significant. Only small non-significant differences in total operative delivery rate were found (total operative delivery rate, MU versus SU P= 0.57 and MU versus SU P= 0.44). There is a challenge in recruiting participants to studies like this because of the fact that women today often have their own preference for place of birth.28 This fact led to a longer recruiting period than expected in this trial.
BODY.CONCLUSION:
The operative delivery rate, the risk of having a postpartum haemorrhage of more than 1000 ml and the outcome for the newborn were not affected by the level of care for low-risk women without prelabour preferences for level of care. The participants randomised to the MU had a significantly higher chance of giving birth without interventions like augmentation by oxytocin or epidural analgesia. Further research is needed to determine the influence of women's own preference for birth care unit. | 3,187,863 | {
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"There were no significant differences in postpartum haemorrhage, sphincter injuries or in neonatal outcomes.",
"Neonatal outcomes were evaluated by Apgar score <7 at 5 minutes, metabolic acidosis and transfer to NICU within 2 hours of birth. An Apgar score <7 at 5 minutes was observed in 1.0, 1.4 and 0.4% of cases in the MU, NU and SU, respectively. An umbilical cord pH test was taken in 57.7, 68.8 and 77.3% of the cases in the MU, NU and SU, respectively. Metabolic acidosis was stated in 2.2, 2.8 and 2.0% in the MU, NU and SU, respectively. Transfers to the NICU were conducted in 7.8, 6.2 and 6.7% of the cases in the MU, NU and SU, respectively (Table 3). None of these outcomes showed a statistically significant difference between the units (Table 2)."
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TITLE: Immunogenicity and Smoking Cessation Outcomes for a Novel Nicotine Immunotherapeutic
ABSTRACT:
NicVAX®, a nicotine vaccine (3'AmNic-rEPA), has been clinically evaluated to determine if higher antibody concentrations are associated with higher smoking abstinence rates and if doses and frequency of administration are associated with increased antibody response. This randomized, double-blinded, placebo-controlled multicenter clinical trial (N=301 smokers) tested 200 and 400 μg doses administered 4 or 5 times over 6 months compared to placebo. 3'AmNic-rEPA recipients with the highest serum anti-nicotine antibody response (top 30% by AUC) were significantly more likely to attain 8 weeks continuous abstinence from weeks 19 through 26 than the placebo recipients (24.6% vs. 12.0%, p=0.024, OR=2.69, 95% CI, 1.14–6.37). The 5 injection 400 μg dose regimen had the greatest antibody response and had significantly higher abstinence rates than placebo. This study demonstrates proof-of-concept that 3'AmNic-rEPA elicits antibodies to nicotine and is associated with higher continuous abstinence rates, justifying its further development as a treatment for nicotine dependence.
BODY.INTRODUCTION:
Worldwide, smoking prevalence is 1.2 billion and approximately 5 million people die each year of smoking caused illnesses [1]. The global rate of smoking and smoking related deaths is anticipated to increase over the next 20 years unless significant public health measures are instituted. These include effective cessation interventions such as pharmacological treatments, which improve cessation rates by 1.5 to 3 fold over placebo intervention [2, 3]. Approved pharmacotherapies (e.g., nicotine replacements, bupropion SR, varenicline) for smoking cessation act on the central nervous system, each with a different mechanism of action. Other novel medications are being developed including immunotherapeutics targeting nicotine. Nicotine conjugate vaccines stimulate the immune system to develop nicotine specific antibodies (Abs) using an immunogen comprised of nicotine covalently linked to a larger carrier protein. Conceptually, the mechanism of action is that anti-nicotine antibodies bind nicotine molecules and the resulting complex is too large to cross the blood-brain barrier. With increasing Ab levels more nicotine is captured and sequestered in the blood and prevented from entering the brain, leading to less reinforcing effects from nicotine. Animal studies have demonstrated that passive or active immunization results in approximately 30% to 90% less nicotine entering the brain compared to control rats [4–7] and attenuated locomotor [4, 5] and behavioral [8, 9] responses to nicotine. Furthermore, vaccination reduced nicotine elimination from the body in a study with rats [10, 11], which may also contribute to reduced smoking. Although human studies are limited, published data evaluating different nicotine vaccines support the general concept that nicotine vaccines can be effective for smoking cessation in some smokers [12, 13]. Unfortunately, these studies either had small sample sizes [12], did not use an intent-to-treat population of smokers [13] or did not perform statistical analysis of the data [14]. The primary aim of the present study was to establish the proof-of-concept that (i) anti-nicotine antibodies are useful as an aid to smoking cessation and (ii) higher serum anti-nicotine antibody concentrations are associated with higher abstinence rates in an intent-to-treat population of smokers. One of the challenges with immunotherapeutics, such as vaccines, is attainment of therapeutic levels of antibody in most people. Therefore, this study tested two different doses of 3'-aminomethylnicotine P. aeruginosa r-exoprotein A - NicVAX (3'AmNic-rEPA) to identify a dose and schedule for further development: 200 and 400 μg across two different schedules (4 or 5 injections) compared to placebo for immunogenicity, efficacy and safety.
BODY.RESULTS:
A total of 301 subjects were randomized. Figure 2 shows the disposition and number of subjects within each treatment group. No significant group differences were observed in the demographic or smoking history by treatment or antibody levels (see Table 1).
BODY.RESULTS.COMPLIANCE:
All 301 subjects received injection 1, 96.7%, 84.1%, 72.4% and 61.2% received injections 2, 3, 4 and 5 (Schedule 2 subjects only), respectively. No significant differences were observed across treatment groups for subjects receiving injections 2 through 4 for Schedules 1 and 2. Mean in-study duration was 286 ± 121 days.
BODY.RESULTS.PROOF-OF-CONCEPT.EFFECTS OF HIGH AB ON ABSTINENCE:
High Ab responders to 3'AmNic-rEPA were defined as the top 30% of responders by AUC (0 to 26 weeks) and the low Ab group as the remaining bottom 70% of responders. 3'AmNic-rEPA recipients in the high Ab group were significantly more likely to attain 8 weeks of continuous abstinence from weeks 19 through 26 than placebo (24.6% vs. 12.0%, p=0.024, OR=2.69, 95% CI, 1.14–6.37). No significant differences were observed between the 3'AmNic-rEPA low Ab group vs. placebo (9.3% vs. 12.0%., p=0.46). As a secondary outcome, continuous abstinence rate (CAR) to 52 weeks were evaluated from weeks 19 to 52 and were significantly higher for the high Ab group vs. placebo (19.7% vs. 10.0%, p=0.044, OR=2.64, 95% CI, 1.03–6.79) with no significant difference between the low Ab group and placebo (7.1% vs. 10.0%, p=0.43). 7-day point prevalence abstinence results show that subjects with high Ab levels were significantly more likely to abstain compared to placebo at 26 weeks (36.1% vs. 16.0%, p=0.0024, OR=3.30, 95% CI, 1.53–7.13) and 52 weeks (31.1% vs. 12.0%, p=0.0021, OR=3.69, 95% CI, 0.42–2.14). No significant differences were observed in the point prevalence abstinence rates between the low Ab group and placebo at 26 and 52 weeks (12.9% vs. 16.0%, p=0.51 and 11.4% vs. 12.0%, p=0.89, respectively). As shown in Figure 3A, abstinence rates remained essentially the same following the target quit date (TQD) for the duration of the study. To further validate the proof-of-concept, the relationship between abstinence during the final eight weeks of the study and anti-nicotine Ab concentrations (AUC) is shown in Figure 3B for all subjects receiving the vaccine. Continuous abstinence rates from week 45–52 are displayed for each 10th percentile increase in AUC. The proportion of abstinent subjects increased with increasing AUC percentile, and the ordered ranking maintained.
BODY.RESULTS.PROOF-OF-CONCEPT.EFFECTS OF HIGH AB ON TIME TO CONTINUOUS ABSTINENCE:
An exploratory analysis examined the rate and time to continuous abstinence through study end (Figure 3C). Most smokers quit soon after the TQD, with a clear divergence of the high Ab group from the placebo and low Ab group. Among the 18 high Ab continuous abstainers, 12 initiated abstinence prior to the primary endpoint while 6 initiated their abstinence after the start of the primary endpoint. Furthermore, 3 of the 15 subjects who abstained during the primary endpoint relapsed by the end of the study. Cox proportional hazards analysis demonstrated superiority of the high Ab group compared to placebo (p=0.0069, hazard ratio of 2.76).
BODY.RESULTS.PROOF-OF-CONCEPT.EVALUATION OF LONG-TERM ABSTINENCE:
As most subjects achieved abstinence shortly after their TQD, additional analyses were undertaken to evaluate prolonged abstinence to 6 and 12 months allowing for a 2 week grace period after the TQD [15]. (Prolonged abstinence is defined as not a single puff during the period from 2 weeks after the TQD for 20 weeks and 44 weeks, respectively). Prolonged abstinence rates to 6 months were significantly higher in the high Ab group vs. placebo (19.7% vs. 6.0%, p=0.0060, OR=4.41, 95% CI, 1.53–12.71) with no significant differences between the placebo and low Ab groups (7.9% vs. 6.0%, p=0.60). Subjects with high Ab were also significantly more likely to be abstinent for 12 months compared to placebo (18.0% vs. 6.0%, p=0.014; OR of 3.84; 95% CI, 1.32–11.20). The low Ab group did not differ significantly from placebo (7.1% vs. 6.0%, p=0.67).
BODY.RESULTS.PROOF-OF-CONCEPT.CIGARETTE SMOKING IN NON-QUITTERS:
Statistically significant differences were observed in reduction of daily cigarette consumption and cotinine between non-abstainers (weeks 19–52) with high Ab levels and non-abstainers in the placebo group (p=0.0015 and 0.019, respectively; see Figures 4A and 4C. The difference in the median reduction in cigarette consumption, following the TQD, between the high Ab non-abstainers and placebo non-abstainers was on average 4.6 cigarettes per day. Similarly, cotinine geometric mean concentrations (GMCs) were 19.0% lower on average following the target quit date in the high Ab non-abstainers as compared to placebo non-abstainers. Median cigarettes per day and cotinine GMC for placebo and low Ab group are nearly identical over the study period. Differences in mean CO were not observed across all three groups (see Figure 4B). 15 out of the 301 subjects smoked more than a 2-fold higher number of cigarettes following the TQD as compared to baseline with no significant difference between the placebo (n=4/100) and 3'AmNic-rEPA (n=11/201) groups. The highest smoking levels observed post-TQD were 5-fold baseline in the placebo and 4-fold baseline in the 3'AmNic-rEPA groups. Elevated smoking levels for 11 of these 15 subjects returned to below 2-fold baseline by study end. Subjects with remaining elevated levels were similar between the 3'AmNic-rEPA group (n=3/201) and placebo (n=1/100). Individual subjects with CO levels elevated by 2-fold or higher than baseline were also assessed and results were similar with no significant difference between the placebo (n=5/100) and 3'AmNic-rEPA (n=13/201) groups.
BODY.RESULTS.PROOF-OF-CONCEPT.WITHDRAWAL SYMPTOMS:
Significant differences were not observed in overall withdrawal severity between placebo and the high and low Ab groups (p >0.22).
BODY.RESULTS.EFFECTS OF DOSE AND SCHEDULE.IMMUNOGENICITY AND EFFICACY BY STUDY GROUP:
Figure 5 depicts immune response by study group from baseline to week 52. Anti-nicotine Ab GMCs increased across all active treatment groups after each vaccination, with each subsequent dose resulting in a higher Ab response than the previous dose. Schedule 2 showed a higher initial increase in Ab concentrations. The 400 μg/Schedule 2 group demonstrated the highest Ab concentrations. However, no significant differences (p >0.05) were observed in AUC, Cmax and Cavg across the treatment groups to 26 or 52 weeks likely because the study was not powered to detect such difference. An intent-to-treat analysis demonstrated that the Schedule 2, 400 μg dose group had significantly higher prolonged abstinence to 6 months as compared to placebo (17.6% vs. 6.0%; p=0.015; OR of 4.14; 95% CI, 1.32–13.02), although not significant for the Schedule 2, 200 μg dose (14.0% vs. 6.0%, p=0.054; OR=3.23; 95% CI, 0.98–10.67) or between placebo and Schedule 1 for each of the doses (p >0.84). The Schedule 2, 400 μg dose group also had the highest rates of prolonged abstinence to 12-months, significantly higher than placebo (15.7% vs. 6.0%, p=0.038; OR=3.44; 95% CI, 1.07–11.04), but not significant for the Schedule 2, 200 μg dose (14.0% vs. 6.0% for 200 (p=0.056; OR=3.21; 95% CI, 0.97–10.63) or between placebo and Schedule 1 for each dose (p >0.88).
BODY.RESULTS.EFFECTS OF DOSE AND SCHEDULE.SAFETY:
Table 2 lists the number of subjects experiencing local and systemic reactogenicity. Reactogenicity events were aggregated over all injections. Overall, ache and tenderness were the most commonly reported local events, with at least one report by nearly all subjects (86% to 98%) in each treatment group. Myalgia, malaise, and headache were the most commonly reported systemic events (64% to 88% of subjects). Swelling, heat, burning, erythema, and nausea were reported by about half the subjects. Fever and vomiting were less common (4% to 16%). A total of 1184 treatment-emergent adverse events (AEs), predominantly rated mild or moderate, were reported by 266 of 301 subjects; 87.1% of 3'AmNic-rEPA recipients and 91.0% of placebo recipients. On average, 3.7 and 4.3 events were observed per person in the vaccinated and placebo groups, respectively, including subjects with no events. The distribution of 161 physician-determined treatment-related AEs, according to severity and relationship to treatment, was similar for the 3'AmNic-rEPA and placebo arms. Seven 3'AmNic-rEPA recipients (3.5%) and 2 subjects in the placebo arm (2.0%) withdrew from the study due to adverse events. 18 Serious AEs were reported: 8 events in the 3'AmNic-rEPA treatment groups among 7 subjects (3.5% of the 3'AmNic-rEPA recipients) and 10 events in the placebo group among 5 subjects (5.0% of the placebo recipients). Only one of these SAEs (anaphylactic reaction in a 3'AmNic-rEPA 400 μg/Schedule 2 recipient) was considered by the Investigator to be treatment related. This subject, who had a history of urticaria to penicillin and seasonal allergies, experienced difficulty breathing, throat tightness, facial erythema and urticaria 70 minutes after the initial vaccination. The subject was treated with a single injection of subcutaneous epinephrine and diphenhydramine, which resolved the symptoms. Herpes Zoster was reported in 6 subjects; one occurring within 3–5 hours after the first vaccination which would be impossible to link to vaccination. Of the remaining cases, 4 (2%) occurred in 3'AmNic-rEPA recipients; while 1 occurred in placebo (1%). In contrast, the related herpes virus, simplex infection was reported in 4 3'AmNic-rEPA recipients (1%) and 3 placebo recipients (2%).
BODY.DISCUSSION:
Results demonstrated the proof-of-concept that smokers who achieved higher anti-nicotine Ab concentrations were more likely to quit and remain abstinent from smoking. The high Ab group demonstrated the highest abstinence rates independent of the time period of ascertainment. Similarly, in a separate study conducted by Cornuz and coworkers [13] testing a different nicotine vaccine (nicotine derivative conjugated to a virus-like particle derived from bacteriophage Qβ), post hoc analysis showed subjects stratified to the highest Ab group had a significantly higher quit rate than placebo. However, unlike the current study, which used the intent-to-treat (ITT) population to establish proof of concept, the reported finding by Cornuz et al. [13] was observed after eliminating about a third of the subjects who used nicotine replacement therapies during the course of the study or who had incomplete Ab titer values. In the present 3'AmNic study, subjects in the high Ab group had observed odds ratios of 4.4 (95% CI 1.5–12.7) and 3.9 (95% CI 1.3–11.2) for prolonged abstinence rates to 6 and 12 months versus placebo. Although no direct comparisons can be made, these odds ratios are not unlike ones observed in the meta-analyses conducted for the U.S. Clinical Practice Guideline where the reported odds-ratios ranged from 1.5 (95% CI 1.2–1.7) for nicotine gum to 3.1 (95% CI 2.5–3.8) for varenicline at 6 months post-quit [3]. If current study findings are confirmed in larger studies, imunotherapeutics are likely to emerge as an important aid to smoking cessation. No significant compensatory smoking in response to the presence of anti-nicotine antibodies, as determined by the number of cigarettes smoked per day, carbon monoxide levels or cotinine levels, was observed in this study. This result is consistent with observations from other studies [12, 13]. In the current study, subjects in the high Ab group who did not abstain smoked significantly lower number of cigarettes (median reduction of ~5 cigarettes/day) and experienced lower cotinine levels (~20%) than placebo subjects along with no differences observed between the low Ab and placebo groups. However, a small number of individual subjects (N=15/301) smoked more than 2-fold the number of cigarettes at baseline with no significant differences between the active treatment and placebo groups. A major challenge for immunotherapeutics is to stimulate high Ab levels in the vast majority of smokers trying to quit. Vaccine dose and frequency of vaccination have an impact on the Ab levels attained. The 5 injection/400 μg dose was associated with the highest Ab response, although not statistically significant, possibly due to the small sample size. Importantly, this dose and schedule demonstrated statistically significant improved 44-week CAR compared to placebo. Because the 4 injection/400 μg dose was not associated with higher abstinence rates, this result demonstrates that consideration of both dose and schedule of injection are critical. In an independent, follow-up immunogenicity study to examine if peak Ab levels could be elevated, a total of 74 subjects received 6 injections of 400 μg 3'AmNic-rEPA at week 0, 4, 8, 12, 16, and 26. More than 80% of subjects receiving the 6-dose immunization regimen exceeded a target level of Ab (25 μg/ml) by week 14. In contrast, only 50% of subjects receiving 5 injections of the 400 μg dose achieved this level by week 14 in the current study and, only 7% of subjects attained this level by the target quit date. This finding suggests that more frequent injections and a later quit date may increase treatment success. In general, 3'AmNic-rEPA was well-tolerated. The frequencies of local and systemic vaccine reactogenicity events were similar in the vaccine and placebo groups and similar to licensed adult vaccines containing Alum adjuvant [16]. The slight increase in cases of herpes zoster observed in this study may be spurious, but continued monitoring is necessary to determine if a causal relationship exists. The occurrence of a single anaphylactic reaction would suggest a need for continued monitoring and follow-up, even considering the subjects' history of prior drug allergy to penicillin.1 In summary, results from this study support the concept that high anti-nicotine Ab levels are associated with higher rates of abstinence. These findings suggest that vaccines attaining high Ab levels by the target quit date may be more effective. Other future strategies may include examining additional ways to increase Ab levels across all individuals. Nonetheless, this study demonstrates that 3'AmNic-rEPA has significant potential as a smoking cessation, and perhaps a relapse prevention aid.
BODY.METHODS.STUDY POPULATION:
Smokers were recruited via advertisement across nine geographically diverse U.S. sites. Interested subjects were screened over the telephone and more extensively screened at the first Screening Visit. Subject informed consent was obtained prior to screening. Subjects were 18 years of age or older, smoked ≥15 cigarettes/day, had exhaled CO ≥10 ppm; wanted to quit smoking, and were in good general physical and mental health. Exclusion criteria included recent use of any medications or drugs that might interfere with immune response, interact with the vaccine, and pharmacotherapies or other treatments for smoking cessation. For females, a negative urine pregnancy test at enrollment and active use of acceptable birth control or documentation of surgical sterility was required.
BODY.METHODS.STUDY DESIGN:
This Phase 2 study was a randomized double-blind, placebo-controlled, parallel-arm trial design (see Figure 1). Four treatment groups varied the dose and/or schedule of intramuscular vaccination: 200 or 400 μg of 3'AmNic-rEPA or placebo according to Schedule 1 (weeks 0, 6, 12, and 26) or Schedule 2 (weeks 0, 4, 8, 16, and 26). Subjects (N=150) were first randomized within Schedule 1 groups in a 1:1:1 ratio (200 μg: 400 μg: placebo) and then 151 subjects randomized within Schedule 2 groups in the same ratio. The TQD was 1 week after the second injection (end of week 7 for Schedule 1 and end of week 5 for Schedule 2). If the subjects relapsed (seven consecutive days of smoking) after the quit date, a second quit date coinciding with a future clinic visit was allowed between time of relapse and week 18. Cessation counseling (based on the USDHHS Clinical Practice Guidelines [17]) for the first quit attempt involved 5 standardized face-to-face sessions (≤10 minutes) and for the second quit attempt, a face-to-face session plus 2 post-quit telephone counseling sessions. Subjects were followed for 52 weeks after randomization and the first injection on Day 0 for a total of 21 visits. During the injection day, subjects remained at the study site for 30 to 60 minutes for observation and attended a visit 24 hours after each injection to assess side effects. Otherwise, visits ranged from weekly to bi-weekly and were less frequent after later injections. Subjects who failed to quit smoking on their TQDs were encouraged to remain in the study and continue to attempt to achieve abstinence. Subjects who terminated from the study were not replaced and presumed to be smokers. Institutional Review Board approval was obtained from all institutions involved in the study. A Data and Safety Monitoring Board (DSMB) met four times during the study.
BODY.METHODS.INVESTIGATIONAL PRODUCT:
The active investigational product was purified 3'-aminomethylnicotine conjugated to P. aeruginosa r-exoprotein A. For the 200 and 400 μg/mL dose, each single-use syringe contained 3'-aminomethylnicotine conjugated to 200 or 400 μg rEPA, respectively, adsorbed to 1.2 mg aluminum hydroxide adjuvant (Alhydrogel 85) in 1 mL phosphate buffered saline (0.15 M NaCl, 0.002 M NaPO4, pH 7.2, 0.01% polysorbate 80; PBS). For the placebo dose, PBS with 1.2 mg Alhydrogel 85 was included in a 1 mL single-use syringe.
BODY.METHODS.MEASURES:
Cigarette use was recorded daily on an electronic diary for 182 days, and then weekly for the remainder of the study. Exhaled CO and urine cotinine were measured at each study visit, except for visits within 24 hours of vaccination. Questionnaires were collected via electronic diary: Fagerström Test for Nicotine Dependence [18] (administered days 0, 210, 364), Minnesota Nicotine Withdrawal Scale [MNWS, 19] (administered weekly until Month 6) and data on other tobacco usage. Sera were collected for immunogenicity measurements at 16–17 time points (schedule-dependent) from baseline to week 52. Anti-nicotine antibody concentrations were measured using ELISA (Enzyme-linked Immunosorbent Assay) [12]. Subjects recorded standard local and systemic reactogenicity events for 7 days after each injection. All reactogenicity events were followed until resolution or study completion. Treatment emergent AEs were recorded until 4 weeks after the last dose, with the exception of SAEs, which were collected through week 52. Subjects were also periodically monitored at clinic visits for vital signs, weight, hematology, chemistry and urinalysis.
BODY.METHODS.STATISTICAL ANALYSIS:
The Intent-to-Treat (ITT) population was used for evaluation of efficacy, safety and immunogenicity. The ITT population was defined as all subjects who were randomized to treatment. The primary endpoint was continuous smoking abstinence for a total of 8 weeks measured from the beginning of week 19 to the end of week 26 (determined from subject diaries confirmed by exhaled CO ≤8 ppm). The analysis for proof-of-concept stratified the active-treatment recipients into high (top 30% AUC from weeks 0 to 26) and low (bottom 70% AUC from weeks 0 to 26) Ab responders, regardless of treatment group. An a priori decision was made to establish the antibody cutoff between 50% and 25%. Top 30% by AUC group was selected as the largest group of high antibody responders between the 25% and 50% cutoffs that demonstrated statistical significance as compared to placebo. Smoking outcomes were compared between subjects with high Ab and pooled placebo recipients using logistic regression. Secondary aims of this study were to assess a) 7-day point prevalence abstinence at various times, CARs during 52 weeks and time to sustained abstinence defined as attaining 8 weeks of continuous abstinence at anytime prior to week 46 and maintaining continuous abstinence through 52 weeks; b) impact on compensatory smoking amongst non-abstainers; c) withdrawal symptoms and d) immunogenicity, efficacy and safety of administration of either 4 or 5 of the 200 and 400 μg doses. Secondary smoking cessation analyses used logistic regression for binary outcomes and Cox proportional hazards regression models and log-rank tests for time-to-sustained abstinence analyses. Mixed-effects repeated-measures analyses of the number of cigarettes smoked, CO and cotinine adjusted for baseline were utilized in assessing compensatory smoking among non-abstainers or in assessing withdrawal symptoms. Anti-nicotine Ab responses were summarized as GMC with 95% confidence intervals. Safety was assessed throughout this study primarily using reactogenicity and adverse events (AEs). Reactogenicity data for 7 days after each injection were tabulated, and the proportions of subjects with any post-vaccination reactogenicity, aggregated over all injections, among the five treatment groups were compared using the Generalized Cochran-Mantel-Haenszel test. When a subject dropped out of the study, they were assigned presumed to be smokers. Otherwise, all missing diary data related to cigarette use were imputed utilizing the Last Observation Carried Forward principle. No imputation was carried out for CO level. The missing serology data were imputed by first defining a set of injection windows for each schedule. The missing serology was imputed by using the next available measured serology in its corresponding window; if the next value was not available the value of the nearest previous time point in that window was used. The AUC for anti-nicotine Ab was calculated based on imputed data. For Ab values one week after the target quit date, the value at week 9 was used for Schedule 1 as sera were not collected at week 8. | 4,106,715 | {
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TITLE: Trends in Use of Referral Hospital Services for Care of Sick Newborns in a Community-based Intervention in Tangail District, Bangladesh
ABSTRACT:
The Projahnmo-II Project in Mirzapur upazila (sub-district), Tangail district, Bangladesh, is promoting care-seeking for sick newborns through health education of families, identification and referral of sick newborns in the community by community health workers (CHWs), and strengthening of neonatal care in Kumudini Hospital, Mirzapur. Data were drawn from records maintained by the CHWs, referral hospital registers, a baseline household survey of recently-delivered women conducted from March to June 2003, and two interim household surveys in January and September 2005. Increases were observed in self-referral of sick newborns for care, compliance after referral by the CHWs, and care-seeking from qualified providers and from the Kumudini Hospital, and decreases were observed in care-seeking from unqualified providers in the intervention arm. An active surveillance for illness by the CHWs in the home, education of families by them on recognition of danger signs and counselling to seek immediate care for serious illness, and improved linkages between the community and the hospital can produce substantial increases in care-seeking for sick newborns.
BODY.INTRODUCTION:
The timely and appropriate use of health services is crucial to reduce maternal and child mortality (1–4). Many lifesaving interventions, such as caesarean section, blood transfusion, oxygen, and intravenous antibiotics, can only be made available through health facilities. Evidence suggests that bringing women and children to facilities to receive these services is associated with reductions in mortality (1, 4). Countries that have achieved high rates of deliveries in facilities for basic or comprehensive essential obstetric care have witnessed significant and sustained decreases in maternal mortality (4), while countries, such as Sri Lanka, with elevated rates of care-seeking for sick children, have much lower rates of mortality among children aged less than five years (under-five mortality) than would be predicted from their per-capita income (1). Numerous studies have examined community-based interventions to improve care-seeking and referral for maternal emergencies from the community to first- and second-level facilities (3–8). Murray and Pearson have recently published a systematic review and proposed a research agendum to identify how programmes can better promote timely and appropriate maternal referral (9). Sibley has reviewed the effectiveness of traditional birth attendants (TBAs) in promoting referral from the community to facilities offering emergency obstetric care (10). Much less is known about referral of sick newborns from the community to health facilities. While several studies have examined referral of children, aged less than five-years, from first-level to second-level facilities (11–13), few studies have specifically examined referral from the community to facilities (14), and even less is known about referral of newborns from the community to facilities. Many factors affecting referral and care-seeking for maternal conditions from the community to health facilities could be applicable to promoting care for sick newborns. First, there is a need to act rapidly for certain maternal and newborn conditions, such as severe postpartum haemorrhage and birth asphyxia. So, research needs to examine not only recognition of danger signs, but also how long it takes for recognition of the problem to occur. The constraints on rapid action by families, such as distance, poor conditions of road, lack of transport, and lack of money, are common to both. Macintyre and Hotchkiss have developed a conceptual framework of factors at the individual, household, and community levels affecting referral in Africa which is equally applicable to other regions of the world (15). Second, in both mothers and newborns, many important causes of morbidity and mortality have signs and symptoms that "lie on a continuum, from normal to abnormal" (16). For such signs and symptoms, there can be both over-reporting of non-serious conditions, such as transient tachypnoea of the newborn or upper respiratory viral infection, or under-reporting of truly serious conditions, as happens when families fail to recognize excessive loss of maternal blood after delivery (16). Finally, patterns of decision-making within the household may lead to a significant delay, especially when permission of the husband is needed before seeking care but he is away, or when it is not clear to the family where to seek care from among a range of formal and informal sector providers (17–19). While there is much to learn from previous research on care-seeking and referral for older children, there are also obstacles to promoting early and appropriate care that are specific to newborns. In many cultures, families practise a period of postpartum confinement of both mother and newborn lasting from one to six week(s) or more (20). Additional efforts may be needed during this period to convince families to seek care outside the home. Sometimes, it is also difficult to detect danger signs in sick newborns, and families may not understand the significance of signs, such as hypothermia, feeding problems, or lethargy (21). This paper describes the trends in compliance by families with referrals when sick newborns were identified by community health workers (CHWs) and were referred to the Kumudini Hospital for care. In this project, families are educated about danger signs, and the CHWs visit the home during the postpartum period and examine newborns for any signs indicating the need for urgent medical care. Actions to increase the rate of compliance with referrals and their effects are also described.
BODY.MATERIALS AND METHODS.STUDY SITE:
The Projahnmo-II Project in Mirzapur upazila (sub-district) of Tangail district in central Bangladesh is implementing an intervention aimed at improving maternal and newborn-care practices and care-seeking for maternal and newborn conditions through: (a) behaviour change communication, (b) identification and referral of sick newborns in the community, and (c) strengthening of neonatal care in health facilities. The cluster-randomized trial has two arms: an intervention arm with CHWs delivering a package of maternal and newborn-care interventions in the home and a comparison arm. Mirzapur upazila has 13 unions, with a population of around 24,000 each; of these, six were randomly allocated to each study arm, excluding the one urban union. Given the need to have sick neonates assessed and treated in the hospital to identify aetiology of infections, a major focus of the problem is to identify barriers to care-seeking and design of strategies to address those barriers. The Kumudini Hospital, a 750-bed private hospital run by the Kumudini Welfare Trust, is situated at the centre of the project area. The hospital has a large paediatric unit (total 65 beds, including one separate neonatal ward) with two full-time consultants and 7–8 regular physicians.
BODY.MATERIALS AND METHODS.DESCRIPTION OF THE INTERVENTION MODEL:
In the Projahnmo-II project, 36 CHWs were recruited and provided one month of initial training to equip them to provide a package of maternal and newborn care. These CHWs had a minimum of 10th grade education and resided in the population they would serve. Each CHW was responsible for about 4,000 people. The CHWs carried out bi-monthly pregnancy surveillance and registration of married women of reproductive age (MWRA) and made home-visits in the third and the eighth month of pregnancy to counsel families on birth and neonatal care preparedness (BNCP). After delivery, the CHWs made home-visits to promote evidence-based domiciliary newborn care and to identify and refer sick newborns and mothers on day 0 (day of birth), 3, 6, and 9. Improvements were made in maternal and neonatal healthcare at the designated referral facility (Kumudini Hospital), and the CHWs facilitated referrals of sick newborns they identified during home-visits to this hospital. For families that refused referral and for babies who had at least one danger sign of very severe disease, or any two from possible very severe disease, the CHWs carried out home-treatment of cases with suspected serious infection with oral co-trimoxazole. The Field Supervisors supervised the daily activities of CHWs in the community and also reviewed the key performance and process indicators relating to coverage and quality every fortnight and provided feedback to the CHWs. Figure 1 is a model that shows how the intervention package helps promote hospital care for sick newborns. During the antenatal period, families were educated about signs indicating the need to seek care and sources of care by health workers during antenatal care visits at health facilities and by CHWs during antenatal home-visits (left side of Fig. 1). This should lead to an increased recognition by families of danger signs in newborns. This, in turn, should lead them either to seek care directly (self-referral) from the Kumudini Hospital and other appropriate sources of care, or notify the CHW to come to the house and assess the child. The CHW may also come in contact with a sick newborn during the course of her routine postnatal home-visits, and all findings are recorded in a Visit Record Form (VRF). The criteria for referral of sick newborns are: (a) in the case of birth asphyxia: if breathing difficulty continues 20 minutes after birth despite resuscitation efforts; (b) if there is one or more signs/symptoms of very severe disease, such as fever or lethargy; (c) jaundice—any where in the body within 24 hours of birth; (d) eyes discharging pus (possible gonococcal eye infection); and/or (e) diarrhoea with blood in stool and/or dehydration. Fig. 1.Intervention model: promotion by community health workers of care for sick newborns at Kumudini Hospital between April 2004 and September 2005 (Table 1) Dotted arrow indicates action not anticipated in the intervention model
*Coverage estimates from the second adequacy survey, September 2005
Sources of data: Project management information system (records maintained by CHWs and hospital registers) and household survey (second adequacy survey in September 2005)
ANC=Antenatal care;
BNCP=Birth and neonatal care preparedness;
CHWs=Community health workers A standard algorithm adapted from integrated management of childhood illness (IMCI) for use in the community by the CHWs is followed to assess and classify sickness in newborns. If the newborn requires referral, the CHW facilitates referral to the Kumudini Hospital. The community-based system of facilitated referral was in place by 19 February 2004 and initially consisted of the following elements, in addition to home-visits by the CHWs: (a) referral slips for the CHWs to fill in when referring a sick newborn to the hospital; (b) Birth and Neonatal Care Preparedness (BNCP) Cards, with an identification number, are supplied to families during antenatal home-visits by the CHWs. Families can carry the BNCP Card with them to the Kumudini Hospital in the event that the CHW is not available to issue a referral slip to the family when the newborn falls ill; (c) a referral-tracking form; (d) free inpatient care at the Kumudini Hospital for newborns arriving with a referral slip; (e) a system of emergency transport; and (f) training of TBAs, so that they could also promote referral to hospital for newborns with danger signs. If referral to the Kumudini Hospital fails, additional follow-up visits in the home are made to follow the condition of the child and treat presumptively with antibiotics, if appropriate. The CHW makes a final visit—called a graduation visit—as soon as the baby crosses 28 days of life. At that time, the completed VRF goes to the Mirzapur field office for review and is then sent to the main project office in Dhaka for data entry and further review.
BODY.MATERIALS AND METHODS.MODIFICATIONS TO THE INTERVENTION MODEL:
The CHWs helped families to arrange transportation, convinced family members to have the newborn treated outside the home, and provided a transport allowance to the poorest families to reach the Kumudini Hospital. After three months of initial implementation of the programme, further changes were made to improve coverage with home-visits and compliance with referrals. A referral-tracking form was introduced in April 2004, and every two weeks, the number of newborns referred and the outcome of referral were reviewed in a meeting with the supervisors and CHWs. In early 2005, a decision was made to emphasize more the management and referral of birth asphyxia and low-birth-weight newborns. The CHWs started to use digital weighing machines in February 2005 to obtain the weight of the newborn at first contact. In April 2005, the CHWs received refresher training on how to counsel families during antenatal home-visits on low birth-weight and birth asphyxia.
BODY.MATERIALS AND METHODS.MONITORING OF FUNCTIONING OF THE REFERRAL SYSTEM:
Data are presented from the project management information system (MIS) for the April 2004–September 2005 period, which includes the records maintained by the CHWs and registers maintained in the referral hospital (Kumudini Hospital). In addition, in-depth interviews were undertaken at baseline and during implementation to investigate the factors affecting compliance. Results of the interviews with parents appearing at the Kumudini Hospital and from those who did not comply with referral advice were shared with the CHWs and Field Supervisors to identify ways to improve counselling on referral.
BODY.MATERIALS AND METHODS.SAMPLING AND SAMPLE SIZE:
A baseline household survey among recently-delivered women was conducted in early 2003. Demographic and socioeconomic information of the listed households was collected, and information on birth-history and neonatal mortality was collected from all 14,526 women who had a pregnancy outcome in the 36 months preceding the survey. Information on knowledge, practices, and coverage of pregnancy, childbirth, and postpartum/postnatal care of mothers and newborns was collected from a randomly-selected sub-set of 4,611 recently-delivered women who had a pregnancy outcome in the last one year. Two interim household adequacy surveys were conducted in January and September 2005 to measure the adequacy of project inputs and selected process indicators to assess progress in early changes in behavioural patterns, including care-seeking. Identified through a systematic random-sampling method, in total, 1,200 women who had a pregnancy outcome in the last 7–8 months in each of the intervention and comparison arms were interviewed in each of the interim household surveys. Eighty-four randomly-selected parents arriving in the Outpatient Department of the Kumudini Hospital during January-June 2005 were asked why they had come to the hospital. Reasons for non-compliance with referral were analyzed on a continual basis and contributed to fine-tuning of the system of facilitated referral. Randomly-selected parents of 162 newborns who were referred for care but did not comply with referral during the same period mentioned above were interviewed regarding their reasons for non-compliance. Structured brief questionnaires were used in both instances.
BODY.RESULTS.FUNCTIONING OF THE REFERRAL SYSTEM:
Results of the second adequacy survey conducted in September 2005 showed that 72.5% of the recently-delivered women had attended at least one antenatal care visit, and 87.6% had received at least one antenatal BNCP visit by a CHW. Table 1 shows the trends between April 2004 and September 2005 in assessment, referral, and admission of sick newborns in the study intervention arm. Figure 1 presents data for the entire period. Although the project staff judged that the CHWs succeeded in identifying most pregnant women, the CHWs documented deliveries for only 3,354 (74.4%) of the 4,508 women estimated to have their due date during this period. The primary reason for this lower-than-expected figure was that significant numbers of women, particularly primigravidae, migrated at some point prior to delivery to live in another household located outside the intervention arm of the study. In most cases, they left the household of their husband's family (shashurbari) to reside in their natal home (baperbari), a phenomenon also observed in other sites in Bangladesh (20). Of 3,354 women who did not change residence, 3,228 (96.2%) received at least one home-visit by the CHW during the first 28 days of life of the baby. Table 1. Trends over time in assessment, referral, and admission of sick newborns in Mirzapur sub-district, Tangail district, Bangladesh between April 2004 and September 2005 (*indicates that figures are also displayed in Fig. 1 ) Variable and statistical assessment of trends Apr-Jun 2004 Jul-Sep 2004 Oct-Dec 2004 Jan-Mar 2005 Apr-Jun 2005 Jul-Sep 2005 Total Apr 2004-Sept 2005* Assessment and referral of sick newborns in the community by CHWs Home-deliveries 417 574 870 541 433 519 3,354* CHW-visit within first 28 days 324 443 862 659 436 504 3,228* Newborns assessed as sick 134 156 190 84 111 119 794* Referred to Kumudini Hospital 115 148 161 71 87 102 684* Percentage of sick newborns who were referred 85.8 94.9 84.7 84.5 78.4 85.7 86.1 Chi-square for linear trend=NS Arrival and admission at outpatient/emergency department of Kumudini Hospital Neonates reaching Kumudini Hospital OPD/emergency after self-referral or referral by CHWs 89 146 211 128 159 188 921* Neonates reaching Kumudini OPD/emergency after self-referral 25 55 82 75 95 111 443* Neonates reaching Kumudini Hospital OPD/emergency with CHW referral slip 64 91 129 53 64 77 478* Chi-square for linear trend=43.5, df=1, p<0.00001 71.9 62.3 61.1 41.4 40.3 41.0 51.9 Percentage of newborns referred by CHWs who arrived at Kumudini Hospital OPD/emergency 55.7 61.5 80.1 74.6 73.6 75.5 69.9 Chi-square for linear trend=12.97, df=1, p=0.00032 CHW=Community health worker; df=Degree of freedom; NS=Not significant; OPD=Outpatient department The CHWs identified 794 newborns as sick during this period, excluding newborns with feeding problems. Of these, 684 (86.1%) were referred by the CHWs to the Kumudini Hospital for care. The proportion of sick newborns who were referred stayed essentially constant between April 2004 and September 2005 (non-significant chi-square test for linear trend). Newborns arriving from households located in the intervention arm could either (a) have been referred by the CHW after she examined the child during a home-visit and issued a referral slip, or (b) the family could have taken the decision to seek care directly without first contacting the CHW, a situation we refer to as self-referral. Overall, of the 921 newborns arriving at the outpatient or emergency departments of the Kumudini Hospital during this period, 443 (48.1%) arrived after self-referral, and 478 (51.9%) arrived with a referral slip issued by the CHWs. The proportion of all cases who arrived with a referral slip declined continuously during this period (Row 8 of Table 1), from 71.9% at the beginning of implementation between April and June 2004 to 41.0% between July and September 2005, a trend which was highly significant (chi-square for linear trend=43.5, df=1, p<0.00001). Compliance with referral to the Kumudini Hospital by the CHWs increased from 55.7% during the first three-month period of implementation to 80.1% during the third three-month period of implementation (Row 9 of Table 1) and was thereafter maintained at 75–80%. The overall trend was significant (p=0.00032).
BODY.RESULTS.INTERVIEWS ON FACTORS AFFECTING COMPLIANCE:
Eighty-four parents arriving in the Outpatient Department of the Kumudini Hospital were asked why they had come to the hospital. They mentioned (multiple responses allowed) that the CHWs advised them to visit the Kumudini Hospital because treatment was available (65.5%), treatment was of high quality (34.5%) and free of charge (21.4%), the hospital was the nearest one to their home (2.4%), and other reasons (4.8%). Parents of 162 newborns who were referred for care but did not comply with referral were interviewed. The reasons cited for non-compliance (multiple responses allowed) included: nobody was available to accompany the child (and the mother) to the health facility (24.7%); the child was given a traditional treatment instead (19.1%); bad weather or general strikes (17.9%); the family disliked hospital treatment (12.3%); symptoms resolved on their own (7.4%); unwillingness of the family or the TBA to refer the baby for other reasons (6.2%); and other issues (12.3%), such as illness of the mother; the child was too young to be taken for outside care; and lack of transport. Although distance was a commonly-cited reason for failure to seek care from the health facilities, the proportion of cases referred by the CHWs in the farthest unions in the intervention arm, Warsi (2 hours away), Ajgana (1.5 hours away), and Bahuria (1.5 hours away) were at approximately the same level (79.3%, 80.6%, and 82.7% respectively) as the closest unions that were 0.5 hours away from the Kumudini Hospital, Banail (87.9%), and Bhatgram (81.6%).
BODY.RESULTS.EVALUATION OF TRENDS IN CARE-SEEKING:
Table 2 demonstrates the changes in care-seeking/self-referral to the Kumudini Hospital and other providers between the baseline survey (January 2003) and the first (January 2005) and the second (September 2005) adequacy survey. Caution is necessary in assigning significance to the observed trends as the two adequacy surveys are based on much smaller samples than the baseline survey. At the time of the baseline household survey in January 2003, there was no significant difference between the intervention arm and the comparison arm of the study in the proportion of sick newborns who were taken outside the home for care from any qualified provider (including Kumudini Hospital), to the Kumudini Hospital specifically, or to an unqualified provider, most commonly an unlicensed 'village doctor'. Table 2. Trends in care-seeking for sick newborns from Kumudini Hospital and other providers based on population-based household surveys Measures of care-seeking Baseline survey: January 2003 First adequacy ssurvey: January 2005 Second adequacy survey: September 2005 Intervention arm Comparison arm Intervention arm Comparison arm Intervention arm Comparison arm Reported sickness among newborns in the sample Total number of newborns in the sample 2,053 2,290 523 550 520 548 Number of newborns reported to have been sick (%) 818 (37.5) 780 (37.6) 255 (48.8) 279 (50.7) 207 (39.8) 257 (46.9) Reported care-seeking outside home Proportion of sick newborns reported to have been given any care in or outside home 92.9 93.7 93.3 93.2 93.2 95.3 Proportion of sick newborns for whom care was sought from outside home 66.1 66.4 82.8 81.4 82.6 77.4 Reported care-seeking from qualified providers ( Fig. 2 ) Proportion of sick newborns for whom care was sought from qualified providers 31.2 29.6 55.7 38.4 60.4 33.9 Odds ratio for care from qualified providers, intervention vs comparison (95% CI) 1.08 (0.86–1.34) (p=0.499) 2.02 (1.41–2.90) (p<0.0001) 2.98 (2.00–4.44) (p<0.0001) Chi-square trend test for care from qualified providers, intervention group Chi-square for linear trend=80.13, df=1, p<0.00001 Chi-square trend test for care from qualified providers, comparison group Chi-square for linear trend=3.42, df=1, p=0.065 Reported care-seeking from Kumudini Hospital ( Fig. 3 ) Proportion of sick newborns for whom care was sought from Kumudini Hospital 17.9 17.6 42.0 21.9 46.4 23.0 Odds ratio for care from Kumudini Hospital, intervention vs comparison (95% CI) 1.02 (0.78–1.33) (p<0.882) 2.58 (1.74–3.84) (p<0.0001) 2.90 (1.91–4.41) (p<0.0001) Chi-square trend test for care from Kumudini Hospital, intervention Group Chi-square for linear trend=93.40, df=1, p<0.00001 Chi-square trend test for care from Kumudini Hospital, comparison Group Chi-square for linear trend=4.47, df=1, p=0.035 Reported care-seeking from unqualified providers ( Fig. 4 ) Proportion of sick newborns for whom care was sought from unqualified providers 66.7 67.9 49.8 66.0 36.7 65.0 Odds ratio for care from unqualified providers, intervention vs comparison (95% CI) 0.95 (0.76–1.17) (p<0.609) 0.51 (0.36–0.74) (p=0.0002) 0.31 (0.21–0.47) (p<0.0001) Chi-square trend test for care from unqualified providers, intervention group Chi-square for linear trend=71.01, df=1, p<0.00001 Chi-square trend test for care from unqualified providers, comparison group Chi-square for linear trend=0.90, df=1, p=0.34 CI=Confidence interval; df=Degree of freedom Between the time of the baseline and the first adequacy survey, there was a significant increase in care-seeking in both intervention and comparison arms of the study (Row 4 of Table 2). This difference could be due to both increased awareness of the newborn's health problems and/or changes in how the survey was administered. Figure 2 demonstrates that there was a highly significant (p<0.00001) increase in the proportion of families that sought care from qualified providers for sick newborns in the intervention arm (Fig. 2 and Rows 5 and 7 of Table 2) and a non-significant increase in the comparison arm (Rows 5 and 8). Figure 3 shows that care-seeking for sick newborns specifically from the Kumudini Hospital increased significantly in both intervention and comparison arms, but the increase was of a much greater magnitude in the intervention arm (Fig. 3 and Row 9–12 of Table 2). Finally, Figure 4 demonstrates that the proportion of families who sought care from unqualified providers, such as unlicensed village doctors, remained unchanged in the comparison arm, but declined significantly in the intervention arm (Fig. 4 and Row 13–16 of Table 2). Fig. 2.Trend in proportion of sick newborns for whom care was sought from qualified providers*p<0.0001; Chi-square for linear trend (intervention) 80.13 (p<0.00001)
OR=Odds ration Fig. 3.Trend in proportion of sick newborns for whom care was sought from Kumudini Hospital*p<0.0001; Chi-square for linear trend (intervention) 93.4 (p<0.00001)
OR=Odds ratio Fig. 4.Trend in proportion of sick newborns for whom care was sought from unqualified providers*p<0.0001; Chi-square for linear trend (intervention) 71.01 (p<0.00001)
OR=Odds ratio
BODY.DISCUSSION:
Significant reductions in neonatal mortality must be made to reach the Millennium Development Goal for under-five mortality. One key to reducing neonatal mortality is to ensure that sick newborns are assessed and treated quickly either in the home (22, 23) or in a health facility. Practices of postpartum confinement of mothers and newborns found in many cultures, difficulties in transport, and patterns of household decision-making are among the factors that can delay or prevent care-seeking outside the home. Data presented in this paper demonstrate that it is possible to achieve high rates of care-seeking from hospitals or other qualified providers and to significantly decrease care-seeking from unqualified providers, even in a low-income rural area where all these factors are present. The trends observed in the intervention arm included increased care-seeking, increased proportion of sick newborns arriving at the Kumudini Hospital after self-referral rather than referral by a CHW, increased compliance after referral by the CHWs, increased care-seeking from the qualified providers (Fig. 2) and from the Kumudini Hospital (Fig. 3), and decreases in care-seeking from the unqualified providers (Fig. 4). In the comparison arm, an increase in care-seeking from the Kumudini Hospital was also observed, but the proportions seeking care from the qualified and unqualified providers did not change significantly. Reasons for the increasing trend in the proportion of cases in the intervention arm arriving at the Kumudini Hospital after self-referral have not yet been fully elucidated, but include increasing awareness of the signs of illness in newborns and experience with the services offered by the Kumudini Hospital. There also appeared to be some cases where the CHWs judged that the newborns did not require referral, but the family decided to seek care from the Kumudini Hospital anyway. In a number of these cases, the child had physiologic jaundice, a condition which the family felt warranted further investigation, despite reassurances provided by the CHWs. The project investigators are currently investigating this situation further. Substantial increases in referral compliance for newborn illness were likely related to (a) education of families on danger signs by the CHWs; (b) active surveillance for illness by the CHWs during routine postnatal home-visits; (c) facilitated referral by the CHWs, including counselling, use of referral slips along with improved linkages between community and hospital; (d) incentives for labour/birth notification; (e) enhanced capacity at the referral-care centre to manage sick newborns; and (f) availability of subsidized treatment. Sustained community-level education enhanced the empowerment of families towards decision-making for self-referral. In low-income countries with high rates of neonatal mortality, sick newborns can either be treated presumptively in the home (22, 23) or referred to health facilities. This paper demonstrates that it is possible to achieve high rates of compliance with referral, but to do this requires an extensive infrastructure of CHWs or other community contact persons (8) to assess newborns and facilitate referrals. Alternatively, an increased emphasis could be placed on community mobilization, education on danger signs, and facilitation of self-referral, perhaps with similar results. This paper is one of the only studies to provide data on levels of referral compliance achieved through facilitated referral (12, 14). Whether the emphasis is on treatment in facilities or treatment in the community, substantial investments will need to be made in the creation of demand with the community, community and family education, and facilitation of referral.
BODY.ACKNOWLEDGEMENTS:
This study was supported primarily through the generous support of the Infectious Disease Initiative of the Wellcome Trust–Burroughs Wellcome Fund. Additional support was provided by the Department for International Development (DFID), UK; the United States Agency for International Development, Office of Health, Infectious Diseases, and Nutrition, Global Bureau through the Global Research Activity Cooperative Agreement (No. GHS-A-00-03-00019-00); the Government of Bangladesh (Improved Health for the Poor); and Save the Children-USA through a grant from the Bill and Melinda Gates Foundation. The authors thank the study participants in Mirzapur upazila, Bangladesh, who were generous with their time and patience with interviewers through the several rounds of interviews. | 3,001,156 | {
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TITLE: Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome
ABSTRACT.INTRODUCTION:
In acute respiratory distress syndrome (ARDS), adequate positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by minimising overinflation and cyclic recruitment-derecruitment of the lung. We evaluated whether setting the PEEP using decremental PEEP titration after an alveolar recruitment manoeuvre (ARM) affects the clinical outcome in patients with ARDS.
ABSTRACT.METHODS:
Fifty-seven patients with early ARDS were randomly assigned to a group given decremental PEEP titration following ARM or a table-based PEEP (control) group. PEEP and inspired fraction of oxygen (FiO2) in the control group were set according to the table-based combinations of FiO2 and PEEP of the ARDS network, by which we aimed to achieve a PEEP level compatible with an oxygenation target. In the decremental PEEP titration group, the oxygen saturation and static compliance were monitored as the patients performed the ARM along with the extended sigh method, which is designed to gradually apply and withdraw a high distending pressure over a prolonged period, and the decremental titration of PEEP.
ABSTRACT.RESULTS:
The baseline characteristics did not differ significantly between the control and decremental PEEP titration groups. Initial oxygenation improved more in the decremental PEEP titration group than in the control group. However, dynamic compliance, tidal volume and PEEP were similar in the two groups during the first week. The duration of use of paralysing or sedative agents, mechanical ventilation, stay in the intensive care unit and mortality at 28 days did not differ significantly between the decremental PEEP titration and control groups.
ABSTRACT.CONCLUSIONS:
The daily decremental PEEP titration after ARM showed only initial oxygenation improvement compared with the table-based PEEP method. Respiratory mechanics and patient outcomes did not differ between the decremental PEEP titration and control groups.
ABSTRACT.TRIAL REGISTRATION:
ClinicalTrials.gov identifier: ISRCTN79027921.
BODY.INTRODUCTION:
Two recent randomised controlled trials involving patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) demonstrated that mortality can be reduced significantly by setting a low tidal volume (VT) [1] and by setting both a low VT and adequate positive end-expiratory pressure (PEEP) levels titrated by pressure-volume curves [2,3]. However, this strategy favours further lung collapse or derecruitment, especially when used with a high inspired fraction of oxygen (FiO2) [4]. The importance of opening the lung and keeping it open seems increasingly significant in this era of lung-protective ventilatory support because the use of a small VT for this strategy may worsen progressive lung collapse. Moreover, the alveolar and systemic inflammatory responses can be attenuated by minimising overinflation and cyclic recruitment–derecruitment of the lung by reducing VT and increasing PEEP in ARDS [5]. The best method of setting optimal PEEP after recruitment to prevent recollapse is still a matter of debate [6]. In the ALVEOLI study, mortality rates and the number of ventilator-free days did not differ significantly between the lower- and higher-PEEP study groups [7]. This result may have reflected the use of the same PEEP level (combination of FiO2 and PEEP) for the heterogeneous patient group and an inappropriately high PEEP in the nonrecruiters, which may have resulted in overdistension. Gattinoni and colleagues reported that the percentage of potentially recruitable lung tissue may be different in patients with ARDS and that the use of a higher PEEP level in patients with a lower percentage of potentially recruitable lung may be harmful [8]. These studies did not evaluate completely the effect of using individualised PEEP on the survival rate of patients with ARDS. The higher PEEP levels should be adjusted according to individual lung morphology. However, the strategies for setting PEEP using a plateau pressure or recruitment manoeuvre do not decrease mortality [9,10]. We designed an individual PEEP strategy using decremental PEEP titration after an alveolar recruitment manoeuvre (ARM) for each patient with ARDS. An ARM is a way to standardise the history of lung volume [11]. The objective of this study was to evaluate whether setting the PEEP using decremental PEEP titration after ARM affects the oxygenation and outcome of patients in the early stage of ARDS compared with the table-based combinations of FiO2 and PEEP in the ARDS network [1].
BODY.MATERIALS AND METHODS.STUDY POPULATION:
Fifty-seven consecutive patients (35 men and 22 women) admitted to the medical intensive care unit (MICU) of Asan Medical Center, in Seoul, Korea, who were diagnosed with ARDS of various aetiologies were enrolled in the study between July 2004 and September 2006. Patient selection for the study was based on the criteria of ARDS proposed by the American–European Consensus Conference on ARDS [12]: acute onset, presence of hypoxaemia (partial arterial pressure of oxygen (PaO2)/FiO2 (PF ratio) ≤ 200 mmHg regardless of the PEEP level), bilateral and diffuse opacities seen on frontal chest x-ray and absence of left ventricular failure with pulmonary arterial occluded pressure of 18 mmHg of less. The study protocol was approved by the institutional board of the ethics committee and written informed consent was obtained from the patients' families.
BODY.MATERIALS AND METHODS.VENTILATOR PROCEDURES:
Patients were given ventilatory support primarily in the supine position and ventilated according to the ARDS network strategy. FiO2, PEEP and respiratory rate were set to achieve an arterial oxygen saturation (SaO2) of between 88 and 92% [2]. The target VT was 6 ml/kg of predicted body weight, with allowances of up to 8 ml/kg if the SaO2 were below 88% or less than 7.2 of arterial pH by severe hypercapnoea. The patients were randomly assigned with the use of a randomisation scheme to either the decremental PEEP titration group or the control (table-based PEEP setting) group (Figure 1). Figure 1Study groups of patients. Four patients who withdrew from the study were excluded from the analysis. ARDS = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure.
BODY.MATERIALS AND METHODS.PATIENT GROUP.TABLE-BASED PEEP SETTING (CONTROL) GROUP:
The FiO2-PEEP strategy has been used in previous ARDS Network studies (Figure 2). PEEP and FiO2 were set according to the table of lower PEEP/higher FiO2 combinations (the lower PEEP strategy of the ALVEOLI study), with the goal of obtaining a lower PEEP level compatible with an oxygenation target. Figure 2Study protocol. (a) Table-based positive end-expiratory pressure (PEEP) setting (control) group. (b) Decremental PEEP titration group after alveolar recruitment manoeuvre (ARM). FiO2 = inspired fracture of oxygen.
BODY.MATERIALS AND METHODS.PATIENT GROUP.DECREMENTAL PEEP TITRATION GROUP:
The ARM was performed immediately after enrollment in the study and was applied once a day usually in the morning for one week. The ventilatory circuit was not disconnected after ARM to avoid lung derecruitment. The ARM was also repeated when the ventilatory circuit was disconnected (incidentally or for bronchoscope) or if FiO2 requirement was increasing again in the patient, who showed initial improvement of oxygenation by ARM. If the weaning trial was performed within one week, the ARM was stopped earlier than the usual schedule. During the ARM, all patients were sedated and paralysed by continuous infusion of midazolam-ketamine and vecuronium bromide. No changes were made in the doses of inotropic agents or fluid infusion during the ARM. The ARM used the extended sigh method, which is designed to gradually apply and withdraw a high distending pressure over a prolonged period. It takes about 15 to 20 minutes for two cycles of ARM according to our protocol (Figure 2) [13]. We changed the ventilatory mode from pressure-controlled mode to the volume-controlled mode during ARM. The distending pressure was determined by the delivered VT, PEEP increment and the pause time (0.5 seconds). During the ARM, PEEP was added from baseline to 15, 20 and 25 cmH2O sequentially (every 30 seconds from the baseline PEEP until 25 cmH2O). The VT was decreased by 25% from the baseline VT during the incremental PEEP trial phase, and then returned to baseline levels during the decremental PEEP trial phase. Therefore, the distending pressures were changed depending on the patient's VT and lung mechanics. However, we did not allow the peak airway pressure to go above 55 cmH2O during the ARM. The decremental PEEP titration at the second cycle of ARM was performed with progressive decreases in PEEP in steps of 1 cmH2O every 30 seconds from 20 cmH2O while continuously monitoring saturation and static compliance. The decrease in PEEP was continued until a decrease of more than 2% of saturation from the previous SaO2 and drop of static compliance was identified. This PEEP level was considered the alveolar collapsing pressure and the optimal PEEP after the ARM was set 2 cmH2O above this pressure. No patients showed significant arrhythmia or gross barotraumas of any type during ARM.
BODY.MATERIALS AND METHODS.PATIENT GROUP.RESCUE THERAPY:
If the level of inspired oxygen was not decreased to 0.6 or oxygenation improvement was not achieved after PEEP readjustment in all patients, rescue therapies such as prone position or nitric oxide inhalation were performed.
BODY.MATERIALS AND METHODS.OUTCOME MEASURES AND DATA COLLECTION:
The primary end point was improvement in oxygenation (improvement of PaO2/FiO2 (PF) ratio). The secondary end points included respiratory mechanics (PEEP and dynamic compliance), ICU stay, duration of sedatives and paralysing agents and patient outcomes (28-day mortality, 60-day mortality, duration of mechanical ventilation). Responders were defined by a 20% improvement in the PF ratio on day 1 compared with day 0 (baseline) after PEEP adjustment [14].
BODY.MATERIALS AND METHODS.OUTCOME MEASURES AND DATA COLLECTION.RESPIRATORY MECHANICS:
Airway pressure and flow were monitored continuously. VT, dynamic compliance (in ml/cmH2O), and peak airway, mean airway and minute ventilation were recorded at 30 minutes after the change of PEEP level in both groups. Because pressure control mode was the main ventilatory strategy, we monitored and compared the dynamic compliance and peak airway pressure in both group.
BODY.MATERIALS AND METHODS.OUTCOME MEASURES AND DATA COLLECTION.HAEMODYNAMICS AND GAS EXCHANGE:
We collected arterial blood samples to measure partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), pH, and SaO2 30 minutes after reapplication of PEEP. Haemodynamic variables monitored included heart rate and systolic, diastolic and mean systemic arterial pressure.
BODY.MATERIALS AND METHODS.DATA ANALYSIS:
Sample size calculation showed that 36 patients per group would provide 80% power at a two-sided α level of 0.05 to detect a 20% difference in the improvement of oxygenation (improvement of PF ratio). All data were analysed using SPSS for Windows (version 11.0; SPSS Inc., Chicago, IL, USA). Statistical analyses were based on the intention-to-treat principle and involved all patients who had undergone randomisation. All values are expressed as the mean ± standard error of the mean or as the number and percentage of patients. Probability of mortality and differences between the groups were compared using a log-rank test. The chi-squared test or Fisher's exact test was used to compare categorical data, and Student's t test or the Mann-Whitney U test was used to compare continuous data. Significance was defined as p < 0.05.
BODY.RESULTS.CHARACTERISTICS OF THE PATIENTS:
We enrolled 61 patients in the study, 30 of whom were randomly assigned to the control (table-based PEEP setting) group and 31 to the decremental PEEP titration group. Fifty-seven patients completed the study (27 in the control group and 30 in the decremental PEEP titration group) and contributed data for the analyses. Most baseline characteristics were similar in the two study groups (Table 1). The most common cause of ARDS was pneumonia. The initial ventilatory setting and severity index did not differ between the control and decremental PEEP titration groups. Table 1 Baseline characteristics of the patients at enrollment Control group (n = 27) Decremental PEEP titration group (n = 30) Age (years) 62.0 ± 2.2 55.0 ± 3.7 Percentage of women 37 40 APACHE II score 20.0 ± 1.4 22.0 ± 1.1 Lung injury score 2.5 ± 0.1 2.8 ± 0.2 Tidal volume (ml/kg of predicted body weight) 8.0 ± 1.4 7.9 ± 1.9 Respiratory rate (breaths/minute) 22.0 ± 3.0 22.2 ± 3.2 Peak airway pressure (cmH 2 O) 25.9 ± 5.9 27.8 ± 5.5 Positive end-expiratory pressure (cmH 2 O) 7.0 ± 3.7 8.4 ± 3.1 Dynamic compliance (Cdyn, ml/cmH 2 O) 25.7 ± 8.1 24.3 ± 7.6 PF ratio (PaO 2 :FiO 2 ) 110.8 ± 6.3 115.0 ± 8.5 Co-morbidities, n Haematological malignancy 3 7 Solid organ malignancy 6 4 Chronic liver disease 5 3 Connective tissue disease 2 1 Others a 3 3 Cause of lung injury (ARDSp:ARDSexp) 18:9 20:10 Pneumonia 15 17 Sepsis 7 7 Massive transfusion 2 1 Pulmonary alveolar haemorrhage 1 1 Others b 2 4 Data was presented as mean ± standard error of the mean. a including complicated diabetes mellitus (n = 4), Crohn's disease (n = 1) and AIDS (n = 1). b including leptospirosis (n = 3), near-drowning (n = 1), contusion (n = 1) and scrub typhus (n = 1). APACHE = acute physiology and chronic health evaluation; ARDSp = pulmonary ARDS; ARDSexp = extrapulmonary ARDS; FiO 2 = inspired fracture of oxygen; PaO 2 = partial arterial pressure of oxygen; PEEP = positive end-expiratory pressure.
BODY.RESULTS.RESPIRATORY MECHANICS AND OXYGENATION:
Figure 3 shows the ventilatory setting and respiratory variables at baseline and follow-up during the first week of treatment. The peak pressure was significantly higher on days 3 and 5 in the decremental PEEP titration group than in the control group, and the mean pressure was significantly higher in the decremental PEEP titration group because of the higher PEEP during the first week. Dynamic compliance and VT during the first week were similar in the two groups. Oxygenation improved compared with the baseline PF ratio in both groups (Figure 4). Initial oxygenation improved more in the decremental PEEP titration group than in the control group. The partial arterial pressure of oxygen (PaCO2) level was significantly higher in the decremental PEEP titration group than in the control group on day 1, suggesting increased dead space ventilation. However, the improvement of oxygenation and PaCO2 level were not different between the two groups during follow-up. Figure 3Respiratory values during the first week of treatment. The closed circles indicate the control group and the open circles denote the decremental positive end-expiratory pressure (PEEP) titration group. Values are expressed as the mean ± standard error of the mean (bars). *p < 0.05 between the control and decremental PEEP titration groups; †p < 0.05 compared with day 0 in the control group; ‡p < 0.05 compared with day 0 in the decremental PEEP titration group. Figure 4Oxygenation changes and PaCO2 levels during the first week of treatment. All patients showed improved oxygenation during treatment. The level of partial arterial pressure of carbon dioxide (PaCO2) at day 1 was increased significantly in the decremental positive end-expiratory pressure (PEEP) titration group than the control group. The black bars indicate the control group and gray bars denote the decremental PEEP titration group. Values are expressed as the mean ± standard error of the mean (bars). *p < 0.05 between the control and decremental PEEP titration groups, †p < 0.05 compared with day 0 in the control group, ‡p < 0.05 compared with day 0 in the decremental PEEP titration group.
BODY.RESULTS.CLINICAL OUTCOMES:
The overall mortality at 28 days was 37%. Mortality at 28 days was 33% in the control group and 40% in the decremental PEEP titration group (Table 2). Using Cox regression for 28-day mortality, the survival rate in the decremental PEEP titration group was not different (p = 0.725; hazard ratio = 1.168; 95% confidence interval = 0.493 to 2.768). However, 60-day mortality was significantly increased to 55.6% (p = 0.031) compared with 28-day mortality (33.3%) in the control group only. Table 2 Clinical outcomes according to treatment group Control group (n = 27) Decremental PEEP titration group (n = 30) p value Responder (%) 44.4 70 0.046 Clinical outcomes Duration of mechanical ventilation, days 15.2 ± 3.2 19.8 ± 0.5 0.380 Intensive care unit stay, days 21.4 ± 5.3 25.1 ± 5.6 0.643 Duration of paralysing agent, days 9.0 ± 2.3 11.8 ± 2.0 0.358 Duration of sedative agents, days 14.2 ± 2.4 18.7 ± 3.4 0.303 Weaning trial within seven days 8 6 Tracheostomy 5 8 Reintubation 5 2 Barotrauma 3 3 Ventilator-associated pneumonia 5 5 Mortality, number (%) Mortality at 28 days 9 (33.3) 12 (40) 0.784 Death in the intensive care unit 13 (48.1) 14 (46.7) 1.000 Mortality at 60 days 15 (55.6) 14 (46.7) 0.599 Cause of in-hospital death, number (%) Progressive respiratory failure 8 (53.3) 8 (57.1) Refractory septic shock 4 (26.7) 2 (14.3) Hepatic failure 3 (20) 2 (14.3) Myocardial infarction 2 (14.3) Rescue therapy (%) Prone position 44.4 50.0 0.792 Nitric oxide inhalation 48.1 53.3 0.793 Data was presented as mean ± standard error of the mean. PEEP = positive end-expiratory pressure. Eight patients (30%) in the control group and six patients (20%) in the decremental PEEP titration group had performed the weaning trial within a week of enrollment. The incidence of barotrauma was similar in both groups. The durations of mechanical ventilation, ICU stay and use of paralysing or sedative agents did not differ between the groups (Table 2).
BODY.DISCUSSION:
As suggested by Lachmann more than 10 years ago [15], "open up the lung and keep the lung open" appears advantageous to recruit the lungs of patients with ARDS and to prevent subsequent lung derecruitment [12]. Clinical outcomes were similar regardless of whether lower or higher PEEP levels were used in the ALVEOLI trial [7]. The problem of the ALVEOLI trial was the higher PEEP strategy, which was table-based like the one on the current study, matched on the oxygenation target regardless of any patient-related variable. A reasonable approach to determining the appropriate level of PEEP requires maintaining PEEP-induced reopening of atelectatic areas and avoiding PEEP-induced lung overinflation. Higher than traditional PEEP levels together with lung-recruiting maneuvers seems to be a way to find an appropriate PEEP level [16]. Experimental data suggest that the effects of ARM on alveolar recruitment are transient if the preceding PEEP levels are maintained after the manoeuvre [14]. Once the alveoli have been recruited, higher PEEP levels are required to keep them aerated [17]. The right level of PEEP as an anti-derecruiting force is important in preserving the effect of the ARM. We previously reported that a sufficient level of PEEP after ARM is important as an anti-decruitment strategy [18]. We hypothesised that the decremental PEEP trial would be an appropriate method to establish the PEEP level after ARM at bedside. Because higher PEEP and the ARM performed in patients with mild lung injury may have fewer benefits and more adverse effects, we only focused on ARDS patients to address our assumption. We found that daily decremental PEEP titration after ARM showed only initial oxygenation improvement compared with the table-based PEEP method and did not improve the respiratory mechanics within a week. We performed the ARM and PEEP titration daily during the first week in the decremental PEEP titration group. However, no significant differences were observed in the 28-day mortality, ICU stay and 60-day mortality. Although the responder rate was higher in the decremental PEEP titration group than in the control group, the earlier improvement in oxygenation was not associated with increased survival rate. Our finding showed the 60-day mortality in the control group was significantly increased compared with the 28-day mortality. We could not explain whether this finding was associated with the protective effect of ARM to the ventilator-induced lung injury. To add any relevant information, further study will be needed for the biomarkers such as proinflammatory cytokines. The lower dynamic compliance in the decremental PEEP titration group was an unexpected result, although there was no significant difference between the two groups. We speculated that a higher peak airway pressure might affect the lower dynamic compliance in the decremental PEEP titration group than the control. A reason for this result might be related to the subjects' characteristics. Most of the patients with ARDS had pneumonia, which did not respond well to the applied PEEP [19]. We included mostly pulmonary ARDS with severe underlying diseases, which would be a common phenomenon in a university hospital MICU. That may be the reason why mortality related to progressive respiratory failure was higher in our study group. The mortality of patients with pneumonia was 43.3% and the mortality of patients without pneumonia was 29.6%. The baseline lung conditions of these patients was a higher proportion of refractory consolidation to the distending pressure which may also have influenced the PF ratio of less than 250 and PEEP levels less than 15 cmH2O after ARM. Talmor and colleagues reported that a low lung distending pressure was applied in the patients with a stiff chest wall [20]. We did not measure the chest-wall mechanics or the recruitable lung, so we could not address this possibility as a cause of low PF ratio. One limitation of our study is that we could not evaluate whether recruitment manoeuvre maximised the alveolar collapse. If the recruitment effect of our ARM was not sufficient, the effect of a decremental PEEP trial might be insufficient. Borges and colleagues reported that a peak airway pressure of more than 60 cmH2O could recruit the collapsed lung [21]. Another limitation is that our indicators of oxygen saturation and static compliance to find an appropriate PEEP level might be insensitive to detect the collapsing pressure of the lung. Finally, small sample size in a single centre limits the power of the study outcomes.
BODY.CONCLUSION:
The daily decremental PEEP titration after ARM did not show the persistent improvement of oxygenation, the respiratory mechanics and the mortality rate of patients with ARDS compared with the table-based PEEP setting. Further investigations are needed to find the correct level of PEEP in ARDS with reference to chest wall compliance and alveoli mechanics.
BODY.KEY MESSAGES:
• The daily decremental PEEP titration after ARM method did not show a persistent improvement of oxygenation. • Respiratory mechanics such as dynamic compliance, VT and PEEP were not significantly different between the daily decremental PEEP titration after ARM group and the table-based PEEP setting group. • The daily decremental PEEP titration after ARM without the reference of lung mechanics did not reduce the dependence of ventilator or mortality rate of patients with ARDS compared with the table-based PEEP setting.
BODY.ABBREVIATIONS:
ALI: acute lung injury; ARDS: acute respiratory distress syndrome; ARM: alveolar recruitment manoeuvre; FiO2: inspired fracture of oxygen; MICU: medical intensive care unit; PEEP: positive end-expiratory pressure; PaCO2: partial arterial pressure of carbon dioxide; PaO2: partial arterial pressure of oxygen; PCO2: partial pressure of carbon dioxide; PO2: partial pressure of oxygen; SaO2: arterial oxygen saturation; VT: tidal volume.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
JWH recruited patients, analysed the data and wrote the manuscript. HJ and HSC helped to recruit patients and analysed the data. SBH and CML recruited patients and interpreted the data. YK designed the study, interpreted the data and wrote the paper. All authors read and approved the final manuscript. | 2,688,140 | {
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TITLE: Ertapenem Once a Day Versus Piperacillin–Tazobactam Every
6 Hours for Treatment of Acute Pelvic Infections:
A Prospective, Multicenter, Randomized, Double-Blind Study
ABSTRACT:
Objective: To compare ertapenem therapy with piperacillin–tazobactam therapy for the management of acute
pelvic infections.
Methods: In a multicenter, double-blind study, 412 women with acute pelvic infection were assigned to one of
two strata, namely obstetric/postpartum infection or gynecologic/postoperative infection, and were then
randomized to ertapenem, 1 g once a day, or piperacillin–tazobactam, 3.375 g every 6 hours, both administered
intravenously.
Results: In total, 163 patients in the ertapenem group and 153 patients in the piperacillin–tazobactam group were
clinically evaluable. The median duration of therapy was 4.0 days in both treatment groups. The most common
single pathogen was Escherichia coli . At the primary efficacy endpoint 2–4 weeks post therapy, 93.9% of patients
who received ertapenem and 91.5% of those who received piperacillin–tazobactam were cured (95%
confidence interval for the difference, adjusting for strata, –4% to 8.8%), indicating that cure rates for both
treatment groups were equivalent. Cure rates for both treatment groups were also similar when compared by
stratum and severity of infection. The frequency and severity of drug-related adverse events were generally
similar in both groups.
Conclusions: In this study, ertapenem was as effective as piperacillin–tazobactam for the treatment of acute pelvic
infection, was generally well tolerated, and had an overall safety profile similar to that of piperacillin–tazobactam.
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TITLE: Incisional hernia after upper abdominal surgery: a randomised controlled trial of midline versus transverse incision
ABSTRACT.OBJECTIVES:
To determine whether a transverse incision is an alternative to a midline incision in terms of incisional hernia incidence, surgical site infection, postoperative pain, hospital stay and cosmetics in cholecystectomy.
ABSTRACT.SUMMARY BACKGROUND DATA:
Incisional hernias after midline incision are commonly underestimated but probably complicate between 2 and 20% of all abdominal wall closures. The midline incision is the preferred incision for surgery of the upper abdomen despite evidence that alternatives, such as the lateral paramedian and transverse incision, exist and might reduce the rate of incisional hernia. A RCT was preformed in the pre-laparoscopic cholecystectomy era the data of which were never published.
ABSTRACT.METHODS:
One hundred and fifty female patients were randomly allocated to cholecystectomy through midline or transverse incision. Early complications, the duration to discharge and the in-hospital use of analgesics was noted. Patients returned to the surgical outpatient clinic for evaluation of the cosmetic results of the scar and to evaluate possible complications such as fistula, wound dehiscence and incisional hernia after a minimum of 12 months follow-up.
ABSTRACT.RESULTS:
Two percent (1/60) of patients that had undergone the procedure through a transverse incision presented with an incisional hernia as opposed to 14% (9/63) of patients from the midline incision group (P = 0.017). Transverse incisions were found to be significantly shorter than midline incisions and associated with more pleasing appearance. More patients having undergone a midline incision, reported pain on day one, two and three postoperatively than patients from the transverse group. The use of analgesics did not differ between the two groups.
ABSTRACT.CONCLUSIONS:
In light of our results a transverse incision should, if possible, be considered as the preferred incision in acute and elective surgery of the upper abdomen when laparoscopic surgery is not an option.
BODY.INTRODUCTION:
The rate of incisional hernia after midline incision is commonly underestimated but probably lies between 2 and 20% [1–5]. Thus, incisional hernia is a major postoperative problem. The treatment of incisional hernia is complicated by high rates of recurrences. Recently, in a randomised controlled trial published by Burger et al. [6], midline incisional hernia repair has been shown to be associated with a 10-year cumulative recurrence rate of 63 and 32% for suture and mesh repair, respectively. The midline incision is the preferred incision for surgery of the upper abdomen, despite evidence that alternatives, such as the lateral paramedian and transverse incision, exist and might reduce the rate of incisional hernia [7]. Various approaches to opening the abdomen have been advocated over time. The choice for a certain incision is dependent on the exposure necessary for the desired procedure to succeed. A midline incision, be it supraumbilical, infraumbilical or both, is an approach especially suited for emergency and exploratory surgery because of the quick and generous exposure that can be achieved within a few minutes [8, 9]. The avascular nature of the linea alba minimises blood loss during this procedure. A supraumbilical transverse incision may be utilised in case exposure of the upper abdomen is desired. During this incision, the damage inflicted to the segmental arteries and nerves is previously described as being minimal [10]. Previously, only one randomised controlled trial, comparing transverse and true midline incisions, has been published specifically addressing incisional hernia incidence [11]. To determine whether the use of a transverse incision is an alternative to a midline incision for open cholecystectomy in terms of incisional hernia incidence, surgical site infection, postoperative pain and hospital stay, this randomised controlled trial was performed. This trial was conducted in an era when laparoscopic cholecystectomy was not yet available. The possibility of low incisional hernia rates after transverse incisions and the fact that little is known about potential advantages incited us to publish the relevant results of this randomised controlled trial which has been performed in the past and has only been reported in a Dutch thesis by one of the authors (H.L.). The primary endpoint of this study was the incisional hernia incidence after 12 months of follow-up. Secondary endpoints included pain and cosmetic appearance.
BODY.METHODS.PROTOCOL:
Some 150 consecutive female patients were randomly assigned to a midline or transverse incision as an approach for elective cholecystectomy or combined cholecystectomy and cholangiography (with or without consecutive choledochotomy) (75 and 75 patients, respectively). Emergency procedures were excluded from participation. The sample size is based on an incisional hernia rate reduction from 20 to 6% at a power of 80% and an error rate of 5%. Obtaining informed consent was conducted in accordance with the ethical standards of the Helsinki Declaration of 1975. The investigation reported was performed with informed consent from all of the patients and followed the guidelines for experimental investigation with human subjects and was approved by the medical ethics committee. An independent statistician prepared closed, tamper-proof envelopes containing the random allocation (Fig. 1). Patients were randomised for one of the procedures in theatre through the opening of the envelopes.Fig. 1Flow chart of patient inclusion and follow-up Patient-related factors that were recorded were age, body mass and length and date of operation. Operation-related factors that were recorded were the exact nature of the operation, length of the incision, the thickness of the subcutaneous fat, surgeon performing the procedure, as well as the duration of the operation (skin-to-skin time). In the immediate postoperative period, the use, dose and type of analgesics was recorded and a pain score was administered. The use of analgesics (morphine 7.5 mg intra-muscular injection, 4 h minimum interval between consecutive injections) was monitored for 48 h after surgery; the pain score was administered for the first 6 days after surgery. In patients assigned to surgery through a midline incision, the skin was incised from just below the xyphoid process to just above the umbilicus. The abdominal wall was opened in the midline by incising the linea alba. A Collin type (two-bladed) self-retaining retractor was used to maintain exposure. The abdominal wall was closed in one layer using single polygalactin 910 sutures (Vicryl; Ethicon, Amersfoort, The Netherlands). The skin was consequently closed using running monofilament nylon sutures (Ethilon; Ethicon, Amersfoort, The Netherlands). Patients randomised for a transverse incision received a right-sided unilateral transverse incision between 3 and 4 cm below the costal margin. The rectus muscle was incised. The fibres of the external and internal obliques and the transverse muscles were separated in the direction of their course. Exposure was achieved through the use of a manually held single-bladed retractor. Closure of the abdominal wall was achieved by closure of the peritoneum and the posterior rectus fascia using a continuous, polygalactin 910 suture (Vicryl; Ethicon, Amersfoort, The Netherlands). The anterior rectus sheath and the fascia of the internal and external transverses were closed using simple interrupted polygalactin 910 sutures (Vicryl; Ethicon, Amersfoort, The Netherlands). Towards the end of both procedures, a Redon low-vacuum drain catheter was placed, which was guided outside the abdominal cavity approximately 5 cm from the incision. The skin was consequently closed using continuous monofilament nylon suture (Ethilon; Ethicon, Amersfoort, The Netherlands). All patients received a dose of 5,000 IU of sodium–heparin on the morning of the procedure as thrombosis prophylaxis.
BODY.METHODS.STATISTICAL ANALYSIS:
The Pearson χ2 test was used for comparing percentages. In case of small expected numbers, a Fisher's exact test was performed. Continuous variables were analysed using the Mann–Whitney test. A P-value of 0.05 or less (two-sided) was considered to be statistically significant. Means and medians are expressed ±standard deviation (SD).
BODY.METHODS.FOLLOW-UP:
Patients returned to the surgical outpatient clinic for evaluation of the cosmetic results of the scar and to evaluate possible complications, such as fistula, wound dehiscence and incisional hernia, after a minimum of 12 months follow-up. The patient and the surgeon evaluated the cosmetic results independently and were asked to rate the scar as unsatisfactory, satisfactory or fine. Furthermore, the length and width of the scar was measured.
BODY.RESULTS.STUDY GROUP:
Some 150 consecutive patients were randomised for participation in this study during an inclusion period from April 1977 until July 1979. Seventy-five patients received a transverse incision and 75 patients a midline incision (Fig. 1). One patient was withdrawn from further follow-up after developing peritonitis and consequent acute respiratory distress syndrome (ARDS) not related to the closure of the abdominal wall 2 days after surgery (transverse incision group). The patients' average age was 51.9 and 51.4 years for the midline and the transverse incision groups, respectively. Furthermore, no differences were found in the body mass and average length between the two groups (Table 1). A cholecystectomy was performed using a transverse incision in 52 patients and utilising a midline incision in 52 patients also. Fifteen and 16 patients, respectively, underwent a combined cholangiography/cholecystectomy. A further 7 and 6 patients, respectively, were treated with a cholangiography/cholecystectomy plus additional choledochotomy and the postexploratory placement of a T-tube.Table 1Baseline characteristics of the patients undergoing surgery, according to study groupVariableMidline incisionTransverse incisionn = 75n = 74Average age (years) ± SD51.9 ± 14.851.4 ± 13.8Average weight (kg) ± SD71.3 ± 14.568 ± 14.3Average length (cm) ± SD163.5 ± 7.8164 ± 7.3
BODY.RESULTS.SURGEON:
Staff surgeons performed 17% (13/75 patients) of all procedures performed through a midline incision. The remainder of the procedures through a midline incision was carried out under staff surgeon supervision. Staff surgeons performed 14% of all procedures in the transverse incisions study group (10/74 patients) and supervised the remainder. No statistically significant difference was found between the two randomised groups (P = 0.65).
BODY.RESULTS.DURATION OF SURGERY:
No significant difference was noted in the skin-to-skin time (in min) for the two different incisions (Table 2). Surgery utilising midline and transverse incision took 56.9 ± 29.3 and 53.2 ± 26.8 min, respectively (P = 0.35). The total duration of the procedures until extubation (in min) did not differ between the midline and transverse incisions (71.0 ± 30.5 and 67.0 ± 27.3, respectively, P = 0.34).Table 2Length of incision, thickness of subcutaneous fat and skin-to-skin time, according to study groupVariableMidline incisionTransverse incisionP-valueLength of incision (mm) ± SDa164 ± 28140 ± 24<0.0001Thickness of subcutaneous fat (mm) ± SDa34.5 ± 13.030.3 ± 12.40.05Skin-to-skin time (min) ± SDa56.9 ± 29.353.2 ± 26.80.40Width of scar (mm) ± SDb8.3 ± 1.43.3 ± 1.2<0.0001aMeasured during surgery in 75 midline and 74 transverse incisionsbMeasured at follow-up in 63 and 60 midline and transverse incisions, respectively
BODY.RESULTS.PAIN AND ANALGESICS:
Significantly more patients, having undergone a midline incision, reported pain on day one, two and three postoperatively (P < 0.0001, Table 3). In the midline incision group, 28/75 patients required no or only one dose of analgesics; the remainder required two or more doses. Thirty-one patients operated through a transverse incision required no analgesics or only one dose; 43 patients (the remainder) required two or more. No significant difference in the use of analgesics was found between the groups (P = 0.69).Table 3Postoperatively reported pain, according to study group, shown as the number of patients reporting pain at the time points indicated (percentage), with the remainder of patients reporting no painTime point after surgeryMidline incision n = 75Transverse incision n = 74P-valuePatients reporting pain, n (%)Patients reporting pain, n (%)3–4 h68 (91)60 (81)0.09First day64 (85)39 (53)<0.0001Second day57 (76)23 (31)<0.0001Third day28 (37)9 (12)<0.0001Fourth day5 (7)3 (4)0.72Fifth day0 (0)1 (1)0.50Sixth day0 (0)1 (1)0.50
BODY.RESULTS.COMPLICATIONS:
Postoperative complications (Table 4) were seen in 16 out of 75 patients (21%) from the midline incision group and in 15% from the transverse incision group (11 patients) (P = 0.30). Briefly, one patient in each group developed cardiac complications; 8 and 6 patients developed urinary retention after the midline and transverse incisions, respectively (P = 0.59). Surgical site infections were diagnosed in 7 and 3 patients, respectively (P = 0.33).Table 4Rate of complications after surgery, according to study group, shown as the number of patients diagnosed with complications (percentage)ComplicationMidline incisionTransverse incisionP-valuen = 75 n (%)n = 75 n (%)Cardiac1 (1)1 (1)1Urinary retention8 (12)6 (8)0.59ARDS01 (1)0.50Surgical site infection7 (9)3 (4)0.33Haemorrhage1 (1)00.50Pneumonia01 (1)0.50Total17 (23)12 (16)0.30
BODY.RESULTS.DISCHARGE:
Forty-five (60%) and 42 (57%) patients from the patients having undergone a midline or a transverse incision, respectively, were discharged on day 6 or 7 postoperatively. The remaining patients from each group left hospital care on day 8 or later. The duration of hospital admission did not differ between the two types of incision (P = 0.74).
BODY.RESULTS.COSMETICS:
The width and length of all incisions was measured during the follow-up visit (Table 2). The mean width of the scar after the healing of the midline incisions was found to be 8.3 ± 1.4 mm. The mean width of the scar after the healing of the transverse incisions was measured to be 3.3 ± 1.2 mm. This observed difference is significant (P < 0.0001). The length of the incisions was 140 ± 24 mm and 164 ± 28 mm for the transverse and the midline incisions, respectively. The difference in scar length was found to be significant (P < 0.0001).
BODY.FOLLOW-UP:
Eighty-one percent of all patients operated through a transverse incision were seen during the follow-up examination (n = 60). Of the patients operated through a midline incision, 63 out of 75 were seen at the outpatient clinic (84%). The patients that were lost to follow-up could either not be traced or had deceased (Fig. 1). The minimum follow-up for the evaluation of cosmetic results and hernia incidence was 12 months and the maximum was 36 months.
BODY.FOLLOW-UP.INCISIONAL HERNIA:
From the patients that had undergone the procedure through a transverse incision, one (1/60; 2%) presented with an incisional hernia as opposed to 9 patients from the midline incision group (9/63; 14%); 95% confidence interval (CI) 7.5–25.4%. This difference in hernia incidence is significant (P = 0.017). No significant correlation was found between the incisional hernia rate and surgical site infection (P = 0.07).
BODY.FOLLOW-UP.SUBJECTIVE COSMETICS:
Patients and surgeons alike were asked to rate the appearance of the scar during the postoperative follow-up outpatient clinic visit. Both the surgeons and the patients found the scar resulting from the transverse incision to be more cosmetically pleasing (P < 0.0001 and P = 0.03, respectively, Table 5).Table 5Number of patients and surgeons rating the cosmetics of a scar at follow-upScoreMidline incision (n = 63)Transverse incision (n = 60)Patients, n (%)Surgeons, n (%)Patients, n (%)Surgeons, n (%)Unsatisfactory6 (10)25 (40)2 (3)6 (10)Satisfactory16 (25)27 (43)9 (15)12 (20)Fine41 (65)11 (17)49 (82)42 (70)Total63636060Difference between type of incision: patients P = 0.03; surgeons P < 0.0001
BODY.DISCUSSION:
This prospective randomised study of transverse and midline incisions for open cholecystectomy shows that a significant reduction of incisional hernia incidence can be achieved through the use of a transverse incision. Only one other study (published in 1980) reported the incidence of incisional hernia after upper abdominal midline and unilateral transverse incision in a randomised trial. No difference between the two techniques (8 and 6% incisional hernia, respectively) was found, but the relatively short follow-up of 6 months, however, may be held accountable for this finding [11]. Three retrospective studies showed rates of incisional hernia of 3.2, 5.4 and 16.5% for midline incision and 1.3, 6.7 and 13.4% for transverse incision without statistically significant differences [12–14]. The possible reason for the rather high incidence of incisional hernia in the midline incision group (14%) may lie in the use of resorbable 910 polygalactin sutures. Nevertheless, the use of the same type of resorbable suture in the closure of the transverse incisions resulted in a 2% hernia rate. There is evidence for the importance of proper technique and choice of incision as a means to reduce incisional hernia being more important than the use of suture material [7]. Furthermore, as mentioned above, it is known that the incidence of incisional hernia in the case of a midline incision lies between 2 and 20%. From our data, the NNT (numbers needed to treat) is calculated to be 8 (95% CI 5–30) and the RRR (relative risk reduction) is 88% (95% CI 23–100%). Luijendijk et al. [15] have published a hernia rate of 2% after Pfannenstiel incisions closed using 910 polygalactin, which is in agreement with our findings in the patients randomised for a transverse incision, emphasising the importance of the incision over the choice of suture material. In our study, significantly fewer patients reported pain on day 1, 2 and 3 after transverse incisions, a result that was also described by other authors [16, 17]. Greenall et al. [18] published a contradictory report (in 1980) in which no significant difference in postoperative pain was found between midline and transverse incisions. The previously mentioned study, however, only analysed 46 out of 572 patients (8%) with regard to pain, which may explain the finding. In the same way, Lacy et al. suspended visual analogue pain scoring in a study comparing midline and transverse incisions for abdominal aortic surgery. Remarkably, the two groups in our study did not differ in terms of postoperative analgesia, a finding that is also reported by Lindgren et al. [17] and Donati et al. [19]. In our study, surgeons as well as patients were significantly more satisfied with the aesthetic appearance after a transverse in comparison with a midline incision. The scars after transverse incisions were found to be significantly shorter and less wide than the midline incisions, which may account for the observed difference. A possible reason for this is that a transverse incision is executed parallel to the prevailing direction of the skin lines on the abdomen and, therefore, the tension on the wound and consequent scar is low. Cholecystectomy has come a long way since this trial. The introduction and widespread acceptance of laparoscopic technique as the treatment of choice has rendered open cholecystectomy to be an operation for exceptional, and perhaps surgically difficult, circumstances. Nowadays, the study reported is hardly feasible, yet, the results are still applicable and very relevant for other surgical procedures in the (upper) abdomen. Knowledge of the favourable results of a transverse incision may aid surgeons in their choice when finding themselves in the unfortunate position of needing conversion to open cholecystectomy. In conclusion, this investigation on transverse incisions might be helpful in reducing the incidence of incisional hernia in patients after open cholecystectomy. The midline incision is a preferred manner to achieve exposure of the abdominal cavity and is considered to be easily performed and quick. Although the midline incision is generally accepted, the incidence of incisional hernias is surprisingly high [1–5]. The choice for a particular incision should not only be based on exposure, but also on hernia incidence reduction, especially since recurrence rates after hernia repair are reported to be very high. Furthermore, the recurrence rate after incisional hernia repair is a disappointing 63 and 32% for suture and mesh repair, respectively [6]. In the light of these results, incisional hernia prevention is warranted. In this investigation, it is shown that a significant reduction (from 14.5 to 1.7%) of incisional hernia incidence was achieved by using a transverse incision. Hence, a transverse incision should be considered as the preferred incision in acute and elective surgery of the upper abdomen in which laparoscopic surgery is not an option. Full exposure of two quadrants is feasible through the use of a unilateral transverse incision in, for example, biliary, bariatric, liver and colonic surgery. The transverse incision should be part of the abdominal surgeon's armamentarium and is a preferable incision to prevent the high incidence of incisional hernia after abdominal surgery. | 2,690,844 | {
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TITLE: Randomized controlled trial of clopidogrel to prevent primary arteriovenous fistula failure in hemodialysis patients
ABSTRACT:
The optimal vascular access for chronic maintenance hemodialysis is the arteriovenous fistula (AVF). Several studies suggest a role for antiplatelet agents in the prevention of primary AVF failure. A double-blind, randomized trial was conducted to assess the efficacy and safety of clopidogrel in hemodialysis patients. Ninety three patients were randomized to receive 75 mg/daily of clopidogrel or placebo. The treatment was initiated 7–10 days prior to scheduled access surgery and continued up to six weeks postoperatively, and then patients were monitored for six months. The primary outcome was AVF failure eight weeks after fistula creation. With a permuted block randomization schedule, 46 patients received clopidogrel and 47 patients received control placebo. The primary AVF failures at two months were 21.6% in placebo group and 5.2% in clopidogrel group (P = 0.03). The hazard ratio for the incidence of primary AVF failure was 0.72 (CI 95%, 0.41–1.01). Analysis of covariables indicated that this effect occurred principally as a result of clopidogrel administration. First hemodialysis from newly created AVF in clopidogrel group was significantly more successful than placebo group (P = 0.008). No life-threatening adverse event or severe bleeding was recorded in both groups. Clopidogrel seems to be effective and safe for prevention of primary AVF failure in hemodialysis patients.
BODY.INTRODUCTION:
Performance of a successful hemodialysis procedure requires a functional vascular access. The preferred type of access is a native fistula because they have the lowest risk of complications, lowest need for intervention, and the best long-term patency.[1] Once an arteriovenous fistula (AVF) is created, it must develop to the point that it is usable. Vascular access dysfunction is one of the most important causes of morbidity in the hemodialysis population.[2] Primary failure of native fistulas occurs as a result of either thrombosis within the first several weeks following surgical creation (early thrombosis), or inadequate maturation of the vein.[3] The primary AVF failure rate is approximately 9–50%.[4–6] Fistula evaluation 4–6 weeks after creation should be considered mandatory.[7] The clinical manifestations of early fistula failure are failure to develop adequately to permit repetitive cannulation for dialysis, inadequate flow to support dialysis, and thrombosis. The characteristic pathology that results in AVF failure is a juxta-anastomotic stenosis.[8] Whether primary AVF failure can be prevented with pharmacologic agents has not been extensively examined. Several studies have indicated that the frequency of AVF failure and loss can be reduced with antiplatelet agents.[9–18] Although those results are encouraging, they do not provide conclusive evidence of the efficacy of antiplatelet agents among patients with AVF. On the basis of these considerations, we performed a randomized, double-blind trial to test the hypothesis that clopidogrel, would prevent primary AVF failure among hemodialysis patients.
BODY.MATERIALS AND METHODS:
The study was a randomized, double-blind trial. Patients of minimum age 18 years close to the initiation of chronic hemodialysis requiring AVF, and patients who were undergoing chronic hemodialysis but requiring a new AVF at a different site were the inclusion criteria. Exclusion criteria included patients with a history of gastrointestinal bleeding or previous bleeding episodes within six months prior to initiation of the study, patients already receiving chronic anticoagulation therapy (antiplatelet agents or warfarin), patients with terminal or life-threatening disease, pregnancy, malignant hypertension, a platelet count of <100,000/mm3, and other demonstrated medical conditions that would make antiplatelet therapy dangerous. All patients were recruited from the outpatient hemodialysis program at Jondi Shapour University, and the same surgical team placed all fistulas. Randomization was performed centrally, by the coordinating center. The randomization was stratified according to medical center with a permuted block scheme, with a block size of four and equal allocation. After identifying and obtaining consent from eligible participants, the local study coordinator telephoned the coordinating center to obtain a randomization number, which corresponded to a specific medication bottle available in the local research pharmacy. Neither the details of the randomization sequence nor the identity of the medication assignment was known to the participant or any personnel at the participating sites. Consenting eligible participants were randomized to receive either clopidogrel (75 mg/daily) or matching placebo (47 patients in placebo group and 46 patients in clopidogrel group). The treatment was initiated 7–10 days prior to scheduled access surgery and continued up to six weeks postoperatively, with full approval by the Jondi Shapour University Institutional Review Board. Patients were monitored for occurrence of complications, need for hemodialysis until six months after trial. The primary null hypothesis of the study was that clopidogrel would have no preventive effect on the incidence of primary AVF failure. The primary outcome was AVF failure eight weeks after fistula creation. Fistula failure was determined by a member of the study team (either the study coordinator or the site principal investigator), who was blinded to the treatment allocation. The fistula was classified as patent if a bruit was detectable along the vein at least 8 cm proximal to the arteriovenous anastomosis throughout systole and diastole. Secondary outcomes included adverse events and mortality. Platelet hemostatic function was measured monthly, as whole-blood bleeding time. Routine blood chemistry profiles, dialysis prescriptions, body weights, medications, and complications for all patients were recorded in a computerized database, and thus were available for inclusion in the final data analysis. We obtained detailed information on bleeding events. Assessment of the severity of bleeding episodes was performed by a panel blinded to the treatment assignments. Discontinuation of the study drug following any bleeding event was the rule.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Data are presented as mean ± SE for continuous variables and as percentages for categorical variables. All data were tested for normality using the method of Kolmogorov-Smirnov. Statistical analyses were performed on an intention-to-treat basis. The t test was used when the means of two groups were compared. On the basis of intention-to-treat principles, all other participants for whom study medications were discontinued continued to be monitored according to the protocol. All hypothesis tests were conducted by using a significance level of 0.05 (two-sided). The statistical program SPSS version 13 (SPSS, Chicago, IL) was used to analyze the data.
BODY.RESULTS:
Between December 2006 and March 2008, a total of 93 patients met the study criteria for enrollment. The demographic and baseline laboratory findings for each group are summarized in Table 1. There were no significant differences in covariables between groups. None of the covariables (covariables thought to influence the risk of AVF included age, gender, diabetes mellitus, bleeding time, and blood pressure) measured at baseline or follow-up times was correlated with the development of AVF failure. All patients were taking study medication 7–10 days prior to surgery. However, the medication had to be discontinued prematurely in 18 (19.4%) patients because of no intention to complete trial by six cases and complication occurring in 11 cases. One patient died before the end of trial. Two patients in clopidogrel group and three patients in placebo group were enrolled after creation of a second fistula. Prior AVFs failed because of late fistula failure in all of them. Finally, 75 patients completed trial (38 patients in clopidogrel and 37 patients in placebo groups). None of the patients was lost to follow-up. Table 1 Patients characteristics at baseline Characteristic All patients (%) Clopidogrel (%) Placebo (%) P value Age (years) 45.03 ± 1.2 44.23 ± 3.36 45.8 ± 2.84 0.47 Males 48 (51.6) 24 (25.8) 24 (25.8) 0.91 Diabetes mellitus 25 (26.9) 14 (15.1) 11 (11.8) 0.44 Patients on hemodialysis 63 (67.7) 29 (31.2) 34 (36.6) 0.33 Drug use by the end of trial 75 (80.6) 38 (40.9) 37 (39.8) 0.63 Five and three fistulae in clopidogrel-treated and placebo groups were proximal AVFs. Two patients in clopidogrel-treated group (5.26%) showed an early failure of the AVF compared to eight patients (21.62%) in placebo group (P < 0.05) [Table 2]. There was significant benefit of active treatment in the prevention of AVF failure. The hazard ratio for the incidence of primary AVF failure was 0.72 (CI 95%, 0.41–1.01). Fistula locations had no effects on the development of AVF failure in either group. During follow-up from eight weeks to six months no important complication occurred. Sixty patients required hemodialysis during this time. Hemodialysis was tried in 26 patients of clopidogrel group within six months after AVF creation and it was successful in 24 patients (92.3%). In placebo group, hemodialysis from new AVF was tried in 34 patients and it was successful in 24 cases (70.5%). First hemodialysis from newly created AVF in clopidogrel group was significantly more successful than placebo group (P = 0.008). The cumulative incidence of bleeding was similar between groups [Table 3]. No severe bleeding episode such as intracranial hemorrhage or life-threatening bleeding was recorded during active treatment period. There were no deaths attributable to bleeding in either treatment group. Bleeding times were similar at baseline for clopidogrel group (8.1 ± 0.3 min) and placebo group (8.4 ± 0.6 min) and remained stable (8.5 ± 0.4 min for clopidogrel group and 8.6 ± 0.3 min for placebo group) throughout the study period (P = 0.21). In addition, there were no differences between baseline and follow-up hematocrit values or changes in recombinant human erythropoietin doses during the study period for either group. Table 2 Clinical outcomes at the end of trial Outcome All patients (%) Clopidogrel (%) Placebo (%) P value Primary AVF failure Drug use by the end of trial 10 (26.88) 2 (5.26) 8 (21.62) 0.03 Premature cession of drug 2 (2.15) 0 (0) 2 (2.15) Table 3 Complications and mortality Complication All patients (%) Clopidogrel (%) Placebo (%) P value GI bleeding 5 (5.3) 2 (2.1) 3 (3.2) 0.31 Non GI tract bleeding 9 (9.6) 5 (5.3) 4 (4.3) 0.63 Death events 4 (4.3) 2 (2.1) 2 (2.1) 0.47
BODY.DISCUSSION:
Chronic maintenance hemodialysis requires stable and repetitive access to the intravascular compartment in order to deliver high rates of blood flow to the extracorporeal circuit. The AVF is the method of choice for the establishment of hemodialysis vascular access in patients with endstage renal disease.[1] The fistula is relatively simple to perform under local anesthesia and, when successfully established, is easy to needle and relatively free from complications. However, a significant proportion (9–50%) of fistulas fails early within three months of surgery.[4–6] An AVF with primary failure is defined as a fistula that never provided reliable hemodialysis.[18] Vascular access failure is the most common reason for hospitalization among hemodialysis patients.[19] The typical lesion of access thrombosis is neointimal vascular smooth muscle cell proliferation in the anastomotic draining vein. Platelet activation from endothelial injury may play an important role in stimulating platelet aggregators such as PDGF and thromboxane A2, in addition to directly stimulating vascular intimal proliferation.[18] Therefore, the therapeutic potential of antiplatelet agents including aspirin, sulfinpyrazone, dipyridamole, and ticlopidine were tested.[9–17] Our study was undertaken to determine the effects of clopidogrel on the incidence of primary AVF failure among newly created AVFs. We observed a significant risk reduction in the primary AVF failure in active treatment group compared to placebo group. The results of our analysis suggest that daily administration of 75 mg of clopidogrel, beginning 7–10 days prior to AVF creation, was successful in preventing the development of vascular failure with acceptable side effects. We were unable to account for the differences observed in our clinical trial on the basis of age, gender, diabetes mellitus, bleeding times, hematocrit levels, or weekly doses of recombinant human erythropoietin. This finding suggests that the risk reduction in vascular failure might be attributed to clopidogrel administration. Our results are supported by recent Cochrane report.[20] This meta-analysis confirmed the beneficial effect of antiplatelet treatment as an adjuvant to increase the patency of AVFs in the short term. However, there have been multiple studies showing variable results of antiplatelet agents on vascular access failure. Yevzlin et al., showed a negative association between antiplatelet therapy and access patency.[21] In this trial, usage of some drugs was not associated with significant risk reduction in access failure. Moreover, antiplatelet therapy in patients with access failure was associated with significantly increased risk of access failure. Kaufman et al., demonstrated no change in the risk of graft thrombosis with aspirin plus clopidogrel therapy.[22] They also noted that in chronic hemodialysis patients there is a trend toward increased thrombosis with aspirin therapy. Also Kooistra et al., were unable to demonstrate a benefit with low-dose aspirin on thrombovascular events in 68 hemodialysis patients.[23] In contrast, combining all the studies of antiplatelet agents in patients with new primary fistulae in which there was a placebo control group, the thrombosis rate in the control group was significantly higher than active treatment group.[20] Three trials compared ticlopidine with placebo with a total number of 312 participants undergoing AVF formation or graft interposition. All three trials comparing ticlopidine with placebo favored treatment in both AVF and vascular grafts. In the Fiskerstrand study, two out of six patients in the ticlopidine group compared with five out of nine in the placebo group, developed fistulae thromboses at one month (OR = 0.40, CI 95%, 0.05– 3.42).[15] In the earlier Grontoft study, only two out of 19 who received treatment developed fistulae thromboses compared to eight out of 17 on placebo (OR = 0.13, CI 95%, 0.02–0.76).[13] In Gontoft 1998, 16 out of 130 patients who received ticlopidine developed thromboses in the fistulae compared with 25 out of 131 in the placebo group (OR = 0.60, CI 95%, 0.30–1.18).[14] The overall result of the meta-analysis also favored treatment (OR = 0.47, CI 95%, 0.26–0.85). The overall P-value was 0.01.[20] We also assessed the effect of clopidogrel on the successful initiation of hemodialysis via AVF. The rate of the performing successful first hemodialysis via AVF was greater in clopidogrel group. The overall incidence of bleeding events was 15% in our study. According to Kaufman et al., we expected to encounter with 16 episodes of bleeding during six months in our patients.[22] However, the incidence of bleeding episodes was lower than expected. This finding might be related to restrictive exclusion criteria. This study is the first carefully monitored trial that was limited to AVF. It is a well-known fact that AVFs have lower thrombosis rates compared with AVF grafts. In multiple studies, AVFs have been shown to have significantly improved patency rates and lower complication and infection rates. Some studies pointed out that antiplatelet therapy might be more effective in fistulas than in arteriovenous grafts.[1422] We studied this hypotheses for first time. Our results suggested that clopidogrel is an effective therapy in prevention of primary AVF failure. The major limitation of our study is the small number of patients, but in view of the promising results we believe that our preliminary findings deserved prompt communication. However, the data must be interpreted with caution because the pharmacological approach to prevent vascular access thrombosis in hemodialysis is still in its infancy. Overall, the effect of antiplatelet agents on vascular access patency needs further investigation. A prospective randomized controlled trial with larger number of patients is warranted. Currently the National Institutes of Health sponsored Dialysis Access Consortium is conducting an ongoing double-blind multicenter randomized evaluation of clopidogrel in AVF patency.[24]
BODY.CONCLUSION:
Primary AVF failure remains a major problem for hemodialysis patients. Vascular access thrombosis prophylaxis needs to start early in the ESRD patient. Clopidogrel, beginning 7–10 days prior to AVF creation and continuing for six weeks, seems to prevent primary AVF failure with acceptable side effects in selected hemodialysis patients. | 2,847,809 | {
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TITLE: Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease
ABSTRACT:
Background: Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study. Objective: This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD. Methods: This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo. Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1. Results: Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p ≤ 0.004). Both budesonide/formoterol doses were more effective than placebo (p ≤ 0.006) for controlling dyspnoea and improving health status (St George's Respiratory Questionnaire). All treatments were generally well tolerated. The incidence of pneumonia was not different for active (3.4–4.0%) and placebo (5.0%) groups. Conclusions: Budesonide/formoterol pMDI (320/9 μg and 160/9 μg) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD. Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co-primary variables compared with formoterol DPI 9 μg. Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo.
ABSTRACT.ELECTRONIC SUPPLEMENTARY MATERIAL:
Supplementary material is available for this article at 10.2165/00003495-200969050-00004 and is accessible for authorized users.
BODY.BACKGROUND:
In patients with chronic obstructive pulmonary disease (COPD) and frequent exacerbations, the combination of a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended.[1] Budesonide and formoterol delivered via a single dry powder inhaler (DPI; Symbicort® Turbuhaler®; AstraZeneca, Lund, Sweden) have been shown to improve pulmonary function[2,3] and reduce COPD exacerbation rates.[2,3] Fixed-combination budesonide/formoterol is available in the US in a hydrofluoroalkane pressurized metered-dose inhaler (pMDI; Symbicort® Inhalation Aerosol; AstraZeneca LP, Wilmington, DE, USA). While most patients with COPD can benefit from either a pMDIor DPI, the pMDI formulation allows patients whomay have inadequate peak inspiratory flow for optimal delivery from a DPI to use the pMDI effectively. A recent 6-month study demonstrated the efficacy and tolerability of budesonide/formoterol pMDI in patients with moderate to very severe COPD.[4] Treatment with budesonide/formoterol pMDI resulted in significant improvements in pulmonary function, dyspnoea and health-related quality of life; however, the duration of the study was limiting with respect to the analysis of low-frequency events, such as COPD exacerbations, and precluded an assessment of safety outcomes with long-term exposure.[4] In this study, the long-term efficacy and tolerability of two dosage strengths of budesonide/formoterol pMDI were assessed over 12 months in patients with moderate to very severe COPD.
BODY.PATIENTS AND METHODS.PATIENTS:
The inclusion criteria were designed to select a population with moderate to very severe COPD with previous exacerbations (i.e. appropriate candidates for combination ICS/long-acting β2-adrenoceptor agonist [LABA] therapy): age ≥40 years, diagnosis of symptomatic COPD for >2 years, ≥10 pack-year smoking history, prebronchodilator forced expiratory volume in 1 second (FEV1) of ≤50% of predicted normal and prebronchodilator FEV1/forced vital capacity (FVC) of <70%. Patients were to have a Modified Medical Research Council dyspnoea scale score of ≥2 and a history of at least one COPD exacerbation requiring oral corticosteroids or antibacterials within 1–12 months before the first study visit. Additional enrolment criteria were the same as those in a similar 6-month study by Tashkin et al.[4]
BODY.PATIENTS AND METHODS.STUDY DESIGN:
This was a randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre trial (ClinicalTrials.gov identifier: NCT00206167) conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. The study protocol was approved by a local institutional review board and ethics committee, and written informed consent was obtained from patients. The study was designed to conform with the Declaration of Helsinki, and was consistent with the International Conference on Harmonisation and Good Clinical Practice and applicable regulatory requirements. After meeting eligibility criteria, patients entered a 2-week run-in period, during which they received ICS monotherapy if previously stable on ICS (alone or in combination) and ipratropium bromide at a fixed dose if previously receiving anticholinergics. Albuterol (salbutamol) was permitted for rescue use throughout the study. At randomization, all previous ICSs were discontinued and patients were randomized to one of four treatments (figure 1). Patients who were treated with ipratropium bromide during the run-in period were allowed to continue on it throughout the study period. Other allowed and disallowed concomitant medications were the same as those reported in the study by Tashkin et al.[4]
Fig. 1Study design. To maintain blinding, patients received both a pressurized metered-dose inhaler (pMDI) and a dry powder inhaler (DPI) containing either active treatment or double-dummy placebo (PL) as appropriate. This study used formoterol (FM) DPI (Oxis® Turbuhaler®, AstraZeneca, Lund, Sweden) as the FM comparator because FM is not available as a hydrofluoroalkane pMDI in the US. A previous study in asthma patients reported equivalent FM-related bronchodilatory effects when FM was administered in combination with budesonide (BUD) via pMDI or alone via DPI.[5] Patients were asked to return to the clinic for follow-up visits 3–8 at the end of months 1, 2, 4, 6, 9 and 12, and received a telephone call 4 weeks after the last clinic visit. bid = twice daily; R = randomization.
BODY.PATIENTS AND METHODS.EFFICACY EVALUATIONS:
The co-primary efficacy variables, measured at all clinic visits, were pre-dose FEV1 and 1-hour post-dose FEV1. Additional pulmonary function variables included pre-dose and 1-hour post-dose FVC measured at all clinic visits, and morning and evening peak expiratory flow (PEF) recorded daily in patient diaries. In a subset of patients (n = 491 of 1964; 25%) who agreed to undergo spirometry testing, 12-hour serial spirometry was performed and pre-dose and 1-hour post-dose inspiratory capacity (IC) were collected at randomization and months 6 and 12. FEV1 was measured pre-dose and at 5, 15, 30, 60, 120, 180, 240, 360, 480, 600 and 720 minutes post-dose. Baseline-adjusted average 12-hour FEV1 was calculated as the area between the 12-hour post-dose FEV1-over-time curve and the baseline pre-dose FEV1, divided by observation time. Spirometry was performed according to American Thoracic Society guidelines.[6] Crapo-predicted normals for FEV1 were used.[7] Secondary efficacy endpoints included COPD exacerbations, dyspnoea (separate and composite scores) and health status, all assessed as previously described.[4] A COPD exacerbation was defined as worsening of COPD requiring an oral corticosteroid or hospitalization.[4] Dyspnoea was assessed daily before the evening dose of study medication using the Breathlessness Diary, a validated single-item component of the Breathlessness Cough and Sputum Scale (BCSS).[8] Health status was assessed at months 1, 2, 6 and 12 using the St George's Respiratory Questionnaire (SGRQ).[9,10] Sleep score, percentage of awakening-free nights (sleep score of 0) and study rescue medication use were assessed as previously described by Tashkin et al.[4]
BODY.PATIENTS AND METHODS.SAFETY EVALUATIONS:
Safety was assessed by adverse event (AE) reporting. Pneumonia events were reported by physicians based on the Medical Dictionary for Regulatory Activities (version 10.0) pneumonia-related preferred terms (pneumonia, bronchopneumonia, lobar pneumonia or pneumonia staphylococcal). Vital signs and 12-lead ECGs were evaluated as previously described by Tashkin et al.[4] Subsets of patients were assessed for 24-hour urinary cortisol (n = 179), 24-hour Holter monitoring (n = 520), bone mineral density (BMD) at the hip and spine regions (n = 326), and ophthalmological assessments (n = 461), including intraocular pressure and progression of lenticular opacities. In all patients, blood and urine samples were collected, and comprehensive physical examinations were carried out at the time of screening and at the end of month 12. Blood and urine samples were analysed by a central laboratory (Quest Diagnostics Clinical Laboratories, Van Nuys, CA, USA). Vital signs, including heart rate and blood pressure, were measured at all study visits. Samples to assess 24-hour urinary cortisol levels were collected in a subset of patients at or before randomization and within 1 week before the 6- and 12-month visits, and analysed by Quest Diagnostics. 24-Hour Holter monitoring was performed at screening and months 1 and 4, BMD assessments (two sets of dual energy x-ray absorptiometry scans in the hip and spine regions) were performed at screening and the end of month 12, and ophthalmology assessments (intraocular pressure and lenticular opacities) were performed at screening and the end of months 6 and 12.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSES:
The efficacy analysis set (i.e. intent-to-treat population) included all randomized patients who received at least one dose of randomized study medication and contributed sufficient data for at least one co-primary or secondary efficacy endpoint to be calculated during the randomized treatment period. The safety analysis population included all randomized patients who received at least one dose of randomized study medication and from whom any post-randomization data were available. For the subsets of patients who underwent serial spirometry, 24-hour urinary cortisol, BMD, 24-hour Holter monitoring and ophthalmological analyses, analysis sets were defined as those patients who received at least one dose of randomized study medication and had baseline and on-treatment values for the variable being assessed. Patients who discontinued prematurely completed final visit (month 12) assessments at the time of discontinuation, followed by the 4-week follow-up. A sample size of approximately 400 patients per treatment group was calculated to allow 90% power to detect a reduction in the number of COPD exacerbations of approximately 30%, adjusting for overdispersion of 2.3. This sample size ensured >95% power to detect a difference of 0.10L in FEV1, given an estimated standard deviation of 0.3 L. All tests were two-sided, with p ≤ 0.05 considered significant. The prespecified primary comparators were formoterol DPI for pre-dose FEV1 to demonstrate the contribution of budesonide and placebo for 1-hour post-dose FEV1. To address issues of multiplicity relating to multiple-dose comparisons and multiple variables of interest, a fixed-sequence testing procedure was adopted. The primary comparisons were prespecified as budesonide/formoterol pMDI 320/9 μg compared with (i) placebo for pre-dose FEV1 and 1-hour post-dose FEV1; and (ii) formoterol DPI 9 μg for pre-dose FEV1. If significant differences were obtained, comparisons continued with budesonide/formoterol pMDI 320/9 μg compared with placebo for (i) dyspnoea; (ii) SGRQ total score; and (iii) number of exacerbations. If significant differences were obtained for each of these key secondary variables, the lower dose of budesonide/formoterol pMDI was tested on the co-primary variables, as previously described, and, if significant differences were obtained, testing continued with number of exacerbations, dyspnoea and SGRQ total score compared with placebo. For all secondary efficacy variables, the primary comparison was budesonide/formoterol pMDI versus placebo. Primary and secondary variables were assessed as the change from baseline to the average over the randomized treatment period except for average 12-hour FEV1, mean FEV1 at 12 hours and SGRQ at end of treatment. Changes from baseline in the co-primary efficacy variables were analysed via analysis of co-variance (ANCOVA), adjusting for treatment, country and baseline value. The following three key secondary efficacy variables were identified: (i) dyspnoea; (ii) SGRQ total score; and (iii) exacerbations. Secondary variables were analysed similar to the co-primary efficacy variables; however, exacerbation rate (number/patient-treatment year) was analysed using a Poisson regression model, adjusted for country and differential randomization time, and time to first COPD exacerbation was described via Kaplan-Meier plot and analysed using the log-rank test. The number and percentage of patients experiencing clinically meaningful changes (based on a prespecified minimal important difference) in dyspnoea were analysed using the Cochran-Mantel-Haenszel test, adjusting for country. Geometric mean 24-hour urinary cortisol levels at end of treatment were compared between treatment groups using a multiplicative ANCOVA model. Mean changes from baseline to the average during the randomized treatment period in 12-lead ECG, and Holter variables and ophthalmology variables were analysed using a model similar to that used for the co-primary variables. BMD variables (natural logarithm of the analysis timepoint minus the natural logarithm of the respective baseline value for hip and spine) were analysed using an ANCOVA model adjusting for country, treatment and natural logarithm of the baseline value. Other safety data were summarized using descriptive statistics. No formal hypothesis testing of the safety data was performed.
BODY.RESULTS.PATIENTS:
Of 1964 randomized patients, 1355 completed the study (figure 2). Discontinuation was greater with placebo versus budesonide/formoterol and formoterol driven by withdrawal of consent. Time to discontinuation was significantly (p ≤ 0.004) prolonged in both budesonide/formoterol groups versus placebo. AE was the most common reason for study discontinuation, with a similar incidence across treatments (12.1–13.5%). Approximately 60% of patients had documented use of an ICS, either alone or in combination before entering the study. The percentage of patients who discontinued from the study in the formoterol and placebo groups was slightly higher in patients previously treated with ICS (34.9% and 38.0%, respectively) compared with those not previously receiving ICS before the study (26.8% and 33.9%, respectively). In contrast, patients in the budesonide/formoterol 320/9-μg group previously receiving ICS had a lower discontinuation rate compared with those not previously receiving ICS (23.1% vs 34.1%, respectively). In the budesonide/formoterol 160/9-μg group, the percentage of patients who discontinued the study was similar for those who were previously receiving an ICS (29.5%) and those who were not (28.2%).
Fig. 2Patient disposition. AE = adverse event; bid = twice daily; BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; med = medication; PL = placebo; pMDI = pressurized metered-dose inhaler. Most demographic and disease characteristics at baseline were similar across treatments (table I). However, in the serial spirometry subset (n = 491), mean percentage reversibility was greater in the budesonide/formoterol 320/9 μg (19.9%), budesonide/formoterol 160/9 μg (20.7%) and placebo (19.5%) groups versus formoterol (16.9%). COPD severity[1] was moderate in 17.8%, severe in 60.4% and very severe in 21.5% of patients. Common co-morbid conditions included hypertension (41.6%), lipid profile abnormalities (22.0%), cardiac disease (17.7%), diabetes mellitus (11.0%), osteoporosis (10.5%), cataracts (5.2%), atrial fibrillation/arrhythmia (4.3%) and congestive cardiac failure (2.9%).
Table IPatient demographic and baseline clinical characteristics of randomized patients
BODY.RESULTS.EFFICACY EVALUATIONS.PULMONARY FUNCTION.CO-PRIMARY ASSESSMENTS:
Improvements in pre-dose FEV1 were significantly greater for budesonide/formoterol 320/9 μg compared with formoterol (primary comparison; p = 0.008) and for both budesonide/formoterol dosages compared with placebo (p < 0.001) [figure 3a]. Although improvements in 1-hour post-dose FEV1 were significantly greater for both budesonide/formoterol dosages compared with placebo (primary comparison; p < 0.001), budesonide/formoterol 320/9 μg also resulted in significantly greater improvements compared with formoterol (p = 0.023) [figure 3b]. Improvements from baseline were apparent at the first assessment (pre-dose FEV1 at end of month 1; 1-hour post-dose FEV1 at day of randomization) and overall maintained over the 12-month treatment period for both budesonide/formoterol dosages (figure 3a and b).
Fig. 3Co-primary efficacy endpoints. Least squares mean change from baseline by study visit over the randomized treatment period in (a) pre-dose forced expiratory volume in 1 second (FEV1) and (b) 1-hour post-dose FEV1. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p < 0.001 vs placebo; † p ≤ 0.023 vs FM.
BODY.RESULTS.EFFICACY EVALUATIONS.PULMONARY FUNCTION.SECONDARY ASSESSMENTS:
Morning and evening PEF improved significantly for all active treatments compared with placebo (p ≤ 0.012) and for both budesonide/formoterol dosages compared with formoterol (p ≤ 0.017) [table II]. Results for pre-dose and 1-hour post-dose FVC are presented in the online supplement (see figures S1a and b in the supplementary material ['ArticlePlus'] at http://links.adisonline.com/DGZ/A5).
Table IIMean (SD) changes from baseline in additional pulmonary function assessments In the serial spirometry subset, a ≥15% improvement in FEV1 was observed at 5 minutes after dose administration (first assessment) with all active treatments on the day of randomization (budesonide/formoterol 320/9 μg, 17.7%; budesonide/formoterol 160/9 μg, 20.3%; formoterol 9 μg, 16.5%) and at end of treatment (budesonide/formoterol 320/9 μg, 21.8%; budesonide/formoterol 160/9 μg, 22.4%; formoterol 9 μg, 15.0%) [figures 4a, b and c]. There was no evidence of a diminished effect at end of treatment over the 12-hour period in the budesonide/formoterol groups. Mean FEV1 at 12 hours and baseline-adjusted average 12-hour FEV1 were significantly improved with both budesonide/formoterol dosages compared with placebo on the day of randomization and at end of treatment (p ≤ 0.002) [table II]. Although both budesonide/formoterol dosages demonstrated significant improvements in mean FEV1 at 12 hours and in baseline-adjusted average 12-hour FEV1 compared with formoterol on the day of randomization (p ≤ 0.029), only budesonide/formoterol 320/9 μg demonstrated this effect at the end of treatment (p ≤ 0.004) [table II].
Fig. 4Mean percentage change from baseline in forced expiratory volume in 1 second (FEV1) over 12 hours at randomization and end of treatment (EOT) for (a) budesonide (BUD)/formoterol (FM) 320/9 μg twice daily (bid) vs placebo, (b) BUD/FM 160/9 μg bid vs placebo and (c) FM 9 μg bid vs placebo. DOR = day of randomization; DPI = dry powder inhaler; pMDI = pressurized metered-dose inhaler. No significant differences in pre-dose IC were observed among the treatment groups (figure 5a). Improvements from baseline to the average over the randomized treatment period in 1-hour post-dose IC were significantly greater with both budesonide/formoterol dosages compared with placebo (p < 0.001) and formoterol (p ≤ 0.018) [figure 5b]. Both dosages of budesonide/formoterol resulted in a 350 mL (≈25%) improvement from baseline to the average over the randomized treatment period in 1-hour post-dose IC, and formoterol resulted in a 210 mL (17%) improvement in 1-hour post-dose IC.
Fig. 5Least squares mean change from baseline by study visit over the randomized treatment period in (a) pre-dose inspiratory capacity (IC) and (b) 1-hour post-dose IC. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p < 0.001 vs placebo; † p = 0.01 vs FM; ‡ p < 0.05 vs FM; § p < 0.01 vs placebo.
BODY.RESULTS.EFFICACY EVALUATIONS.CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) EXACERBATIONS:
Time to first COPD exacerbation was significantly prolonged with both budesonide/formoterol dosages compared with placebo (p ≤ 0.004) and with budesonide/formoterol 320/9 μg compared with formoterol (p = 0.026) [figure 6]. In addition, significant reductions in the overall number of exacerbations per patient-treatment year were observed with budesonide/formoterol 320/9 μg and 160/9 μg versus placebo (37% and 41%, respectively; p < 0.001) and formoterol (25% and 29%, respectively; p ≤ 0.004) [see figure S2 in the supplementary material]. These reductions were driven by exacerbations treated with oral corticosteroids, the rate of which was reduced with budesonide/formoterol 320/9 μg and 160/9 μg versus placebo (37.5% and 42.9%, respectively) and formoterol (24.1% and 30.6%, respectively) [p ≤ 0.006]. In addition, the percentage of patients in the budesonide/formoterol 320/9 μg, budesonide/formoterol 160/9 μg, formoterol and placebo groups who experienced an exacerbation was greater in those receiving ICS therapy either alone or in combination before the study (33.7%, 38.2%, 39.9% and 40.1%, respectively) compared with those not previously receiving ICS (25.8%, 24.9%, 29.4% and 32.8%, respectively).
Fig. 6Kaplan-Meier probability curve for the time to first chronic obstructive pulmonary disease exacerbation during randomized treatment. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p ≤ 0.004 vs placebo; † p = 0.026 vs FM.
BODY.RESULTS.EFFICACY EVALUATIONS.HEALTH STATUS AND COPD SYMPTOMS:
Improvements in SGRQ total score were significantly greater for both budesonide/formoterol dosages compared with placebo (p ≤ 0.006) and for budesonide/formoterol 160/9 μg compared with formoterol (p = 0.006; table III). The improvements from baseline in SGRQ total score in the active treatment groups were not clinically meaningful versus placebo (i.e. decrease of ≥4 points). Significantly greater improvements in COPD symptom variables were observed for both budesonide/formoterol dosages versus placebo for all variables (BCSS, dyspnoea score, cough score, sputum score, sleep score, percentage of awakening-free nights and total daily rescue medication use) [p ≤ 0.003]. Compared with formoterol, mean improvements were significantly greater with budesonide/formoterol 320/9 μg (p ≤ 0.038) for all COPD symptom variables except sputum score and percentage of awakening-free nights, and with budesonide/formoterol 160/9 μg (p ≤ 0.047) for all COPD symptom variables except BCSS, dyspnoea and sputum score (table IV).
Table IIIMean changes (SD) in SGRQ total and domain scores from baselinea to end of treatmentbTable IVMean (SD) changes in chronic obstructive pulmonary disease (COPD) symptom variables from baselinea to the average over the randomized treatment period Improvements (i.e. reductions) in dyspnoea scores were significantly greater for all active treatments versus placebo (p ≤ 0.003) and for budesonide/formoterol 320/9 μg versus formoterol (p = 0.032; table IV). All active treatment arms demonstrated ≥0.2 points (minimal important difference) change from baseline, but only budesonide/formoterol 320/9 μg had an increase of ≥0.2 points over placebo. A significantly (p < 0.001) greater percentage of patients in both budesonide/formoterol groups and in the formoterol group experienced clinically meaningful improvements in dyspnoea versus placebo (see figure S3 in the supplementary material).
BODY.RESULTS.SAFETY EVALUATIONS:
Mean treatment exposure was lowest for placebo (270 days) compared with budesonide/formoterol 320/9 μg (305 days), budesonide/formoterol 160/9 μg (299 days) and formoterol (289 days). The most commonly reported AE (irrespective of causality) was COPD, which had a lower incidence with budesonide/formoterol 320/9 μg versus placebo and a slightly higher incidence with budesonide/formoterol 160/9 μg versus placebo (table V). AEs considered by the investigator to be related to study medication were generally similar among treatment groups with the most commonly reported being oral candidiasis, COPD and dysphonia (see table SI in the supplementary material).
Table VOverall adverse events (AEs) [irrespective of relationship to study medication] reported by ≥3% of patients The total incidence of pneumonia-related AEs (pneumonia, bronchopneumonia, lobar pneumonia and pneumonia staphylococcal) was similar for budesonide/formoterol 320/9 μg and 160/9 μg (4.0% and 3.4%, respectively) compared with formoterol (3.4%) and placebo (5.0%) [see table SII in the supplementary material]. For potential lung infections other than pneumonia, the incidence was slightly higher in the active treatment groups versus placebo, which was driven largely by bronchitis (see table SII in the supplementary material). AEs typically or potentially associated with local and systemic effects of inhaled corticosteroids (local effects: aphonia, dysphonia, oral candidiasis and candidiasis; systemic effects: weight gain, adrenal suppression, ocular effects, skin effects, psychiatric disorder, diabetes control, thirst, taste effects and bone effects) were more frequent with budesonide/formoterol 320/9 μg (10.3% and 4.0%, respectively) and budesonide/formoterol 160/9 μg (5.7% and 4.5%, respectively) than formoterol (0.6% and 2.6%, respectively) and placebo (2.5% and 2.7%, respectively). The overall incidence of LABA class effects (i.e. tremor, palpitation, tachycardia, potassium changes, glucose changes, headache, agitation, anxiety, sleep effects and muscle cramp) was low, but higher among active treatment groups (budesonide/formoterol 320/9 μg [9.5%], budesonide/formoterol 160/9 μg [8.9%] and formoterol [6.5%]) versus placebo (4.8%). The incidence of cardiac-related AEs was higher for all active treatments (10.5–11.3%) versus placebo (6.9%). The most common cardiac-related AEs were hypertension and angina pectoris (budesonide/formoterol 320/9 μg [2.4% and 1.2%, respectively], budesonide/formoterol 160/9 μg [1.6% and 0.8%, respectively], formoterol [2.6% and 1.8%, respectively] and placebo [2.1% and 1.0%, respectively]). Although the number of atrial fibrillation AEs was low, all cases occurred within the active treatment groups. Discontinuations due to AEs (DAEs) occurred in 238 patients, with a similar incidence observed across treatment groups (range 11.3–12.5%) [see table SIII in the supplementary material]. The most common DAE was COPD, which was highest in the formoterol group (7.3%) and lowest in the budesonide/formoterol 320/9 μg group (4.0%); the incidence was similar in the budesonide/formoterol 160/9 μg (6.1%) and placebo (6.0%) groups (see table SIII in the supplementary material). The overall incidence of non-fatal serious adverse events (SAEs) was highest with formoterol (17.8%) compared with the other treatment groups and higher with budesonide/formoterol 320/9 μg (15.6%) and budesonide/formoterol 160/9 μg (13.6%) versus placebo (12.1%) [see table SIV in the supplementary material]. The most common non-fatal SAEs (occurring in five or more patients [all treatment groups combined]) were COPD (6.8%), pneumonia (1.5%), atrial fibrillation (0.5%), angina pectoris (0.3%), bronchitis (0.3%) and coronary artery disease (0.3%). These non-fatal SAEs occurred at a similar incidence in all treatment groups, except for COPD, which was slightly more common in the active treatment groups (budesonide/formoterol 320/9 μg [7.1%], budesonide/formoterol 160/9 μg [6.7%] and formoterol [7.9%]) versus placebo (5.6%). Fifteen patients died during the randomized treatment period with no imbalance across treatments: three in the budesonide/formoterol 320/9 μg group; six in the budesonide/formoterol 160/9 μg group; two in the formoterol group; and four in the placebo group. Fifteen patients died after the randomized treatment period (≥2 days after stopping study treatment) with no imbalance across treatments: five in the budesonide/formoterol 320/9 μg group; two in the budesonide/formoterol 160/9 μg group; four in the formoterol group; and four in the placebo group. None of the deaths were considered drug related by the investigator. Clinically significant changes in vital signs, 24-hour urinary cortisol, and 12-lead ECGs, QT interval and Holter assessments were rare. The geometric mean values of 24-hour urinary cortisol at 6 months and end of treatment were lower in both budesonide/formoterol dosage groups compared with formoterol and placebo (see table SV in the supplementary material). Significant differences in 24-hour urinary cortisol were observed between the budesonide/formoterol 320/9 μg and placebo groups (p = 0.035) at month 6 and between the budesonide/formoterol 320/9 μg and formoterol groups (p = 0.044) at end of treatment. Corrected QT (QTc) intervals ≥450 msec were experienced by similar percentages of patients across all treatment groups, whereas few patients experienced QTc intervals ≥500 msec or a QTc change ≥60 msec (see table SVI in the supplementary material). Data from ECG and Holter recordings showed a similar incidence of new onset atrial fibrillation in the active and placebo groups. BMD was stable over the 1-year study period in all treatment groups, with small but statistically significant differences in changes from baseline observed for budesonide/formoterol 320/9 μg compared with all other treatments for total lumbar spine BMD (p ≤ 0.037) and for budesonide/formoterol 320/9 μg versus formoterol for total hip BMD (p = 0.012) [see table SVII in the supplementary material]. The differences between the treatment groups in changes from baseline in BMD were of unclear clinical relevance, as the geometric least squares mean ratios for these treatment group comparisons were close to 1 (range 0.98–0.99). Minor increases in lenticular opacities and intraocular pressure were noted across all treatment groups in the ophthalmological analysis subset; the magnitude of these changes was similar among the treatment groups (see table SVIII in the supplementary material). Small but significant differences were observed for the change from baseline in posterior subcapsular score between the budesonide/formoterol groups (p = 0.022). Clinically significant changes in ophthalmological assessment were infrequent.
BODY.DISCUSSION:
In this study, both budesonide/formoterol dosage strengths resulted in significant improvements from baseline over the randomized treatment period in pulmonary function, health status and COPD symptoms, as measured by dyspnoea, cough and sputum production, and a clinically significant reduction in COPD exacerbation rate compared with placebo. In addition, both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol alone and placebo. The results of this 12-month study confirm those from the earlier related 6-month study by Tashkin et al.[4] and are consistent with those from studies of budesonide/formoterol DPI.[2,3] Taken together, the results demonstrate that this ICS/LABA combination provides benefits beyond formoterol alone in the treatment of COPD. The contribution of budesonide to improvements from baseline in pulmonary function and COPD symptoms was demonstrated by the greater efficacy of budesonide/formoterol 320/9 μg compared with formoterol alone for the co-primary variables of pre-dose FEV1 and 1-hour post-dose FEV1, and for dyspnoea and total BCSS scores, supporting use of the higher-dose combination for COPD symptoms. Both budesonide/formoterol dosage strengths demonstrated greater improvements from baseline compared with formoterol alone in morning and evening PEF, 12-hour FEV1, symptom scores and rescue medication use. In addition, the 25–29% reduction in exacerbation rate observed with both budesonide/formoterol dosage strengths beyond the substantial reduction achieved with formoterol alone further demonstrates the important contribution of budesonide to the combination product. The magnitude of the reduction in exacerbation rates reported in this study is similar to that reported previously for fixed-dose regimens of budesonide/formoterol 320/9 μg twice daily[2–4] and fluticasone propionate/salmeterol[11–13] relative to LABA alone. A key difference between this 12-month study and the 6-month study of similar design reported by Tashkin et al.[4] is that this study was powered to show a difference in exacerbations, while the 6-month study was not. This study demonstrated a significant reduction in exacerbation rates in patients treated with budesonide/formoterol 320/9 μg and 160/9 μg compared with those receiving formoterol or placebo. The fact that a greater percentage of patients in the formoterol and placebo groups who previously received ICS therapy, either alone or in combination, experienced exacerbations compared with those who did not previously receive ICS therapy may result in a skewing of the data; however, a similar response was observed in combination budesonide/formoterol patients with a greater percentage of patients who previously received ICS experiencing exacerbations compared with patients who were not previously treated with ICS therapy. Similarly, a greater percentage of patients who previously received ICS therapy discontinued in the formoterol and placebo groups than those who did not previously receive ICS therapy; however, this trend was reversed in the combination budesonide/formoterol groups. The long-term nature of this study allowed for a more thorough assessment of tolerability compared with the 6-month study.[4] No differences in pneumonia incidence were observed among treatment groups in this study or in the 6-month study, despite a shorter exposure time in the placebo group.[4] These results contrast with previous COPD studies that showed an increased incidence of pneumonia with fluticasone propionate/salmeterol treatment.[11–14] However, in this study and the 6-month study,[4] the incidence of potential lung infections other than pneumonia was slightly higher in all active treatments compared with placebo; these differences were largely driven by an increased incidence of bronchitis. The incidence of SAEs, including COPD SAEs, was slightly higher in both budesonide/formoterol groups compared with placebo. This finding may be attributed to the earlier discontinuation in the placebo group, which resulted in a shorter study drug exposure (35 and 29 fewer days vs budesonide/formoterol 320/9 μg and 160/9 μg, respectively). Although the overall incidence of atrial fibrillation, a known LABA class effect, was small (1.1%), an imbalance was noted between the formoterol-containing arms and placebo. However, no differences in new-onset atrial fibrillation were apparent among groups based on 24-hour Holter monitoring or ECG data collected at repeated visits during the randomized treatment period. Overall, the safety profile of budesonide/formoterol pMDI in this 12-month study was similar to that reported in the 6-month study by Tashkin et al.,[4] suggesting no increase in safety concerns with a longer duration of treatment.
BODY.CONCLUSIONS:
Both dosage strengths of budesonide/formoterol pMDI (320/9 μg and 160/9 μg) were effective and well tolerated over 1 year of treatment in this population of patients with moderate to very severe COPD. In addition, budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy compared with formoterol for pre-dose FEV1, suggesting that the higher dosage strength containing twice the daily dose of budesonide is appropriate in this patient population.
BODY.ELECTRONIC SUPPLEMENTARY MATERIAL:
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"Outcome": [
"Time to first COPD exacerbation",
"1-hour post-dose FEV1 improvements",
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TITLE: Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial
ABSTRACT.BACKGROUND:
Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI.
ABSTRACT.METHODS:
A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score ≤ 8 were enrolled in the study. A prospective, randomized, placebo-controlled trial of progesterone was conducted in the Neurotrauma Center of our teaching hospital. The patients were randomized to receive either progesterone or placebo. The primary endpoint was the Glasgow Outcome Scale score 3 months after brain injury. Secondary efficacy endpoints included the modified Functional Independence Measure score and mortality. In a follow-up protocol at 6 months, the Glasgow Outcome Scale and the modified Functional Independence Measure scores were again determined.
ABSTRACT.RESULTS:
Of the 159 patients randomized, 82 received progesterone and 77 received placebo. The demographic characteristics, the mechanism of injury, and the time of treatment were compared for the two groups. After 3 months and 6 months of treatment, the dichotomized Glasgow Outcome Scale score analysis exhibited more favorable outcomes among the patients who were given progesterone compared with the control individuals (P = 0.034 and P = 0.048, respectively). The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). The mean intracranial pressure values 72 hours and 7 days after injury were lower in the progesterone group than in the placebo group, but there was no statistical significance between the two groups (P > 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found.
ABSTRACT.CONCLUSION:
Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug.
ABSTRACT.TRIAL REGISTRATION:
ACTRN12607000545460.
BODY.INTRODUCTION:
Traumatic brain injury (TBI) remains one of the leading causes of injury-related death and severe disability. The management of TBI currently includes preventing further neurological insults, managing the intracranial pressure (ICP), and surgical procedures. It is very important to search for clinically effective neuroprotective drugs to prevent secondary brain injury after TBI. In spite of many neuroprotective agents showing efficacy in experimental models of TBI, none has produced significant neuronal protection when tested in clinical trials [1,2]. Progesterone, a hormone, has steroidal, neuroactive and neurosteroidal action in the center neuronal system. Neuroprotective effects of progesterone have recently been shown in a variety of animal models, including ischemic and traumatic brain insult models [3-6]. Postinjury administration of progesterone in experimental models of head injury confers significant protection against TBI-induced cerebral edema and secondary neuronal death, promoting behavioral recovery [7,8]. Experimental evidence suggests that postinjury treatment with progesterone decreases brain edema, attenuates free radical damage, and reduces neuronal loss in TBI animal models [8-13]. Progesterone also reduces the inflammatory response and attenuates neurological abnormalities after ischemia and spinal cord injury [14-18]. In a recently published controlled study of progesterone, Wright and colleagues conducted a phase II, randomized, double-blind, placebo-controlled trial to assess the safety and benefit of administering progesterone to patients with acute TBI [19]. No serious adverse events were found in the 77 patients who received progesterone, and the patients with moderate TBI who received progesterone were more likely to have a moderate to good outcome than those were randomized to placebo at 30 days post injury. The 30-day mortality in the progesterone group was less than one-half that of the control group. This outcome suggests that progesterone causes no harms and may be a beneficial treatment for TBI [19]. Despite these potential advantages and the good safety profile of progesterone described in studies utilizing animals or humans as subjects, there is relatively little information available from assessing neuroprotective properties of progesterone in the patients with acute severe brain trauma. The effects of progesterone on neurological outcome of the TBI patients remain unclear. The purpose of the present pilot clinical study was to assess the longer-term efficacy of progesterone on improving the neurological outcome of patients with acute severe TBI.
BODY.MATERIALS AND METHODS.PATIENTS:
Patients with acute severe TBI and a Glasgow Coma Scale (GCS) score ≤ 8 after resuscitation and stabilization were entered into the study. Two hundred and thirty patients from the Neurotrauma Center of our teaching hospital were included. Male or female patients between the ages of 18 and 65 years were studied. The patients received progesterone within 8 hours after the documented time of injury. All patients admitted to the Neurotrauma Center, Clinical Medical College of Hangzhou between March 2004 and February 2007 were consecutively eligible for enrollment. We excluded patients who had received any investigational drugs 30 days prior to the enrollment, such as progesterone, estrogen and investigational compound, patients with severe anoxic intracerebral damage or brain death, and patients whose clinical condition was unstable (partial pressure of oxygen < 60 mmHg or a systolic blood pressure < 90 mmHg, or both). We also excluded pregnant patients and lactating female patients, and those for whom there was doubt whether the neurological status resulted from head trauma or acute or chronic spinal cord injury. The study was conducted in compliance with the clinical protocol approved by the Institutional Review Board and the ethical committees of Clinical Medical College of Hangzhou, according to Good Clinical Practice standards. Because of the nature of patients' injuries, subjects in this clinical study were incapable of granting informed consent. Investigators therefore obtained informed consent from the subject's legal guardian or health proxy before administering the drug. Given the urgent circumstances, we were unable to obtain permission from a legal guardian or health proxy within the stipulated time window for some patients (n = 53). Investigators therefore sought approval from the Institutional Review Board to use deferred consent. If the Institutional Review Board determined that these regulatory criteria were satisfied, the investigators were permitted to enroll subjects without consent. When the drug was administered without proxy consent, the Institutional Review Board was notified within 2 working days. We continued to try to contact the proxy consent after drug administration, and documented those attempts to the Institutional Review Board. Once contacted, the family or legally authorized representative was notified of the patient's enrollment and asked to provide written approval for the patient's continued participation. If attempts to contact proxy consent were unsuccessful, or if the patient died before the family could be contacted, we notified the Institutional Review Board and placed a full report in the patient's record and study file.
BODY.MATERIALS AND METHODS.STANDARD CLINICAL MANAGEMENT:
After head computerized tomography scanning, the patients were delivered to the neurosurgical intensive care unit of the teaching hospital immediately or following surgical evacuation of an intracranial hematoma. All patients received the standard treatment for management of severe TBI based on the guidelines for the management of severe head injury of the American Association of Neurologic Surgeons [20]. Particular emphasis was placed on the prevention and treatment of secondary insults, the avoidance of intracranial hypertension, maintenance of a normovolemic state as well as normothermia and normoglycemia, with ventilation to maintain the oxygen pressure at a minimum of 100 mmHg and the carbon dioxide pressure at approximately 35 mmHg.
BODY.MATERIALS AND METHODS.RANDOMIZATION AND MEDICATION ADMINISTRATION:
The prospective, randomized, placebo-controlled, double-blind study was conducted in our neurosurgical intensive care unit. Subjects enrolled in the study were randomized to receive either progesterone (Tianjing Jinyao Pharmaceutical Co. Ltd, Tianjing, China) or matching placebo within 8 hours of the documented time of injury. Qualifying patients were randomly assigned in a 1:1 manner to receive the matching treatment with random numbers. Patients for the treatment group were given progesterone at 1.0 mg/kg via intramuscular injection and then once per 12 hours for 5 consecutive days. A single-dosage volume equivalent to 0.05 ml/kg was used in each subject. In a double-blind manner, progesterone and placebo were supplied via identical-looking solutions in identical glass vials with or without progesterone. The appearance, packaging and administration of placebo and progesterone injections were the same for the two groups. All patients, treating physicians, nursing staff, and pharmacists were blinded throughout the study period.
BODY.MATERIALS AND METHODS.CLINICAL MEASUREMENTS:
The ICP was monitored continuously using ICP monitoring apparatus (CAMINO. MPM-1; Integra Co., San Diego, CA, USA). A computerized tomography scan was obtained in all patients at admission and this was categorized according to the modified Marshall computerized tomography scan classification: I, intracranial pathology not visible on the computerized tomography scan; II, cisterns present with shift ≤ 5 mm; lesions present, but no high-density or mixed-density lesions > 25 cm3, with bone fragments and foreign bodies; III, cisterns compressed or absent, shift ≤ 5 mm, with no high-density or mixed-density lesions > 25 cm3; IV, shift > 5 mm, with no high-density or mixed-density lesions >25 cm3; V, any surgically evacuated lesion; and VI, high-density or mixed-density lesions >25 cm3 without surgical evacuation. The patient's condition – body temperature, heart rate and respiratory rate, blood pressure, and pulse blood oxygen saturation – was monitored continuously at the bedside with monitoring apparatus (Hewlett-Packard, Palo Alto, CA, USA). Daily evaluations of neurologic status over the initial 14-day period were performed via the GCS score, adverse experiences, surgical procedures, and intracranial complications. Intake and output of fluids were also recorded. Laboratory tests including hematology, the coagulation profile and clinical chemistry were performed daily and then for 1 week after injury. A urine pregnancy test was performed at enrollment for female patients (as necessary).
BODY.MATERIALS AND METHODS.NEUROLOGIC OUTCOME MEASUREMENTS:
The neurologic outcome was evaluated according to the Glasgow Outcome Scale (GOS) score, which contains five levels of outcome: good recovery, moderate disability, severe disability, vegetative survival, or death. For statistical analysis, GOS scores were dichotomized into favorable or unfavorable outcomes. Patients in the upper two GOS outcome groups (good recovery and moderate disability) were considered of favorable outcome, and patients in the other groups (severe disability, vegetative state, or death) were considered of unfavorable outcome. Secondary efficacy endpoints were the modified Functional Independence Measure (FIM) score and mortality. Based on previous reports [21,22], the modified FIM measurements of disability in three areas of activity (domains of self-care, motor function, and cognitive function) were chosen from the 18 items in the full FIM. Each of three items (expression, feeding, and locomotion) includes four possible levels of function ranging from total dependence (1) to independence (4). The total modified FIM scores therefore ranged from 3 to 12. The patients were assessed using the same measures both at 3 and 6 months in the follow-up protocol.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Descriptive statistics, including proportions, means and standard deviations, were compiled for all demographic and outcome measures. Demographic and clinical data were analyzed using Fisher's exact test. The statistical analyses were conducted to assess the differences between the treatment group and the control group on specific variables. Statistical analysis was performed using contingency analysis (chi-squared) for categorical data and Student's t test for continuous data. P < 0.05 was considered statistically significant. SPSS 11.0 software package (SPSS Inc., Chicago IL, USA) was used for statistical analysis.
BODY.RESULTS.PATIENTS:
Between March 2004 and February 2007, a total of 230 patients were screened in the present study. Of these, 159 patients meeting the protocol stipulation and condition were recruited and randomized to receive either progesterone (n = 82) or placebo (n = 77). Data were available for 154 patients (96%) at the 3-month follow-up and for 135 patients (84%) at the 6-month follow-up. Nineteen patients (11%) were lost to follow-up, three patients (1%) refused follow-up, and two patients (1%) withdrew from the trial. No subjects were enrolled in violation of the protocol stipulations (Figure 1). Figure 1Trial profile. The demographics of the progesterone and placebo groups are presented in Table 1. The cohorts were well balanced with no significant differences between the two groups. The medication history of patients, medication administration, and medical procedures were not significantly different among treatment groups. Table 1 Clinical and demographic characteristics between the two groups Admission characteristic Placebo (n = 77) Progesterone (n = 82) P value Males 57 (74) 58 (70) 0.64 Females 20 (25) 24 (29) 0.64 Mean (standard deviation) age (years) 31 (9) 30 (11) 0.52 Mean (standard deviation) time injury to administration (hours) 3.65 (1.46) 3.80 (2.03) 0.59 Mean (standard deviation) qualifying Glasgow Coma Scale score 6.1 (1.3) 6.0 (1.8) 0.68 Glasgow Coma Scale 3 to 5 20 (25) 22 (26) 0.90 Mechanism of injury Motor vehicle 62 (80) 63 (76) 0.57 Fall 8 (10) 10 (12) 0.71 Assault 4 (5) 7 (8) 0.40 Other 3 (3) 2 (2) 0.59 Surgical procedures 24 (31) 22 (26) 0.54 Pupillary response Bilaterally normal 26 (33) 26 (31) 0.78 Abnormal 51 (66) 56 (68) 0.78 Marshall computerized tomography scan classification I 0 0 II 9 (11) 7 (8) 0.50 III 22 (28) 28 (34) 0.44 IV 13 (16) 12 (14) 0.69 V 24 (31) 22 (26) 0.54 VI 9 (11) 13 (15) 0.44 Data presented as n (%) unless indicated otherwise.
BODY.RESULTS.GLASGOW OUTCOME SCALE SCORES:
The 3-month and 6-month GOS scores between the progesterone and placebo groups are summarized in Table 2. There was a better recovery rate for the patients who were given progesterone than for those in the control group at 3-month follow-up (P = 0.044). A dichotomized analysis revealed significant differences in neurologic outcome between the treatment and control groups (Figure 2). The analysis using the dichotomization of GOS scores at 3 months post injury revealed a favorable outcome in 47% of the patients receiving progesterone and in 31% of the placebo group (P = 0.034). There was an unfavorable outcome in 53% of the patients receiving progesterone and in 70% of the placebo group (P = 0.022). At 6-month follow-up, the dichotomized GOS scores also showed a significant statistical difference between the two groups, similar to those 3 months after injury. The percentage of favorable outcome was 58% for the patients who were given progesterone and was 42% in the placebo group (P = 0.048). Forty-one percent of patients who were given progesterone and 57% of the placebo group exhibited an unfavorable outcome (P = 0.048). Table 2 Comparison of Glasgow Outcome Scale scores between the progesterone and placebo groups patients at 3-month and 6-month follow-up Glasgow Outcome Scale scores Progesterone (n = 82) Placebo (n = 77) 3 months Good recovery 21 (25) 10 (12) Moderate disability 18 (21) 14 (18) Severe disability 16 (19) 13 (16) Vegetative survival 13 (15) 16 (20) Death 15 (18) 25 (32) 6 months Good recovery 26 (31) 19 (24) Moderate disability 22 (26) 14 (18) Severe disability 9 (10) 11 (14) Vegetative survival 10 (12) 8 (10) Death 15 (18) 25 (32) Data presented as n (%). Figure 2Dichotomized Glasgow Outcome Scale scores for patients receiving either progesterone or placebo. There was a remarkably more favorable outcome among patients who were given progesterone compared with patients receiving placebo (P = 0.034) 3 months postinjury. At 6-month follow-up, the significant difference in the dichotomization of Glasgow Outcome Scale scores between the progesterone and placebo groups was similar to that after three-month injury (P = 0.048). Subgroup analysis for women also showed a significant difference in the percentage of favorable outcome between the two groups at 6-month follow-up (35% in the placebo group and 66% in the progesterone group, P = 0.036). The patients who were given progesterone in the group with GCS of 6 to 8 showed a more favorable outcome (43%) compared with the placebo group (28%) at 6-month follow-up (P = 0.044). There was no significant difference, however, in dichotomized outcomes in the group with GCS of 3 to 5 (P > 0.05).
BODY.RESULTS.MODIFIED FUNCTIONAL INDEPENDENCE MEASURE SCORES:
Figure 3 shows the modified FIM scores at 3-month and 6-month follow-up. There was a significant difference in the mean modified FIM score between two groups both at 3-month and 6-month follow-up. At the 3-month follow-up, the scores were 7.35 ± 1.89 for the placebo group and 8.02 ± 1.73 for the progesterone group (P < 0.05). Six months after injury, the placebo group showed a score of 8.95 ± 1.05 and the progesterone group presented 9.87 ± 1.17 (P < 0.01), suggesting good functional outcome in the patients treated with progesterone. Figure 3Modified Functional Independence Measure scores for patients receiving either progesterone or placebo. Modified Functional Independence Measure (FIM) scores at 3-month and 6-month follow-up from patients receiving either progesterone or placebo show that the scores in the progesterone group were significantly higher than those in the placebo group at both 3-month and 6-month follow-up. Data expressed as the mean ± standard deviation. Different from the placebo group: *P < 0.05, **P < 0.01.
BODY.RESULTS.MORTALITY:
During the 6 months of follow-up, a total of 40 patients (25%) died in the present study (37 patients died during their hospital stay). Seventy percent of deaths occurred within 1 week after trauma. Mortality was attributed to the heavy head injury in each case. The mortality rate in the progesterone treatment group was significantly lower at 6-month follow-up compared with the placebo group (18% versus 32%, P = 0.039).
BODY.RESULTS.INTRACRANIAL PRESSURE:
Figure 4 shows the ICP in the progesterone group patients and in the placebo group patients at 24 hours, 72 hours and 7 days after injury. The ICP was monitored continuously for 75 patients (47%), 40 in the progesterone group and 35 in the placebo group. The mean ICP shows no apparent difference at 24 hours after trauma between the two groups (progesterone group, 22.1 ± 4.3 mmHg versus placebo group, 23.2 ± 4.6 mmHg; P = 0.121). At 72 hours and 7 days after injury, the mean ICP of patients who were given progesterone was slightly lower than those of patients who received placebo, but the differences were not statistically significant (16.9 ± 3.8 mmHg and 14.8 ± 3.8 mmHg for progesterone-treated patients versus 18.2 ± 5.1 mmHg and 15.9 ± 4.1 mmHg for placebo-treated patients, respectively; P > 0.05). Figure 4Comparison of intracranial pressure between patients receiving either progesterone or placebo. The mean intracranial pressure between the progesterone and placebo group patients shows no significant differences 24 hours, 72 hours and 7 days after injury between the two groups (P > 0.05). Data expressed as the mean ± standard deviation.
BODY.RESULTS.GLASGOW COMA SCALE SCORES AND CLINICAL MEASUREMENTS:
The mean GCS scores increased progressively in the two groups during the 14-day acute phase of the study, with no apparent differences among the treatment groups. Meanwhile, there was no obvious difference in average body temperature, heart and respiratory rates, blood pressure, pulse blood oxygen saturation, and laboratory testing between the progesterone and placebo groups.
BODY.RESULTS.COMPLICATIONS AND ADVERSE EVENTS:
Progesterone was well tolerated in the treated patients with acute severe TBI. No complication and adverse event associated with the administration of progesterone was found in this clinical study during the hospitalization periods.
BODY.DISCUSSION:
The results of the present trial showed for the first time that progesterone administration had a longer-term efficacy on clinical outcomes in acute TBI patients. A significant increase in the proportion of patients with a favorable outcome in the progesterone group compared with the placebo group up to 6 months indicates the possibility of progesterone for treatment of acute TBI. Moreover, there were more surviving TBI patients in the treatment group than in the control group. Our results suggest the efficacy of progesterone in the treatment of acute severe TBI. Previous reports showed the evidence of efficacy in TBI animal models [8-14]. In the present study, the efficacy and safety of progesterone was confirmed in patients with acute severe TBI. Furthermore, our results using the modified FIM and GOS scores showed that progesterone administration remarkably enhanced functional recovery 6 months after injury and reduced the mortality of the patients with acute severe TBI (GCS = 6 to 8), although there was no statistical significance in the outcome improvement for GCS = 3 to 5 patients with and without progesterone treatment. The evidence of improved outcome for women patients also suggested, in part, a beneficial efficacy and feasibility of progesterone in women with TBI, in spite of the limited number of female patients in the trial. It is recognized that the pathophysiology of TBI is a multifactorial process involved in a complex and interwoven series of pathologic process following the onset of insult, such as increased extracellular glutamate concentrations, increased intracellular Ca2+, free radical overproduction and exacerbated inflammatory response. Medication targeted at a pathological single injury factor could therefore not sufficiently recover functional deficits following TBI. The ideal drugs should be able to block multiple cellular events leading to brain damage following TBI. Neuroprotective strategies currently focus on acting on only one of the mechanisms. Some efforts have been made, however, to combine agents or interventions to increase the probability of success in this setting [23,24]. Nevertheless, the use of a single pharmacologic agent or procedure to slow or block damaging chemicals that are released after brain injury is highly desirable. Progesterone has several features that make it an attractive potential drug candidate for TBI. First, progesterone could protect against brain damage via multiple mechanisms[13,15-18]. The pharmacokinetics of progesterone and its pattern of adverse reactions are well known since the drug has been safely used for a long time [25,26]. Second, with a wide therapeutic window of progesterone, a single bolus given up to 24 hours post injury may significantly reduce cerebral edema [7]. Third, progesterone may rapidly cross the blood–brain barrier and reach equilibrium with the plasma within 1 hour of administration [27-29]. Administration of progesterone soon after TBI would probably benefit the recovery of the patient. In the present double-blind trial, progesterone or placebo was dissolved in the same camellia oil and taken daily for 5 days by patients with acute TBI. Those patients administered progesterone experienced significant improvements in functioning outcome, indicating neuroprotective properties of progesterone in acute severe TBI. There was no adverse event after administration of progesterone and no further late toxicity up to 6 months in the trial. Goss and colleagues suggested that low and moderate doses of progesterone (4 to 8 mg/kg) were optimal for facilitating recovery of select behaviors, and that postinjury progesterone treatment permitted a wider dose range than preinjury treatment in rats with medial frontal cortical contusions [30]. In addition, 5 days of postinjury progesterone treatment are needed to reduce significantly the neuropathological and behavioral abnormalities found in a rodent model of TBI [13]. Wright and colleagues used intravenous progesterone at a dose of 0.71 mg/kg, followed by 0.5 mg/kg progesterone per 12 hours during the 3 following days, which appeared safe in the treatment of TBI patients [19]. In our study, the patients were received a single intramuscular injection of 1.0 mg/kg progesterone and the same dose per 12 hours for 5 consecutive days. The results in our trial showed that single higher-dose progesterone as protective therapy did not lead to any serious side effects. No obvious symptoms of hormone reaction were observed in our study. Accordingly, it can be anticipated that progesterone may be a promising treatment for severe TBI patients as it is inexpensive, widely available and has a long track record of safe use in humans to treat other diseases. The data in the present study provide very encouraging and favorable conditions that could lead to the assessment of GOS and FIM scores in TBI patients in a clinical trial. The GOS score, although useful, provides only a global assessment of function and dependence; it may not differentiate specific difference in cognitive function, motor function, or daily activities. The modified FIM score selects only three items from the 18-item score, and also distinguishes only four (as opposed to seven) levels of function. Subtle or complex deficiencies, particularly in cognitive function, may not have been identified in the dataset. A deficiency in using any one scale to measure outcome is that it is limited in its scope of measurement. The present clinical study was therefore designed to evaluated functional outcome according to the GOS and the modified FIM score. Intracranial hypertension has been considered an important factor affecting the outcome of the patients with acute severe TBI. Progesterone administration showed to decrease cerebral edema [9]. In an experimental study with male rats, there was a linear correlation between the serum progesterone level and brain edema after experimental TBI. The higher the serum progesterone level, the lower the cerebral edema [31]. In the current trial, however, no statistically significant difference was found in ICP monitoring between the groups given progesterone or placebo. It seems that progesterone treatment has little effect on directly reducing the ICP of patients with acute severe TBI. As a result of randomization, all of these parameters were homogeneous between the progesterone and placebo groups in our clinical trial. Nevertheless, some limitations are observed in the current study. The results could be influenced by a single-center trial and local perioperative standard of care. Therefore, it is necessary to use a sufficient power to assess progesterone's effects on neurologic outcomes. Our result of the significant differences in outcomes between two groups of patients emphasizes the potential value of using GOS and FIM to tailor progesterone administration and the likelihood of observing similar differences in a larger patient population; however, the possibility exists that a statistical error may have occurred because of an inadequate sample size. Further studies are needed to determine the mechanisms of action underlying the neurologic effect observed.
BODY.CONCLUSION:
The present pilot study indicated that the use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 6 months after injury, providing a potential benefit to the treatment of acute severe TBI patients. Our results strongly support further large, multicenter clinical trials to examine the ways in which progesterone is achieving the profound neurologic effect and to decipher optimal conditions in which it can be used to lengthen the duration of and improve the degree of neuroprotection.
BODY.KEY MESSAGES:
• Many neuroprotective agents have been shown to be efficient on TBI in animal models, and there is no single agent that shows improvement in outcome for head injury patients. • A number of experimental models have suggested that administration of progesterone has a potential benefit for head injury. • The present clinical trial reveals that progesterone may be used as a potential safe drug for the treatment of acute severe head trauma patients.
BODY.ABBREVIATIONS:
FIM = Functional Independence Measure; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; TBI = traumatic brain injury.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
GMX and WQY participated in the trial design and were involved in the study analysis and summary. GMX and WMW obtained the data. GMX, JW, ZHL and WMW participated in the data analysis and interpretation of the results. All authors reviewed the final version. | 2,447,617 | {
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TITLE: Clinical and radiological evaluation of Trabecular Metal and the Smith–Robinson technique in anterior cervical fusion for degenerative disease: a prospective, randomized, controlled study with 2-year follow-up
ABSTRACT:
A prospective, randomized, controlled study was carried out to compare the radiological and clinical outcomes after anterior cervical decompression and fusion (ACDF) with Trabecular MetalTM (TM) to the traditional Smith–Robinson (SR) procedure with autograft. The clinical results of cervical fusion with autograft from the iliac crest are typically satisfactory, but implications from the donor site are frequently reported. Alternative materials for cervical body interfusion have shown lower fusion rates. Trabecular Metal is a porous tantalum biomaterial with structure and mechanical properties similar to that of trabecular bone and with proven osteoconductivity. As much as 80 consecutive patients planned for ACDF were randomized for fusion with either TM or tricortical autograft from the iliac crest (SR) after discectomy and decompression. Digitized plain radiographic images of 78 (98%) patients were obtained preoperatively and at 2-year follow-up and were subsequently evaluated by two senior radiologists. Fusion/non-fusion was classified by visual evaluation of the A–P and lateral views in forced flexion/extension of the cervical spine and by measuring the mobility between the fused vertebrae. MRI of 20 TM cases at 2 years was successfully used to assess the decompression of the neural structures, but was not helpful in determining fusion/non-fusion. Pain intensity in the neck, arms and pelvis/hip were rated by patients on a visual analog scale (VAS) and neck function was rated using the Neck Disability Index (NDI) the day before surgery and 4, 12 and 24 months postoperatively. Follow-ups at 12 and 24 months were performed by an unbiased observer, when patients also assessed their global outcome. Fusion rate in the SR group was 92%, and in the TM group 69% (P < 0.05). The accuracy of the measurements was calculated to be 2.4°. Operating time was shorter for fusion with TM compared with autograft; mean times were 100 min (SD 18) and 123 min (SD 23), respectively (P = 0.001). The patients' global assessments of their neck and arm symptoms 2 years postoperatively for the TM group were rated as 79% much better or better after fusion with TM and 75% using autograft. Pain scores and NDI scores were significantly improved in both groups when compared with baseline at all follow-ups, except for neck pain at 1 year for the TM group. There was no statistically significant difference in clinical outcomes between fusion techniques or between patients who appeared radiologically fused or non-fused. There was no difference in pelvic/hip pain between patients operated on with or without autograft. In our study, Trabecular Metal showed a lower fusion rate than the Smith–Robinson technique with autograft after single-level anterior cervical fusion without plating. There was no difference in clinical outcomes between the groups. The operative time was shorter with Trabecular Metal implants.
BODY.INTRODUCTION:
Anterior surgery of the cervical disc with fusion using autograft from the iliac crest was introduced in the 1950s [10, 40]. The clinical results are typically satisfactory, with at least 75–80% of the patients satisfied, reporting reduced pain intensity, improved function and neurological restitution [9, 24, 27, 30, 32, 35]. However, infections, hematomas and longstanding pain [12, 25, 28, 33, 36, 37, 50] are frequently reported complications from the donor site. Allografts have been widely used, but imply risks of producing immunogenic response from the host, which might disturb fusion healing and involve the risk of transmitting infections [2, 5, 16, 26]. The risk is low, but can still be important if the infection is severe, as shown, e.g., when HIV is detected [7]. The ideal substitute for autograft should provide all three of its fundamental properties: osteogenicity, osteoconductivity and osteoinductivity. Several implants have been tested, but no ideal substitute or surgical method has been found [44]. Previously we have reported a low fusion rate for a cervical body interfusion with carbon fiber cage (Brantigan) [45]. Trabecular Metal (TM) is a porous tantalum biomaterial with structure and mechanical properties similar to trabecular bone (Fig. 1) and has been shown to be more osteoconductive than other commercially available biomaterials [4, 11, 22].Fig. 1Trabecular MetalTM implant The objectives of the study were to measure and compare the radiological and clinical outcomes of anterior cervical decompression and fusion (ACDF) with Trabecular Metal (TM) devices and the traditional Smith–Robinson (SR) procedure with autograft.
BODY.METHODS:
All patients scheduled for single-level anterior cervical decompression and fusion (ACDF) and fulfilling the criteria for the study were consecutively invited to participate during the period February 2002 to September 2003. Five patients declined participation and the remaining 80 provided informed consent. Study inclusion criteria were cervical radiculopathy with or without myelopathy due to degenerative disc disease (including disc herniation and/or spondylosis) with compatible MRI and clinical findings. Exclusion criteria were previous cervical spine surgery, posttraumatic neck pain, inflammatory systemic disease, another neurological disease and drug or alcohol abuse. No patient had spontaneous fusion at the adjacent segments. A flowchart of the study is presented in Fig. 2.Fig. 2Flowchart for the study After discectomy, the subchondral bony end plates were roughened by the burr until they bled, taking care that they would be able to function as a bearing surface for the implant. The posterior longitudinal ligament was removed in the majority of cases, and consequently osteophytes, if present, were removed. After decompression had been completed, randomization to fusion group was performed in the theater by a nurse using sealed envelopes. This late randomization was used to avoid surgeons' bias to treatment group during as much as possible of the surgical procedure. An implant size that could be positioned between the end plates by light tapping was chosen. The tricortical autografts were taken from the iliac crest using a saw with a twin blade. A subcutaneous catheter was placed at the donor site for administration of ropivacaine hydrochloride (NaropR) 2 or 3 days postoperatively, to reduce the pain. All patients used a soft collar for 6 weeks postoperatively. The randomization procedure yielded similar group distributions of age, gender and smoking habits (Table 1). The operated segment was C3/4 in 2 patients (both SR), C4/5 in 4 patients (2 TM, 2 SR), C5/6 in 50 patients (26 TM, 24 SR), C6/7 in 23 patients (11 TM, 12 SR) and C7/T1 in 1 patient fused with TM. See Table 2 for implant size. The operations were performed by five senior surgeons, and 70 out of the 80 patients were operated on by one of the two authors (HL, LV).Table 1Patient dataTotalTMSRAge median (range) (years)49 (27–70)48 (38–59)49 (27–70)Sex, male (no.)502426Smokers (no.)261610Myelopathy* (no.)422* All had radiculopathyTable 2Trabecular Metal implant sizeSize H × D × W (mm)No. of patients5 × 11 × 1415 × 14 × 1416 × 11 × 1466 × 14 × 14127 × 11 × 1467 × 14 × 14118 × 14 × 143Total40
BODY.METHODS.CLINICAL FOLLOW-UP:
Pain intensity in the neck, arms and pelvis/hip were rated by patients on a visual analog scale (VAS, 0–100), and neck function was rated using the Neck Disability Index [46] (NDI, 0–100) the day before surgery, and 4, 12 and 24 months postoperatively. Pain drawings were obtained at the same intervals. Follow-ups at 12 and 24 months were performed by an unbiased observer (ME), and patients also assessed their global outcomes at these same follow-up intervals.
BODY.METHODS.RADIOLOGICAL FOLLOW-UP:
Digitized plain radiographic images of 78 (98%) patients were obtained preoperatively, immediately postoperatively and at 2-year follow-up, and were subsequently evaluated by two senior radiologists. Consensus about fusion or non-fusion was reached after the first evaluation in 49 cases (62%) and after the second evaluation in the remaining 29 cases (38%). The second measurement was used to calculate intra-observer variability. The entire data set was analyzed to assess inter-observer variability of radiographic measurements and associated precision of the measurements. Fusion/non-fusion was classified by visual evaluation of the A–P and lateral views in forced flexion/extension of the cervical spine, i.e., (1) the presence/absence of bone-bridging or interface lucencies between TM and bone, and (2) by measuring the differences between the angles of the spinal processes of the fused vertebrae at flexion and extension. Fusion was classified as either clearly fused (I), probably fused (IIA), probably non-fused (IIB) and clearly non-fused (III) (Figs. 3, 4, 5). Finally, the material was dichotomized so that groups I and IIA were combined to fused, and groups IIB and III to non-fused. The same classification had been used in a previous study of the Brantigan carbon fiber cage [45]. For classification in group I, radiological signs of bone bridging were required and mobility of up to 1.0° was accepted. Cases classified in group II had uncertain signs of bone fusion. Group IIA had mobility of 2.0° or less and group IIB had more than 2.0°. Group III required both the absence of bone bridging and mobility of 3.0° or more.Fig. 3Clearly fused (group I) after surgery with autograft (SR)Fig. 4Clearly fused (group I) after surgery with Trabecular Metal (TM)Fig. 5Clearly non-fused (group III) after surgery with Trabecular Metal (TM). Note the radiolucent zone above the implant. Mobility is seen between images in flexion and extension MRI was performed on 20 consecutive TM cases at 2-year follow-up. Several parameter sets suggested for TM in the published literature were tested [21, 47] in addition to our standard protocol for the degenerative cervical spine, and the parameter sets below were ultimately chosen. The scans were performed on a Siemens Vision 1.5 T MRI scanner using a cervical spine coil with a protocol consisting of T1-sagittal images (TR 500, TE 12, se), T2/PD sagittal images (TR 4000, TE 128, tse and TR 1300, TE 120, se), PD sagittal images (TR 1300, TE 60, se), T1 axial images (TR 600, TE 15, se), T2 axial images (TR 620, TE 10, 25°, Fl2d), T2 oblique images (TR 4000, TE 128, tse), T2 coronal images (TR 1485, TE 120, se) and finally PD coronal images (TR 1485, TE 60, se). Slice thickness was 4 mm in all images.
BODY.METHODS.RADIOLOGICAL FOLLOW-UP.STATISTICAL METHODS:
A rank-invariant non-parametric method for analysis of pairs ordered categorical data was used to compare the pain ratings (VAS) and NDI for the groups. The method makes it possible to separately measure order-preserved individual changes attributable to the group change, as well as an individual change in category that is different from the change of pattern in the group [41, 42]. Clinically relevant improvement, set at 10, was calculated for VAS and NDI. χ2 tests were used to compare the groups. Student's t test was used to analyze the operative and hospital time. Fischer's exact test was used to compare the fusion rate in the groups. Inter- and intra-observer correlation was calculated using kappa analysis. A value of P < 0.05 was considered to be statistically significant.
BODY.RESULTS.SURGERY:
Operation times were shorter for fusion with TM as compared to autograft; mean times were 100 min (SD 18) and 123 min (SD 23), respectively (P = 0.001). There was no difference in intra-operative bleeding between the implant groups. Of the 80 patients, 72 had less than 50 ml of bleeding. There was no statistically significant difference in the hospital time between the groups; TM mean was 3.6 days (SD 1.1) and SR mean, 4.1 days (SD 1.7) (P = 0.18).
BODY.RESULTS.CLINICAL OUTCOME:
For patients receiving TM, the maximal pain (VAS) was reduced from median 57 in the neck and 45 in the arm before surgery, to 40 and 14 at 1 year and to 41 and 24 at 2 years postoperatively. In the group with autografts, the corresponding VAS ratings were reduced from median 66 in the neck and 60 in the arm before surgery to 36 and 28 at 1 year, and to 24 and 28 after 2 years (Fig. 6a, b). The number of patients showing clinically relevant improvement (set to at least 10 for VAS) in neck pain was 39% with TM and 63% with SR (P = 0.07), and in arm pain 50 and 58%, respectively.Fig. 6Pain rating (VAS) and Neck Disability Index preoperatively and at the follow-ups. The box plots illustrate the 25th and 75th percentiles with the median value marked in between. The range is shown by whiskers, but extreme outliers are separately shown by circles. There were no statistically significant differences between the surgical methods NDI improved from median 36 preoperatively to 30 after 2 years in patients with TM, and from 44 to 25 in the SR group (Fig. 6c). Clinically relevant improvement in NDI (set to at least 10) was found in 53% of the patients with TM and 61% with SR. The patients' global assessment of their neck and arm symptoms 2 years postoperatively for the TM group were: 41% much better, 38% better, 10% unchanged, 8% worse, and (one patient) 3% much worse. In the SR group, the assessments were: 42% patients much better, 33% better, 13% unchanged and 12% worse, i.e., 79% were much better or better after fusion with TM and 75% using autograft. At all follow-ups of 4, 12 and 24 months, pain scores (VAS) in both neck and arm, and NDI scores were significantly improved in both groups when compared with baseline, except for neck pain (VAS) at 12 months in patients fused with TM (P = 0.06). No statistically significant difference was found between the Trabecular Metal and autograft techniques for pain scores, NDI or the patients' global assessments, and at all follow-up intervals. A trend toward a higher proportion of patients with clinically relevant improvement in neck pain (at least 10 mm VAS) was measured after 2 years in patients with autografts (P = 0.07). The clinical results and corresponding P values are presented in Table 3.Table 3The clinical results and corresponding P valuesTMSRP valueMedianq1–q3Medianq1–q3TM vs. SRTM vs. baselineSR vs. baselineMaximal neck pain (VAS)Preoperative5733–726629–774 months224–55173–500.40.0002<0.0011 year403–63363–710.60.060.0052 years415–74246–660.60.0480.002Maximal arm pain (VAS)Preoperative4518–776027–734 months62–2570–340.9<0.0001<0.0011 year142–62283–720.40.0060.0462 years240–72284–630.80.0340.008Maximal pelvic pain (VAS)Preoperative00–2120–54 months00–420–120.20.50.91 year00–420–120.20.30.62 years00–1500–80.80.50.8Neck Disability IndexPreoperative3625–474430–511 year288–44279–490.80.0050.0012 years3012–47258–440.80.0010.001Clinically relevant improvement inNeck pain (at least 10 for VAS)39%63%0.07Arm pain (at least 10 for VAS)50%58%0.6NDI (at least 10)53%60%0.6Patients' global assessment at 2 years (%)Much better4142Better3833Unchanged1013Worse812Much worse30Better/much better79750.5Bold values are P values < 0.05 No differences in clinical outcomes were seen between patients who appeared radiologically fused or non-fused (P = 0.6). There was a tendency toward poorer clinical outcome for smokers compared with non-smokers, estimated by the patients' global assessments (P = 0.07).
BODY.RESULTS.PELVIC PAIN:
There was no difference in pelvic/hip pain (at the donor site) preoperatively and at 4, 12 or 24 months, between patients fused with and without autograft. Further analysis of the pain drawings showed eight patients with markings at the right iliac crest (four SR, four TM). However, the majority had marked this as related to the pain caused by lumbago/sciatica or generalized pain. Only one patient, who had been fused with TM, marked localized pain in this area. In summary, no remaining donor site pain was marked in the pain drawings, and none was seen in the VAS scoring.
BODY.RESULTS.COMPLICATIONS.FURTHER SURGERY:
Three patients were reoperated: two of them because of non-fusion and one due to graft dislocation. All had been primarily fused with autografts (SR). They were all clearly fused 2 years postoperatively. One patient fused with TM was operated on at the adjacent segment after 19 months. The only patient with remaining symptoms due to complications 2 years after surgery had a sensory deficit below the donor site at the iliac crest (SR). Further complications in the SR group included three patients with wound infections at the iliac crest, and one of them with an infected hematoma. One patient had pneumonia and one had a lower urinary tract infection (cystitis). All infections were cured after antibiotic treatment. One patient developed a fissure in the autograft during the primary surgery. A plate was added to the fixation directly, and the fusion healed without further complications. Among the patients fused with TM, two had transient hoarseness, and one of them also had swallowing disturbances. One patient was treated with antibiotics for a urinary tract infection. In summary, nine patients in the SR group and three patients in the TM group had complications, but only one patient (SR) had symptoms 2 years after surgery.
BODY.RESULTS.RADIOLOGICAL OUTCOME:
The fusion rate shown by the radiological analysis is presented in Table 4. All patients in group III (clearly non-fused) showed at least 4° of mobility (the limit for the group set by the classification was 3.0°). There was no statistically significant difference in the fusion rate between smokers (92%) and non-smokers (74%) (P = 0.2). Smokers operated on with TM showed an 87% fusion rate. Kappa analysis showed 0.63 and 0.66 for the intra-observer correlation, and 0.58 for inter-observer correlation.Table 4Radiological fusionFusion groupTMSRNo.PercentageNo.PercentageI (clearly fused)18463589IIA (probably fused)92313IIB (probably non-fused)51300III (clearly non-fused)71838Fusion rate (I + IIA)6992
BODY.RESULTS.MAGNETIC RESONANCE IMAGING:
MRI, of 20 TM cases was successfully used to assess decompression of the neural structures, but was not helpful in determining fusion/non-fusion attributable to metal artifacts in the area immediately surrounding the implants.
BODY.DISCUSSION:
Autograft is referred to as the gold standard for spinal fusion [43] due to its unique combination of osteogenicity, osteoconductivity and osteoinductivity. We had hypothesized that similarly high fusion rates for TM as for autograft could be obtained, but without the risk of complications from the donor site associated with autograft. The fusion rate of carbon fiber cages used in the treatment for the degenerative cervical spine was 62% in our previous study of the Brantigan cage [45], which led us to discontinue the use of the device. TM cages were chosen for the present study because of the unique microstructure of the material and because of the published affinity of osteocytes to tantalum metal [22]. These factors were hypothesized to promote bone ingrowth and enhance fusion. The fusion rate for TM in the present study was higher than for the carbon fiber cages, but lower than that of the SR group. In a recent study, Fernández-Fairen et al. [14] compared TM used as a stand-alone cage with autograft used with plate. The fusion rate was 89% for TM and 85% for autograft with plate. No statistically significant difference in radiological fusion or in clinical outcome was found between the groups. Criteria for fusion were that "segments were deemed fused when there was evidence of bony bridging around the implant and/or <2° of variation of Cobb's angle on F/E radiographs or <2 mm of variation in the interspinous distance, in the absence of periimplant radiolucency". We had similar criteria for fusion, besides measuring the movement between the spinal processes. The criterion accepting <2 mm movement is probably wider compared to the criterion of <2° variation of the angle [8, 13]. With less stringent criteria for fusion (more motion allowed), the apparent fusion rates increase, as demonstrated by Fasset [13]. Smokers were excluded from the study by Fernández-Fairen et al. [14], while we had 40% smokers in the group fused with TM. We found no statistically significant difference between smokers and non-smokers in our study, but it is still possible that smoking had some adverse influence on the fusion healing. On the other hand, the fusion rate in our control group with autograft was 92%, while it was 85% after autograft with plate in the study by Fernandez et al., though 25% of our patients operated on with autograft were smokers. Our patients were not randomized to fusion group until the major part of the surgical procedure including the decompression was completed, which reduced the risk for surgeons' bias, while the preoperative randomization in the study by Fernandez et al. might have had an adverse influence on the control group. Wigfield et al. [49] have presented a study with tantalum interbody implant, where inclusion of patients was halted after radiographs 6 weeks postoperatively had shown inferior end-plate lucency, raising concerns about delayed fusion or non-fusion. However, fusion was subsequently noted in all 15 patients available for follow-up at 12 months of the 17 patients operated on with tantalum implant, but the study numbers were too small for statistical analysis. Fusion was defined as less than 4° angulation between flexion and extension radiographs and absence of radiolucency extending over more than 50% of the implant/end plate interface. Baskin and Travnelis [3] compared TM with autograft in an RCT that was terminated due to concerns over delayed fusion after 39 patients had been enrolled. Of the 28 patients operated on with TM, 6 out of 16 patients (37%) who were examined with radiographs at 24 months were fused. A low fusion rate with TM was found by Zoëga and Lind [51] as well. Two years after ACDF with TM cage, none of the 13 patients had fusion. Those authors used radiostereometric analysis (RSA) for the follow-up, which is a very sensitive method for detecting motion [17, 29, 53]. Clinical outcome data showed no statistical difference between non-fused and fused patients in the present study. Earlier studies have shown divergent results concerning correlation between fusion and clinical outcome, with some pointing to the importance of the fusion for the clinical outcome [9, 27, 48] and others denying such a connection [12, 25, 31]. Addressing the fusion rate alone (without considering the clinical outcome), the use of TM as stand-alone device does not seem sufficient. The fusion rate with TM might be enhanced with an anterior plate, considering published results of TM with and without pedicle screws used in the porcine lumbar spine [54], as well as fusion rates for TM with allograft and anterior plate [35]. The use of an anterior plate in these studies suggests that initial stability may be an important factor in achieving fusion [36]. Because of the results obtained, we now use TM together with an anterior plate. Because our earlier study of the Brantigan cage showed closer correlation between radiological fusion and clinical outcome 5 years postoperatively as compared with 2 years [27], the present study will be extended. It has been advocated that a fusion cage can avoid subsidence better than an autograft, due to collapse of the latter. Some studies support this [45], while others show similar subsidence with the cage as well [15, 23]. This question was not addressed in the present study, where the radiological evaluation focused on whether the operated segment was fused or not. The accuracy of measurements of motion on digitized radiograph images was considerably higher in the present study (2.4°, 95% CI) than in our previous experience measuring on conventional radiographic films. The accuracy of measurements on conventional radiograph images has previously been estimated at 5° [17] and the cutoff for mobility has been set at 4° for studies of cervical implants. The described method using digitized radiograph images has reduced the difference in accuracy compared to the much more complex and expensive radiostereometry (RSA). We estimated the accuracy for RSA in the cervical spine at about 1° in a previous study [25, 29], which is less accurate than in the lumbar spine, mainly owing to the small size of the cervical vertebral bodies. With distortion-compensated roentgen analysis (DCRA), another technique for computerized analysis of conventional radiographs, Leivseth found an error of 2.4° [20]. MRI of 20 TM cases was successfully used to assess decompression of the neural structures, but was not helpful in determining fusion/non-fusion. The artifacts from the implants could be limited to the structures immediately surrounding the implants. Hence, the spinal canal and the foraminae could be visualized, and the decompression assessed, but interpretation of the interface between implant and vertebral body was disturbed. This is in contrast to the experience in the lumbar spine [personal communication, D Robertson] and is mainly due to the smaller size of the cervical vertebrae. The primary advantage of using an implant rather than autograft bone for ACDF is that it avoids complications associated with the donor site. Several previous studies have reported persistent pain in 15–40% of the patients 2 years after surgery [6, 12, 25, 33, 37, 50], though some studies show that this is less frequent [1, 34]. In our earlier study of the Brantigan cage, we found more donor site pain immediately postoperatively when using a conventional graft from the iliac crest as compared with using a percutaneous technique [45]. In the present study, no residual donor site pain was found at 4 months or later after surgery. In the early postoperative period, donor site pain is frequent, and it was experienced by our patients, but no assessment of the pain was made in this period. The administration of ropivacaine hydrochloride (NaropR) subcutaneously for the first few postoperative days resulted in pain reduction in our patients. This postoperative pain reduction might have reduced the tendency to persisting pain as well, due to less central sensitization caused by the postoperative pain [18, 19]. Sing et al. [38] have shown the good effects of continuous local anesthetic infusion on the acute graft-related pain as well as a remaining effect 4 years postoperatively [39]. In both groups in our study, 10% of the patients marked the pelvic/hip region on the pain drawing at 2 years, which illustrates the importance of having a control group for all follow-ups. Patients operated on with autografts were at risk of rare complications, such as neuralgia, although this did not occur in the moderate number of studied patients. Despite absence of chronic pain, we still found donor site morbidity; one patient had lasting sensory disturbance and three were treated for local infections. The clinical outcome in the present study showed 28 and 22 mm reduction in pain rating (VAS) in the neck and arm, respectively, 12 points improvement in NDI, and improvement for 77% of the patients in the global assessment. This is in accordance with earlier studies [9, 24, 25, 30, 32, 35, 45, 52].
BODY.CONCLUSIONS:
This study of uninstrumented single-level ACDF showed a lower fusion rate with Trabecular Metal than with the Smith–Robinson technique with autograft after single-level anterior cervical fusion without plating. There were no differences in the clinical outcomes between the groups, and there were no differences in outcomes between patients who appeared radiologically fused or non-fused. The operating time was shorter with Trabecular Metal implants. No remaining donor site pain at the iliac crest was seen at 4 months or later. | 2,899,760 | {
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TITLE: A heart failure self-management program for patients of all literacy levels: A randomized, controlled trial [ISRCTN11535170]
ABSTRACT.BACKGROUND:
Self-management programs for patients with heart failure can reduce hospitalizations and mortality. However, no programs have analyzed their usefulness for patients with low literacy. We compared the efficacy of a heart failure self-management program designed for patients with low literacy versus usual care.
ABSTRACT.METHODS:
We performed a 12-month randomized controlled trial. From November 2001 to April 2003, we enrolled participants aged 30–80, who had heart failure and took furosemide. Intervention patients received education on self-care emphasizing daily weight measurement, diuretic dose self-adjustment, and symptom recognition and response. Picture-based educational materials, a digital scale, and scheduled telephone follow-up were provided to reinforce adherence. Control patients received a generic heart failure brochure and usual care. Primary outcomes were combined hospitalization or death, and heart failure-related quality of life.
ABSTRACT.RESULTS:
123 patients (64 control, 59 intervention) participated; 41% had inadequate literacy. Patients in the intervention group had a lower rate of hospitalization or death (crude incidence rate ratio (IRR) = 0.69; CI 0.4, 1.2; adjusted IRR = 0.53; CI 0.32, 0.89). This difference was larger for patients with low literacy (IRR = 0.39; CI 0.16, 0.91) than for higher literacy (IRR = 0.56; CI 0.3, 1.04), but the interaction was not statistically significant. At 12 months, more patients in the intervention group reported monitoring weights daily (79% vs. 29%, p < 0.0001). After adjusting for baseline demographic and treatment differences, we found no difference in heart failure-related quality of life at 12 months (difference = -2; CI -5, +9).
ABSTRACT.CONCLUSION:
A primary care-based heart failure self-management program designed for patients with low literacy reduces the risk of hospitalizations or death.
BODY.BACKGROUND:
Limited literacy skills are common among adults in the United States [1]. Low literacy is associated with increased risk of hospitalization and worse control of chronic diseases [1-4]. Heart failure is a common chronic illness requiring multiple medications and significant self-care. Heart failure is the leading cause of hospitalization in the Medicare population [5]. The complexity of care for heart failure puts people with low literacy at considerable risk for adverse outcomes including hospitalization, worse quality of life, and mortality. Heart failure disease-management interventions appear effective in reducing rehospitalizations and improving quality of life [6]. Most randomized clinical trials of heart failure disease management completed over the last 10 years have enrolled patients during, or shortly after, hospitalization and reported the outcome of readmission [6]. Although the designs of these programs vary, several have tested education and support to enhance patient self-management as the main component of the intervention [7-10]. The content of self-management education usually includes teaching to understand medications, reduce salt intake, monitor daily weights, and recognize symptoms. Most programs include structured follow-up either by home visit, phone, or mail. Only a few, uncontrolled studies specifically ask patients to self-adjust their diuretics [11,12]. Heart failure self-management programs may be particularly effective for vulnerable populations, such as those with poor literacy [13,14]. However, to our knowledge, no previous studies have explicitly examined the role of self-management programs in a low literacy population. A recently published study and accompanying editorial suggested that such self-management support may be most effective among vulnerable populations [13,14]. Low literacy may represent a vulnerability for which we should design our programs. Disease management for patients with low literacy may require refined approaches to foster self-management skills. We developed a heart failure self-management program for use by patients with a variety of literacy levels [15]. We performed a randomized controlled trial comparing our self-management program to usual care among outpatients to test if the program could reduce hospitalizations and improve heart failure-related quality of life.
BODY.METHODS.STUDY DESIGN:
We conducted a randomized controlled trial in the University of North Carolina (UNC) General Internal Medicine Practice, which serves a wide socioeconomic range of patients. The practice, staffed by over 20 attending faculty and 70 medical residents, cares for over 500 patients with heart failure.
BODY.METHODS.STUDY PARTICIPANTS:
To be eligible, patients had to have a clinical diagnosis of heart failure confirmed by their primary provider through a direct interview, and one of the following: 1) chest x-ray findings consistent with heart failure, 2) ejection fraction <40% by any method, or 3) a history of peripheral edema. They also had to have New York Heart Association class II-IV symptoms within the last 3 months. Patients were excluded if they had moderate to severe dementia (based on the treating physician's clinical judgment), terminal illness with life expectancy less than 6 months, severe hearing impairment, blindness, current substance abuse, a serum creatinine >4 mg/dl or on dialysis, a requirement of supplemental oxygen at home, lacked a telephone, or were scheduled to undergo cardiac surgery or awaiting heart transplant. We did not exclude patients on the basis of literacy skill because we felt patients of all literacy levels would benefit from this intervention. Patients who read well often prefer information presented in an easy-to-read format [16]. We accepted referrals from the cardiology clinic if patients met eligibility criteria. This study was approved by the Institutional Review Board of the UNC School of Medicine, and all participants gave informed consent prior to enrollment. For participants who could not adequately read the informed consent document, the research assistant read and explained it to them. They were asked to sign a short form indicating that the informed consent document was reviewed and they agreed to participate. When the short form was used, a witness was asked to attest to the adequacy of the consent process.
BODY.METHODS.PROCEDURES:
Participants were recruited between November 2001 and April 2003 from the General Internal Medicine and Cardiology Practices at UNC Hospitals. A trained research assistant screened all patients age 30–80 for use of furosemide. If the patient was on furosemide, their physician was queried about the presence of heart failure. If the patient met eligibility criteria and consented to participate, baseline data were collected. We then randomized patients by concealed allocation based on a random number generator to receive the intervention or usual care. All patients were followed for one year. All data were collected in the General Internal Medicine Practice.
BODY.METHODS.INTERVENTION:
The intervention was delivered in the General Internal Medicine Practice. The educational materials and disease management intervention were previously described in detail, and the intervention is summarized here [15]. The intervention began with a 1-hour educational session with a clinical pharmacist or health educator during a regular clinic visit. Patients were given an educational booklet designed for low literacy patients (written below the 6th grade level and extensively pre-tested in focus groups and a pilot study [15]) and a digital scale. The educator and patient reviewed the booklet together, including management scenarios. As part of the educational session, patients were taught to identify signs of heart failure exacerbation, perform daily weight assessment, and adjust their diuretic dose. Because this intervention was aimed at patients with low literacy, the health educator used pedagogic strategies felt to improve comprehension for patients with low literacy [17]. For example, the educator had the patient teach back the information [18], engaged the patient in filling out the notebook, and used brainstorming to help the patient incorporate self-management into their lives. The educator, patient, and primary care physician collaborated to establish the patient's "good weight" (i.e., where the patient's heart failure was stable) and baseline diuretic dose. The educator then filled in the management plan in the patient's notebook to help the patient better manage weight fluctuations and self-adjust the diuretic dose based on weight (Figure 1). The general plan involved doubling the dosage if weight went up and halving it if weight went down. The program coordinator then made scheduled follow-up phone calls (days 3, 7, 14, 21, 28, 56) and monthly during months 3–6. The follow-up phone calls, each lasting 5–15 minutes, were designed to reinforce the educational session and provide motivation for the patients. Again, the program coordinator had the patient describe their self-management practices and offered feedback to improve them. Patients experiencing worsening symptoms were scheduled acute visits with their physician. We did not provide specialized nursing assessment, care or medication advice beyond diuretic dosing. If the patient's doctor determined that the good weight had changed, the program coordinator would revise the care plan with the patient. Patients enrolled in the control group received a general heart failure education pamphlet written at approximately the 7th grade level, and continued with usual care from their primary physician. The only contacts between the research team and the control patients were at enrollment and data collection.
BODY.METHODS.MEASURES:
We assessed outcomes at 6 and 12 months through in-person interviews and review of the medical record. To be sensitive to low literacy, all interviews were conducted verbally by a trained research assistant. If patients were unable to come to clinic for the interview, it was conducted by phone. The research assistant was not blinded to the patient's study group. Primary outcomes were death or all-cause readmission and heart failure-related quality of life at the end of 12 months. Data on hospitalization dates were obtained from the patient and confirmed by medical chart review. All admissions, regardless of hospital or cause, were counted. For exploratory analyses, we classified reason for admission as cardiac or non-cardiac. Cardiac admissions included those primarily for heart failure (e.g., shortness of breath and edema relieved by diuresis) and other cardiac causes such as chest pain, arrhythmias, or syncope. Cause of admission was determined by chart review by one of the authors (D.D.) who was blinded to treatment allocation. Heart failure-related quality of life was assessed using a modified version of the Minnesota Living with Heart Failure Questionnaire (MLHF). The MLHF is a 21 question instrument with a 6-point Likert scale response option and scores ranging from 0 to 105 [19]. In pilot testing of the MLHF, we found that low literacy patients had trouble answering questions with the standard 6-point Likert scale [15], so we changed the response scale to 4 points, using a visual display with stars to represent increasing severity. The 4-point Likert scale was scored as 0, 1, 3, and 5 to approximate standard scores on the MLHF. Secondary measures included heart failure self-efficacy, knowledge, and behaviors. Self-efficacy was measured with an 8 item scale developed for the behaviors needed in this trial as suggested by self-efficacy scale developers [20]. Respondents used a 4-point Likert scale yielding a total score from 0–24. We assessed heart failure knowledge using a knowledge test previously developed for this population [15], Heart failure self-management behavior was assessed by asking patients how often they weighed themselves. We used patient self-report and the medical chart to measure age, gender, race, insurance status, income, years of education, medication use, years with heart failure, and the presence of co-morbidities. We measured literacy using the Short Test of Functional Health Literacy in Adults (S-TOFHLA) [21], a well-validated scale that correlates well with other measures of reading ability [22]. Patients who scored in the inadequate literacy range on the S-TOFHLA were considered to have "low literacy." The cut-point for inadequate literacy is roughly analogous to the 4th grade reading level.
BODY.METHODS.SAMPLE SIZE:
Sample size was based on pilot study results showing a 9-point improvement in MLHF scores over 3-months with the intervention [15]. Detecting a 9-point difference between intervention and control group with 80% power and alpha set at 0.05 required 70 patients per group. We aimed to enroll 150 patients to account for possible attrition, but stopped at 127 because funding ended. We did not power this study to detect differences in hospitalization, but studies with even smaller numbers of patients have shown a difference for that outcome [7].
BODY.METHODS.STATISTICAL METHODS:
Patients who did not return any phone calls and did not return for follow-up assessment did not have outcome data for analysis. Patients who withdrew from the study were censored at the time of withdrawal; any data collected prior to withdrawal were included in the analysis. Baseline differences between groups were assessed using t-tests for continuous outcomes and chi-squared tests for categorical outcomes. For MLHF, heart failure self-efficacy and heart failure knowledge, we used two-sample t-tests. Non-parametric tests were also performed for all comparisons, but results did not differ from the parametric tests. Because of the small sample size and the unequal distribution of baseline characteristics, we adjusted for baseline differences using linear regression. Analyses of self-reported outcomes, such as MLHF, excluded patients who died or withdrew from the study before 6 or 12 month data was collected. For hospitalization or death, we used negative binomial regression and censored patients at the time of death or withdrawal from the study. Based on the likelihood ratio test, negative binomial regression was a better fit for the data than a Poisson regression. Additionally, the Vuong test confirmed that a zero-inflated model was inappropriate [23]. Because of uneven distribution of baseline characteristics, we performed analysis of covariance with negative binomial regression to control for baseline differences [24]. We identified the following variables that could contribute to hospitalization or death based on previous studies: age, race, gender, literacy level, hypertension, diabetes, creatinine, MLHF score, use of β-blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), use of digoxin, and presence of systolic dysfunction [7,25]. Variables were not included in the model if the relationship between the variable and the study group or outcome had a p value greater than 0.3. We started with a model including the following items to arrive at the best point estimate: age, gender, hypertension, creatinine, MLHF, use of β-blockers, and use of ACE inhibitors or ARBs. We then eliminated variables from the model if p > 0.30, and if the point estimate remained within 10% of the initial estimate. We prespecified a subgroup analysis in patients with low literacy to analyze if the intervention had a similar effect. The same analysis described above was repeated for the subgroups of patients with low literacy and those with higher literacy. The initial multivariate model for the subgroups analysis included: age, gender, hypertension, MLHF, use of β-blockers, and use of ACE inhibitors or ARBs.
BODY.METHODS.ROLE OF THE FUNDING SOURCE:
The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
BODY.RESULTS.PATIENTS:
We screened 919 patients on furosemide between November 2001 and April 2003. 127 met eligibility criteria and agreed to participate (Figure 2). Of those not enrolled, 407 did not have heart failure according to their physician, 367 did not meet eligibility criteria and 27 declined to participate. Of those randomized to the control group, 1 never returned after the first visit, 1 withdrew during the study and 4 died during the study. Follow-up was completed for all of the remaining participants (98%) (Figure 3). Of those randomized to the intervention group, 3 never returned after the first visit, 4 withdrew during the study and 3 died during the study. Follow-up was completed for all of the remaining participants (93%). At baseline, most characteristics were similar between the two groups (Table 1). However, the control group had more participants with hypertension, fewer with diabetes, and fewer men. Of heart failure related characteristics, the control group had more participants with systolic dysfunction, and taking β-blockers. The intervention group had more participants taking ACE inhibitors or ARBs, and digoxin. Regardless of these differences, none were statistically significant. The control group did have statistically significantly higher baseline MLHF scores representing worse symptoms at baseline.
BODY.RESULTS.HOSPITALIZATION OR DEATH:
There were 68 hospitalizations (65) or deaths (3) in the intervention group and 111 (107 hospitalizations, 4 deaths) in the control group. The crude all-cause hospital admission or death incidence rate ratio (IRR) was 0.69 (95% CI 0.40, 1.19). After adjusting for age, gender, use of ACE inhibitor or ARB, use of a β-blocker, presence of hypertension, and baseline MLHF, intervention patients were less likely to have the outcome (IRR = 0.53; 95% CI 0.32, 0.89). 61% of patients in the control group had at least one hospitalization or died, and 42% of patients in the intervention group had at least 1 hospitalization or died (p = 0.13).
BODY.RESULTS.CARDIAC HOSPITALIZATION:
39% of patients in the control group and 34% of patients in the intervention group had at least one hospitalization for cardiac causes (p = 0.55). The unadjusted IRR was 0.79 (95% CI 0.42, 1.5). After adjusting for baseline differences, the IRR was 0.85 (95% CI 0.44, 1.7).
BODY.RESULTS.HEART FAILURE-RELATED QUALITY OF LIFE:
In unadjusted analysis, the control group, on average, improved 5 points on the MLHF and the intervention group improved by 1 point. The difference was not statistically significant (3.5 points, 95% CI 11, -4, p = 0.36). After adjusting for baseline differences between the groups, the difference was 2 points (95% CI 9, -5, p = 0.59) suggesting no effect on heart failure-related quality of life.
BODY.RESULTS.OTHER OUTCOMES.KNOWLEDGE:
Heart failure related knowledge improved more in the intervention group than in the control group. Mean difference in score improvement was 12 percentage points (95% CI 6, 18; p < 0.001).
BODY.RESULTS.OTHER OUTCOMES.SELF-EFFICACY:
Heart failure self-efficacy improved more in the intervention group than in the control group. Mean difference in score improvement was 2 points (95% CI 0.7, 3.1; p = 0.0026).
BODY.RESULTS.OTHER OUTCOMES.SELF-CARE BEHAVIOR:
Significantly more patients in the intervention group than in the control group reported daily weight measurement at 12 months (79% vs. 29%, p < 0.001).
BODY.RESULTS.SUBGROUP ANALYSES ACCORDING TO LITERACY:
Twenty-four patients in each group had inadequate literacy based on the S-TOFHLA (Table 2). Among these patients, there was no difference in quality of life score in unadjusted and adjusted analyses (difference = -1.6; 95% CI -15, 12); p = 0.81). For the combined outcome of hospitalization or death, the unadjusted IRR was 0.77 (95% CI 0.30, 1.94). After adjusting for baseline differences, the IRR was 0.39 (95% CI 0.16, 0.91). Seventy-five patients had marginal or adequate literacy based on the S-TOFHLA. We found no difference in quality of life score in unadjusted and adjusted analyses (difference = -4.2; 95% CI -14, 6; p = 0.40). Among patients in the higher literacy group, the unadjusted IRR for hospitalization or death was 0.65 (95% CI 0.33, 1.3). After adjusting for baseline differences, the IRR was 0.56 (95% CI 0.30, 1.04). We did not find a statistically significant effect modification between literacy and the intervention.
BODY.DISCUSSION:
A heart failure self-management program designed for patients with low literacy reduced the rate of the combined endpoint of hospitalization or death. The prespecified subgroup analyses suggest that patients with low literacy benefited as much from the intervention as the patients with higher literacy. The success of our intervention reflects the goals of our program. We designed an easy-to-read and use educational booklet and self-management plan, and focused on overcoming barriers to learning self-management [15]. Our intervention was founded on teaching self-management. We focused on helping patients understand signs and symptoms of worsening heart failure and perform self-adjustment of diuretics based on weight fluctuation. Many care providers would not attempt to teach patients, particularly those with low literacy, how to self-adjust their diuretic medication. We found that, with careful teaching, many patients incorporated this strategy into their daily routine successfully, as demonstrated by improved self-care behaviors. Teaching self-adjustment of diuretics, rather than the conventional teaching to call the care provider if weight fluctuates, empowers patients to take more control over their illness. Self-adjustment of diuretic dose is a prominent aspect of the self-management training we provided to the intervention patients. Other programs to improve patient self-management have not been explicit in teaching patients to self-adjust their diuretic dose based on weight fluctuation. Although our outcomes are comparable to others', using this approach puts more control into the hands of the patient. Furthermore, our intervention appears effective among patients with low literacy skills, a group often overlooked for empowering interventions. Our study adds to the growing literature on disease management programs for patients with heart failure [6], particularly those that focus on self-management training [7-10]. Studies focusing on self-management training have demonstrated comparable improvements in hospitalization rates to more comprehensive programs that aim to improve the quality of pharmaceutical prescribing, provide home visits, and take place in specialized cardiology clinics [6]. Such comprehensive programs have also been shown to reduce mortality, but self-management programs have not [6]. We did not detect any difference in heart failure related quality of life which was the outcome we powered our study to detect. Other self-management studies that have found improved quality of life have enrolled patients during a heart failure hospitalization [8,9]; however, we enrolled patients in the outpatient setting while they were clinically stable. Improving quality of life for stable outpatients may be more difficult for this type of intervention. We have previously reported that patients with diabetes and low literacy benefited more from a disease management intervention than those with higher literacy skills [26]. A similar result in two different chronic diseases substantiates the claim that appropriately designed disease management programs may have greater effect for low literacy or vulnerable populations, who are most at risk for adverse outcomes with usual care. This finding is particularly important in light of the recent study by DeBusk and colleagues that did not find a reduction in hospitalization with a well-designed comprehensive intervention [13]. The authors and an accompanying editorial [14] suggested that the failure to detect improvement may have occurred because the patients studied were less at-risk than in other studies. They called for more research to determine better ways of targeting disease management. We believe that low literacy is an important marker for vulnerability to adverse outcomes, and that disease management programs targeted to patients with low literacy may be an effective way of focusing resources on those most able to benefit. If patients with low literacy are to be preferentially recruited for such programs, innovative outreach and screening efforts will likely be required, as patients with low literacy may face particular barriers to accessing such care. This study should be interpreted in light of its limitations. Research assistants were not blind to group assignment during the assessment of self-reported outcomes. As such, patients in the intervention may have been more likely to inflate their responses in an effort to please the interviewer. This effect would tend to inflate patient responses to the subjective assessments of heart failure-related quality of life, self-efficacy, and self-care behaviors. The MLHF questionnaire was modified from its original form to make it easier for patients with low literacy to respond. This change in the scale may have changed its ability to detect important changes in heart failure related quality of life. Because the groups' mean scores were almost identical, we do not feel this limitation changed our results. In a similar vein, most questionnaires are not validated in low literacy populations, raising questions as to their ability to perform to the same standards. Our sample size was small, which did not allow for an even distribution of baseline variables among the groups. We controlled for baseline differences between groups in our analysis. While it is controversial whether or not to control for baseline differences in randomized controlled trials, some analysts have argued that doing so improves the power without introducing bias [24]. A larger, multi-site study would offer better control of confounders, better generalizability, and more power to determine differences in effect according to literacy. We did not collect data on the resources needed to implement this type of intervention in usual settings, and such a study and cost-effectiveness analysis would be helpful for most interventions of this type. We used health educators, not nurses or physicians, to deliver the intervention. By using less highly trained individuals to deliver the intervention, we enabled nurses and physicians to perform clinical tasks more commensurate with their training. Other studies that have performed global cost estimates have found that the savings from reductions in hospitalizations exceed the cost of the intervention [6].
BODY.CONCLUSION:
In conclusion, our heart failure self-management program, designed for patients of all literacy levels, appears to reduce rates of hospitalization and death. Patients with low literacy, and other vulnerable patients, may stand to benefit most from these programs. Further research into the design, implementation, and dissemination of disease management programs for low literacy patients will be crucial for meeting the health care needs of the growing population of patients with chronic illness.
BODY.COMPETING INTERESTS:
Drs. DeWalt and Pignone have received honoraria and grants from Pfizer, Inc., Dr. Rothman has received grants from Pfizer, Inc., and Dr. Sueta is in their speakers bureau.
BODY.AUTHORS' CONTRIBUTIONS:
DD conceived of the study, participated in its design and coordination, performed statistical analyses, interpretation of the data, and drafted the manuscript. RM, MB conceived of the study and participated in its coordination. MK, KC coordinated the study, and collected the data, RR, CS participated in study design and interpretation of the data. MP conceived of the study, participated in its design and coordination, and interpretation of the data. All authors reviewed the manuscript for important intellectual content and gave final approval.
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TITLE: A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated
ABSTRACT.BACKGROUND:
Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.
ABSTRACT.METHODS AND RESULTS:
In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.
ABSTRACT.CONCLUSION:
Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.
ABSTRACT.TRIAL REGISTRATION:
Current controlled trials ISRCTN36463274
BODY.BACKGROUND:
In response to widespread resistance of Plasmodium falciparum parasites to the commonly used drugs chloroquine (CQ) and sulphadoxine-pyrimethamine (SP), many African countries recently adopted artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. The combination artemether-lumefantrine (AL) proved to be highly effective and well-tolerated in several studies in Africa [1-5]. Disadvantages of this drug combination are the twice-daily dosing and the fact that it should be administered with a fat-rich meal [6-8] or at least a cup of soya milk [2]. In Uganda, in an area of intense malaria transmission, recurrence of parasitaemia within 28 days occurred in 29% of AL treated patients, in 8.9% adjusted by genotyping, indicating recrudescence [4]. Another ACT, dihydroartemisinin combined with piperaquine (DP), which was originally developed in China, is increasingly used in Southeast Asia [9,10]. Piperaquine is an orally active bisquinoline with a half-life elimination time of 2.5–4 weeks [9]. The drug is structurally related to CQ, but still active against highly CQ-resistant P. falciparum strains [1,11]. This relatively inexpensive drug was well tolerated and highly effective in Southeast Asia [1,7,11-13] as was the case in two studies in Africa [4,14]. Consequently, both AL and DP are considered to be amongst the most promising artimisinin-based drugs [4,14]. Artemisinin-based drugs also act on gametocytes and thus on transmission, at least in low transmission areas [15-17]. In high transmission areas of Africa, not much information is yet available on gametocytaemia after ACT treatments and on possible influence on transmission. In a comparative study of AL and DP in Uganda, the appearance of gametocytes in those who did not have gametocytes at the start of treatment was lower from day 15 to day 42 of follow up in those treated with DP than in those treated with AL [4]. A limitation of this study was the fact that gametocytaemia was assessed by microscopic examination only. It has recently been shown that sub-microscopic gametocyte densities may significantly contribute to the transmission of malaria [18]. Adequate assessment of gametocytaemia is important. Quantitative nucleic sequence based amplification technique (QT-NASBA) has been shown to be much more sensitive for the detection of gametocytes than microscopy [3,18-20]. In this study, the post-treatment prevalence of gametocytes in children in Mbita, western Kenya was assessed, after treatment with AL and DP. Microscopy and QT-NASBA for the quantification of gametocytaemia were compared and effectiveness of both drugs regarding clinical symptoms, clearance of parasites and tolerability was assessed.
BODY.MATERIALS AND METHODS.STUDY SITE AND POPULATION:
The study was conducted in Mbita, western Kenya, at the shores of Lake Victoria during the high malaria transmission season of April-July 2007. Mbita, is an area with highly variable transmission that depends on the local environmental circumstances that can support mosquito conditions. The EIR is calculated to be 6 infectious bites per person per month [21]. Children (6 months-12 years of age) visiting the out-patient clinic of the health centre and diagnosed with uncomplicated malaria were included after informed consent from parents or guardians. Inclusion criteria were: uncomplicated P. falciparum malaria with initial parasitaemia between 1,000 and < 200,000 parasites/μl blood, axillary temperature ≥ 37.5°C (measured with a digital thermometer) or a history of fever. Children with severe malaria, mixed infection or other underlying illness were excluded from the study. In total 146 children were recruited for the present study. Ethical approval for this study was obtained from appropriate local authorities and The Kenya Medical Research Institute (KEMRI, Nairobi, Kenya) Ethical Steering Committee (SSC protocol No 948). The trial was registered as an International Standard Randomized Controlled Trial at current controlled trials (ISRCTN36463274).
BODY.MATERIALS AND METHODS.STUDY DESIGN AND TREATMENT:
Following diagnosis (at day 0), the patients were randomly allocated to one of the two treatment groups following a computer generated randomization list. One group was assigned DP (Sigma-Tau, Italy) once per day for three days. One tablet of the study drug contained 20 mg of dihydroartemisinin and 160 mg of piperaquine (paediatric formulation). Treatment was according to body weight as follows: children between 4–7 kg received half a tablet per dose, those between 7–13 kg 1 tablet, 13–24 kg 2 tablets per dose and children between 24–35 kg 4 tablets. The other group was assigned to AL (Novartis Pharma, Switzerland). Each tablet contained 20 mg artemether and 120 mg lumefantrine. Patients received treatment according to bodyweight; i.e. children between 5–14 kg received one tablet per dose, those between 15–24 kg two tablets and those between 25–34 kg received three tablets per dose. Doses were given twice daily. All treatments were given with a glass of milk under direct supervision at the clinic or, for the 2nd dose of AL, at home.
BODY.MATERIALS AND METHODS.OUTCOMES: EFFICACY:
Efficacy was assessed using the WHO in vivo test with a follow-up period of 28 days [22]. At enrollment (day 0) a full clinical examination was performed; information was recorded on a case record form. At initial diagnosis (day 0) and during follow-up (day 1, 2, 3, 7, 14, and 28), finger prick blood samples were collected for microscopy, measurement of haemoglobin level and molecular analysis. Haemoglobin was measured with Hemocue 201+ analyser and cuvettes (HemoCue diagnostics B.V. Waarle, The Netherlands). Response to treatment was measured and defined according to WHO guidelines [22]. Patients showing complications or treatment failure were treated with appropriate supportive therapy. Children developing danger signs or severe malaria on day 1 or 2 of the study were withdrawn from the study, referred to the hospital, and given alternative treatment. Adverse events were recorded on the case record forms. An AE was defined as an unfavourable and unintended symptom, sign or disease. A serious adverse event (SAE) was defined as a symptom or sign that is temporally associated with the drugs administered to the patient that is life threatening or results in hospitalization, permanent and significant disability or death. SAE's were immediately reported to the ethical committee of KEMRI and the drug safety department of Sigma-Tau, Italy.
BODY.MATERIALS AND METHODS.OUTCOMES: PARASITE CLEARANCE AND GAMETOCYTE DYNAMICS:
Parasite clearance and gametocyte dynamics were assessed microscopically as well as with quantitative nucleic acid sequence based amplification assay, QT-NASBA.
BODY.MATERIALS AND METHODS.MICROSCOPY:
Giemsa-stained thick and thin smears were prepared according to WHO guidelines. Two independent experienced microscopists, who were blinded to the treatment and clinical status of the patient, examined the smears for the presence of parasites and identified the observed parasite species. Parasitaemia was determined by counting the number of parasites against 200 leukocytes for the asexual stages (assuming that there are 8,000 leukocytes/μl blood). The presence of gametocytes was examined against 500 leukocytes.
BODY.MATERIALS AND METHODS.QT-NASBA:
Finger prick blood (50 ul) for NASBA analysis was collected on Whatman 903 filter paper (Whatman international Ltd. Maidston, United Kingdom) and air-dried at room temperature. Nucleic acid extraction was performed as previously described by Boom et al [23]. Real-time 18S rRNA QT-NASBA was applied to study asexual parasite clearance below microscopical threshold [20]. In order to quantify the number of parasites in blood, a 10 fold serial dilution of 106 to 10 in vitro cultured parasites/ml was used as reference and processed and analysed with NASBA. Furthermore, to assess prevalence of gametocytes below the detection limit of microscopy, QT-NASBA targeting Pfs25 mRNA as described by Schneider et al [20] was used on blot spots collected during follow-up.
BODY.MATERIALS AND METHODS.GENOTYPING:
In order to discriminate between re-infection (RI) and recrudescence (RE), merozoite surface protein 1 and 2 (msp1 and msp2) and glutamate rich protein (GLURP) genotyping was performed as described by Snounou [24] on blood spots obtained at primary (day 0) and secondary infection (time point of re-occurrence). Blood spots were collected on Whatman 903 filter paper (Whatman international Ltd. Maidston, United Kingdom) and air-dried at room temperature for PCR analysis. DNA was isolated as described by Boom et al [23]. Molecular analysis was performed at Royal Tropical Institute, Amsterdam and was done blinded from the treatment that was given to the patients.
BODY.MATERIALS AND METHODS.SAMPLE SIZE AND STATISTICAL ANALYSIS:
The aim of the study was to compare gametocytaemia after AL and DP and to compare assessment of gametocytaemia by microscopical examination versus QT-NASBA All data were entered in excel and analysed with SPSS for windows (version 12.0). Parasite densities were analysed after natural log-transformation. Where appropriate, proportions were compared with the χ2-test and means were compared with the one-way ANOVA or Student t-test. A simplified trapezoid area under the curve (AUC) analysis using gametocyte data from days 0, 3, 7, 14 and 28, as a surrogate for the infectiousness of the participants in the different treatment groups, was performed.
BODY.RESULTS.PATIENT RECRUITMENT:
In total 1882 cases suspected of uncomplicated malaria were screened for eligibility into the study during an 8-week recruitment period in April and May 2007. 1,736 children were excluded because they did not meet the inclusion criteria (Figure 1). 146 patients fulfilling the inclusion criteria entered the study; 73 were randomly allocated to the DP arm and 73 to the AL arm. Both study groups were comparable at baseline for their demographical and clinical characteristics and parasite densities (Table 1). On completion of follow up (day 28) data of 134 patients (92%) were available for analysis. Table 1 Baseline characteristics of patients included in the study at the time of enrollment in the study Characteristic DHA-PQP (n = 73) ALN (n = 73) Sex ratio male:female 33:40 40:33 Age (in months), median (IQR) 60 (44) 52 (44) Body weight, mean kg (range) 17.62 (6–37) 17.32 (6–42) Temperature, mean °C ± SD 38.1 ± 0.99 37.8 ± 0.73 Haemoglobin mmol/L ± SD 6.33 ± 1.29 6.28 ± 1.27 Parasites/μl geometric mean (range) as determined by microscopy 12145 (1000–72640) 13379 (1080–72000) Figure 1Schematic representation and flowchart of the study. Twelve patients did not reach the study endpoint. Seven patients were lost during follow up, one was unable to take oral medication, one developed severe anaemia, one did not receive the proper drugs, one withdrew from the study and one patient died.
BODY.RESULTS.TREATMENT OUTCOME:
There were no early treatment failures during the first three days of follow up. Only one patient in the AL arm had a recurrent parasitaemia (43,880 parasites/μl) at day 28 of follow up. Genotyping analysis revealed that this patient had a reinfection with P. falciparum. All other 133 patients who completed follow-up had an adequate clinical and parasitological response. After one day of treatment, over 90% of the patients had no microscopically detectable asexual parasites. In the AL group no parasites could be detected with microscopy in any of the patients at day two. One patient was still microscopically positive at day two in the DP group with 40 parasites/μl, but this patient was also microscopically negative at day 3. The parasite reduction ratios at 48 hours reproduction cycle (parasite count on admission/parasite count at 48 hours) was 8.96 * 105 at 48 hours for the AL treatment and 2.06 * 104 at 48 hours for the DP treatment. NASBA was also applied to monitor parasite dynamics below sub-microscopical level. Humidity in some of the filter papers degraded the RNA in the blood spots of some of the samples. This led to several extraction failures. In order to have a clear picture of parasite dynamics only those series with a full range of follow-up samples, i.e. 56 DP and 54 AL treated patients, were analysed. Both treatment arms showed a steep decline in parasitaemia from the day of enrollment (day 0) to day 1; 62% reduction after DP treatment and 89% reduction in the AL arm. At day 2, the level of parasitaemia was reduced to 1.2% in the AL group and 2.75% in the DP group.
BODY.RESULTS.HB CONVALESCENCE, FEVER CLEARANCE AND ADVERSE EVENTS:
At baseline Hb levels in both treatment groups were comparable (Table 1). At day 28 all groups had a significant increase of Hb however no significant difference between the treatments on the Hb convalescence was found. Final mean Hb levels were 7.15 mmol/l ± 1.07 for the DP treatment group and 6.79 mmol/l ± 1.24 for the AL group. A possible influence of anaemia on gametocyte carriage at enrollment was not observed in the present study (p > 0.05). Fever clearance was defined as the time from receiving the assigned treatment to the time a normal body temperature was recorded (≤ 37.5°C), in study cases who presented with fever. Fever clearance was rapid in both study groups. On day 1, 10 cases (13.7%) in the DP group presented with fever and six cases (8.2%) were observed in the AL group. In the DP group fever was observed on day 2 in four cases (5.5%) and three cases (4.1%) on day 3. In the AL group cases with fever also presented on day 2 (12 study subjects, 16.4%) and on day 3 (two individuals, 2.7%). Fever was not observed during follow-up after day 7, with the exception of the child that presented with a P. falciparum reinfection on day 28 in the AL group and the child that developed broncho-pneumonia (case presented below). Furthermore the presence of fever at recruitment was no predictor for gametocyte carriage (p > 0.05) Most adverse events were mild, self limiting and consistent with symptoms of malaria. There was no significant difference between the two study groups (Table 2). One patient died. The child (63 months) had been ill for two weeks prior to presentation at the clinic. Plasmodium falciparum infection with parasitaemia of 20,120 parasites/μl was diagnosed. There was a fever (38.6°C), but there were no other complaints and no signs of severe anaemia (Hb: 6.4 mmol/L). On day 3, there were no signs of illness. On day 7, the child presented with fever (38.6°C), cough and complaints of anorexia. There was no history of significant illness or allergies. After examination (microscopy was negative for malaria parasites), broncho-pneumonia was diagnosed and the child was treated with oral phenoxymethylpenicillin for five days and Paracetamol syrup. On day 14, the child did not attend the follow-up visit, the parents reported that the child died a day before in a local health post. The event was assessed as unrelated to the study drug. Autopsy was not performed. Table 2 Summary of adverse events recorded during the study Adverse event DHA-PQP ALN P- value Headache 43 (58.9%) 37 (50.7%) 0.318 Abdominal pain 25 (32.4%) 26 (35.6%) 0.862 Weakness 19 (26.0%) 30 (41.1%) 0.035 Anorexia 8 (10.9%) 10 (13.7%) 0.439 Diarrhea 9 (12.3%) 7 (9.6%) 0.785 Cough 16 (21.9%) 17 (23.3%) 0.843 Vomiting 11 (15.1%) 9 (12.3%) 0.806 Pruritis 4 (5.5%) 3 (4.1%) 0.698
BODY.RESULTS.GAMETOCYTE DYNAMICS:
The presence of gametocytes in clinical samples was assessed by microscopy and NASBA and is presented in Table 3. At the start of the study, three patients in the DP arm (4.5%) and six patients in the AL arm (9.0%) carried microscopically detectable gametocytes. Microscopical follow-up of the presence of gametocytes during the whole study period revealed that in total 39 samples (distributed over 13 patients) in the DP arm and 18 samples (distributed over nine patients) in the AL arm carried gametocytes (not significantly different). It was observed that the microscopical detection of gametocytes in blood slides during the study was subjected to fluctuations (for example a case positive on day 0, negative on day 1 and subsequently again positive at day 3), which is probably due to the fact that gametocytes circulate at low levels. However, on day 7, three patients in the DP group and 1 in the AL group showed gametocyte positive slides for the first time. On day 28, in none of the cases gametocytes were observed by microscopy. There was no difference between children older than 60 months and younger as regards carriage of gametocytes and density. Table 3 Occurrence of gametocytes as detected by microscopy or NASBA in the different study groups at the start of the study and during subsequent follow-up. Gametocyte positive samples Day 0 Day 1 Day 2 Day 3 Day 7 Day 14 Day 28 DP group microscopy (n = 67) Total number of positive cases 3 7 7 10 7 5 0 Number of new cases observed 5 2 0 3 0 0 DP group Nasba (n = 56) Total number of positive cases 22 34 a 33 a 17 8 Number of new cases observed 13 8 5 0 AL group microscopy (n = 67) Total number of positive cases 6 3 3 3 2 1 0 Number of new cases observed 1 1 0 1 0 0 AL group Nasba (n = 54) Total number of positive cases 21 20 11 12 5 Number of new cases observed 6 4 6 0 a Number of gametocyte carriers detected with NASBA is significantly higher in the DP treated group compared to the AL treated group. NASBA analysis on 56 DP treated subjects and 54 AL treated subjects detected strikingly more gametocyte carriers at the start of the study compared to microscopy; i.e. 22 study subjects in the DP arm (39.3%) and 21 in the AL (38.9%) were harbouring gametocytes before. The pfs25 NASBA revealed that 34 cases (60.7%) were gametocyte positive in the DP group on day 3, of which 13 cases were newly identified compared to day 0. In contrast, a significantly lower number of patients (20; 37%) were gametocyte positive in the AL treatment group on day 3, of which six new cases. This trend was also observed on day 7: the DP arm had 33 (58.9%) gametocyte positive samples, whereas the AL treated group had a significantly lower number of gametocyte positive samples (11, 20.3%). However on day 14 (AL: 12 positive [22.2%], six new; DP: 17 [30.4%], five new) and day 28 (AL: 5 positive [9.3%], no new cases; DP: 8 [14.3%], no new cases) of follow-up no significant difference in gametocyte carriage was observed between both treatment groups. The AUC (day 0–28) of the two treatment groups was calculated to be 20.0 infectious persons/day for the DP treatment arm and 10.5 infectious persons/day for the AL treatment arm. Stratifying the data for age under and above 60 months showed no difference in either of the groups.
BODY.DISCUSSION:
Several studies have analysed the efficacy and tolerability of AL and DP and all show very good results [1,4,6,7,12,14,25]. In the present study, the two drugs showed to be similar with respect to effectiveness and tolerability compared to other studies. However, most of these studies have a follow up of 42 days which makes a direct comparison of the results difficult. No adverse events other than those related to malaria itself were observed in the current study, which is in line with other reports. In the present study, all children experienced haemoglobin convalescence without difference between the two treatment arms, in contrast to the study of Kamya et al, who found a greater increase in the DP treated patients [4]. The difference in follow-up time and the numbers of patients included in both studies may be responsible for this difference. Further studies with comparable study length should be done to give an answer to these discrepancies. The effects on gametocytaemia and possibly malaria transmission deserve further study. Whereas asexual parasites were cleared in three days after the initiation of the two treatment schedules, gametocytaemia appeared different when assessed by microscopy as well as with NASBA. Gametocytes were present in low numbers throughout follow-up in both study groups. Artemisinin derivatives have in general a negative effect on gametocyte development and survival and thus influence malaria transmission, at least in low transmission areas [15-17]. In this study, the actual infectiousness of the remaining gametocyte populations in both treatment arms was not assessed; the presence of gametocytes does not necessarily mean that they actually contribute to transmission. Several studies have shown that gametocytes persist in a large population of previously infected and treated children [5,19,26,27]. A large proportion of these carriers has a parasite load below microscopical detection limit, a load that can be detected with molecular assays like NASBA. Patients with submicroscopic parasite densities may still be infectious to mosquitoes and may contribute to transmission [14,19], as confirmed with membrane feeding experiments [18,28]. Studies that include reduction of transmission as a component of efficacy of drugs, thus need to incorporate highly sensitive molecular assays to reliably assess gametocyte densities. The present study showed a limited effect of DP on gametocyte development in comparison with AL when a sensitive tool like NASBA is used for gametocyte detection, which could limit the usefulness of DP to areas with low transmission but this finding should be further investigated in larger studies in different study sites with different transmission intensities. It is not clear if plasma concentrations of dihydroartemisinin in the blood could play a role. Dihyrodartemisinin is the major and the active metabolite of artemether. So far, no studies have been performed that compare the plasma levels of dihydroartemisinin when given as such or after administration of artemether and subsequent metabolisation. This should be further investigated together with effect on gametocytogenesis, which should incorporate a sensitive detection tool for gametocytes such as NASBA. The effect that drugs can have on gametocyte clearance as measured with NASBA could have some implications for the introduction drugs and especially the introduction of new drugs. This study showed that with sensitive detection tools a difference in parasite clearance can be observed but these results should be confirmed in larger studies and in other study areas with different malaria transmission intensities. Transmission intensity varies significantly in the different African countries and within a country high and low transmission areas can often be identified. Malaria endemic countries generally have a national malaria drug policy for the whole country. Although this is logical from a practical and logistical point of view, it may not be the best approach for effective malaria control. It could, therefore, be more effective if a country develops specific drug policies to suit regional instead of national requirements.
BODY.COMPETING INTERESTS:
The authors declare not to have a conflict of interest. The organizations that provided financial support had no influence in the design, the actual field and laboratory work, analysis and writing.
BODY.AUTHORS' CONTRIBUTIONS:
PM was involved in the conception of the study, carried out the molecular analysis of the samples, carried out the statistical analysis of the results and drafted the manuscript. PS coordinated the study in the field and was responsible for the clinical examination and treatment of the participants. SvA collected clinical data and blood samples in the field and did the clinical data analysis. SO coordinated the study in the field an arranged the logistics in the field. IV carried out the NASBA assays and the subsequent analysis. HS was involved in the design of the study and contributed to the drafting of the manuscript. PK as involved in the design of the study, critically read and improved the manuscript. All authors read and approved the final manuscript | 2,600,646 | {
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TITLE: Randomized Clinical Trial of Laparoscopic Versus Open Repair of the Perforated Peptic Ulcer: The LAMA Trial
ABSTRACT.BACKGROUND:
Laparoscopic surgery has become popular during the last decade, mainly because it is associated with fewer postoperative complications than the conventional open approach. It remains unclear, however, if this benefit is observed after laparoscopic correction of perforated peptic ulcer (PPU). The goal of the present study was to evaluate whether laparoscopic closure of a PPU is as safe as conventional open correction.
ABSTRACT.METHODS:
The study was based on a randomized controlled trial in which nine medical centers from the Netherlands participated. A total of 109 patients with symptoms of PPU and evidence of air under the diaphragm were scheduled to receive a PPU repair. After exclusion of 8 patients during the operation, outcomes were analyzed for laparotomy (n = 49) and for the laparoscopic procedure (n = 52).
ABSTRACT.RESULTS:
Operating time in the laparoscopy group was significantly longer than in the open group (75 min versus 50 min). Differences regarding postoperative dosage of opiates and the visual analog scale (VAS) for pain scoring system were in favor of the laparoscopic procedure. The VAS score on postoperative days 1, 3, and 7 was significant lower (P < 0.05) in the laparoscopic group. Complications were equally distributed. Hospital stay was also comparable: 6.5 days in the laparoscopic group versus 8.0 days in the open group (P = 0.235).
ABSTRACT.CONCLUSIONS:
Laparoscopic repair of PPU is a safe procedure compared with open repair. The results considering postoperative pain favor the laparoscopic procedure.
BODY.INTRODUCTION:
The incidence of perforated peptic ulcer (PPU) has declined over the past several years because of the introduction of anti-ulcer medication and Helicobacter eradication therapy [1, 2]. Nevertheless the incidence and mortality of PPU is 5–10%. The mortality will increase up to 50% if the perforation exists for more than 24 h [3, 4]. There are several options for treatment of PPU, but the preferred treatment is surgery by upper abdominal laparotomy [5, 6]. Mouret et al. published the first results of laparoscopic repair in 1990 [7]. He concluded that it was a good method that probably reduced postoperative wound problems and adhesions. After the success of laparoscopic cholecystectomy and other laparoscopic procedures, it was thought that patients would have less pain and a shorter hospital stay after laparoscopic correction of PPU [8, 9]. Various studies have shown that laparoscopic suturing of the perforation is feasible, but there is still no proof of real benefits of laparoscopic correction [3, 6, 10–12]. Therefore we performed a multicenter randomized trial comparing open correction of PPU with laparoscopic repair.
BODY.METHODS.PARTICIPANTS:
Patients with symptoms of the clinical diagnosis of PPU were included in nine medical centers in the Netherlands participating in the LAMA (LAparoscopische MAagperforatie) trial between March 1999 and July 2005. Eligible patients were informed of the two surgical approaches and were invited to participate in the study. Exclusion criteria were the inability to read the Dutch language patient information booklet, inability to complete informed consent, prior upper abdominal surgery, and current pregnancy. The ethics committees of all participating institutions approved the trial.
BODY.METHODS.RANDOMIZATION:
Surgeons contacted the study coordinator after the patients had provided informed consent and randomization took place by opening a sealed envelope. The envelope randomization was based on a computer-generated list provided by the trial statistician.
BODY.METHODS.SURGICAL PROCEDURE:
All patients received intravenous antibiotics prior to operation and were allocated for Helicobacter pylori eradication therapy according to established guidelines [13]. The open surgical procedure was performed through an upper abdominal midline incision. Closure of PPU was to be achieved by sutures alone or in combination with an omental patch. After repair of the defect cultures were drawn from the peritoneal fluid, after which the peritoneal cavity was lavaged. During lavage it was permissible to insufflate the stomach to test for leakage of the closed defect. No method was specified for closing the abdomen. Laparoscopic repair was performed with the patient and the team set up in the "French" position. Trocars were placed at the umbilicus (video scope) and on the left and right midclavicular line above the level of the umbilicus (instruments). If necessary a fourth trocar was placed in the subxiphoid space for lavage or retraction of the liver. Surgeons were free to use either 0° or 30° video scopes for the procedure. The rest of the procedure was identical to that described above for open repair. No method was specified for closing the trocar incisions.
BODY.METHODS.POSTOPERATIVE FOLLOW-UP:
Postoperative pain was scored by means of a visual analog scale (VAS) for pain on days 1, 3, 7, and 28 ranging from 0 (no pain) to 10 (severe pain). In addition, the days during which opiates were used by the patients were registered. All complications, minor and major, were monitored. The treating surgeons determined time of discharge on the basis of physical well-being, tolerance of a normal diet, and ability to use the stairs. For this reason, this was an unblinded trial. Postoperative hospital stay without correction for time spent in hospital as a result of non-medical reasons (inadequate care at home) was calculated. Patients were invited to attend the outpatient clinic at 4 weeks, 6 months, and one year postoperatively. They were asked to complete forms related to pain and use of analgesics.
BODY.METHODS.STATISTICAL ANALYSIS:
Data analysis was carried out according to the intention-to-treat principle as established in the trial protocol. Data were collected in a database, and statistical analyses were performed with the Statistical Package for Social Sciences for Windows (SPSS 15.0, SPSS Inc., Chicago, IL). A researcher blinded to the nature of the procedures performed all data analyses. The primary outcome of the trial was duration of hospital stay. The power analysis was performed on basis of a reduction in hospital stay by 1.5 days (10–8.5 days from admission) in favor of the laparoscopically treated group using a β of 0.80 and an α of 0.05. This resulted in a trial size of 50 patients per group. The Pearson chi-squared test was used to compare categorical variables, and the Mann-Whitney U-test was used to compare continuous variables as we could not assume normal distribution because of the relatively small numbers. In Tables 1–6 medians and interquartile ranges (IQR) are reported. All data were analyzed according to the intention-to-treat principle; i.e., patients remained in their assigned group even if during the procedure the surgeon judged the patient not to be suitable for the technique assigned or if conversion was required. Null hypotheses were tested two-sided and a P value of 0.05 or less was considered statistical significant.Table 1Baseline parametersLaparoscopic repairOpen repairP valuen = 52 n = 49 Male:female ratio1.3:11.9:1Median age (years) + IQR 66 (25.8)59 (29.5)0.185Median BMI (kg/m2) + IQR23 (4)22 (5)0.118Median duration of symptoms (h) + IQR11 (17)11 (19)0.948Median blood pressure systolic (mmHg) + IQR125 (38.5)130 (36.5)0.457Median blood pressure diastolic (mmHg) + IQR75 (25.5)75 (24.5)0.596Median heart rate (beats/min) + IQR 88 (34.0)92 (21)0.403Median body temperature (°C) + IQR 36.9 (0.92)36.8 (1.5)0.658Mannheim Peritonitis Index + IQR19.5 (8.25)16 (14)0.386Median white cell count (×109/l) + IQR 12.1 (8.9)12.1 (7.75)0.467Median ASA score + IQR 1.0 (1.0)1.5 (1.0)0.902IQR interquartile range, difference between 25th percentile and 75th percentile; BMI body mass indexASA American Society of Anesthesiologists Association score
BODY.RESULTS.PATIENTS:
A total of 109 patients were included in the trial based on a high suspicion of PPU (Fig. 1). Eight patients were excluded during operation because no gastric perforation was detected or a defect in other parts of the digestive tract was uncovered. Data for these patients were not collected and the patients were excluded from further analysis. The remaining 101 patients made up the study population; their baseline parameters are given in Table 1. Fifty-two patients were randomized for laparoscopic repair and 49 for open repair of the perforation. Forty patients were female. The mean age of the patients was 61 years. The BMI (body mass index) was equally distributed between the groups, with a median of 22.5. Patients in both groups had been suffering from symptoms for a mean duration of 11 h, and those in the laparoscopy group presented with a median Mannheim Peritonitis index [14] of 19.5, whereas those in the open group had a median Mannheim Peritonitis index of 16.Fig. 1Patient flow chart Thirty patients reported the use of non-steroidal anti-inflammatory drugs (NSAIDs; 17 laparoscopic versus 13 open), and 10 patients used proton pump inhibitors (6 laparoscopic versus 4 open). Patient history revealed gastric ulcer disease in 19 patients.
BODY.RESULTS.INTRAOPERATIVE FINDINGS:
The discovered ulcer perforations were found to have a mean diameter of 10 mm, which did not differ between groups (Table 2). Location of the perforated ulcers was distributed equally between groups. Defects were located in the prepyloric region (n = 41), the postpyloric region (n = 34), and at the pylorus (n = 20). The median volume of lavage fluid used was 1,000 ml (range: 100–5,000 ml). The surgeon decided the amount of lavage used. There was no consensus on how much was necessary. Median blood loss did not differ between groups. Skin-to-skin time differed by 25 min, favoring open repair of PPU (Table 2).Table 2Intraoperative findingsLaparoscopic repairOpen repairP valuen = 52n = 49Median size of perforation (mm) + IQR10.0 (7.0)7.0 (6.0)0.379Number of patients with defect Pyloric812 Postpyloric2014 Prepyloric1922 Median volume of lavage (ml) + IQR1,000 (1,500)1,000 (1,425)1.000 Median bloodloss (ml) + IQR10.0 (40.0)10.0 (50.0)0.423 Skin to skin time (min) + IQR75 (47.2)50 (25.5)0.000
BODY.RESULTS.INTRAOPERATIVE COMPLICATIONS:
Conversion to open surgery was required in four patients (8%). Reasons for conversion included the inability to visualize the ulcer defect because of bleeding (n = 1/52; 2%), inability to reach the defect because of perforation in the vicinity of the gastroduodenal ligament and because of a dorsal gastric ulcer (n = 2/52; 4%), and inability to find the perforation (n = 1/52; 2%).
BODY.RESULTS.POSTOPERATIVE COMPLICATIONS:
Complications were statistically equally distributed between the two groups (Table 3). There were 12 complications in 9 patients in the laparoscopic group and 24 complications in 15 patients in the open group. Mortality was 4% in the laparoscopic group and 8% in the open group. In the laparoscopic group death was caused by sepsis due to leakage at the repair site. In the open group 3 patients died because of pulmonary problems (ARDS, pneumonia), and 1 patient died after complications following a cerebrovascular accident (CVA) combined with respiratory insufficiency.Table 3Postoperative complicationsLaparoscopic repairOpen repairP valuen = 52n = 49Pneumonia21Respiratory insufficiency13ARDS1Cardiac problems22Sepsis31Leakage at repair site2Abscess3Ileus1Fascial dehiscence1Wound infection3Urinary tract infection2Incisional hernia1Cerebrovascular accident1Death24Total complications12240.061Total of patients with complications ≥19 (18%)15 (36%)
BODY.RESULTS.DISCHARGE:
Time to discharge was similar for the two groups, with a median difference of 1.5 days (Table 4). Nasogastric decompression could be stopped after 2–3 days in both groups (Table 4).Table 4Duration of hospital stay, nasogastric decompressionLaparoscopic repairOpen repairP valuen = 52n = 49Median hospital stay (days) + IQR6.5 (9.3)8.0 (7.3)0.235Median duration of nasogastric decompression (days) + IQR2.0 (3.0)3.0 (1.3)0.334
BODY.RESULTS.PAIN:
Visual analog pain scores were in favor of laparoscopic repair (Table 5; p < 0.005). Although the median duration of opiate use in the two groups was 1.0, the mean duration in the open group was found to be 0.6 days longer than in the laparoscopic group (Table 6).Table 5Postoperative painMedian VAS pain scoreMedian VAS pain scoreP valueLaparoscopic repairOpen repairDay 1 + IQR3.8 (3.0)5.15 (2.5)0.001Day 3 + IQR2.1 (2.5)3.0 (2.4)0.035Day 7 + IQR1.0 (2.0)1.85 (2.8)0.036Day 28 + IQR0.3 (0.7)0.0 (1.7)0.748Table 6Postoperative opiate usageOpiate requirementOpiate requirementP valueLaparoscopic repairOpen repairMedian duration (days) + IQR1.0 (1.25)1.0 (1.0)0.007Mean duration (days) ± SD1.0 ± 0.91.6 ± 0.90.007
BODY.RESULTS.VAS APPEARANCE OF SCAR:
The VAS score for appearance of the scar left by the respective procedures (subjectively recorded in the same way as pain) differed by 2.3 points, favoring the laparoscopic procedure (7.7 vs. 5.4; P = 0.033)
BODY.DISCUSSION:
The need for surgery for PPU has declined enormously in Europe and America with reported rates ranging from 50% to 80%, thanks to effective gastric acid-reducing medication [15]. For this reason, as well as because many surgeons prefer upper laparotomy, it took more time than expected to include 100 patients in our study. Reasons given by surgeons who prefer open repair were that it is a more familiar procedure and it can be completed faster than laparoscopy. It was also noted that patients often undergo operation at night, when the surgeon on call was not always laparoscopically trained. Other randomized trials have already shown the feasibility of laparoscopic repair of PPU [3, 4, 6, 10]. Only a few had more than 100 patients, and some emphasized results from subgroups of patients [8, 11, 12]. We did not subdivide our patients and included patients with risk factors for developing sepsis or conversion [10]. In eight of the original 109 patients (7%) it became evident during the operation that the patient had a diagnosis different from PPU. In the patients who were randomized for laparoscopy this discovery revealed the benefit of laparoscopy as a diagnostic procedure indicating either an upper or lower abdominoplasty or continuation of the laparoscopy [16]. Conversion rate in the laparoscopy group was 8% (4/52). This is much lower than that reported in literature, where conversion rates as high as 60% were found [3, 4, 6]. This maybe partially explained by the fact that only trained and experienced laparoscopic surgeons (those performing at least 50 laparoscopic procedures a year) participated in this trial, confirming the belief that this procedure should only be done by experienced surgeons [3–5]. Operating time was significantly longer in the laparoscopy group (75 min versus 50 min), which is comparable to reports in the literature [3, 10]. A possible explanation for the longer operative time is that laparoscopic suturing is more demanding [9, 17], especially if the edges of the perforation are infiltrated and friable. Sutures easily tear out and it is more difficult to take large bites and to tie knots properly. Use of a single-stitch method described by Siu et al. [18], fibrin glue, or a patch might solve this problem [12, 19]. Another reason for the increase in operating time is the irrigation procedure. Irrigating through a 5-mm or even a 10-mm trocar is time consuming, and suction of fluid decreases the volume of gas and reduces the pneumoperitoneum. There is no evidence that irrigation lowers the risk of sepsis [20], so it might only be necessary if there are food remnants in the abdomen; perhaps there is no need for it at all. One of the suspected risks of laparoscopic surgery is that of inducing sepsis by increasing bacterial translocation while establishing a pneumoperitoneum [6]. This danger could not be confirmed in our trial. Furthermore data suggest that there is a decrease in septic abdominal complications when laparosopic surgery is used [8]. Evidence already exists that laparoscopic correction of PPU causes less postoperative pain [6, 12, 17, 18]. The meta-analysis published by Lau [6] showed that eight out of ten studies showed a significant reduction in dosage of analgesics required in the laparoscopic group. Also, the three studies that had included VAS pain scores showed consistently lower pain scores, as was observed in our study as well. Whether this will lead to a better quality of life for patients, especially during the first weeks after surgery still needs to be analyzed. Although patients in our series who underwent laparoscopy had less postoperative pain, there was no difference in the length of hospital stay in our two groups. In fact, hospital stay overall in our patients was very long. This was most likely caused by the fact that many patients, especially the elderly, could not be discharged because of organizational reasons. Of the 101 patients, 41% were 70 years or older (24 in the laparoscopic group versus 17 in the open group). It appears that the age of PPU patients is increasing, and this will eventually represent a significant problem in the future [2, 3]. One benefit of the laparoscopic procedure not often mentioned in literature [6] is cosmetic outcome. Nowadays patients are aware of this benefit, and sometimes this is the reason why they demand laparoscopic surgery. In conclusion, the results of the LAMA trial confirm the results of other trials that laparoscopic correction of PPU is safe, feasible for the experienced laparoscopic surgeon, and causes less postoperative pain. Operating time was longer in the laparoscopic group and there was no difference in length of hospital stay or incidence of postoperative complications. | 2,691,927 | {
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TITLE: A prospective, contralateral comparison of photorefractive keratectomy (PRK) versus thin-flap LASIK: assessment of visual function
ABSTRACT.PURPOSE::
To compare differences in visual acuity, contrast sensitivity, complications, and higher-order ocular aberrations (HOAs) in eyes with stable myopia undergoing either photo-refractive keratectomy (PRK) or thin-flap laser in situ keratomileusis (LASIK) (intended flap thickness of 90 μm) using the VISX Star S4 CustomVue excimer laser and the IntraLase FS60 femtosecond laser at 1, 3, and 6 months postoperatively.
ABSTRACT.METHODS::
In this prospective, masked, and randomized pilot study, refractive surgery was performed contralaterally on 52 eyes: 26 with PRK and 26 with thin-flap LASIK. Primary outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), contrast sensitivity, and complications.
ABSTRACT.RESULTS::
At 6 months, mean values for UDVA (logMAR) were −0.043 ± 0.668 and −0.061 ± 0.099 in the PRK and thin-flap LASIK groups, respectively (n = 25, P = 0.466). UDVA of 20/20 or better was achieved in 96% of eyes undergoing PRK and 92% of eyes undergoing thin-flap LASIK, whereas 20/15 vision or better was achieved in 73% of eyes undergoing PRK and 72% of eyes undergoing thin-flap LASIK (P > 0.600). Significant differences were not found between treatment groups in contrast sensitivity (P ≥ 0.156) or CDVA (P = 0.800) at postoperative 6 months. Types of complications differed between groups, notably 35% of eyes in the thin-flap LASIK group experiencing complications, including microstriae and 2 flap tears.
ABSTRACT.CONCLUSION::
Under well-controlled surgical conditions, PRK and thin-flap LASIK refractive surgeries achieve similar results in visual acuity, contrast sensitivity, and induction of HOAs, with differences in experienced complications.
BODY.INTRODUCTION:
Refractive surgery is one of the most commonly performed elective procedures and will likely maintain its popularity as ablation techniques become more refined and understanding of corneal wound healing improves. Two of the most common methods of refractive surgery are photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). The rapid improvement in vision and lack of postoperative pain associated with LASIK has made this the preferred option with patients compared with PRK, which has greater postoperative discomfort and prolonged recovery of visual acuity.1 Recently, there has been renewed interest in PRK because of increasing concerns of complications associated with LASIK flap creation, including dry eye, corneal ectasia, and flap tears.2–5 Thin-flap LASIK attempts to gain benefits of both techniques by creating a flap of between 80 and 90 μm.6–8 Use of a thinner flap results in a more biomechanically stable cornea and decreases incidence of ectasia given the thicker residual stroma.3,9 Cutting a thinner LASIK flap is less invasive to the nerves within the corneal stroma, decreasing the severity and duration of dry eye, possibly by preserving corneal sensation and blinking rate.10–14 Flap creation avoids corneal epithelium removal, allowing reduced healing time and less haze and scarring.15 The present contralateral study compares the outcomes of eyes that have undergone PRK or thin-flap LASIK using the VISX STAR S4 excimer laser (VISX Incorporated, Santa Clara, CA), with flaps created with intended thicknesses of 90 μm using the IntraLase FS60 femtosecond laser (Abbott Medical Optics [AMO], Santa Ana, CA).
BODY.METHODS:
Data from myopic eyes were analyzed, with or without astigmatism, in which the dominant eye was randomized (Research Randomizer software – Urbaniak, www.randomizer.org) to PRK or thin-flap LASIK (90 μm flap) and the nondominant eye underwent the alternative treatment. All PRK and thin-flap LASIK treatments were performed using the VISX Star S4 CustomVue laser at the John A. Moran Eye Center, Salt Lake City, Utah, between February 2008 and July 2009. All surgeries were overseen by two surgeons (M.M., M.D.M.). The research protocol was approved by the University of Utah Hospital Institutional Review Board. All patients included in this study met the US Food and Drug Administration guidelines for VISX CustomVue LASIK. Mean age of patient, 13 men and 13 women, was 30.8 years (range: 23–46). Twenty-six patients (52 eyes) with stable myopia (1.5–8.5 diopters [D]) and astigmatism (0.242–3.11 D) were enrolled in the study. Eleven patients excluded from this study had clinically significant lens opacities, previous corneal or intraocular surgery, keratoconus, unstable refraction, autoimmune disease, immunosuppressive therapy, or were pregnant or breastfeeding. Correction was made for distance and patients desiring monovision correction were excluded. Contact lenses were discontinued 2 weeks prior to screening for soft contact lens wearers and 6 weeks prior to screening for rigid gas permeable lens wearers. All patients had a preoperative examination including assessment of uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), tonometry, slitlamp examination of the anterior segment, and dilated fundus examination. Manifest and cycloplegic refractions were repeated on 2 separate visits to ensure reliability and stability. Corneal topography and thickness were measured using the Orbscan II v.3.0 (Bausch and Lomb, Rochester, NY). All eyes received 5 preoperative wavefront analyses with the VISX CustomVue WaveScan aberrometer v.3.62 (Fourier) (AMO), without pharmacologic intervention, under mesopic conditions, with a minimum pupil diameter of 6.0 mm. The contralateral study design was made so that each eye could act as a control for the fellow eye in each patient, allowing for study groups to be well matched. There were no violations in the randomization; all patients were analyzed as originally assigned. The randomization protocol was generated before the trial and known only to the study coordinator. In all patients, the emmetropic correction target was based on manifest refraction and wavefront analysis. All flaps were created with the IntraLase FS60 femtosecond laser at 60 kHz in a raster pattern with bed energy of 1.15 μJ, side-cut energy of 2.00 μJ, and pocket enabled. The flaps were created with an intended thickness of 90 μm, diameter of 8.4 to 9.0 mm, superior hinge angle of 55°, and a side-cut angle of 70°. Intraoperative pachymetry or optical coherence tomography were not performed to evaluate actual flap thicknesses. If the 8.0 mm maximum intended ablation diameter exceeded the flap diameter, the hinge and flap were shielded during ablation. Postoperatively, each eye undergoing thin-flap LASIK received 1 drop of gatifloxacin 0.3% (Zymar; Allergan Inc, Irvine, CA), prednisolone acetate 1% (Pred Forte, Allergan Inc), ketorolac tromethamine 0.4% (Acular LS, Allergan Inc.), and a bandage soft contact lens (Softlens Plano T, Bausch and Lomb, Rochester, NY). The prednisolone acetate was continued hourly during the first preoperative day and 4 times daily for an additional 6 days. The gatifloxacin was continued 4 times daily for 1 week. In eyes undergoing PRK all eyes had their corneas cooled with 15 mL of BSS (2.8–3.9°C) immediately following ablation. This was followed by 1 drop of a gatifloxacin 0.3% (Zymar), prednisolone acetate 1% (Pred Forte), ketorolac tromethamine 0.4% (Acular LS) and a bandage soft contact lens (Softlens Plano T). Ketorolac tromethamine was continued 4 times a day for 3 days and then discontinued. Gatifloxacin and prednisolone acetate were continued 4 times a day for 1 week with a subsequent steroid taper over 2 to 3 months per surgeon preference. Mitomycin C was not administered to any patient in the study at any time. Both bandage soft contact lenses were removed simultaneously once re-epithelialization was complete, typically on postoperative days 3 to 5. Patients were seen 1 day, 1 week, 1 month ± 10 days, 3 months ±14 days, and 6 months ±14 days. At all follow-up examinations, UDVA and CDVA were tested using a standard Snellen eye chart. Visual acuity was recorded in both Snellen notation and logarithm of the minimum angle of resolution (logMAR) format. Contrast sensitivity was measured in controlled mesopic conditions at 3, 6, 12, and 18 cycles per degree (cpd) using the Vectorvision CSV-1000E chart (Vectorvision, Greenville, OH). Higher-order aberrations (HOAs), including coma Z(3,1), trefoil Z(3,3), and spherical aberration Z(4,0), were measured using the CustomVue WaveScan at a mean diameter of 6 mm. Undilated scans of both eyes were taken preoperatively and 1, 3, and 6 months postoperatively. Primary outcome measures were UDVA, CDVA, contrast sensitivity, and complications. HOAs were measured and trended within groups as secondary measures. After the study was completed, the results were compiled and the data unmasked for statistical analysis. Refractive error, visual acuity, and HOAs were treated as continuous variables and analyzed for significance by independent t-tests. In all tests, P values <0.05 were considered statistically significant. Data analysis was done using Microsoft Excel (Microsoft Corp, Redmond, WA).
BODY.RESULTS:
Mean preoperative measurements of UDVA, CDVA, sphere, and cylinder are shown in Table 1. 25 of 26 patients (50 eyes) completed the study at postoperative 6 months. One eye in the thin-flap LASIK group required PRK retreatment following a flap tear and both eyes from this patient were therefore removed from analysis of visual acuity, contrast sensitivity, and HOAs as the retreatment prevented the ability to distinguish results between the 2 surgical methods. The eyes from this patient were still included in the analysis of complications.
BODY.RESULTS.VISUAL ACUITY:
Table 2 shows visual acuity outcomes at 1, 3, and 6 months postoperatively. Statistically significant differences were found between PRK and thin-flap LASIK in UDVA at 1 month postoperatively, with thin-flap LASIK eyes showing more improvement in UDVA. Visual acuities were not statistically different between the groups at 3 or 6 months.
BODY.RESULTS.STABILITY, EFFICACY, AND PREDICTABILITY:
Table 3 shows stability, efficacy, and predictability outcomes postoperatively at 1, 3, and 6 months. CDVA was statistically different between groups at 1 month, with 24% of the PRK group losing a line or more from preoperative values, while 9% of eyes in the thin-flap LASIK group lost only 1 line at 1 month. No eyes in the thin-flap LASIK group lost more than 1 line. Also, 39% of eyes in the thin-flap group gained a line by 1 month compared with only 12% of eyes in the PRK group. At 6 months 64% and 56% of eyes had gained a line or more of CDVA in the PRK and thin-flap LASIK groups, respectively (P = 0.462).
BODY.RESULTS.CONTRAST SENSITIVITY:
Contrast sensitivity measurements at 3, 6, 12, and 18 cycles per degree (cpd) in each group are shown in Figure 1. There were no differences between groups at any cpd at any time in the study (P ≥ 0.156). The thin-flap LASIK group showed no change in contrast sensitivity postoperatively (P > 0.131), while patients in the PRK group had a slight decrease in contrast sensitivity at 1 month seen at 3 and 12 cpd (P = 0.004) and (P = 0.025), respectively. At 6 months contrast sensitivity in the PRK group was still significantly decreased from baseline at 3 cpd (P = 0.013), although it did not reach a statistically significant difference at 3 months (P = 0.101).
BODY.RESULTS.COMPLICATIONS:
Types of complications differed between the 2 groups. In the PRK group, 2 cases of epithelial defects occurred by 1 week, but had completely resolved by 6 months. Three eyes in the PRK group had mild haze appearing as early as 1 week postoperatively. Haze remained in only 1 eye at 6 months, but was classified as minimal and had no effect on UDVA or CDVA. Nine eyes (35%) in the thin-flap LASIK group experienced complications. In the thin-flap LASIK group, flap debris (1 eye), diffuse lamellar keratitis (DLK, 1 eye), and an epithelial cyst at the edge of 1 flap were observed, with no loss of UDVA or CDVA, and all resolved by 6 months. Microstriae were observed in 6 eyes, one of which was the eye described above with flap debris and the other was the eye with DLK, with no associated loss of UDVA or CDVA, with epithelial proliferation noted as filling the microstria and making them less apparent. Two eyes in the thin-flap LASIK group experienced flap tears intraoperatively – one resulting in mild flap edge scarring by 6 months that had no significant effect on visual function, and the other case affecting vision at 1 month postoperatively which was retreated with PRK at 3 months. As a result of the retreatment with the counter surgical technique, the ability to accurately compare visual acuity, contrast sensitivity, and HOAs between the 2 surgical methods was limited and both eyes from this patient were removed from analysis of these measures, but were still included in the analysis of complications.
BODY.RESULTS.HIGHER-ORDER ABERRATIONS:
At postoperative 1, 3, and 6 months, 24 (96%), 25 (100%), and 24 (96%) eyes, respectively, in each group completed CustomVue WaveScan analysis. Total root-mean square (RMS) HOAs, coma, trefoil, and spherical aberrations are compared in Figure 2. There were no significant differences between groups in any HOAs throughout the study (P ≥ 0.101), with all P values at 6 months ≥0.63. In both groups, total HOAs (P < 0.008), spherical (P < 0.002), and coma (P = 0.008 at 3 months; P = 0.024 at 6 months) aberrations were significantly increased compared with preoperative conditions. Trefoil showed no significant change throughout the study in either group (P = 0.298).
BODY.DISCUSSION/CONCLUSION:
The present study confirms that PRK and thin-flap LASIK are effective surgeries for the correction of low to moderate myopia. Although thin-flap LASIK showed superior visual results in the early postoperative period there was no statistically significant difference in outcomes of UDVA, CDVA, contrast sensitivity, or total RMS HOAs between PRK and thin-flap LASIK by 6 months. In a similar study comparing PRK and thin-flap LASIK, Slade et al also found that UDVA results were better in the thin-flap group early on and equalized by 6 months.16 Our study showed a similar trend, with no significant differences in any of the primary outcomes at 6 months, and with no difference in UDVA at 3 months. Visual regression in our study was similar to outcomes in Slade's study in which 42% of the PRK group lost a line or more of CDVA and 22% of the thin-flap LASIK group lost 1 line at 1 month postoperatively. Despite the use of custom ablation, postoperative increases in total HOAs, sphere, and coma were noted in our study, as also seen by Slade et al, although they noted that the increase in sphere and coma aberrations was significantly higher in the PRK group at 1 and 3 months postoperatively. As found in previous studies, there was no significant change found in trefoil at any time postoperatively.17,18 Our study showed no difference in induction of HOAs between groups at any time. Although increases in HOAs after refractive surgery have been correlated with decreases in contrast sensitivity in other studies, we demonstrate that increases in total RMS, sphere, and coma were seen postoperatively in both groups without a reliable decrease in contrast sensitivity.19,20 Slade's group found that contrast sensitivity was better in the thin-flap group at all postoperative points in the study, which may have been related to their finding of lower induction of sphere and coma aberrations in the thin-flap group compared with the PRK group. The authors recognize that the Slade study had a larger population size (n = 50 per group) and would have increased power to detect significant differences. Our study would have had increased power of analysis with a similar study group size, but results from analysis of HOAs would not likely change as P values for all HOAs at 6 months were ≥0.63. It would be difficult to make any such correlation between contrast sensitivity and HOAs from the results of this study. A loss of CDVA has been associated with the development of corneal haze in other studies, but as mentioned above none of the patients with visual regression developed haze.21–23 Findings in other studies showing that the biomechanics of eyes that have received thin-flap LASIK treatment are indistinguishable from those of PRK have led to suggestions that thin-flap LASIK is the best approach to LASIK.16 Although the present study did not find any statistically significant differences between thin-flap LASIK and PRK in terms of visual quality at 6 months, complications dealing with flap integrity in the thin-flap LASIK group were present which are not complications found in PRK. Although PRK remains a viable option for those unable to undergo LASIK, the use of thinner flaps may eliminate some of the complications seen with traditional LASIK. Larger studies are needed to better compare the complication rates of both methods and to determine how effective thin-flap LASIK will be in achieving the benefits of PRK and LASIK while avoiding the risks associated with each method. While thinner LASIK flaps attempt to preserve the biomechanical stability of the corneal stroma, at the same time, the flap itself becomes less stable, as was noted with the 2 flap tears and other complications occurring in the thin-flap LASIK group in this study. A study by Espandar and Meyer24 showed that most complications in flaps created by IntraLase femtosecond laser occurred at the hinge, which is where the 2 flap tears that occurred in this study. A thinner flap hinge would be biomechanically less stable and would increase the likelihood of intraoperative flap tear occurrence as well. Six of the 9 eyes with complications in the thin-flap LASIK group had microstriae, which are caused by the flattening of a weak corneal flap unable to maintain its curvature over the small area of stroma removed during ablation. The biomechanics of the flap and hinge, however, cannot be evaluated by the design of this study as analysis was done based on intended flap thickness, which has been shown to vary with the IntraLase FS60 femtosecond laser.25 The study could have been strengthened had intraoperative pachymetry or OCT been performed. Creating a flap with increased integrity would help prevent microstriae from forming and would also provide for a stronger hinge that would be less susceptible to flap tear. Possible ways to optimize flap integrity include modification of hinge and side-cut angle creation, as well as improved planarity and microdisruption of flap edges. This will allow improved adhesion of the flap to the underlying stroma. 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TITLE: Effects of high volume saline enemas vs no enema during labour – The N-Ma Randomised Controlled Trial [ISRCTN43153145]
ABSTRACT.BACKGROUND:
Enemas are used during labour in obstetric settings with the belief that they reduce puerperal and neonatal infections, shorten labour duration, and make delivery cleaner for attending personnel. However, a systematic review of the literature found insufficient evidence to support the use of enemas. The objective of this RCT was to address an identified knowledge gap by determining the effect of routine enemas used during the first stage of labour on puerperal and neonatal infection rates.
ABSTRACT.METHODS:
Design: RCT (randomised controlled trial; randomized clinical trial). Outcomes: Clinical diagnosis of maternal or neonatal infections, labour duration, delivery types, episiotomy rates, and prescription of antibiotics Setting: Tertiary care referral hospital at the Javeriana University (Bogotá, Colombia) that attended 3170 births during study period with a caesarean section rate of 26%. Participants: 443 women admitted for delivery to the obstetrics service (February 1997 to February 1998) and followed for a month after delivery. Inclusion criteria were women with: low risk pregnancy and expected to remain in Bogotá during follow up; gestational age ≥ 36 weeks; no pelvic or systemic bacterial infection; intact membranes; cervix dilatation ≤7 cm. Intervention: 1 litre saline enema, versus no enema, allocated following a block random allocation sequence and using sealed opaque envelopes.
ABSTRACT.RESULTS:
Allocation provided balanced groups and 86% of the participants were followed up for one month. The overall infection rate for newborns was 21%, and 18% for women. We found no significant differences in puerperal or neonatal infection rates (Puerperal infection: 41/190 [22%] with enema v 26/182 [14%] without enema; RR 0.66 CI 95%: 0.43 to 1.03; neonatal infection 38/191 [20%] with enema v 40/179 [22%] without enema; RR 1.12, 95% CI 95% 0.76 to 1.66), and median labour time was similar between groups (515 min. with enema v 585 min. without enema; P = 0.24). Enemas didn't significantly change episiorraphy dehiscence rates (21/182 [12%] with enema v 32/190 [17%] without enema; P = 0.30).
ABSTRACT.CONCLUSION:
This RCT found no evidence to support routine use of enemas during labour. Although these results cannot rule out a small clinical effect, it seems unlikely that enemas will improve maternal and neonatal outcomes and provide an overall benefit.
BODY.BACKGROUND:
Enemas are frequently used in obstetric settings because they are thought to reduce the risk of puerperal and neonatal infections, shorten the duration of labour and make delivery cleaner for attending personnel [1,2]. However, the use of enemas is controversial and there is little evidence of their effectiveness. Enemas are upsetting and humiliating for women in labour and increase the workload in labour wards. Enemas cause watery stools and could theoretically increase contamination and infection rates[3,4]. A systematic review of the literature found one trial with 222 women, which found no difference in puerperal or neonatal infections. However, it only followed women while they remained hospitalized; this time may be too short to identify outcomes that could be affected by enemas. The review concluded that there was insufficient evidence to recommend the use of enemas during labour and called for additional RCTs [5]. The main objective of this RCT was to find out if the use of high volume enemas during the first stage of labour modified neonatal and puerperal infectious rates. The null hypothesis stated that proportion of infections was similar for the intervention and control groups. The secondary objectives were to establish if there was an effect on specific neonatal or puerperal infectious rates, and other clinically relevant outcomes such as neonatal infections, maternal pelvic inflammatory disease or suture dehiscence, and antibiotic prescriptions. The protocol for this study was presented and debated at two meetings of the Latin American Clinical Epidemiology Network: Latinclen I in April 1995 in Colombia; and the Latinclen III in September 1997 in Dominican Republic.
BODY.METHODS:
The RCT was conducted at the obstetric service of the Hospital Universitario San Ignacio, a tertiary care referral centre in Bogota, Colombia. Women attending the admission unit of the obstetrics' clinic for delivery were invited to participate. In accordance with the protocol, the examining intern or resident would invite all eligible women to participate in the study. Recruitment rates varied greatly among different interns and residents. Because of the frequent rotation of interns and residents through the admission unit, interns and residents attended standardised monthly training sessions on how to enrol patients on the study. Inclusion criteria included: absence of life threatening events at admission interview (such as placental abruptio, prolapsed cord, or eclampsia); gestational age ≥36 weeks based on the best available estimation such as a reliable last menstrual period date or an appropriate ultrasound; projected permanence in Bogota during the month following delivery; and willingness to participate expressed in a written informed consent. There was no age restriction for participants. However, for women under 18 years of age, an adult witness – most frequently a next of kin, was also asked to participate in the informed consent process. Exclusion criteria included: a clinical diagnosis of any systemic or gynaecological bacterial infection; use of systemic antibiotics during the week prior to admission; rupture of amniotic membranes or uncertainty of their integrity; or a cervical dilatation >7 cm. The trial protocol was approved by the Institutional Review Board of the Medical School of the Javeriana University and by the staff of the Clinical Epidemiology and Biostatistics Unit. Women willing to participate were offered a range of additional services during follow-up. These services were designed to improve outcome detection and adherence to the study. All women received a booklet that addressed questions frequently raised by women during labour and puerperium (30 days following delivery), and informed on early signs for maternal and neonatal infections[6]. The development of the booklet involved semi-structured interviews carried out by a trained nurse who would elicit the issues that worried women during the first day, first week and first month after delivery. The team that designed the booklet included graphic designers and a social communications specialist. The booklet was tested and printed prior to the beginning of the RCT. Participants were offered two programmed health care visits where their concerns could be discussed with a professional nurse. During the visits, the nurse examined the mother and the baby and assessed outcomes. Systematic telephone reminders for these visits were scheduled before the 1st and 4th week after delivery. Women received instructions on how to access a 24-hour paging service which allowed them to contact a health care provider to address any concerns, seek support, inform about problems, or get advice on issues such as emergency medical attention. This allowed retrieving relevant information of visits to other healthcare providers and contacting them to collect data. The local branch of La Leche League International, a volunteer organization delivering support and education on breastfeeding, offered regular free educational sessions for participants. All participants were offered subsidised screening for neonatal hypothyroidism; when this RCT was done, screening for thyroid disease was not mandatory nor covered by health maintenance organisations in Colombia.
BODY.METHODS.ASSIGNMENT AND FOLLOW-UP PROCEDURES:
Randomisation was done in blocks of 2 (20%), 4 (60%) and 6 (20%) using Ralloc® allocation software. Once the participant had completed the informed consent process, an opaque envelope with sequential numbering and instructions was opened. Women randomised to the intervention group received a 1 litre Travad® 2.5% sodium chloride solution enemas applied by a nurse assistant prior to been taken to the labour wards, where participants in both groups would thereafter receive the same care. During the first and third week after delivery, reminders to attend scheduled appointments at the outpatient primary care clinic were delivered by phone and mail. We used a standardised telephone survey to assess if participants had used any other health services or been diagnosed with any particular condition. Newborns were screened for hypothyroidism during the first scheduled visit when the mother agreed to it. Results for the screening tests were scheduled to be delivered at the second visit, but these were also couriered with an explanatory note if the appointment was missed. The screening scheme covered confirmation diagnostic tests, when necessary. The primary outcomes were the diagnosis of infections in newborns or women during the month following delivery. A neonatal outcome was positive if during the first month of life the child was prescribed systemic antibiotics. A neonatal outcome was also positive when the child was diagnosed with any of the following clinical conditions: ocular infection (purulent drainage in the eye after the sixth day of delivery), umbilical infection (foul smell with periumbilical erythema), skin infection (cellulitis or impetigo), lower or upper respiratory tract infection, intestinal infection, meningitis or sepsis. A puerperal outcome was positive when, during the first month after delivery, a health care provider diagnosed the women with any of the following: dehiscence of the episiorraphy suture, purulent effusion from the episiorraphy, urinary tract infection, pelvic inflammatory disease, or vulvovaginitis. The primary outcome of the study was an aggregated maternal and neonatal infection rate: either the mother or the newborn had an infectious outcome (combined infection rate) . A team member visited participating women and newborns in hospital on a daily basis. Throughout the trial, trained research assistants using standardised questionnaires, registered data from telephone calls, hospitalisations, follow-up visits, and any communications with the participants, their families, or their health care providers.
BODY.METHODS.MASKING:
Masking the use of enemas was unfeasible. However, we made efforts to conceal the intervention by not separating documents with information on the allocation from those outcome data collection, by training the team's supporting clinical team (professional nurse, family medicine residents, family medicine staff, and consulting dermatologist) to avoid enquiring in ways that would unmask the allocation. Health care providers in other settings, such as physicians at emergency wards, paediatricians and medics at outpatient clinics were unaware of the allocation and frequently of the specific objectives of the study. Except for the intervention, participants received the same health care, and data retrievers would remain unaware of individual allocations. Interventions remained coded for the analysis and the code was broken once the analysis was completed. Input between data at recruitment and allocation was done weeks before the collection of data on outcomes at follow up.
BODY.METHODS.SAMPLE SIZE DETERMINATION:
We were unable to find reliable data on the incidence of baseline infection rates for puerperal women or newborns so we did a pilot study to have base data that would allow a good estimate of frequencies for sample size calculations. The pilot study, which included the first 44 participants of the control group, estimated the combined infection rate of puerperal women and newborns at 46 percent [7]. Using 5% significance and a 80% power, a sample of 394 participants distributed in two parallel groups was estimated to be required to detect a relative difference of 25% in combined infection rates of women and newborns, following the formulas provided by Duppont and Plummer[8]. Assuming 4% of the participants would be lost to follow-up, an estimated total sample of 410 women was required.
BODY.METHODS.DATA MANAGEMENT AND ANALYSIS:
The database created in Epi-Info v 6.04 b was fed using double data entry and transferred to Stata 5.0© using Stata Transfer 4.0©. A Shapiro-Wilk test was used to determine if the distribution of continuous variables was normal. Non-normal distributions were transformed using a log transformation, and if the distribution was persistently non-normal, a Mann-Whitney test was used to compare groups. Bivariate analyses were done using the chi-square test or Fisher's exact test. Power calculations were done using specialized software developed at the Clinical Epidemiology Unit at the Javeriana University[9].
BODY.RESULTS:
During the twelve months recruitment period (Feb 1997–Feb 1998) 3170 women were admitted for delivery to the obstetric service. The caesarean section rate in the obstetrics service was 26% at the time. Of the 460 women interviewed for recruitment, 16 were non-eligible and 1 declined to participate. We randomised 443 women (see Figure 1), among which we had 12 protocol violations; 4 in the enema group and 8 in the control group. Nevertheless, these women were offered the care and benefits that all other participants had. Protocol violations included admission with ruptured amniotic membranes (5 women in the control group), infection at admission (1 in the control group, 2 in the enema group). Five women didn't fulfil inclusion criteria but were randomised (2 in the control group and 3 in the enema group). The analysis for the remaining women was done by group of allocation. Women who delivered by caesarean section were considered in the analysis. Data were not available to include in an 'intention to treat' analysis the 12 women excluded because of violations to the selection criteria (protocol violations). Follow up was completed by 87% of the participating women and 86% of newborns. Direct examination by a team member at one month follow up was carried out in 20% of women and 19% of newborns (P = 0.51 and P = 0.98 respectively, with similar distribution between groups); standardised telephone interviews with participants and healthcare providers allowed to assess outcomes from the remaining participants. Baseline characteristics were similar in both groups, suggesting that randomisation provided well-balanced and comparable groups (Table 1 [see additional file 2]). Labour duration times and other maternal outcomes were obtained from women's records after delivery and are presented in Table 2 [see Additional file 2]. Neonatal baseline data obtained shortly after delivery from newborns' records are summarised in Table 3 [see Additional file 2]. We found no statistically significant differences between groups for labour duration, delivery types, episiotomy rates, or prescription of antibiotics. Caesarean sections were done in 12% of women with no significant differences in rates between groups. No significant differences were found in the distribution between groups for newborns' "Ballard" score, birth weight, diagnosis of neonatal apnoea, or the administration of ocular and umbilical prophylaxis. Five newborns allocated to the control group and none in the treatment group developed respiratory tract infections, but this difference had no statistical significance. Two out of the five newborns who developed lower respiratory tract infections were delivered by caesarean section. The three newborns with omphalitis belonged to the intervention group, but again this difference was not statistically significant. Similarly, no significant differences were found for ophthalmic infection rates, skin infections, intestinal infections or the need for systemic antibiotics (Table 4 [see Additional file 2]). No statistically significant differences were found for any of the assessed outcomes in puerperal women. Pelvic infections affected 4% of women: one was diagnosed with myometrytis; five with endometritis; three had vulvovaginitis; and six had infected episiorraphy sutures. The frequency and severity of perineal tear was similar in the intervention and control group. No significant differences were found in the rates of suture dehiscence among the 372 women who had epysiorraphy (Table 5 [see Additional file 2]). Breast pain complaints were not categorised as an infectious outcome and affected 31% of women, with 79% of them suffering breast engorgement or nipple cracking and no significant difference between groups (P = 0.75). Summarised outcomes are provided in Table 6 [see Additional file 2]. Overall, one in five newborns had an infectious outcome, and rates were not statistically significant between groups. No significant differences were found for aggregated maternal infections, although the study may have been underpowered to rule out such differences; We found an 8% absolute risk difference and a broad, skewed confidence interval (see Table 6 [see Additional file 2]). The aggregated outcome of "neonatal or puerperal infection" during the 30-day follow-up was higher in the control group than in the intervention group. However, the 6% difference in absolute risk can be due to chance (P = 0.23). Infections affecting both child and mother in the same family were not significantly different (6/183 [3%] with enema v 5/191 [3%] with no enema; P = 0.39). We planned to assess the effect of enemas' on labour duration using multiple linear regression to adjust for parity. However the normality test of the variable was rejected and a Boxcox transformation (with a range between -2 and 2) did not provide an appropriate model. The residuals analysed through a robust regression had a non-normal distribution, so a non-parametric quintile regression was done, finding no significant differences of labour duration within study groups after adjusting for parity (P = 0.07).
BODY.RESULTS.PARTICIPANT FLOW AND FOLLOW-UP:
Described in Figure 1 [see Additional file 1].
BODY.DISCUSSION:
Puerperal and neonatal infections, although seldom life threatening, were very frequent in this study. Ophthalmic infections were the most frequent infections amongst newborns. Breast engorgement and nipple cracking were the most frequent maternal complaints during puerperium. Episiorraphy dehiscence was the most frequent infectious outcome in women. We were impressed by how frequent these outcomes were, and it is likely that these problems are being missed in studies with a shorter follow up, such as those that only follow women during hospitalization. It also suggests that the follow up strategy probably had a good sensitivity. High volume enemas used during the first stage of labour did not have a significant effect in the incidence of puerperal or neonatal infections, or labour duration. This RCT found no significant differences in puerperal or neonatal infection rates with enemas. No statistically significant effects were found when analysing women or newborns separately or when their outcomes were aggregated to analyse them as mother-newborn dyads. The RCT had a power in excess of 80% to find differences as big as 25% in the aggregated infection rates for women and newborns. However, the study may have been underpowered to detect differences for individual outcomes. This RCT had an estimated power of 56% to find differences in neonatal infections, and 61% power to detect puerperal infections. A higher rate of operative vaginal deliveries was found in the enema group, although it did not reach statistical significance. It is worth mentioning this, because operative vaginal deliveries may have an effect in puerperal infection rates. The use of an aggregated outcome helped to reduce sample size but it would have been ideal to have a sample size large enough to establish effects in newborns and puerperal women separately. Despite being practical, aggregating results has important limitations: if the maternal and neonatal outcomes have significantly different magnitudes or point out in different directions, aggregation will cancelled out or underestimate the differences. We didn't have resources to collect information to assess if the population of women admitted to the trial represented all eligible women. However, participation in the trial was apparently determined by the commitment of recruiters, not the participants' risk. The RCT did not evaluate women's preferences or known adverse effects of enemas, such as pain, discomfort, embarrassment, or diarrhoea. Since just one-fifth of the participants were personally examined by trained research assistants at the one-month assessment, measurements of these outcomes may have been imprecise and could potentially disguise existing differences, accounting for the lack of differences (risk of Type II error). Nevertheless, significant misrepresentations of outcomes grave enough as to require hospitalisation, dedicated care, or urgent consultations are unlikely with the follow up strategy we endorsed. Overall, participants and their families were helpful and willing to provide information; and we went to great efforts to use more than one information source and verify abnormal results in both women and neonates.
BODY.CONCLUSION:
Puerperal and neonatal infections had high incidence rates. Severe infections, such as myometritis and omphaylitis, were unusual. In this study enemas didn't significantly modify puerperal or neonatal infection rates. A dramatically larger study would be necessary to determine the effects, if any, of enemas on specific outcomes including life-threatening complications. Enemas cause discomfort, increase workload for health carers and marginally increase the cost of health care. At this time there is no good evidence supporting the routine use of enemas. It seems unlikely that the effect of enemas on the incidence of specific outcomes is large enough to outweigh the inconvenience or adverse effects associated to the routine use of enemas during labour. The data from this study combined from additional RCTs may help better understand the particular effects of enemas, guide policies and elucidate the role of enemas during labour.
BODY.COMPETING INTERESTS:
The author(s) declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
Luis Gabriel Cuervo led the conception and design of the RCT, coordinated its implementation and development, data recollection, analysis and interpretation of data, and leads the writing of this manuscript. María del Pilar Bernal trained research assistants, collected and input data, helped with the day to day management, participated in the writing of this article, and has reviewed its different versions. Natalia Mendoza contributed to the development of data capturing templates, trained research assistants, collected and input data, and participated in the original writing of this article and has reviewed its different versions.
BODY.PRE-PUBLICATION HISTORY:
The pre-publication history for this paper can be accessed here:
BODY.SUPPLEMENTARY MATERIAL:
Additional File 1Participant flow and follow-up.Click here for file Additional File 2Characteristics of participants at admission. Maternal postpartum outcomes. Neonatal baseline data. Neonatal infectious outcomes. Maternal infectious outcomes. Grouped infectious outcomes.Click here for file | 1,468,428 | {
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TITLE: Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF)
ABSTRACT:
An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m−2, LV 500 mg m−2, 24-h 5-FU 2000 mg m−2, and ELF comprised three once-daily doses of etoposide 120 mg m−2, LV 300 mg m−2, 5-FU 500 mg m−2. In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29–1.13, P=0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33–0.97; P=0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P=0.4542), and overall survival was 10.8 vs 8.3 months (P=0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.
BODY:
Gastric cancer is the fourth most common cancer in Europe and the third leading cause of cancer mortality (Bray et al, 2002). Although gastric cancer has declined over the past 50 years, the incidence of tumours at the gastro-oesophageal junction has increased (Blot et al, 1991). The use of chemotherapy for the management of patients with advanced gastric cancer, who have limited treatment options (Hohenberger and Gretschel, 2003), has only become widely acceptable over the last 20 years (Glimelius et al, 1997; Murad et al, 1993; Pyrhonen et al, 1995). 5-Fluorouracil (5-FU), usually in combination with leucovorin (LV, also referred to as folinic acid), forms the basis of most chemotherapy regimens used for the treatment of gastric cancer. A randomised phase III trial compared combinations of 5-FU with other active drugs in advanced gastric cancer: etoposide, LV and 5-FU (ELF) vs infusional 5-FU plus cisplatin (FUP) vs 5-FU, doxorubicin and methotrexate (FAMTX) (Vanhoefer et al, 2000). The overall response rates (ORRs) ranged from 9% (ELF) to 20% (FUP) and median survival times were between 6.7 months (FAMTX) and 7.2 months (both ELF and FUP). The observed differences were not statistically significant and there is still no definitive regimen for the treatment of gastric cancer. The combination of epirubicin, cisplatin and continuous infusion 5-FU (ECF) has been proposed as a standard first-line therapy for gastric cancer as a consequence of its significantly improved response rate (46%) and survival (8.7 months) when compared with FAMTX (Waters et al, 1999). More recently, ELF has been shown to provide better disease control (complete response (CR)+partial response (PR)+stable disease (SD)) for patients with proximal rather than distal tumours (85 vs 48%, P=0.04) (Schulze-Bergkamen et al, 2002). Tolerability, toxicity and ease of administration have become major determinants for selecting an appropriate therapy and ELF has emerged as a convenient, well-tolerated regimen that can be administered on an outpatient basis (Vanhoefer et al, 2000; Schulze-Bergkamen et al, 2002). Irinotecan (CPT-11, Camptosar; Pfizer Oncology, New York, USA) inhibits topoisomerase I thereby disrupting DNA replication and cell division within tumour cells. Response rates between 20 and 23% have been reported for irinotecan monotherapy in untreated gastric cancer (Futatsuki et al, 1994; Kohne et al, 2003). In patients who had failed previous therapy, irinotecan (180 mg m−2) combined with 5-FU (400 mg m−2, bolus) and LV (125 mg m−2) followed by 5-FU infusion (1200 mg m−2 over 48 h) yielded a response rate of 29%, while a further 34% of patients achieved SD (Assersohn et al, 2004). Irinotecan with bolus-LV/5-FU in the first-line treatment of gastric cancer provided a response rate of 22% (Blanke et al, 2001). However, this regimen (irinotecan 125 mg m−2, LV 20 mg m−2 plus 5-FU 500 mg m−2, all given weekly for 4 weeks followed by a 2-week rest) was associated with a high incidence of severe diarrhoea (28%) and neutropenia (36%) infection leading to substantial dose modifications (Blanke et al, 2001). By comparison, the combination of irinotecan with continuous rather than bolus infusions of LV/5-FU exhibited a lower incidence of grade 3 and 4 toxicities in colorectal cancer patients (Douillard et al, 2000; Saltz et al, 2000; Bouzid et al, 2003). Therefore, we have investigated a weekly dose of irinotecan (80 mg m−2) in combination with LV (500 mg m−2) and continuous 5-FU (2000 mg m−2 over 24 h) according to the AIO (Arbeitsgemeinschaft Internistische Onkologie) regimen (i.e. ILF) in gastric cancer patients. In a previous phase I study of ILF in the first- and second-line treatment of gastric cancer, we observed a response rate of 20% with a further 36% of patients reporting SD (Moehler et al, 2003). Importantly, toxicity was sufficiently manageable to allow outpatient-based treatment. Therefore, we initiated the present randomised, controlled, phase II study to compare the efficacy and safety of ILF with ELF in the first-line treatment of metastatic gastric cancer.
BODY.PATIENTS AND METHODS.PATIENTS:
Eligible patients had untreated histologically proven gastric adenocarcinoma, or adenocarcinoma of the oesophagogastric junction with measurable metastatic disease and/or locally recurrent nodal involvement, were aged between 18 and 75 years with a Karnofsky performance score (KPS) ⩾60 and a life expectancy >12 weeks. Patients were required to have adequate haematological (neutrophils ⩾2.0 × 109 l−1, platelets ⩾150 × 109 l−1; haemoglobin ⩾10g dl−1), hepatic (total bilirubin ⩽1.25 × upper normal limit (UNL); aspartate (AST) and alanine (ALT) aminotransferases ⩽3 × UNL) and renal function (creatinine <1.25 × UNL). Patients with previous cancer therapies were excluded from the study. All patients provided signed and dated consent before entering the trial. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and the protocol was initially approved by the Ethics committee of Aerztekammer Rheinland-Pfalz and later by all Ethics committees responsible for participating centres.
BODY.PATIENTS AND METHODS.STUDY DESIGN AND RANDOMISATION:
This was an open-label, multicentre, phase II randomised trial with two treatment arms. Patients were randomly assigned and stratified according to centre, peritoneal involvement (yes/no) and prior gastrectomy (yes/no). The randomisation process was centralised and performed by the Coordination Centre for Clinical Trials (KKS), Mainz, Germany.
BODY.PATIENTS AND METHODS.ADMINISTRATION OF STUDY DRUGS AND DOSE ADJUSTMENT:
Patients assigned to ILF (Arm A) received irinotecan 80 mg m−2 intravenously (i.v.) over 60–90 min followed by LV 500 mg m−2 i.v. over 60 min and then 5-FU 2000 mg m−2 i.v. over 24 h, on day 1. Each cycle comprised six once-weekly treatments followed by a 13-day rest period. Systemic prophylactic atropine (0.25 mg) injections for irinotecan-related acute cholinergic symptoms were allowed for the first cycle but not recommended. Prophylactic treatment for delayed diarrhoea was not permitted. However, patients were carefully informed of the potential risk of delayed diarrhoea and neutropenia and the need for early intervention with loperamide, metoclopramide, antibiotics, or hospitalisation and parenteral rehydration in case of refractory diarrhoea (>48 h). Antiemetic treatment was performed using metoclopramide or HT-3 antagonists in a sequential manner. The prophylactic use of colony-stimulating factors was not permitted. Patients assigned to ELF (Arm B) received etoposide 120 mg m−2 i.v. over 60 min, LV 300 mg m−2 i.v. over 5–10 min and then 5-FU 500 mg m−2 bolus i.v. over 2–4 min, on day 1. Each cycle comprised three applications on consecutive days (1–3) followed by an 18-day rest. All study treatments were administered until disease progression, unacceptable toxicity or withdrawal of consent. In the event of toxicity (defined by the National Cancer Institute of Canada expanded common toxicity criteria; NCIC-CTC), treatment delays or dose reductions could be applied as follows. If at any time during a cycle there were moderate reductions in haematological function (neutrophil count 0.5–1.5 × 109 l−1, platelet count 25–75 × 109 l−1) or moderate diarrhoea or stomatitis (>grade 1), the next administration could be delayed for up to 2 weeks. If at any time haematological abnormalities were noted (neutrophils <0.5 × 109 l−1, neutrophils <1 × 109 l−1 with infection or fever, platelets <25 × 109 l−1) or if there were ⩾grade 3 or 4 diarrhoea or stomatitis, treatment had to be delayed until recovery to moderate levels (as described above) after which the following dose reductions were applied. For Arm A, 5-FU was reduced to 1600 mg m−2 and irinotecan to 65 mg m−2. For Arm B, in the case of haematological toxicity, etoposide had to be reduced to 100 mg m−2 and 5-FU to 400 mg m−2, and in the case of diarrhoea or stomatitis, 5-FU was reduced to 400 mg m−2. If a condition persisted despite dose reduction, or if a patient experienced myocardial infarction, treatment was terminated. In the case of hand–foot syndrome, the dose of 5-FU was to be reduced by 20%. Delayed diarrhoea was treated immediately with loperamide and rehydration and, if associated with severe neutropenia, a broad-spectrum antibiotic. Hospitalisation with i.v. rehydration was required for grade 4 or persistent (>48 h) diarrhoea, concomitant vomiting, fever, or KPS <60%.
BODY.PATIENTS AND METHODS.STUDY EVALUATIONS:
At baseline up to five measurable lesions per organ and 10 lesions in total were to be identified as target lesions, measured using computed tomography (CT), and recorded according to the RECIST system (Response Evaluation Criteria In Solid Tumours; Therasse et al, 2000). The sum of the longest diameters for all target lesions was used as a reference for determining objective tumour response. Tumour responses were evaluated at week 7, week 14 and then every two cycles for patients receiving ILF or every four cycles for patients receiving ELF. Responses were determined according to RECIST as follows: complete response was defined as the disappearance of all target and nontarget lesions with no new lesions and confirmed by two observations at least 4 weeks apart; PR was defined as a reduction of 30% or more in the sums of the longest diameters of all measurable lesions relative to baseline with no new lesions; no change (NC) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) with no new lesions; and PD was defined as ⩾20% increase in the sum of the longest diameters, the occurrence of nontarget lesions (e.g. pleural effusion or ascites) or the appearance of brain metastases independently of performance at sites outside the brain. Safety and tolerability were assessed by regular clinical examinations and assessments of adverse events (weekly, at the end of treatment and at every 3 months of follow-up), disease symptoms, KPS, haematological and biochemical parameters.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS:
The primary end point was objective clinical response (CR+PR) based on an interim analysis following 14 weeks of treatment. The one-sided exact Fisher's test was used to compare the treatment arms at the significance level α=5%. The analyses were performed on an intention-to-treat basis including all patients who were treated in the study. The secondary end points were ORR (for the entire treatment period), time to progression, tumour growth control, time to treatment failure (including progression, death or withdrawal) and survival. Time to event data were described by Kaplan–Meier estimates and treatment groups were compared by log-rank test. Time to event data were further evaluated by appropriate proportional Cox's models and results were summarised by hazard ratio point and 95% confidence interval (CI) estimates, and P-values of Wald χ2 test. Binary data were described by risk ratio (RR) point and 95% CI estimates and treatment groups were compared by exact Fisher's test. Binary data were further evaluated by appropriate logistic regression models and were summarised by odds ratio point and 95% CI estimates and P-values of Wald χ2 test. If not specified otherwise, P-values are presented from two-sided tests and two-sided 95% CI are presented. All analyses were performed using SAS version 6.12.
BODY.RESULTS.PATIENT CHARACTERISTICS:
In all, 120 patients from 17 centres in Germany were randomised into the study between November 2000 and April 2003. Two patients from Arm A and four from Arm B withdrew without receiving study treatment; therefore, the intention-to-treat population contained 114 patients (56 received ILF and 58 received ELF). The baseline characteristics were well balanced between the two treatment groups (Table 1). The median age of patients was 62 years and the median KPS was 90%. In around one-third (31%) of patients, the primary tumour site was the oesophagogastric junction, 62% of patients had liver metastases and in 77% two or more organs were involved.
BODY.RESULTS.RESPONSE RATES:
The objective clinical response rates following 14 weeks of treatment (primary end point) were 30% for ILF compared with 17% for ELF (RR 0.57, 95% CI 0.29–1.13, P=0.0766). The ORRs for the entire treatment period and including all assessments prior to discontinuation were 43% (24 of the 56) for ILF and 24% (14 of the 58) for ELF (Table 2). The increased response rate provided by ILF compared with ELF was statistically significant (RR=0.56; 95% CI=0.33–0.97; P=0.0467.) The tumour control rates (CR+PR+NC) were 63% (35 of the 56) and 41% (24 of the 58), respectively. Logistic regression analysis indicated that a baseline KPS ⩽80% reduced the likelihood of a response by 59% compared with patients whose KPS was greater than 80% (P=0.038) (Table 3). After adjustment for KPS, peritoneal involvement and surgery for primary tumour, the regression model also demonstrated that ILF was 138% more likely to provide a response when compared with the ELF regimen (Table 3, P=0.042).
BODY.RESULTS.PROGRESSION-FREE SURVIVAL, TREATMENT FAILURE AND OVERALL SURVIVAL:
At the last data cutoff, the median follow-up was 9.4 months in Arm A and 5.8 months in Arm B. At this time, 96 of the 114 patients had died. Disease progression was the major cause of death and accounted for 79% of patients in both treatment groups. One patient from the ILF arm did not comply with the provided recommendations for the treatment of prolonged grade 3 diarrhoea and consequently died (i.e. toxic death). One patient in the ELF arm died from a cardiovascular event. Compared with ELF, the ILF regimen extended median progression-free survival, median time to treatment failure and median overall survival (Table 4). However, when the treatment groups were compared by log-rank test, there was no significant difference between the two treatments for any of these parameters (e.g. the Kaplan–Meier survival plot as shown in Figure 1). Investigational analyses found that the risk of progression was increased in patients with a primary tumour in the oesophagogastric junction and in those with metastatic involvement in two or more organs (Table 3). As would be expected, the risk of death was increased in patients with a low KPS, in those with two or more involved organs and in those with peritoneal involvement who received ELF (Table 3).
BODY.RESULTS.SAFETY:
The median number of cycles administered in the study was two for ILF (Arm A) and three for ELF (Arm B) (Table 5). Although the median treatment duration period was over twice as long with ILF than with ELF, there were more dose administration delays (70%) and dose reductions (75%) with ILF than with ELF (52 and 45%, respectively). The main reason for discontinuing study treatment was disease progression; 54% of patients receiving ILF and 72% receiving ELF. Although only one patient in each treatment group withdrew because of treatment-related toxicity, five patients receiving ILF and three patients receiving ELF either withdrew consent or refused further treatment. The incidence of grade 3/4 haematological toxicities was low in both treatment groups with the exception of neutropenia, which was reported by 57% of patients receiving ELF (Table 6). There were more grade 3/4 gastrointestinal toxic events with ILF, notably diarrhoea, which was reported by 18% of patients compared with no reports with ELF. Grade 3/4 alopecia was reported by a significant proportion of patients receiving ELF (28%), but was only seen in 5% of those receiving ILF.
BODY.DISCUSSION:
Although chemotherapy regimens offer at best a slight, albeit statistically significant, improvement in survival for patients with gastric cancer, they are associated with a degree of toxicity that limits their value as a palliative treatment (Vanhoefer et al, 2000; Schoffski, 2002; Diaz-Rubio, 2004). The primary end point of clinical response at 14 weeks was selected so that a statistical comparison at a fixed time point could be made. However, as it is the convention in such studies, patients were treated until progression, and could respond to treatment at a later point. Therefore, the overall response and survival rates obtained from the entire dosing period provide a more clinically significant assessment of the efficacy of these regimens for discussion in relation to other trials in gastric cancer. The irinotecan-based combination provided again a greater ORR than that seen with the commonly used ELF regimen (43 vs 24%, respectively, P=0.0467). Overall response rates for ELF reported in previous studies range from 9 to 23% (Vanhoefer et al, 2000; Schulze-Bergkamen et al, 2002) and this compares well with the 24% response rate reported in this study. Accordingly, an ORR of nearly 50% for ILF, as seen in this study, is a substantial improvement and is in the range of previous reports of the use of this drug combination in this setting (Blanke et al, 2001; Moehler et al, 2003). The overall survival data in the present study also compare well with those from previous studies. The median overall survival with ELF has been reported at 7.2 and 8.0 months (Vanhoefer et al, 2000; Schulze-Bergkamen et al, 2002), which is similar to both the 8.3 months reported here and the data reported for irinotecan-based regimens in the second-line setting between 7.0 and 7.6 months (Moehler et al, 2003; Assersohn et al, 2004). By comparison, there was a nonsignificant trend for increased median survival with ILF in this study (10.8 months) and this compares well with data reported for more recent exploratory combinations such as capecitabine and docetaxel (10.5 months), and epirubicin, docetaxel and cisplatin (11.0 months) (Lee et al, 2004; Park et al, 2004). The same can be said of the progression-free survival period in the ILF group of 4.5 months, which compared well with the 4.1 and 5.2 months reported recently for docetaxel-based regimens (Lee et al, 2004; Park et al, 2004). In other randomised phase II studies, continuous 5-FU/LV infusion plus irinotecan has also provided promising efficacy (ORRs of 40–42%, median progression-free survival periods of 6.5–6.9 months and median overall survival periods of 10.7–11.3 months; Bouche et al, 2004; Pozzo et al, 2004). Consequently, large phase III studies are being considered to investigate irinotecan in combination with continuous 5-FU/LV infusion regimens. When patient histories, disease status and other factors were examined for their effects on clinical outcome, those patients who were in better general health (good performance status, low tumour burden) were more likely to achieve a response and less likely to have a progression event or die, regardless of the treatment arm to which they were randomised. Patients with peritoneal involvement at presentation have a generally poorer prognosis and as a group face a desperate need for improved treatment options (Rau et al, 1996). The data from this study demonstrated that these patients are less likely to suffer a fatal event if treated with ILF rather than ELF. This is potentially an important observation for the management of these difficult to treat patients (Blot et al, 1991; Bray et al, 2002). The extension of meaningful survival remains a major objective for oncologists who must therefore consider the impact of treatment-related toxicity. Overall, the occurrence of the toxicities in this study was consistent with the safety profiles of irinotecan, etoposide and 5-FU/LV. The ILF combination was well tolerated with a low and acceptable incidence of haematological toxicity. Gastrointestinal toxicity is a recognised side effect of ILF therapy (Douillard et al, 2000; Saltz et al, 2000), which can require hospitalisation and urgent medical intervention (Rothenberg et al, 2001). The incidence of grade 3 or 4 diarrhoea in the current study was comparable to the previous data in gastric cancer (Blanke et al, 2001; Moehler et al, 2003; Pozzo et al, 2004). With close monitoring of the patient, suitable medication and rehydration, most cases of diarrhoea can be managed effectively and do not present a significant obstacle to the clinical use of ILF. The toxicity observed in our study was lower than that reported by Douillard et al in the pivotal European first-line trial where patients with colorectal cancer received weekly irinotecan (80 mg m−2) plus an AIO-based regimen of 24-h high-dose 5-FU (2300 mg m−2) preceded by 2-h LV 500 mg m−2, and grade 3/4 diarrhoea was reported by 44% of patients (Douillard et al, 2000). The lower toxicity in our study might be due to the lower daily doses of 5-FU (2000 mg m−2 administered over 24 h). Work is ongoing to identify those patients who carry a specific genetic polymorphism in one of the main enzymes (UGT1A1) involved in the detoxification of irinotecan and are therefore more susceptible to the side effects of irinotecan (Mathijssen et al, 2001). Such work will improve the targeting of this useful therapy and may allow appropriate prescriptive dosing schedules on an individual basis. The present study concurs with similar phase II studies in that the combination of irinotecan with continuous LV/5-FU (ILF) represents a potentially valuable new treatment option for metastatic gastric cancer and requires further evaluation (Bouche et al, 2004; Pozzo et al, 2004). | 2,361,806 | {
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TITLE: Impact and Process Evaluation of Integrated Community and Clinic-Based HIV-1 Control: A Cluster-Randomised Trial in Eastern Zimbabwe
ABSTRACT.BACKGROUND:
HIV-1 control in sub-Saharan Africa requires cost-effective and sustainable programmes that promote behaviour change and reduce cofactor sexually transmitted infections (STIs) at the population and individual levels.
ABSTRACT.METHODS AND FINDINGS:
We measured the feasibility of community-based peer education, free condom distribution, income-generating projects, and clinic-based STI treatment and counselling services and evaluated their impact on the incidence of HIV-1 measured over a 3-y period in a cluster-randomised controlled trial in eastern Zimbabwe. Analysis of primary outcomes was on an intention-to-treat basis. The income-generating projects proved impossible to implement in the prevailing economic climate. Despite greater programme activity and knowledge in the intervention communities, the incidence rate ratio of HIV-1 was 1.27 (95% confidence interval [CI] 0.92–1.75) compared to the control communities. No evidence was found for reduced incidence of self-reported STI symptoms or high-risk sexual behaviour in the intervention communities. Males who attended programme meetings had lower HIV-1 incidence (incidence rate ratio 0.48, 95% CI 0.24–0.98), and fewer men who attended programme meetings reported unprotected sex with casual partners (odds ratio 0.45, 95% CI 0.28–0.75). More male STI patients in the intervention communities reported cessation of symptoms (odds ratio 2.49, 95% CI 1.21–5.12).
ABSTRACT.CONCLUSIONS:
Integrated peer education, condom distribution, and syndromic STI management did not reduce population-level HIV-1 incidence in a declining epidemic, despite reducing HIV-1 incidence in the immediate male target group. Our results highlight the need to assess the community-level impact of interventions that are effective amongst targeted population sub-groups.
BODY.INTRODUCTION:
HIV-1–prevalence declines may now be occurring in some sub-Saharan African countries [1]. However, there remains little direct evidence that prevention measures—rather than natural HIV-1 epidemic dynamics [2] or behaviour change prompted by mortality [3]—have contributed to the slowing of HIV-1 epidemics [4,5]. Syndromic management of sexually transmitted infections (STIs) proved effective early in an HIV-1 epidemic in north-west Tanzania [6]. Peer education to promote safe behaviours showed promise in early process evaluations [7], but a randomised controlled trial (RCT) of factory workers in Harare, Zimbabwe, done in the mid-1990s, proved inconclusive [8]. Subsequent RCTs of syndromic management [9] and mass treatment of STIs [10], together with an information, education, and communication (IEC) behaviour-change programme [9], showed no effect in more mature epidemics. Integrated implementation of synergistic community-based HIV-1 control strategies could be a more cost-effective and sustainable approach to HIV-1 prevention than parallel application of vertical (top-down) programmes [11]. One scientific evaluation of such a strategy has been reported in which a combination of IEC activities amongst the general population and syndromic STI management showed no impact on HIV-1 incidence at the population level [9], although participation in the IEC activities was associated with reduced HIV-1 infection in women [12]. We conducted a cluster-RCT to test the hypothesis that integrated implementation of combined community- and clinic-based HIV-1 prevention, in which IEC activities focus primarily on high-risk populations, can be feasible and effective in reducing HIV-1 incidence in a major maturing epidemic in eastern Zimbabwe (Protocols S1 and S2; Text S1 and S2).
BODY.METHODS.PARTICIPANTS AND RANDOMISATION PROCEDURE:
The study communities comprised six pairs of communities matched by socio-economic type—small town, tea/coffee estate, forestry plantation, roadside trading settlement, and subsistence farming area (two pairs) (Figure 1). Each community included at least one Government or Mission health centre. It was anticipated that HIV-1 incidence would be similar within each pair of communities. Within each pair, one community was assigned at random (un-blinded coin toss by a Ministry of Health official witnessed by programme and research personnel) to receive the additional intervention and the other to be the control. These procedures were designed to ensure that Mission, non-governmental organisation, and private sector programmes (for details, please refer to the following section) would be distributed evenly between intervention and control sites. Figure 1Location of Intervention and Control Communities in Manicaland Province, Eastern Zimbabwe We assessed the effect of the intervention using results from laboratory tests for HIV-1 infection and questionnaire data collected in the baseline and 3-y follow-up rounds of a population-based, closed-cohort survey. The 12 study communities were enumerated in a phased manner, with paired communities being enumerated consecutively to minimise the effects of any seasonal factors. HIV-1–prevention activities were commenced in each intervention community shortly after completion of the baseline survey in that community. In each community, individuals eligible for the study were identified in the first round using data from household listings prepared in an initial census. All males and females aged 17–54 y and 15–44 y at last birthday (the age groups expected to have the highest incidence of HIV infection), respectively, who had slept in a household in the community for at least four nights in the previous month, and who had also done so at the same time 1 y earlier, were considered eligible for the study. In heterosexually driven HIV-1 epidemics, risk of infection can be correlated amongst marital partners [13]. Therefore, to maximise statistical power to detect differences in HIV-1 incidence, enrolment was restricted to one randomly selected member per marital group.
BODY.METHODS.INTERVENTIONS:
Intervention and control communities were to receive standard Government services including basic syndromic STI management, condom distribution from health clinics and Zimbabwe National Family Planning Council outlets, home-based care, and limited HIV/AIDS–focussed IEC activities (e.g., occasional AIDS-awareness meetings and distribution of posters and leaflets). In addition, social marketing of male and female condoms would be provided through an ongoing national programme [14]. The intervention comprised targeted and population-level strategies to promote safer sexual behaviour and to improve treatment of STIs that facilitate HIV-1 transmission. The intervention strategies were implemented by two local non-governmental organisations (Family AIDS Caring Trust and the Biomedical Research and Training Institute) and the Zimbabwe Ministry of Health and Child Welfare through an integrated programme of community- and clinic-based activities. Integration of the individual programme components was achieved through the joint involvement of the participating agencies in the planning and implementation of activities and through the inclusion of biomedical and behavioural aspects within each component. The programme design comprised three key components: (1) peer education and condom distribution amongst commercial sex workers and male clients at workplaces and in the general community, supported by income-generating projects; (2) strengthened syndromic management of STI services at local health centres; and (3) open days with HIV/AIDS IEC activities at health centres to promote safer sexual behaviour and to increase the uptake of local STI treatment services. The peer-education component was based on a model which had been developed by the Project Support Group at the University of Zimbabwe [7] and which had been widely implemented within Zimbabwe and neighbouring countries. Activities were held weekly at workplaces and at locations within the general community (e.g., beer halls and markets) where casual relationships were most frequently formed [15]. The target population comprised sex workers and male clients who form a bridge population in HIV transmission [16] between sex workers and the monogamous (or serial monogamous) majority of women [17,18]. It was posited that the high HIV-1 incidence observed amongst young women could be reduced by altering the behaviour of their older male partners whose own behaviour was intrinsically more risky [19]. The behavioural component would be reinforced in counselling sessions with STI patients and through micro-credit income-generating projects to reduce unmarried women's dependence on commercial sex work. The micro-credit scheme consisted of small interest-free loans repayable over 10 mo, provided to groups and to individuals together with training in small-business management. The targeted activities would be extended to the general population through open days held at local health centres. Besides providing basic HIV/AIDS information, it was envisaged that programme meetings and activities, by their continuous nature, would sustain high levels of awareness of the risks of HIV transmission and would facilitate renegotiation of community social norms, making safer behaviours easier to adopt. The key messages of the programme were: (1) remain faithful to one regular sexual partner; (2) use condoms consistently with any casual sexual partners; and (3) seek prompt and effective treatment for any STIs. Syndromic management of STIs at primary healthcare centres was first introduced in Zimbabwe in the 1980s [20] and formed the basis of STI diagnosis and treatment services at baseline in the intervention and control communities. It was envisaged that these services could be strengthened and made more effective through a programme of regular classroom training and on-site supervision of nursing staff, through the introduction of training in systemic counselling for STI patients, and through the provision of small quantities of treatment drugs to cover delays in routine supplies. Quality-assurance procedures applied in the intervention communities included pre- and post-training tests for peer educators and, for nursing staff, attending the syndromic STI management and systemic counselling courses, regular on-site supervision (including random spot checks) and training, refresher courses, routine planning meetings and monitoring of service statistics, and quarterly workshops where detailed programme procedures were reviewed and updated. An interim qualitative process evaluation of intervention activities was conducted during the inter-survey period, and a report on the findings was provided to the implementing organisations.
BODY.METHODS.OUTCOME AND PROCESS MEASURES:
The primary outcome of the study was HIV-1 incidence at the community level amongst individuals who were uninfected at baseline. Blood was collected onto Whatman No. 3 filter paper and transported to the Biomedical Research and Training Institute laboratory in Harare. Blood spots were air dried at 4 °C and, for long-term (>1 mo) storage, were kept at −20 °C. For baseline studies, blood was eluted into phosphate-buffered saline, and antibodies to HIV were detected using a dipstick dot EIA (ICL-HIV-1/HIV-2 Dipstick, [PATH, http://www.path.org; produced locally in Thailand]) and a standard protocol [21,22]. All positive results and a 10% sample of negative results were confirmed using a plate EIA (Abbott Third-Generation HIV-1/HIV-2 EIA [http://www.abbott.com] or Genelavia MIXT HIV-1/HIV-2 [Sanofi Diagnostics Pasteur, Marnes La Coquette, France]). At follow-up, a similar protocol was followed. Only the samples from those participants recorded as being HIV seronegative at baseline were tested at follow-up, again using a dot EIA (ICL-HIV-1/HIV-2 Dipstick, [PATH, produced locally in India]). Where seroconversion was indicated, the frozen stored baseline sample was retested to confirm the original negative result using the same dot EIA test. Where the baseline result remained negative, the Abbott EIA test was used to confirm both baseline and follow-up results. The change in place of manufacture of the dot EIA and the exclusive use of Abbott test kits to confirm positive sera at follow-up was due only to changes in the supply of test reagents, and not to perceived changes in sensitivity or specificity [23]. Apart from the principal investigators (based in Harare, London and Oxford) and those nurses given permission by participants requesting voluntary counselling and testing (VCT), all research personnel remained blind to the HIV-1 status of individual participants. Secondary outcomes, measured at the community and individual level, were self-reported genital ulcers and urethral or vaginal discharge in the past year (STI cases), STI treatment effectiveness (self-reported cessation of symptoms), indicators of sexual and health-seeking behaviour change, and HIV/AIDS knowledge. The behaviour-change variables assessed were sexual debut, sexual partner change in the past year, non-regular partnerships in the past month, and unprotected sex with regular and casual partners in the past 3 y. The data on sexual partnerships and condom use were collected using the Informal Confidential Voting Interview method for 75% of respondents selected at random in the first round of the survey. This method includes procedures to build rapport, ensure a non-judgemental interview approach, and provide reassurance that there are no right or wrong answers to questions of a personal nature, and uses a simple secret voting-box system to reduce embarrassment and guarantee confidentiality in low-development settings [18]. Its use has been shown to be associated with greater disclosure of socially proscribed behaviour in the study population [24]. Process indicators examined comprised changes in knowledge and psychosocial status and indicators of programme coverage and quality.
BODY.METHODS.SAMPLE-SIZE CALCULATIONS:
Initial sample-size calculations assumed 20% HIV-1 prevalence at baseline, 30% loss to follow-up after 2 y, and 80% power to detect a 40% reduction in HIV-1 incidence in the intervention communities compared with control communities, assuming a background yearly incidence of 2%. Based on six pairs of communities and a co-efficient of variation between communities of 0.15, the required sample size in each community was 1,000. Funding constraints and slower than anticipated implementation of intervention activities led to revisions of the sample size for each community to 800 and the length of follow-up to 3 y, respectively. Assuming a proportionate increase in loss to follow-up to 41%, these arrangements also yielded 80% power to detect a 40% reduction in HIV-1 incidence.
BODY.METHODS.STATISTICAL METHODS:
To test the randomisation with small numbers of communities, HIV-1 prevalence, STI history, and socio-demographic characteristics were compared at baseline for study participants in the intervention and control communities, together with uptake of STI treatment and VCT services offered at baseline. Outcome and process indicators were compared for intervention versus control communities. Analysis of the primary outcome was on an intention-to-treat basis. Incident events and person-years at risk of seroconversion were used to calculate HIV-1 incidence rates and unadjusted and adjusted incidence rate ratios (IRR) with 95% confidence intervals (CIs) for each pair of communities. Adjustment was made for sex, 3-y age group, and community-level baseline HIV prevalence. The overall IRRs (unadjusted and adjusted) were taken to be the geometric means of the IRRs for the six pairs of communities. We calculated 95% CIs for each geometric mean as geometric mean ± 1.96 × standard error of the geometric mean. Paired student t-tests on the logarithms of the pair-specific IRRs were used to test whether these differed significantly from unity [25]. The coefficient of variation between communities was calculated based on baseline HIV prevalence using a standard procedure for pair-matched studies [26]. Analyses of prevalence for secondary outcome and process variables were conducted separately for male and female respondents seen at both survey rounds by fitting logistic regression models to the individual-level data and adjusting for community pair and, where available, value of variable at baseline. Since most programme activities were targeted and overall coverage of programme activities was therefore limited, sub-group analyses, adjusted for community pair, were done for HIV-1 incidence and behavioural outcomes to assess the individual-level effects of attendance at programme meetings. Data were entered and validated using SPSS-PC (http://calcnet.mth.cmich.edu/org/spss/index.htm) and data analysis was conducted in Stata version 7 (http://www.stata.com). Statistical tests were double-sided and results were taken to be significant at the 5% level.
BODY.METHODS.ETHICAL APPROVAL:
All study participants in the intervention and control communities were offered free VCT for HIV-1, an information sheet on HIV/AIDS, results from a diagnostic test for Trichomonas vaginalis [27] (done at baseline only), and free treatment for T. vaginalis and other STIs from a research nurse. Testing and treatment for T. vaginalis was provided because the prevalence of other curable STIs was low in the study areas [22]. Antibodies reactive with T. vaginalis were detected in DBS eluates following a previously described procedure [27,28]. Written informed consent was sought as a condition of enrolment and continuation in the study. Prior ethical approval was obtained from the Research Council of Zimbabwe, number 02187; the Applied and Qualitative Research Ethics Committee in Oxford, United Kingdom, N97.039; and the UNAIDS Research Ethics Committee, ERC 98/03.
BODY.RESULTS.PARTICIPANT FLOW:
In round 1 of the census (July 1998 to February 2000), 5,943 and 6,037 eligible individuals in the intervention (total population size 18,104) and control (18,633) communities, respectively, were selected for recruitment into the study cohort (Figure 2). In round 2, 3 y later (July 2001 to February 2003), 1,044 (23%) and 1,144 (26%) of baseline respondents who were still alive had migrated away from the intervention and control communities, respectively, and were therefore lost to follow-up (Figure 2). At both baseline and follow-up, migrants and non-migrants had similar risks of HIV-1 infection and associated behaviour [29]. Of those still resident in the intervention and control communities, 2,664 (75%) and 2,564 (77%), respectively, were interviewed and blood samples taken for a second time. Temporary absence from the usual place of residence was the main reason for non-participation in the intervention (n = 794, 95%) and control (n = 698, 94%) communities. The overall proportions of baseline respondents followed up at the end of the study were 55% and 56% in the intervention and control communities, respectively. The median follow-up of communities was 3.0 y (range of median within communities, 3.0–3.1). Figure 2Flow-Chart Comparing Participation and Follow-Up Rates in the Intervention and Control CommunitiesIndividuals enrolled in round 1 and still resident in the study communities were considered eligible for participation in round 2.
BODY.RESULTS.BASELINE DATA:
HIV-1 prevalence was higher in the intervention communities than in the control communities (24% versus 21%, risk ratio 1.13 [95% CI 1.05–1.22], p = 0.001). T. vaginalis infection, secondary school education, and spatial mobility were more common in the control communities, whilst history of genital discharge and uptake of STI treatment and VCT services offered in the survey were low overall but more frequent in the intervention communities (Table 1). However, the differences in each case were small and were unlikely to be clinically meaningful. Table 1 Baseline Characteristics of the Study Populations
BODY.RESULTS.OUTCOMES AND ESTIMATION:
Median follow-up per person was 2.9 y (range 1.4–3.9) and 3.0 y (range 1.5–4.1) in the intervention and control communities, respectively. In total, 4,052 individuals had 212 incident events of HIV-1 during 12,009 person-years at risk, giving an HIV-1 incidence rate of 1.77 per 100 person-years at risk. HIV-1 incidence was higher in communities with higher baseline HIV prevalence (IRR 11.49 [95% CI 1.80–73.40], p = 0.010), but this difference disappeared after adjustment for stratification by community type (p = 0.8). HIV-1 incidence was higher in the intervention communities than in the control communities overall, and in each community type, except in the forestry plantations where it was almost identical (Table 2). The difference was not significant after adjustment for sex, age group, and baseline HIV prevalence (IRR 1.27 [95% CI 0.92–1.75], p = 0.012). The observed coefficient of between-community variation was 0.14. Table 2 HIV Prevalence at Baseline and HIV Incidence and IRRs for Intervention Versus Control Communities Looking at outcome indicators for community members (rather than for communities—the unit of randomisation), self-reported STI symptoms were similar in both sets of communities (Table 3). Treatment for STI symptoms in males was effective more frequently in the intervention communities, with men in the intervention community in five of the six matched pairs reporting reduced symptom recurrence. However, more young women in the intervention than in the control communities had started sex, and reports of unprotected sex with a casual partner in the study period were more common in the intervention communities. No differences were observed in consistent condom use with regular partners between the two sets of communities. In the intervention communities, knowledge about HIV/AIDS was enhanced amongst men, and more respondents reported a close relative or family member with AIDS (sex- and age-adjusted prevalence odds ratio 1.22 [95% CI 1.05–1.42], p = 0.009). Slightly more women in the intervention communities reported that condom use within marriage was becoming acceptable, but a greater proportion of men agreed with the statement that "condoms reduce the pleasure of sex". Table 3 Biomedical, Sexual Behaviour, and Psychological Outcomes at Follow-up by Residence in the Intervention and Control Communities A total of 63,261 peer-education meetings were held, and 6.8 million condoms were distributed by the programme in the intervention communities (Table 4). Outputs increased over time as new communities entered the programme. However, owing to high inflation and economic decline, the micro-credit income-generating projects proved impossible to implement. We were able to obtain data on STI episodes treated at clinics in the 11 out of 12 study communities that reported cases to the administrative districts of Mutasa and Makoni. In the three intervention communities each in Mutasa and Makoni, STI cases fell by 66% and 51%, respectively, over the 3-y study period. Similar declines of 67% and 52% occurred at clinics in the four control communities in Mutasa and the one control community in Makoni. Coverage of training in syndromic STI management and systemic counselling for nursing staff was high (Table 4). Table 4 Summary of Service Statistics on Programme Output Most of the activities were targeted at high-risk groups. In the general population sample interviewed in the follow-up survey, 1,779 (35%) and 647 (13%) of 5,098 respondents reported attending an HIV/AIDS meeting and a programme meeting, respectively (Table 5). More respondents in the intervention communities than in the control communities attended an HIV/AIDS meeting (41% versus 28%, prevalence rate ratio 1.44 [95% CI 1.33–1.56], p < 0.001) and a programme meeting (20% versus 5%, 4.27 [95% CI 3.52–5.17], p < 0.001), and participation was higher among men than women (prevalence rate ratio 1.32 [95% CI 1.14–1.53], p = 0.002). Fewer women in the intervention communities had heard about HIV/AIDS from external sources or believed that STI drugs were available at their local clinics. Sixty-two (2%) out of 2,528 respondents in the control communities reported spending at least 1 d in the past month in the intervention communities; the equivalent number for respondents in the intervention communities visiting control communities was 70 (3%) out of 2,683. Table 5 Intervention Coverage
BODY.RESULTS.ANCILLARY ANALYSES:
In exploratory analysis to assess where the intervention failed, we found that HIV-1 incidence was reduced in males (IRR 0.48 [95% CI 0.24–0.98], p = 0.044) who reported attending programme meetings, after adjustment for the targeting of activities to groups with high-risk behaviour (Table 6). Amongst men who reported one or more casual sexual partners in the past 3 y, fewer of those who attended meetings reported unprotected sex with these partners (prevalence odds ratio 0.45 [95% CI 0.27–0.75], p = 0.002). HIV-1 incidence was not associated with programme participation in women. Table 6 HIV Incidence and IRRs by Meeting Attendance and Sex
BODY.DISCUSSION.INTERPRETATION:
We conducted a scientific trial of the feasibility and impact of an integrated community- and clinic-based HIV-1–prevention intervention. The income-generating projects apart, the intervention activities were feasible. The outputs of the programme were extensive with more than 63,000 meetings being conducted and almost 7 million condoms distributed by trained peer educators. Programme messages were considered relevant and realistic. Local STI treatment and counselling services were strengthened and promoted in accordance with the intervention protocol. For male participants, these activities improved HIV/AIDS knowledge, increased the effectiveness of STI treatment, increased consistent condom use with casual partners, and reduced HIV-1 incidence. However, the cluster-RCT results clearly show that the intervention had no positive impact at the community level and suggest possible detrimental effects on the onset of female sexual activity and condom use with casual partners over a 3-y timeframe. Did the cluster-RCT design fail to capture the true effect of the intervention? There are three possibilities: (1) inadequate statistical power; (2) insufficient follow-up; and (3) contamination of intervention within control communities. The study design provided adequate statistical power to detect a meaningful average reduction (40%) in HIV-1 incidence in the intervention versus the control communities over a 3-y observation period. In hindsight, an effect size of 40% was too optimistic and the study had insufficient power to detect a smaller effect. However, there was no trend in the results towards reduced HIV-1 incidence in the intervention communities. Largely due to migration, attrition was close to that anticipated in the study design and was comparable to other recent cohort studies [6,10,9,30]. Migrants had similar characteristics and sexual behaviour to non-migrants [29]. The results of the exploratory sub-group analysis generate the hypothesis that high-risk behaviour was reduced in males attending programme meetings but did not translate into a wider impact on HIV-1 incidence at the population level. Changes in core and bridge populations may take more time to reflect in the general population than was observed in the trial. However, a longer period of follow-up would have increased attrition, and the finding of a possible adverse effect at the population level meant that it would not have been ethical to continue with the same intervention. Future trials of behaviour-change interventions may need to include multiple rounds with phased recruitment and (where interim results are favourable) may need to consider phased intervention implementation. We minimised intervention contamination by selecting physically separated study communities, and movements between intervention and control communities were rare. However, a similar peer-education programme was implemented in one control community (small town), and HIV-1–prevention activity was considerable in all control communities that also had greater access to information from external sources. In some cases, programme messages (e.g., promotion of condom use) conflicted with those of other agencies working in the intervention communities. The effects of these other programmes could have limited our ability to detect a reduction in HIV-1 incidence caused by the current intervention. The absence of an observed effect of the intervention was not explained by differences in HIV-1 prevalence, sexual behaviour, STI cofactors, mobility, or socio-demographic composition at baseline. The earlier sexual debut in females and greater unprotected sex with casual partners seen in the intervention communities during the study period were not present at baseline but could reflect increased willingness to report high-risk behaviours in settings where there was more open discourse about HIV and AIDS. The peer-education programme could have had some effect for male but not for unmarried female participants. Preliminary findings from subsequent qualitative investigations indicate that, in the predominantly rural communities in which the study was conducted, poverty and the associated failure of income-generating projects meant that some peer educators were unable to maintain safer behaviours. Given their increased visibility within the community—intended to enhance their status and self-esteem and, thus, to reinforce their commitment to and role as models for behaviour change—they may, inadvertently, have served as negative role models and, thereby, may have contributed to the greater female early-age sexual activity. Free distribution of condoms by women still engaging in unprotected commercial sex led to their being poorly valued and reinforced their association with promiscuity.
BODY.DISCUSSION.GENERALISABILITY OF FINDINGS:
Epidemiological context can affect the impact of interventions [31], and structural obstacles can limit the pace and extent to which activities are implemented and the quality of these activities [32]. The HIV-1 epidemic stabilised in eastern Zimbabwe during the study period, with HIV-1 prevalence declining by 40%–50% in young adults [23]. This decline was accompanied by delayed sexual debut, reduced sexual partner change, and consistent condom use with casual partners [33,23]. Prevalence of syphilis, gonorrhoea, and Chlamydia is low, but non-curable herpes simplex virus type 2 remains common [22]. Risk reduction makes transmission more fragile, and an intervention could have a larger effect when set against secular behavioural changes [2]. Mathematical model simulations suggest that there would also be a greater chance of detecting a significant effect of the intervention even though there would be fewer seroconversions to power the calculation [34,35]. Structural obstacles to intervention implementation included HIV/AIDS mortality which disrupted the programme by claiming the lives of two programme coordinators and several of the nursing staff and peer-educators. Economic decline made the income-generating projects unfeasible and reduced the effectiveness of other components of the intervention. We believe that the coverage of the peer-education programme was satisfactory, given the focus on highly sexually active individuals. Meeting coverage could have been under-estimated in the survey since one-to-one discussions and activities at beer halls and other public places may not have been recognised as meetings by those present. However, the high level of spatial mobility limited the number of people who were reached at the required level of intensity and consistency, whilst national shortages of foreign currency restricted fuel and drug supplies, hampered attempts to extend community activities into the more remote rural areas, and disrupted the STI treatment programme in both the intervention and control communities. The intervention that we evaluated could have greater effect where an HIV-1 epidemic is younger, HIV-1 incidence is greater, local sexual networks are less diffuse, background STI control is weak, herpes simplex virus type 2 is less common, population mobility is lower, and/or the socio-economic climate is stable. We cannot rule out an effect of peer education in the urban intervention community since similar activities were implemented in the control community. Targeted peer education may work better in towns where bar-based sex work is more extensive. The absence of reduced HIV-1 incidence in farming estates reinforces doubts raised by the Harare factory workers study [8] concerning the efficacy of workplace peer education.
BODY.DISCUSSION.OVERALL EVIDENCE:
These findings are important since the strategies evaluated—i.e., peer education, condom distribution, and syndromic STI management—are theory-based, have the potential for independent effects [11], and are widely promoted [36,37]. Syndromic STI management was effective in a nascent epidemic [6]. However, our disappointing findings echo those from recent trials [9,12] and emphasise the need for alternative strategies of behaviour-change promotion. Social marketing of condoms [14], larger poverty-alleviation programmes to reduce women's reliance on sex work—based on skills training and careful market research rather than on small-scale income-generating projects—and strategies which reach beyond high-activity core groups, such as the Popular Opinion Leader programme [38,39], and client-centred counselling [40], could be more viable and effective in reducing HIV-1 transmission in rural areas. Given the necessary economic conditions, unmarried women may still play a useful role in bar-based programmes since beer halls remain foci for high-risk behaviour [41,15].
BODY.SUPPORTING INFORMATION.TRIAL REGISTRATION:
This trial has the registration number ISRNCT00390949 in the International Standard Randomized Controlled Trial Number Register. Found at: http://www.clinicaltrials.gov/ct/show/NCT00390949?order=1
Protocol S1Protocol(35 KB DOC)Click here for additional data file. Protocol S2Revisions to Protocol(35 KB DOC)Click here for additional data file. Text S1CONSORT Checklist(48 KB DOC)Click here for additional data file. Text S2Ethical Approval, Information Letter, and Consent Forms(2.8 MB PDF)Click here for additional data file. | 1,831,737 | {
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TITLE: Effects of Bladder Training and/or Tolterodine in Female Patients with Overactive Bladder Syndrome: A Prospective, Randomized Study
ABSTRACT:
We compared the effects of bladder training and/or tolterodine as first line treatment in female patients with overactive bladder (OAB). One hundred and thirty-nine female patients with OAB were randomized to treatment with bladder training (BT), tolterodine (To, 2 mg twice daily) or both (Co) for 12 weeks. Treatment efficacy was measured by micturition diary, urgency scores and patients' subjective assessment of their bladder condition. Mean frequency and nocturia significantly decreased in all treatment groups, declining 25.9% and 56.1%, respectively, in the BT group; 30.2% and 65.4%, respectively, in the To group; and 33.5% and 66.3%, respectively in the Co group (p<0.05 for each). The decrease in frequency was significantly greater in the Co group than in the BT group (p<0.05). Mean urgency score decreased by 44.8%, 62.2% and 60.2% in the BT, To, and Co groups, respectively, and the improvement was significantly greater in the To and Co groups than in the BT group (p<0.05 for each). Although BT, To and their combination were all effective in controlling OAB symptoms, combination therapy was more effective than either method alone. Tolterodine alone may be instituted as a first-line therapy, but may be more effective when combined with bladder training.
BODY.INTRODUCTION:
Overactive bladder (OAB), defined as increased frequency and urgency with or without urge incontinence, is a very common condition, especially in middle-aged women, with a reported incidence of approximately 17% of the general female population (1, 2). Since many women may consider OAB as a natural aging phenomenon and thus do not seek treatment, its actual prevalence may be even higher. Despite its common occurrence, however, our understanding (3-5) of the pathophysiology underlying the development of OAB has remained elementary. It is managed most commonly by drug therapy, followed by various behavioral interventions and, less frequently, by surgical methods. Each of these methods, however, has variable efficacy and adverse effects. Classically, urge incontinence has been considered most important, being the key index in treatment outcome assessments. However, since the new consensus by the International Continence Society on the diagnosis of OAB (6), the presence or absence of actual urine leakage was regarded as less important. With the adaptation of this new definition, the number of patients newly diagnosed with OAB is expected to increase, emphasizing the need to develop first-line interventions for their symptoms. The three most commonly employed methods for treating newly-diagnosed OAB are bladder training, anticholinergic therapy and a combination of the two. Here we report a controlled, randomized study comparing the clinical efficacy of these three methods, for the purpose of determining the most appropriate first-line therapeutic modality.
BODY.MATERIALS AND METHODS:
Between May 2001 and April 2002, 139 women presenting with symptoms of urgency and frequency, with or without urge incontinence, were prospectively enrolled in this study. Inclusion criteria included being 18 yr of age or older, having a urination frequency of 8 or more times per day, the presence of urge symptoms that may or may not accompany incontinence, symptom duration of 3 months or longer and no prior history of treatment for OAB. We excluded patients with active urinary tract infection, clinically significant stress urinary incontinence, bladder outlet obstruction, interstitial cystitis, glaucoma or megacolon. Also excluded were patients with a maximal urine flow rate of less than 10 mL/sec or a postvoid residual urine amount that was more than 30% of the total amount voided on uroflowmetry. Upon enrollment, patients were randomly assigned to bladder training (BT, n=46), tolterodine treatment (To, 2 mg twice daily, n=47) or a combination of the two (Co, n=46). Each patient received a physical examination and uroflowmetry with postvoid residual urine scan. In addition, each patient kept a record of urgency scores, with 0 indicating no symptoms, 1 rarely, 2 occasionally, 3 often, and 4 all the time, and a frequency-volume chart. At 12 weeks, satisfaction score was assessed, with 0 representing fully satisfied, 1 much improved, 2 slightly improved, 3 no improvement, and 4 worsened; a change of 2 points or more was considered symptom improvement. The frequency-volume chart and a survey of adverse effects of medication were repeated every 4 weeks. Patients in the BT and Co groups were educated of the bladder drills by a nurse specialist. Gross and functional anatomy of the lower urinary tract and pelvis were demonstrated, with instructions on how bladder drills can increase functional bladder capacity and actual voiding habits. Each patient was instructed to examine her frequency-volume chart to determine the longest interval she could initially hold urination and sustain urge symptoms. Each patient was then taught to increase this interval by 15-min increments, with the aim of achieving a 3 to 4 hr interval and a voided volume of 300 to 400 mL. In addition, whenever urgency occurred, patients were educated to perform Kegel exercises for symptom alleviation. All bladder drill education was performed by one nurse specialist, who telephoned each patient every 2 weeks to make sure she was following the exact drill taught. In the Co group, the bladder drill was started at the same time as the start of medication. Of the 139 patients, 89 (64.0%) completed the 12 week treatment regimen and were subjects of outcome analyses. Voiding frequency, nocturia, urgency score before and after the treatment, satisfaction score at 12 weeks and adverse events were measured in the three groups. Student's t-test was used for statistical analysis, and p<0.05 was defined as statistically significant.
BODY.RESULTS:
Patient characteristics, including age, weight, symptom severity and duration, parity, pretreatment uroflowmetry profile, presence and degree of urge or stress incontinence, and urgency score, were similar among the three treatment groups (Table 1). At 12 weeks, 26 patients (56.5%) in the BT group, 32 (68.1 %) in the To group, and 31 (67.4%) in the Co group had completed the protocol. Mean frequency in the three groups decreased significantly, from 10.9 to 8.1 (25.9%) in the BT group, from 11.6 to 8.1 (30.2%) in the To group, and from 11.9 to 7.9 (33.5%) in the Co group (p<0.05 each) (Fig. 1). Nocturia also decreased significantly in the three groups, from 1.5 to 0.6 per night (56.1%) in the BT group, from 1.7 to 0.6 (65.4%) in the To group, and from 2.0 to 0.6 (66.3%) in the Co group (p<0.05 each) (Fig. 2), as did urgency scores, from 2.6 to 1.4 (44.8%) in the BT group, from 2.8 to 1.1 (62.2%) in the To group, and from 3.0 to 1.2 (60.2%) in the Co group (p<0.05 each) (Fig. 3). When we compared these changes among the three groups, we found that patients in the Co group showed greater improvements in frequency and urgency scores than did patients in the BT group (p<0.05 each), and that urgency scores in the To and Co groups showed significantly greater improvement than in the BT group (p=0.017 and p=0.021, respectively). No difference was observed between the To and Co groups. Satisfaction scores at 12 weeks did not differ among the three groups, being 1.5 in the BT group, with improvement in 53.9%; 1.4 in the To group, with improvement in 63.0%; and 1.3 in the Co group, with improvement in 71.0%. No adverse events were reported from the BT group, whereas 13 patients (40.6%) in the To group and 12 (38.7%) in the Co group reported one or more adverse events (Table 2). Most of the events were mild and well-tolerated, except that severe dry mouth occurred in 2 patients from each group, which led them to discontinue medication (withdrawal rates, 6.3% and 6.5%, respectively).
BODY.DISCUSSION:
Despite extensive research on the complicated interactions involving the neural network of the cerebrum, sacral cord and the detrusor, little is known regarding the pathologic process that occurs during the development of OAB (4, 5, 7). Accordingly, therapeutic approaches for OAB have been diverse, consisting largely of medical therapy, but also including behavioral interventions such as bladder training, pelvic floor muscle exercises with or without biofeedback, and electrical stimulation. Other therapeutic approaches have included neuromodulation of the sacral nerves, intravesical instillations of antimuscarinics and bladder overdistention, with augmentation cystoplasty remaining as the last resort. Naturally, non-invasive methods, including medical therapy and behavioral intervention, have been the initial treatments of choice for OAB symptoms. Although it is not known how bladder drills control and sustain OAB symptoms, it is believed that ill-trained voiding habits leading to decreased bladder compliance by frequent voiding are corrected by progressively increasing the voiding interval, thus increasing the voided volume and the functional bladder capacity. Retraining these patients to void at normal intervals would restore compliance when capacity increases and may contribute to symptom improvement (8-11). Observations on the electrical stimulation of the pelvic floor muscles (12) have shown that, during electrical stimulation, hyperactivity of the bladder was either diminished or completely abolished. This mechanism has been exploited as part of bladder training regimens. Clinically, bladder training has been shown to be effective in the management of urgency and urge incontinence (8, 13-15). When bladder training was compared with medical therapy (200 mg flavoxate hydrochloride plus 25 mg imipramine three times daily for 4 weeks), urge incontinence was completely controlled in 84% of patients in the BT group, with symptom relief in 76%, compared with 56% and 48%, respectively, in the medication group (16). A larger study (17), however, found that addition of behavioral interventions did not seem to offer any additional benefit to medical therapy (tolterodine) after 6 months. Urgency episodes and daytime frequency decreased 83% and 27.3%, respectively, in the tolterodine group, compared with 78.7% and 23%, respectively, in the combination group. Improvements in patients' perception of urinary symptoms were reported by 85.9% of the tolterodine group and 81.7% of the combination group. We found that all patients, a homogeneous group of female patients, regardless of treatment methodology, reported significant improvements in all voiding parameters examined, but that the addition of medication to BT resulted in additional improvements in urgency and frequency. Our finding of better outcomes in the Co than in the To group may be due to the bladder training program and design used here, which was a short-term intensive course of bladder drills. As many authors have emphasized, patients' understanding and compliance are the key factors in bladder training. Accordingly, the exercise program that we used did not simply require patients to contract and relax their pelvic floor muscles for certain periods of time. Instead, patients were given specific goals of 15 min each in sustaining contractions and were instructed how to increase these intervals. Having such a specific aim of what to accomplish with each exercise must have been enforcing and rewarding as well. In addition, repeated instructions, confirmation and reassurance were essential and constantly encouraged patients to stay on the right track for 12 weeks. Similar results have been reported (18), in which patients were provided with written information sheets describing the aims and endpoints of therapy as well as specific instructions on bladder drills. Although there were no formal bladder training sessions or additional follow-up for those in the bladder training-only group, the self-explanatory information sheets the patients kept would have reinforced and encouraged patients while on bladder drills. Thus, patients on medication plus bladder training reported significantly better results after therapy than did patients on medication alone. In the previous study, in which the drills were simplified, it may have facilitated patient adherence to treatment, but without any further reinforcements, the therapeutic benefits of BT may have been compromised (17). In this study, we found that patient adherence to treatment was lowest and discontinuation rate highest in the BT group, although the treatment efficacy results were similar at the end of 12 weeks. This may be attributed to the longer duration of patient maneuvering required before experiencing significant improvement in this BT-only group. Thus, despite many efforts by the physician to make patients stay on the correct treatment regimen, it was evidently easier for patients to take medication twice a day than to repeat exercises many times a day for months. We noted no adverse effects in the BT group, whereas, in the other 2 groups, the most common adverse effect was dry mouth. We found that 6.3% of patients in the BT group and 6.5% in the Co group had to discontinue medication due to severe dry mouth, percentages lower than those previously reported (19, 20). These results indicate that 4 mg/day tolterodine is safe and does not require dose adjustment. 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TITLE: Comparison of intravenous immunoglobulin and plasma exchange in treatment of mechanically ventilated children with Guillain Barré syndrome: a randomized study
ABSTRACT.INTRODUCTION:
Respiratory failure is a life threatening complication of Guillain Barré syndrome (GBS). There is no consensus on the specific treatment for this subset of children with GBS.
ABSTRACT.METHODS:
This was a prospective randomized study to compare the outcome of intravenous immunoglobulin (IVIG) and plasma exchange (PE) treatment in children with GBS requiring mechanical ventilation. Forty-one children with GBS requiring endotracheal mechanical ventilation (MV) within 14 days from disease onset were included. The ages of the children ranged from 49 to 143 months. Randomly, 20 children received a five-day course of IVIG (0.4 g/kg/day) and 21 children received a five-day course of one volume PE daily. Lumbar puncture (LP) was performed in 36 patients (18 in each group).
ABSTRACT.RESULTS:
Both groups had comparable age (p = 0.764), weight (p = 0.764), duration of illness prior to MV (p = 0.854), preceding diarrhea (p = 0.751), cranial nerve involvement (p = 0.756), muscle power using Medical Research Council (MRC) sum score (p = 0.266) and cerebrospinal fluid (CSF) protein (p = 0.606). Children in the PE group had a shorter period of MV (median 11 days, IQR 11.0 to 13.0) compared to IVIG group (median 13 days, IQR 11.3 to 14.5) with p = 0.037. Those in the PE group had a tendency for a shorter Pediatric Intensive Care Unit (PICU) stay (p = 0.094). A total of 20/21 (95.2%) and 18/20 (90%) children in the PE and IVIG groups respectively could walk unaided within four weeks after PICU discharge (p = 0.606). There was a negative correlation between CSF protein and duration of mechanical ventilation in the PE group (p = 0.037), but not in the IVIG group (p = 0.132).
ABSTRACT.CONCLUSIONS:
In children with GBS requiring MV, PE is superior to IVIG regarding the duration of MV but not PICU stay or the short term neurological outcome. The negative correlation between CSF protein values and duration of MV in PE group requires further evaluation of its clinical usefulness.
ABSTRACT.TRIAL REGISTRATION:
Clinicaltrials.gov Identifier NCT01306578
BODY.INTRODUCTION:
Guillain-Barré syndrome (GBS) is, currently, the most common cause of acute flaccid paralysis following the worldwide decline in incidence of poliomyelitis. Incidence varies according to age, geographic areas and diagnostic criteria used for inclusion. Annual incidence in western countries varies from 1.1 to 1.8/100,000 population per year [1-5] with a considerably lower annual incidence of 0.66/100,000 population per year in each of Taiwan [6] and China [7]. GBS usually follows infection by a number of bacterial and viral agents with Campylobacter jejuni representing the most common preceding infection [8-11]. The syndrome is also reported to rarely temporally follow vaccination with measles vaccine [12,13], tetanus toxoid [14], rabies vaccine [15], oral polio vaccine [16], polysaccharide meningococcal vaccine [17], measles-rubella vaccine [18], flu vaccine [19] and hepatitis B vaccine [19]. Since the publishing of the first report of the condition by Guillain, Barré, and Strohl in 1916, GBS has remained a clinically-diagnosed disorder. The condition is a polyneuropathy involving mainly motor but sometimes also sensory and autonomic nerves. It starts with rapidly progressive bilateral and relatively symmetric weakness in the lower limbs with diminished or absent deep tendon reflexes. Paralysis follows an ascending pattern involving trunk, upper limb and, finally, bulbar muscles. There can be numbness, parathesia and muscle pain and tenderness. Labile blood pressure with postural hypotension and labile heart rate with episodes of bradycardia up to asystole rarely occur denoting autonomic neuropathy. van Doorn et al. categorize diagnostic features of the condition into features required for diagnosis, including progressive weakness in both arms and legs, and areflexia or hyporeflexia, and features that strongly support the diagnosis, including progression of symptoms to a nadir over days to four weeks, relative symmetry of symptoms, mild sensory symptoms or signs, cranial nerve involvement, autonomic dysfunction, pain, a high concentration of protein in CSF without increase in cells and typical electro-diagnostic features [20]. A common, yet not an early, feature of GBS is increased cerebrospinal fluid (CSF) protein (> 45 mg/dL) without CSF pleocytosis (< 10 cells/mm3), often referred to as cytoalbuminous dissociation [21]. Electromyography may be used to confirm the diagnosis in the small subset of patients where the diagnosis is not straightforward. It is also useful to sub-classify patients into motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy [22]. A recent study conducted in Egypt on children with GBS found that acute inflammatory demyelinating polyneuropathy, was the most common type (76%) while, acute motor axonal neuropathy, acute motor sensory axonal neuropathy and unclassified forms represented 8% each [23]. Respiratory failure is one of the most serious complications of GBS. It affects 15% of children with the condition [24]. The ability to predict the occurrence of respiratory failure and need for mechanical ventilation (MV) among patients with GBS has long been a target for neurologists and intensivists alike. Some bedside indicators of the likelihood of requiring MV are rapid disease progression, bulbar dysfunction, bilateral facial weakness, or dysautonomia, inability to stand, inability to lift the elbows or head, elevated liver enzymes and abnormal pulmonary function test [25-27]. Electrophysiological evidence of demyelination was also suggested to predict the need for endotracheal MV [28]. Treatment of GBS is a multidisciplinary effort. The general care of the child with muscle weakness includes regular monitoring of pulmonary and cardiovascular function for possible involvement of respiratory muscles and autonomic neuropathy respectively, prevention of infection and deep vein thrombosis, pain management, early physiotherapy, early rehabilitation once muscle power improvement starts and psychosocial support for the affected children and their families [20]. Specific treatment of severely affected children comprises intravenous immunoglobulin (IVIG) or plasma exchange (PE). Performed on more than 200 patients each, two large trials in the mid-1980s confirmed the beneficial role of PE in treatment of patients with GBS compared to the conventional treatment of the time [29,30]. The routine use of IVIG as the first line of treatment in GBS followed the publication of a randomized controlled trial (RCT) in 1992 showing a similar, if not a superior, effect of IVIG compared to PE [31]. A recent systematic review of heterogeneous study populations showed there was no evidence for a better outcome with either of the two modalities of treatment. There is also no evidence of a beneficial effect of adding corticosteroids to the treatment [32]. The objective of this study is to compare PE and IVIG as a first line treatment for children with severe GBS requiring MV regarding the duration of MV, PICU stay and short term neurological outcome.
BODY.MATERIALS AND METHODS:
Children with GBS admitted to the Pediatric Intensive Care Unit (PICU) at Mansoura University Children Hospital, Mansoura, Egypt, with the need for MV were prospectively enrolled in the study. Cases were diagnosed to have GBS according to clinical criteria by van Doorn et al. [20]. Patients were eligible for inclusion if they required MV based on the indications listed below, and if the duration of muscle weakness did not exceed 14 days on enrollment. Children were not eligible for inclusion if they had muscle weakness for longer than 14 days before requiring MV and if IVIG or PE was started prior to enrollment. All patients were ventilated using endotracheal MV. Children were intubated if they were unable to protect their airway, had increased work of breathing (WOB), had PaO2 less than 70 mmHg in room air requiring increasing FiO2, or showed CO2 retention. When children were able to trigger spontaneous breathing, they were changed to a pressure-support spontaneous ventilation mode with continuous positive airway pressure of 5 cm H2O. Pressure support was gradually weaned to 10 cm H2O. If secretions were manageable and airway reflexes intact, a daily spontaneous breathing trial (SBT) was performed using a T-piece for two hours. Patients were extubated if SBT was successful. An SBT was deemed successful if there was no diaphoresis, increased WOB or apnea, tachycardia (defined by increase in the heart rate of 40 bpm or more) and if SpO2, pH, PaO2 and PaCO2 remained close to pre-SBT values. The decisions to initiate, wean and terminate MV were made independently by the attending consultant in accordance with and in strict adherence to the unit guidelines as above. Over a period of three years, from January 2007 to December 2009, 44 children were admitted with GBS requiring MV; 41 children fulfilled inclusion criteria and were randomized to receive either IVIG (20 children) or PE (21 children) for initial treatment. Randomization was done by computer-generated random tables. IVIG was administered in a dose of 0.4 g/kg/day for five days. Patients in the PE group received a daily one-volume PE for five consecutive days. The sample size yields a study power of 86.9%. On admission, the muscle power was recorded using the Medical Research Council (MRC) sum score [33]. Lumbar puncture (LP) was performed in the second week of illness in 36 out of the 41 children (18 in each group). LP was performed at the discretion of the attending consultant. The primary outcome measure was the duration of mechanical ventilation and secondary outcome measures were length of PICU stay and ability to walk unaided within four weeks of PICU discharge. Institutional research ethics committee approval was granted and an informed consent was obtained from legal guardians of children included in the study. Statistical analysis was performed using Statistical Package for the Social Sciences, Version 17 (SPSS, Inc., Chicago, IL, USA). p-value was considered significant if less than .05.
BODY.RESULTS:
Children in the two treatment groups were comparable as regards base line characteristics, such as age, weight, duration of illness prior to requiring mechanical ventilation, presence or absence of preceding diarrhea, cranial nerve affection, severity of muscle weakness on PICU admission and CSF protein when available (Table 1). Table 1 Comparison of IVIG and PE groups regarding base line variables IVIG group ( n = 20) PE group ( n = 21) p- value Age (months) 106.0 ± 22.8 (74.3 to 113.5) 96.0 ± 32.8 (65.5 to 135.0) 0.764 1 Weight (kg) 32.5 ± 7.0 (23.0 to 34.8) 29.0 ± 10.1 (20.0 to 41.5) 0.764 1 DOI (days) 9.0 ± 2.7 (7.0 to 12.0) 9.0 ± 2.8 (6.5 to 11.5) 0.854 1 Diarrhea (%) Yes 13 (65%) 12 (57.1%) 0.751 2 No 7 (35%) 9 (42.9%) Cranial nerve affection (%) Yes 8 (40%) 10 (47.6%) 0.756 2 No 12 (60%) 11 (52.4%) MRC sum score 12.0 ± 4.8 (8.5 to 15.5) 12.0 ± 5.9 (4.0 to 12.0) 0.266 1 CSF protein (mg/dL) 152.1 ± 55.7 (88.3 to 173.6) 148.4 ± 43.0 (117.5 to 166.5) 0.606 1 IVIG, intravenous immunoglobulin; PE, plasma exchange; DOI, Duration of illness prior to requiring mechanical ventilation; MRC, Medical Research Council score. Data presented as median ± SD (interquartile range) 1 Mann Whitney test 2 Chi square test. There was a statistically insignificant better outcome in the PE group compared to the IVIG group. Favorable outcome was defined as the child's ability to walk independently for 10 meters (Grade 2 on GBS disability score) [34] within four weeks from PICU discharge. The post discharge management and physiotherapy were standardized for children in the two groups. In the IVIG group, favorable outcome was observed in 90% (18/20) of children compared to 95.2% (20/21) in the PE group (Table 2). Table 2 Comparison of PICU stay and duration of mechanical ventilation in the IVIG and PE groups PICU stay (days) Mechanical ventilation (Days) Favorable outcome (%) Yes No IVIG group 16.5 ± 2.1 (15.3 to 18.8) 13.0 ± 2.1 (11.3 to 14.5) 18 (90%) 2 (10%) PE group 15.0 ± 2.6 (13.0 to 17.0) 11.0 ± 1.5 (11.0 to 13.0) 20 (95.2%) 1 (4.8%) p- value .094 1 0.037 1 0.606 2 IVIG, intravenous immunoglobulin; PE, plasma exchange. Data presented as median ± SD (interquartile range) 1 Mann Whitney test 2 Chi square test. Children receiving PE had a significantly shorter period of mechanical ventilation compared to those receiving IVIG. The hospital stay was shorter in the PE group without statistical significance (Table 2). For all patients, there was a statistically significant negative correlation between CSF protein and duration of mechanical ventilation (p = .024). Examining the treatment groups separately, the significant negative correlation remained for the PE group (p-value = 0.037) and not for the IVIG group (p-value 0.132) (Table 3). Table 3 Correlation between CSF protein and duration of mechanical ventilation All patients IVIG group PE group CSF protein (mg/dL) 149.3 ± 49.0 (110.5 to 169.0) 152.1 ± 55.7 (88.3 to 173.6) 148.4 ± 43.0 (117.5 to 166.5) Mechanical ventilation (days) 12.0 ± 1.9 (11.0 to 13.0) 13.0 ± 2.1 (11.3 to 14.5) 11.0 ± 1.5 (11.0 to 13.0) p -value 0.024 1 0.132 1 0.037 1 CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin; PE, plasma exchange. Data presented as median ± SD (interquartile range) 1 Pearson test. There was no significant side effect attributable to any of the treatment modalities in any of the studied patients.
BODY.DISCUSSION:
Respiratory failure among children with GBS is a serious complication requiring intensive supportive treatment in addition to the specific treatment. The two treatment groups had no significant complications attributable to treatment intervention apart from minor hypotension episodes responding to fluid boluses in the PE group. This confirms the safety of both IVIG and PE for treating children with GBS. The results of this study suggest that PE is more useful than IVIG as a specific treatment for the subset of children with severe rapidly progressive GBS requiring MV. PE is believed to act by removal of circulating autoantibodies [35,36], while IVIG, among other mechanisms, is thought to work through blocking antibody production both in vivo [37] and in vitro [38,39]. Removal of autoantibodies, by PE, creates a concentration gradient between the lowered blood level and the extravascular space forcing antibody movement from the extra to the intra vascular space to be removed during the subsequent session [40]. Specific anti-ganglioside antibody levels were recently found to be associated with disease severity [41]. Children with severe, rapidly progressive GBS, as those included in this study, most likely have an intense autoantibody production with a high percentage of these antibodies already bound to nerves on development of respiratory failure. This might provide an explanation of why this subset of patients preferentially benefit from removal of already bound antibodies, PE, in comparison to blocking antibody production, IVIG. The clinical usefulness of this relatively small difference in the duration of mechanical ventilation between PE and IVIG groups waits to be confirmed in a larger, probably multi-center, study. CSF protein was elevated in all patients (Table 3) with no statistically significant difference between the two treatment groups (Table 1). On post hoc analysis, there was, however, a negative correlation between CSF protein level and duration of MV in PE but not IVIG group. This finding supports the above explanation of a shorter duration of MV in the PE group especially in view of a RCT showing CSF filtration to be at least as effective as PE for treatment of GBS [42] and the suggestion of a blood-CSF barrier dysfunction in adults and children with GBS [43]. PE group had a tendency for a shorter PICU stay, p = 0.094 with a comparable ability of children to walk unaided within four weeks from PICU discharge (Table 2). So, despite a shorter duration of MV, there was no difference between PE and IVIG groups regarding PICU stay or short term neurological outcome. To our knowledge, this is the first randomized controlled study comparing PE and IVIG for treatment of children with rapidly progressive GBS requiring MV. An RCT conducted in adults with GBS showed no difference in the duration of MV in PE, IVIG and combined treatment groups [44]. This difference can be accounted for by differences in the age and PE protocol used. It would have been more informative to perform an electrophysiological study for the study children to confirm homogeneity of the study population. It would also add to the understanding of these results to study kinetics of autoantibodies in future research with a similar design.
BODY.CONCLUSIONS:
Rapidly progressive GBS necessitating MV in children responds favorably to both IVIG and PE, with PE being superior in regard to the duration of MV but not PICU stay or short term neurological outcome. The finding of a negative correlation between CSF protein values and duration of MV in the PE group might serve as a basis for future research aiming at a better understanding of autoantibody kinetics during treatment of GBS.
BODY.KEY MESSAGES:
• Children with GBS requiring MV respond favorably to both IVIG and PE. • Using a weaning and extubation protocol, children receiving PE had a shorter duration of MV.
BODY.ABBREVIATIONS:
CSF: cerebrospinal fluid; DOI: duration of Illness; GBS: Guillain-Barré syndrome; IVIG: intravenous immunoglobulin; LP: lumbar puncture; MRC: Medical Research Council; MV: mechanical ventilation; PE: plasma exchange; PICU: pediatric intensive care unit; SBT: spontaneous breathing trial; WOB: work of breathing.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
MAE formulated the research idea, designed the plan, performed statistical analysis and proofread the draft. AME co-designed the plan and supervised the plasma exchange making sure of uniformity of the procedure in all studied subjects and proofread the draft. AMA followed up patients on PICU, made sure the plan was followed, and helped MAE in performing statistical analysis. ME followed up patients on PICU, drafted the manuscript, and designed statistical methodology. AAA co-formulated the research idea, co-designed the plan, followed up patients on PICU, and generated and was responsible for the random assignment of the groups. HME followed up patients on PICU, co-drafted the manuscript with ME and made sure PICU management of patients complied with the unit guidelines. All authors read and approved the final manuscript.
BODY.AUTHORS' INFORMATION:
HME is one of the founding members and the current president of the ESPIC (Egyptian Society of Pediatric Intensive Care). MAE is a member of the Board of Directors of WFPICCS (World Federation of Pediatric Intensive Care Societies) and the ambassador of WFPICCS in Egypt. An abstract of this article has been presented by MAE as an oral presentation at the 6th World Congress of Pediatric Intensive Care, Sydney, 2011. | 3,387,601 | {
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TITLE: The Effect of Clofibrate on Decreasing Serum Bilirubin in Healthy Term Neonates under Home Phototherapy
ABSTRACT.OBJECTIVE:
This study was designed to determine the effect of clofibrate on neonatal uncomplicated jaundice treated with home phototherapy.
ABSTRACT.METHODS:
This clinical trial study was performed on 60 newborns with jaundice that received home phototherapy. Inclusion criteria were body weight between 2500 to 4000 gr, breastfed, total serum bilirubin (TSB) between 14 to 20 mg/dl, aged over 72 hours. The neonates were randomly divided into two groups. All received home phototherapy. Group I received a single dose of 50 mg/kg clofibrate and the other group served as control group. Total serum bilirubin level was measured every 24 hours.
ABSTRACT.FINDINGS:
Two groups were matched regarding weight, sex, age and first TSB. At 24 and 48 hours of treatment, the mean values of TSB in the clofibrate group were 13.72 (1.56), 9.5 (0.56) and in the control group 15.30 (1.44), 12.6 (1.44). The results show that TSB was significantly decreased after 24 and 48 hours in clofibrate group (P<0.001). The mean duration of phototherapy in group I was 72(0.0) hours and in the control group 76.80 (±9.76) hours. The duration of phototherapy was significantly shorter in clofibrate group (P<0.001).
ABSTRACT.CONCLUSION:
Clofibrate is effective for outpatients with neonatal hyperbilirubinemia who are under home phototherapy. Of course, further studies are needed for approved routine use of this drug in the treatment of neonatal jaundice.
BODY.INTRODUCTION:
In the first day of life, bilirubin production is increased to an estimated average of 8 to 10 mg/kg of body weight per day, an amount about two or three times greater than that of adults[1]. Approximately two thirds neonates become clinically jaundiced. Phototherapy is the most widely used form of therapy for the treatment and prophylaxis of neonatal hyperbilirubinemia[2]. Several potential complications may occur with the use of phototherapy[3], such as retinal degeneration, fluid imbalance, and bronze baby syndrome. Some reports have demonstrated that home phototherapy may be an effective and safe alternative to prolonged hospitalization for healthy full-term neonates with jaundice. Clear advantages of home-centered phototherapy include: (1) reduced coast; (2) avoidance of parent-infant separation; and (3) parental satisfaction[4]. Although some pharmacological agents such as activated charcoal[5] or agar[6] are suggested to treat neonatal jaundice, further study of this type of therapy is needed before to their routine clinical use. Glucuronyl transferase activity can be increased with administration of phenolbarbital[7] or clofibrate[8]. Clofibrate decreases serum cholesterol and triglyceride levels in adults[9]. This drug has been proposed for treatment of neonatal hyperbilirubinemia[10]. Mohammadzadeh et al studied the effect of clofibrate on reducing serum bilirubin of neonates beyond the first week of life[11]. Badeli and colleagues determined the effect of clofibrate on uncomplicated hyperbilirubinemia of neonates during the first week of life[12]. Mohammadzadeh and badeli studied the effect of 100mg/kg clofibrate. The aim of the present study was determination the effect of 50 mg/kg of clofibrate on tsb of hyperbilirubinemia of neonates under home phototherapy.
BODY.SUBJECTS AND METHODS:
From April 4, 2007 to June 20, 2008 60 neonates with uncomplicated hyperbilirubinemia who were under home phototherapy in rasht, Iran, entered our study. The ethics committee of our university approved the study. Informed consent of the parents was obtained. Inclusion criteria were body weight between 2500–4000 grams with gestational age 38 to 41 weeks, breastfed, and having total serum bilirubin (TSB) between 14 to 20 mg/dl, with postnatal age above 72 hours. Infants with abo or rh incompatibility, g6pd deficiency, and conjugated hyperbilirubinemia or any concomitant disease were excluded. Portable phototherapy units consist of 4 special blue tubes placed 40 cm above the infant as home phototherapy. Patients were examined and a sample of serum bilirubin was taken daily. The neonates (n=60) were randomly divided into two groups and they were matched regarding weight, sex, age and value of the first TSB. 30 neonates were allocated to clofibrate group (group I) and 30 neonates to control group (group II). All neonates in the two groups received home phototherapy. The control group received no placebo. Clofibrate group (group I) was given a single dose of 50 mg/kg clofibrate before starting phototherapy. In the first day, laboratory tests included estimation of total bilirubin (direct and indirect), blood group including rh of the mother and neonate, complete blood count (cbc), g6pD activity, coombs test, reticulocyte count. Direct and indirect, as well as tsb were measured every 24 hours by the same laboratory till tsb dropped under 10 mg/dl. The duration of phototherapy was recorded with a timer. Data were analyzed using spss 10; t-test and ANOVA were used for analyzing the data. P-value less than 0.05 was considered significant.
BODY.FINDINGS:
Among 60 neonates, 30 infants consisting of 18 (60%) females and 12 (40%) males belonged to group I (clofibrate) and 17 (56.7%) females and 13 (43.3%) males to group II (control). There were no statistically significant differences between the two groups regarding weight, age and first tsb value (Table 1). TBS values show significant difference between the two groups 24 and 48 hours after starting phototherapy at home. Group I showed lower value (Table 2). Mean (±SD) phototherapy time in group I was 72(±0.0) hours and in group II 76.80 (±9.76) hours.
Table 1 Mean (±SD) age, weight and first TSB- value in the two groups Parameter Group I Group II Mean (±SD ‡ ) Mean (±SD)
Age (day)
6.80 (3.24) 6.6 (2.50)
Weight (g)
3107 (394.89) 3150 (469.40)
TSB * (mg/dl)
17.24 (1.48) 17.42 (1.44) ‡ SD: standard deviation * TSB: total serum bilirubin Table 2 Comparison of mean total serum bilirubin (mg/dl) after 24 and 48 hours of phototherapy in the two groups Time (hour) Group n Mean(SD * ) total bilirubin (mg/dl)
p - value
24
Clofibrate(I)
30 13.72 (1.56) <0.001
Control (II)
30 15.30 (1.44)
48
Clofibrate(I)
30 9.5 (0.56) <0.001
Control (II)
30 12.6 (1.44) * Standard Deviation The duration of phototherapy was significantly shorter in clofibrate group (P<0.001). All neonates in group I needed phototherapy still after 72 hours but in group II 24 (80%) neonates had to receive phototherapy for 72 and 6 (20%) for 96 hours. Serum bilirubin levels after physician's examining were measured at beginning and 24, 48 hours after phototherapy. Bilirubin of both groups was measured in the same laboratory. On serial daily examination during phototherapy and up to 2 days after that no problems or side effects were observed. Also for a period of two months no complication was detected.
BODY.DISCUSSION:
In this clinical trial study we determined the effect of lower dose (50 mg/kg) of clofibrate on neonatal hyperbilirubinemia in term neonates under home phototherapy. In the present study we demonstrated that in clofibrate group there was lower tsb after 24 and 48 hours home phototherapy compared with control group. Also the neonates in group I needed to receive shorter phototherapy than those in group II. The neonatal hyperbilirubinemia is the most common disease in neonatal period. Although there are advantages of home phototherapy, several potential complications may occur with its use. At present there is no safe drug for treatment of neonatal icterus and shortening of phototherapy time. The effect of numerous drugs on bilirubin metabolism and reducing hyperbilirubinemia has been identified. Metalloporphyrins and d-penicillamine act by inhibition of heme oxygenase, agar and charcoal by decreasing entrohepatic circulation. The clofibrate and phenobarbital are potent inducers of microsomal enzymes that increase bilirubin conjugation and excretion[13]. Clofibrate like phenobarbital is a hepatic bilirubin metabolism inducer, in addition causes 100% increase of hepatic bilirubin clearance within 6 hours with no drowsiness effect in contrast to the latter. Clofibrate when used as an antilipidemic agent in adults, has some side effects such as nausea, gastrointestinal disturbance, vomiting and loose stools[14]. Other possible complications include cramps, fatigue, pruritus and alopecia[14]. None of these side effects were reported in neonates with a single dose of clofibrate[15, 16]. Like phenobarbital, clofibrate increases bilirubin conjugation and excretion and is a better enhancer of glucuronosyl transferase induction causing 100% increase of hepatic bilirubin clearance within 6 hours[17], sooner than phenobarbital[13]. Phenobarbital has a long half life and its effect on severe jaundice is questionable. Phenobarbital also causes drowsiness in neonates and may slow down the oxidation of bilirubin in the brain leading to worse bilirubin toxicity[18]. Although we detected in our studies no side effects in infants with a single dose of clofibrate, determination of minimum and effective dose would be important. This study demonstrated that a single dose of clofibrate (50mg/kg) significantly reduces indirect hyperbilirubinemia in healthy breastfed term newborns with home-based phototherapy. This result is similar to the studies of mohammadzadeh et al and badeli et al, noting that they used 100 mg/kg of the drug in hospitalized patients. Our study demonstrated that lower dose of clofibrate is effective on neonatal hyperbili-rubinemia receiving home phototherapy as well. Glabilan[17] used clofibrate in the treatment of early jaundice in full term neonates. He found significant reduction in bilirubinemia at 16 hours and decrease in the intensity and duration of jaundice and also phototherapy requirement. Lindenbaum showed significant reduction 16 hours after treatment with clofibrate in TSB of 47 neonates[19]. Other studies in Iran and France confirmed the beneficial effect of clofibrate for reducing of TSB in babies with no risk factor for hemolysis[20]. In conformity with those previous studies, we did not detect any untoward complications during therapy and after two months follow up. Twenty mothers discontinued home phototherapy because of their own concern or others' comments; they were excluded of the study.
BODY.CONCLUSION:
This study suggests that a lower dose of clofibrate is effective in outpatients with neonatal hyperbilirubinemia under home phototherapy. Similar to other studies we found no complications. Further studies are needed for approved routine use of this drug in non-hemolytic hyperbilirubinemia of healthy term inewborns as outpatients. | 3,446,002 | {
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TITLE: Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial
ABSTRACT.OBJECTIVES::
To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda.
ABSTRACT.DESIGN::
Randomized single-blinded clinical trial.
ABSTRACT.SETTING::
Apac, Uganda, an area of very high malaria transmission intensity.
ABSTRACT.PARTICIPANTS::
Children aged 6 mo to 10 y with uncomplicated falciparum malaria.
ABSTRACT.INTERVENTION::
Treatment of malaria with AL or DP, each following standard 3-d dosing regimens.
ABSTRACT.OUTCOME MEASURES::
Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.
ABSTRACT.RESULTS::
Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%–26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%–19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%–12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%–16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs.
ABSTRACT.CONCLUSION::
DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.
BODY.INTRODUCTION:
In Africa, treatment of uncomplicated malaria is undergoing dramatic changes. In response to widespread resistance of the parasite to commonly used monotherapies, particularly chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), many countries have recently adopted artemisinin-based combination therapy (ACT) as a first-line regimen for the treatment of uncomplicated malaria [1]. In Uganda, artemether-lumefantrine (AL) was chosen to replace the combination of CQ + SP as the first-line regimen for malaria in 2004, with amodiaquine + artesunate (AQ + AS) offered as an alternative regimen. Although data on AL were limited at that time, subsequent studies from Uganda [2,3] and elsewhere in Africa [4–6] showed that AL was highly efficacious and well tolerated for uncomplicated malaria. Indeed, in the two published studies of AL from Uganda the risk of treatment failure due to recrudescence was reported to be less than 2% [2,3]. However, despite the promise of AL, there are substantial limitations to this regimen, including twice-daily dosing and need for administration with fatty food. A concern with all antimalarial regimens, particularly in areas of high transmission, is frequent recurrence of malaria after therapy. This concern was highlighted in a recent study comparing efficacies of the ACTs AL and AQ + AS in Tororo, Uganda, an area with very high malaria transmission [3]. In that study, both regimens were highly efficacious for eradication of infections but risks of reinfection were extremely high, with 50% of AL-treated and 66% of AQ + AS–treated patients developing recurrent parasitemia within 28 d. Dihydroartemisinin-piperaquine (DP) is a fixed-dose ACT that has recently become available in Africa. In studies from Southeast Asia, DP appeared to be well tolerated and highly efficacious against multidrug-resistant falciparum malaria [7–11]. However, the epidemiology of malaria and patterns of antimalarial drug use are quite different in Africa than in Asia [12,13]. In the only published study evaluating DP in Africa, DP was highly efficacious with a good safety and tolerability profile at three sites in Rwanda [14]. To compare the performance of DP with the new first-line therapy in Uganda, we conducted a randomized clinical trial comparing the efficacy and safety of AL and DP for the treatment of uncomplicated falciparum malaria in Apac, an area of extremely high transmission intensity.
BODY.METHODS.STUDY SITE:
The study was conducted at Aduku Health Centre, Apac District, Uganda. The district experiences perennial holoendemic malaria. The entomological inoculation rate in Apac, a measure of transmission intensity, was measured at 1,564 infectious bites per person per year [15]. The study protocol was approved by the Makerere University Research and Ethics Committee, the Uganda National Council of Science and Technology, and the University of California San Francisco Committee for Human Research.
BODY.METHODS.PARTICIPANTS:
Consecutive patients presenting to the health center with symptoms suggestive of malaria and a positive screening thick blood smear were referred to study physicians for further assessment. Patients were enrolled if they fulfilled the following selection criteria: (1) age 6 mo to 10 y; (2) weight ≥ 5 kg; (3) history of fever in the last 24 h or axillary temperature ≥ 37.5 °C; (4) no history of serious side effects to study medications; (5) no evidence of a concomitant febrile illness; (6) provision of informed consent by a parent or guardian; (7) no danger signs or evidence of severe malaria; and (8) Plasmodium falciparum monoinfection with parasite density 2,000–200,000/μl of blood. Because laboratory results were generally not available until the following day, a patient could be excluded after randomization.
BODY.METHODS.PROCEDURES:
At enrollment, we asked children's parents or guardians about prior antimalarial therapy, use of other medications, and presence of common symptoms. Axillary temperature and weight were measured, and a physical examination was performed. A brief neurological assessment, consisting of simple clinical tests for fine finger dexterity (ability to pick up a small object), was undertaken. We also obtained blood by fingerprick for thick and thin blood smears, for hemoglobin assessment, and to store on filter paper for molecular analysis. Patients were asked to return for follow-up on days 1, 2, 3, 7, 14, 21, 28, 35, and 42, and any other day that they felt ill. Follow-up evaluation consisted of a standardized history and physical examination, including neurological assessment on all days of follow-up. We obtained blood by fingerprick for thick blood smears and storage on filter paper on all follow-up days except day 1. Hemoglobin measurement was repeated on day 42 or the day of recurrent symptomatic malaria. If patients did not return for follow-up, they were visited at home. Blood smears were stained with 2% Giemsa for 30 min. Parasite densities were determined from thick blood smears by counting the number of asexual parasites per 200 white blood cells (WBCs), or per 500 if the count was less than 10 parasites/200 WBCs, assuming a WBC count of 8,000/μl. A smear was considered negative if no parasites were seen after review of 100 high-power fields. We also assessed gametocytemia from thick blood smears. Thin blood smears were reviewed for non-falciparum infections. A second microscopist, who was unaware of the results of the first reading, re-read all slides. A third microscopist unaware of the first two readings resolved discrepant slides. Hemoglobin measurements were made using a portable spectrophotometer (HemoCue, http://www.hemocue.com).
BODY.METHODS.INTERVENTIONS:
On day 0, patients were randomly assigned to receive AL or DP. A nurse administered study medications according to weight-based guidelines for administration of fractions of tablets. We administered all drugs orally as follows: AL (Coartem, Novartis, 20 mg artemether/120 mg lumefantrine tablets), administered according to weight as one (5–14 kg), two (15–24 kg), three (25–34 kg), or four (≥ 35 kg) tablets given twice daily for 3 d; DP (Duocotexin, Holley Pharm, 40 mg dihydroartemisinin/320 mg piperaquine tablets), targeting a total dose of 6.4 and 51.2 mg/kg of dihydroartemisinin and piperaquine, respectively, given in three equally divided daily doses to the nearest quarter tablet. We used a pill cutter to ensure that the tablet fractions were as close to the nearest quarter tablet as possible. Participants in the DP group also received placebo tablets administered in the evening over 3 d to simulate the AL dosing schedule. Study medications were administered with water, and patients were given a glass of milk after each dose of study medication. All treatment was directly observed. Participants were given the option either to wait at the clinic for the evening dose (lunch was provided) or to leave the clinic and return in the evening (transport was provided). After each dose, children were observed for 30 min, and the dose was readministered if vomiting occurred. All patients were provided with a 3 d supply of acetaminophen for treatment of febrile symptoms. Children with hemoglobin of less than 10 g/dl were treated according to Integrated Management of Childhood Illness guidelines with ferrous sulfate for 14 d and antihelminthic treatment if appropriate. Households of all patients were given two long-lasting insecticide-treated bed nets (ITNs) (PermaNet, Vestergaard Frandsen, http://www.vestergaard-frandsen.com) on the day of enrollment, with instructions for one net to be used by the study patient.
BODY.METHODS.OBJECTIVES:
The objectives of the study were to compare the efficacy and safety of AL and DP for the treatment of uncomplicated falciparum malaria at a high transmission–intensity site in Uganda.
BODY.METHODS.OUTCOMES: EFFICACY:
Treatment outcomes were classified according to 2006 World Health Organization (WHO) guidelines as early treatment failure (ETF; danger signs or complicated malaria or failure to adequately respond to therapy days 0–3); late clinical failure (LCF; danger signs or complicated malaria or fever and parasitemia on days 4–42 without previously meeting criteria for ETF or LPF); late parasitological failure (LPF; asymptomatic parasitemia days 7–42 without previously meeting criteria for ETF or LCF); or adequate clinical and parasitological response (absence of parasitemia on day 42 without previously meeting criteria for ETF, LCF, or LPF) [16]. Patients were treated with quinine sulfate (10 mg/kg three times daily for 7 d) on the day that they fulfilled criteria for early treatment failure or late clinical failure. Patients with late parasitological failure were followed, and were given quinine only if they developed fever with parasitemia or remained parasitemic on the last day of follow-up. Patients were excluded from further follow-up after enrollment if any of the following occurred: (1) use of antimalarial drugs outside of the study protocol; (2) withdrawal of consent; (3) loss to follow-up; (4) protocol violation; or (5) death due to a nonmalarial illness. The primary efficacy outcomes were the 28- and 42-d risks of early treatment failure or recurrent parasitemia (LCF or LPF), unadjusted and adjusted by genotyping. Secondary efficacy outcomes included prevalence of fever and parasitemia during the first 3 d of follow-up, change in mean hemoglobin from day 0 to day 42 or day of repeat therapy, and prevalence of gametocytemia (presence of gametocytes on thick smears) during follow-up in participants lacking gametocytes at enrollment. Molecular genotyping techniques were used to distinguish recrudescent from new infections for all patients with LCF or LPF response. Briefly, parasite DNA was isolated from filter paper blood samples collected at enrollment and on the day of recurrent parasitemia using chelex extraction. Paired samples were genotyped in a stepwise fashion using merozoite surface protein (msp)-2, msp-1, and four microsatellites [17]. If, for any of the six loci, an allele was not shared between day 0 and day of recurrence, the infection was classified as a new infection. If at least one allele was shared between day 0 and day of recurrence at all six loci, the infection was classified as a possible recrudescence. The term "possible recrudescence" was used because the complexity of infection (number of infecting parasite strains) was very high in our setting, making it difficult to distinguish definitively a true recrudescence from a new infection.
BODY.METHODS.OUTCOMES: SAFETY:
Secondary safety outcomes included risks of serious adverse events and common adverse events of any severity. An adverse event was defined as any untoward medical occurrence, irrespective of its suspected relationship to the study medications [18]. At each follow-up visit, patients were assessed for any new or worsening event. All events were graded by severity (none, mild, moderate, severe, life-threatening) and relationship to study treatment (none, unlikely, possible, probable, or definite) using guidelines from the World Health Organization (Toxicity Grading Scale for Determining the Severity of Adverse Events) [19]and the United States National Institutes of Health, Division of Microbiology and Infectious Diseases (Pediatric Toxicity Tables, May 2001) [20]. A serious adverse event was defined as any adverse experience that resulted in death, life-threatening experience, inpatient hospitalization, persistent or significant disability or incapacity, or specific medical or surgical intervention to prevent serious outcome.
BODY.METHODS.SAMPLE SIZE:
We calculated sample size to test the hypothesis that the risk of recurrent parasitemia after 42 d would differ between the two treatment groups. Based on previous data, the risk of recurrent parasitemia (unadjusted by genotyping) after 42 d was estimated to be 50% after treatment with AL [3]. Using this estimate, we calculated that 200 patients (allowing for 10% loss to follow-up) would need to be enrolled in each treatment arm to detect a 15% risk difference between the treatment groups with a two-sided type I error of 0.05 and power of 80%.
BODY.METHODS.RANDOMIZATION: SEQUENCE GENERATION, ALLOCATION CONCEALMENT, IMPLEMENTATION:
A randomization list was computer generated by an off-site investigator without the use of blocking or stratification. Sequentially numbered, sealed envelopes containing the treatment group assignments were prepared from the randomization list. The study doctors assigned treatment numbers sequentially and the study nurse allocated treatment by opening the envelope corresponding to the treatment number. The randomization codes were secured in a locked cabinet accessible only by the study nurse. Participants were enrolled by the study physicians, and treatments were assigned and administered by the study nurse.
BODY.METHODS.BLINDING:
Only the study nurse was aware of treatment assignments. All other study personnel, including the study physicians and laboratory personnel involved in assessing outcomes, were blinded to the treatment assignments. Patients were not informed of their treatment regimen, but the color of the two study medications was not the same (DP and placebo tablets were light blue; AL tablets were light yellow).
BODY.METHODS.STATISTICAL METHODS:
Data were entered and verified using Epi Info version 6.04 and analyzed using STATA version 8.0 (STATA, http://www.stata.com). Efficacy and safety data were evaluated using a modified intention-to-treat analysis which included all patients who fulfilled enrollment criteria. Patients who were randomized to therapy but not enrolled in the study due to laboratory results available on day 1 were not included in the analysis. Risks of recurrent parasitemia at 28 and 42 d of follow-up (adjusted and unadjusted by genotyping) were estimated using the Kaplan-Meier product limit formula. Data were censored for patients who did not complete follow-up and for new infections when estimating outcomes adjusted by genotyping. Patients with LCF or LPF due to non-falciparum species were censored as non-failures at the time they were classified as LCF or LPF. The Z-test was used to compare the Kaplan-Meier estimates of treatment efficacy at fixed points in time between the treatment groups. Confidence intervals around the difference between Kaplan-Meier estimates were calculated using normal approximation and Greenwood's estimates of standard errors. Categorical variables were compared using Chi-squared or Fisher exact test and continuous variables were compared using the independent samples t-test. All reported p-values are two sided without adjustment for multiple testing and were considered statistically significant if below 0.05.
BODY.RESULTS.PARTICIPANT FLOW:
Of 572 patients screened, 509 were randomized to treatment, and 421 were enrolled in the study (Figure 1). Primary efficacy outcomes, unadjusted and adjusted by genotyping, were available for 417 (99%) and 416 (99%) enrolled participants, respectively. One patient with an unsuccessful genotyping result in the AL group was not included in the analysis when adjusting for genotyping. Figure 1Trial Profile
BODY.RESULTS.RECRUITMENT:
The study was conducted between March and July 2006.
BODY.RESULTS.BASELINE DATA:
Among patients enrolled in the study, there was no difference at baseline of gender, age, temperature, parasite density, hemoglobin, or recent antimalarial use between the two treatment groups (Table 1). Among patients treated with AL, the mean total doses (standard deviation [SD]) were 13.1 (2.8) mg/kg for artemether and 78.8 (17.1) mg/kg for lumefantrine. Among patients treated with DP, the mean total doses (SD) were 7.3 (1.0) mg/kg for dihydroartemisinin and 58.4 (8.0) mg/kg for piperaquine. Table 1 Baseline Characteristics of Participants According to Treatment Group
BODY.RESULTS.OUTCOMES AND ESTIMATION.PRIMARY EFFICACY OUTCOMES.:
There were no early treatment failures in the first 3 d following initiation of therapy. Episodes of recurrent parasitemia were first detected 14 d following therapy in the AL arm and 21 d following therapy in the DP arm (Figure 2; Table 2). The risk of recurrent falciparum parasitemia unadjusted by genotyping was significantly lower for participants treated with DP than for those treated with AL after 28 d of follow-up (11% versus 29%; risk difference [RD] = 18%, 95% confidence interval [CI] 11%–26%) and after 42 d of follow up (43% versus 53%; RD = 9.6%, 95% CI 0%–19%) (Table 3). Similar trends were seen when results were adjusted by genotyping. The risk of recurrent parasitemia due to possible recrudescence was significantly lower for participants treated with DP than for those treated with AL after 28 d of follow-up (1.9% versus 8.9%; RD = 7.0%, 95% CI 2.5%–12%) and after 42 d of follow up (6.9% versus 16%; RD = 9.5%, 95% CI 2.8%–16%) (Table 3). Among patients with recurrent parasitemia, the median time to recurrent parasitemia was significantly shorter in patients treated with AL compared to patients treated with DP (28 d versus 35 d, p < 0.0001). Additionally, patients treated with AL had a higher risk of recurrent parasitemia due to non-falciparum species (all were either P. malariae or P. ovale) compared to patients treated with DP (5.2% versus 0.9%, p = 0.01). Results were similar when restricting the analyses to children under the age of 5 y, as 94% of patients enrolled were in this age range. Figure 2Cumulative Risk of Recurrent Parasitemia Stratified by Treatment Group Table 2 WHO Treatment Outcomes after 42 Days of Follow-Up Table 3 Estimates of Comparative Efficacy Patients with asymptomatic recurrent parasitemia (LPF) were not treated unless they developed symptomatic malaria or reached the end of the 42-d follow-up period. Among 121 patients with LPF occurring before day 42, only six (5%) spontaneously cleared their parasites without treatment, 86 (53/75, 71% in AL group and 33/46, 72% in DP group) went on to develop symptomatic malaria by day 42, 28 (23%) had persistent asymptomatic parasitemia at day 42, and one (1%) took other antimalarials prior to day 42. Overall, 81 (39%) of 210 patients treated with AL went on to develop recurrent symptomatic malaria, compared to 52 (25%) of 211 patients treated with DP (p = 0.002).
BODY.RESULTS.OUTCOMES AND ESTIMATION.SECONDARY EFFICACY OUTCOMES.:
The prevalence of fever (either subjective or documented) was similar over the first 3 d of follow-up in the two treatment groups. Both treatments produced rapid clearance of parasitemia with no parasites detected by day 3 (Table 4). The appearance of gametocytes not present at enrollment was significantly lower over the last 4 wk of follow-up in DP group (Table 4). Patients treated with DP had a higher mean increase in hemoglobin levels, which was of borderline statistical significance (1.9 versus 1.5 g/dl, p = 0.05). However, among patients with recurrent parasitemia there was no difference in the prevalence of anemia (Hb <10 g/dl) on the day of failure in the AL group (33/117, 28%) compared to the DP group (25/92, 27%) (p = 0.87). Table 4 Secondary Outcomes
BODY.RESULTS.ADVERSE EVENTS:
Both drugs were well tolerated. Most adverse events were of mild or moderate severity and consistent with symptoms due to malaria. Overall, there was no difference in the proportion of study participants who experienced any adverse event of moderate or greater severity between the DP (46%) and AL (42%) treatment groups (p = 0.47). There was also no difference in the proportion of patients who experienced common adverse events of any severity (Table 4). Serious adverse events occurred in six participants and included three febrile convulsions, one case of acute otitis media, one acute asthma attack, and one case of pyomyositis. All serious adverse events were judged to be unrelated to study medications. No patients were withdrawn from the trial for drug-induced vomiting that would have required alternative treatment.
BODY.DISCUSSION.INTERPRETATION:
In this randomized clinical trial, AL and DP were both highly efficacious at initial clearance of parasitemia and well tolerated for treatment of uncomplicated malaria in Apac, Uganda, an area with extremely high malaria transmission intensity. Importantly, DP-treated patients had a significantly lower risk of recurrent parasitemia in both falciparum and non-falciparum infections. Accurate distinction between recrudescent and new falciparum infections following therapy was challenging due to the complexity of infection in this high transmission setting, despite the use of 6-locus genotyping. However, DP clearly offered better post-treatment prophylactic effect following therapy compared to AL and our data suggest a reduced risk of treatment failure due to recrudescent parasites. DP also offered other benefits, including a lower risk of gametocytemia after therapy and better hemoglobin recovery. The significantly lower risk of recurrent parasitemia after treatment with DP compared to AL is likely explained by differences in the terminal elimination half-lives of the two partner drugs. Piperaquine, a bisquinoline, is estimated to have an elimination half-life of 2–3 wk [21] compared to lumefantrine, a quinoline, which has an estimated elimination half-life of 4–10 d [22]. Selecting the ideal partner drug to combine with artemisinins in ACT regimens remains a challenge. Extended elimination half-lives may provide better post-treatment prophylaxis, but may also increase the risk for the selection of drug-resistant parasites, especially in areas of intense malaria transmission [23]. Resistance may develop to partner drugs during the elimination phase of the drug (due to their longer half-life), when newly infecting parasites are exposed to subtherapeutic levels of the drug. As ACT use becomes widespread in areas with high levels of malaria transmission, it will be important to monitor closely for the selection of parasites that are resistant to artemisinin partner drugs, since the benefits of a regimen that offers decreased recurrent infection must be balanced with the consequences of increased selection of resistant parasites.
BODY.DISCUSSION.GENERALIZABILITY:
Our study was conducted in an area of very high malaria transmission and highlights the importance of level of transmission in determining the overall efficacy of an antimalarial treatment regimen [24]. In a high-transmission setting, differences in the post-treatment prophylactic effect of ACTs may have a significant impact on the timing and frequency of recurrent episodes of malaria, as seen in this study. In areas with lower transmission intensity, a drug's post-treatment prophylactic effect would be expected to be of lesser importance. This is illustrated in a study from three sites in Rwanda with differing transmission intensity [14]. At a periurban site with relatively low transmission intensity, the risk of recurrent parasitemia after 28 d was equally low in patients treated with DP (4%) and patients treated with AQ + AS (7%). In contrast, at two rural sites with high transmission intensity, the risk of recurrent parasitemia was significantly lower with DP (12%) compared to AQ + AS (23%). One limitation of this study was the difficulty of accurately distinguishing recrudescence from new infections among patients with recurrent parasitemia, due to the high complexity of infection. Among episodes classified as "possible recrudescence," the mean complexity of infection was over five clones on day 0 and approximately four clones on the day of recurrent parasitemia. Even using six-locus genotyping, the probability of a new infection being misclassified as a recrudescence may be relatively high. Thus, the reported 42-d risks of recurrent parasitemia adjusted by genotyping of 16% in the AL treatment arm and 6.9% in the DP treatment arm likely overestimate the true risks of recrudescence. In this study we followed the new WHO outcome classification system where a patient is classified as a failure after the first reappearance of parasitemia, regardless of whether the patient is symptomatic [16]. Previously, patients with asymptomatic parasitemia following therapy were distinguished from those with recurrent symptomatic malaria based on the assumption that asymptomatic parasitemia may not be clinically important in areas of high transmission intensity [25]. However, in this study, where semi-immunity is expected to be high, the vast majority of patients with asymptomatic parasitemia following therapy went on to develop symptomatic malaria, strongly supporting the new WHO protocol recommendations and suggesting the weakness of natural immunity in clearing these parasites.
BODY.DISCUSSION.OVERALL EVIDENCE:
In this study, DP was shown to offer benefits over AL, including lower risks of recurrent parasitemia and gametocytemia following therapy and improved hemoglobin recovery. Both DP and AL are fixed-dose coformulated ACTs. However, DP has a simpler, once-daily dosing schedule compared to AL, which is provided twice daily, ideally with a fatty meal. Our results could have important policy implications. Currently AL is the recommended first-line therapy for treatment of uncomplicated malaria in Uganda, with AQ + AS recommended as an alternative if AL is not available. DP is now registered for use in Uganda, and appears to offer an additional highly efficacious ACT for our limited antimalarial armamentarium. In studies from Southeast Asia, DP appears to be well tolerated and highly efficacious against multidrug-resistant falciparum malaria [7–11]. In the only published study evaluating DP in Africa, DP had a cure rate of over 95% and had a significantly lower risk of recurrent parasitemia and adverse events compared to AQ + AS and AQ + SP in Rwanda [14]. Based on available data, DP warrants serious consideration as a first-line therapy for uncomplicated malaria in Africa. DP may also have a role for presumptive treatment of fever through the program for home-based management of fever (HBMF). Currently prepackaged CQ + SP (Homapak) is being distributed in the HBMF program. However, the CQ + SP combination is no longer efficacious [24], and there are plans to incorporate ACTs in the future. Use of DP for HBMF might be attractive because of its simple dosing schedule. There are also potential advantages of having more than one first-line therapy, one for facility-based management of malaria and another for HBMF, in reducing the selective pressure of using one ACT. Despite the excellent initial parasite clearance of both ACT regimens in this study and the provision of ITNs at enrollment, approximately half of all participants experienced recurrent parasitemia within 42 d. This finding emphasizes the need for more aggressive approaches to malaria control in areas with very high malaria transmission. A study done in an area of South Africa with lower-intensity transmission found that the combination of vector control measures including indoor residual spraying and provision of AL dramatically decreased the malaria burden [26]. In order to reduce new malaria infections in our study population, we anticipate that combining several malaria control measures, including treatment with ACTs, provision of ITNs (with education about their use), and potential use of indoor residual spraying, as in South Africa, will likely decrease the malaria burden and reduce drug pressure due to repeated use of ACTs. Monitoring of the impact of these combined control measures will be critical to assess our success in malaria control in Uganda.
BODY.SUPPORTING INFORMATION:
CONSORT ChecklistAL versus DP Trial, Apac Uganda(49 KB DOC)Click here for additional data file. Trial ProtocolComparison of AL and DP for Treatment of Uncomplicated Malaria in Uganda: Evaluation of Efficacy, Safety, and Tolerability at Three Sites with Varying Transmission Intensity(1.1 MB DOC)Click here for additional data file. | 1,876,597 | {
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TITLE: Six-week high-intensity exercise program for middle-aged patients with knee osteoarthritis: a randomized controlled trial [ISRCTN20244858]
ABSTRACT.BACKGROUND:
Studies on exercise in knee osteoarthritis (OA) have focused on elderly subjects. Subjects in this study were middle-aged with symptomatic and definite radiographic knee osteoarthritis. The aim was to test the effects of a short-term, high-intensity exercise program on self-reported pain, function and quality of life.
ABSTRACT.METHODS:
Patients aged 36–65, with OA grade III (Kellgren & Lawrence) were recruited. They had been referred for radiographic examination due to knee pain and had no history of major knee injury. They were randomized to a twice weekly supervised one hour exercise intervention for six weeks, or to a non-intervention control group. Exercise was performed at ≥ 60% of maximum heart rate (HR max). The primary outcome measure was the Knee injury and Osteoarthritis Outcome Score (KOOS). Follow-up occurred at 6 weeks and 6 months.
ABSTRACT.RESULTS:
Sixty-one subjects (mean age 56 (SD 6), 51 % women, mean BMI 29.5 (SD 4.8)) were randomly assigned to intervention (n = 30) or control group (n = 31). No significant differences in the KOOS subscales assessing pain, other symptoms, or function in daily life or in sport and recreation were seen at any time point between exercisers and controls. In the exercise group, an improvement was seen at 6 weeks in the KOOS subscale quality of life compared to the control group (mean change 4.0 vs. -0.7, p = 0.05). The difference between groups was still persistent at 6 months (p = 0.02).
ABSTRACT.CONCLUSION:
A six-week high-intensive exercise program had no effect on pain or function in middle-aged patients with moderate to severe radiographic knee OA. Some effect was seen on quality of life in the exercise group compared to the control group.
BODY.BACKGROUND:
Exercise is considered to be one of the most important treatments for patients with mild to moderate knee osteoarthritis [1,2]. Positive effects on pain and function, as well as cost-effectiveness have been reported [3,4]. The effect size obtained on pain experience is similar to that of pharmacological treatment [3,5]. The side effects have also been reported to be favorable, including reduced risk of inactivity-related disorders, such as cardiovascular disease and diabetes [2,6,7]. Moderate levels of physical activity are not associated with radiographic progression, but activities involving a risk of severe knee injury are closely related to increased risk of developing radiographic knee osteoarthritis [8-12]. The dose-response relationship of exercise on symptoms and function is not clear and exercise recommendations in osteoarthritis guidelines are based mostly on studies on elderly people, i.e. mean age ≥ 65 [3,13-15]. It is not clear whether exercise has a similar effect on pain and function in middle-aged patients compared with elderly patients. The aim of this study was to examine the effects of a short-term, high-intensity exercise program in middle-aged subjects (age 36–65) with definite radiographic knee osteoarthritis on self-reported pain, function, and quality of life.
BODY.METHODS.SUBJECTS:
A flow chart of the recruitment process is given in Figure 1. Radiologists and orthopedic surgeons at the Halmstad County Hospital, in the south-west of Sweden, and general practitioners within the catchments area of this hospital, were informed about the study and asked to list patients with radiographic knee osteoarthritis on a "patients eligible for research" list. Between October 1998 and October 2001 121 patients, referred by their general practitioner for radiographic examination because of long standing knee pain, were listed. Ninety-seven fulfilled the inclusion criteria: age 35–65, living in the defined geographic area, and diagnosis of radiographic osteoarthritis of Kellgren and Lawrence grade III or more, i.e. definite osteophytes and joint space narrowing. All listed patients received written information about the study. One week after the information was sent, patients were contacted by telephone, and invited to participate in the study. Twenty-eight patients declined participation for various reasons, the most common reason being lack of time and interest. To ensure only patients with symptoms due to knee osteoarthritis and eligible for exercise intervention were included, the following exclusion criteria were used: inflammatory joint disease, anterior cruciate ligament injury, known symptomatic injury to the menisci, hip symptoms more aggravating than the knee symptoms, about to have knee replacement surgery within 6 months, and co-morbidities not allowing exercise (Figure 1). Figure 1Flowchart of recruitment process and included patients. When eight or more patients fulfilled the inclusion criteria they were invited to baseline interview and examination for determination of exclusion criteria. Randomization was performed after the baseline examination. All patients were informed that they could be randomly allocated to either the exercise or the control group. After written informed consent, sixty-five subjects were randomized. Randomization was performed by the patient drawing a sealed envelope containing a piece of folded paper with either the word "exercise" or "control" written on it. Four persons were falsely randomized (one was too old at inclusion, one had severe hip osteoarthritis, one had fibromyalgia, and one had only joint space narrowing and no significant osteophytes), and thus 61 subjects entered the study. Thirty persons were allocated to the exercise group and 31 to the control group. Patients in the control group were offered exercise classes after the six-month follow-up period.
BODY.METHODS.SUBJECTS.EXERCISE GROUP:
The number of participants exercising together varied from two to nine. There were eight intervention groups in all. One-hour exercise sessions, twice a week for six weeks, were supervised by a physical therapist (CT). The program consisted of weight-bearing exercises aimed at increasing postural control and endurance and strength in the lower extremity (see additional file 1 for the complete exercise program). Exercises were performed at five stations at submaximal intensity (minimum 60% of maximum heart rate (HRmax)). Intensity was gradually and individually increased during the six weeks by increased lever arms or range of motion. Patients were encouraged to exercise at their most vigorous intensity possible, without losing quality in performance or severely exacerbating pain. Pain during exercise was not considered as an obstacle if the patient perceived it as "acceptable" and no increased symptoms were persistent after 24 hours [16]. If pain exceeded this level, exercise intensity was reduced occasionally, until the "acceptable" level was found. On every occasion, the heart rate of two random participants was estimated at each station using Polar pulsimeters (Polar® Accurex Plus, Polar, Sweden). The other patients had their heart rate measured by the physical therapist or themselves, palpating their carotid arteries. Notes were taken by the supervising physical therapist, on every occasion and on all patients, about exercise intensity, heart rate, and perceived exertion according to Borg's Rate of Perceived Exertion scale (RPE) at each station [17]. These data were used to give the physical therapist a view of exercise intensity and to assure the preservation or increase of intensity from time to time. Patients were encouraged to keep up and increase intensity whenever possible throughout the six weeks. Patients received a thera band to perform daily pulley exercises at home. In addition, three exercises, which were considered as the most challenging to the individual, were chosen as daily home exercises. Patients were recommended to perform some kind of weight bearing submaximal activity, such as walking or their home exercises, for at least 30 minutes or two times 15 minutes every day.
BODY.METHODS.SUBJECTS.CONTROL GROUP:
The controls were told not to make any lifestyle changes. They met the physical therapist (CT) for one hour at three times; baseline, follow up at 6 weeks and 6 months. After six months they were offered exercise classes or instructions and a home-exercise program.
BODY.METHODS.OUTCOME MEASURES.PRIMARY OUTCOME:
The primary outcome measure was the disease-specific Knee injury and Osteoarthritis Outcome Score (KOOS) [18,19]. The KOOS assesses the patients' self-report of pain, other symptoms, activities of daily living, sport and recreation function, and knee-related quality of life, in 42 questions which take about 10 minutes to complete. The KOOS is scored from 0 to 100, separately for each subscale, 0 indicating extreme problems and 100 indicating no problems. A change of 10 points or more is considered a clinically significant change [20]. The questionnaire and scoring manual can be found at . The Western Ontario and McMaster Osteoarthritis Index (WOMAC) [21] is included in the KOOS, and WOMAC scores can also be calculated.
BODY.METHODS.OUTCOME MEASURES.SECONDARY OUTCOME:
Secondary outcome measures were the Short Form-36 item (SF-36), ergometer test, and five tests of functional performance. The SF-36 is a generic, widely used measure of general health status, which comprises eight subscales: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE) and Mental Health (MH) [22]. The SF-36 is self-explanatory and takes about 10 minutes to complete. The SF-36 is scored from 0 to 100, 0 indicating extreme problems and 100 indicating no problems. The subscales assessing mainly physical components (PF, RP, BP, GH) were summarized to a physical component summary score (PCS), and the mental subscales (VT, SF, RE, MH) to a mental component summary score (MCS) [23]. Values are norm-based scored, using the U.S. general population norms from 1998. Each scale has the mean of 50 and standard deviation of 10. Scale score below 50 indicates a health status below average, and a score above 50 indicates a health status above average. Questionnaires were distributed prior to randomization at baseline, after 6 weeks, and 6 months. A bicycle ergometer test and five tests of functional performance were assessed (Figure 2). Figure 2Tests of functional performance. A) Åstrand's cycle-ergometer test [24]. B) Rising on one leg from sitting on lowest possible height [25,26]. C) One-leg hop [25], [27]. D) Lateral step-up [28]. E) One-leg semi squatting; maximum number during 30 sec. [26]. F) Heel-rising on one leg; maximum number during 20 sec. [26], [29]. 1. Åstrand's bicycle-ergometer test [24] (Fig 2A). 2. Rising on one leg, from sitting on lowest possible height [25,26] (Fig 2B). 3. One-leg hop [25,27] (Fig 2C). 4. Lateral step-up [28] (Fig 2D). 5. One-leg semi squatting; maximum number during 30 seconds [26] (Fig 2E). 6. Heel-raising on one leg; maximum number during 20 seconds [26,29] (Fig 2F). Tests of functional performance were recorded on three occasions: prior to randomization at baseline, after 6 weeks, and at 6 months. To assess compliance the number of exercise occasions attended was noted.
BODY.METHODS.STATISTICS:
Post-hoc, a power analysis was performed to estimate the number of patients needed to show a clinically significant difference between groups. Estimating the least clinical significant difference to be 11 ± 15 KOOS points, a total of 30 subjects in each group were needed to detect a difference with 80% power, p = 0.05. Data were analyzed using nonparametric tests. P-values of less than or equal to 0.05 were considered to be significant, and all tests were two-tailed. To compare groups, Mann-Whitney U-test was used. Friedman's test was used for repeated measures analysis of variance. Six weeks was considered as the time-point of primary interest, and 6 months as follow-up. Wilcoxon signed rank test was performed to compare changes from baseline to six weeks and 6 months respectively. Analyses were performed using SPSS 12.0.1 for Windows [30]. The study was approved by the Research Ethics Committee at Lund University, Sweden (LU 99–98), and is in compliance with the Helsinki Declaration.
BODY.RESULTS.SUBJECTS:
The mean age of the 61 included subjects was 56 ± 6 years, and the mean BMI was 29.5 ± 4.8 kg/m2. Patient characteristics are shown in table 1. Twenty-eight patients in each group were available for follow-up. The reasons for dropout were lack of time, reorganization at work, sudden illness, and increased knee symptoms (Figure 1). There were no clinically significant differences in baseline characteristics between the groups. Patient characteristics are shown in table 1. Table 1 Patient characteristics at baseline Exercise group n = 30 Control group n = 31 p-value Age (years) mean ± SD (range) 54.8 ± 7.1 (36–64) 57.3 ± 4.7 (46–65) 0.16 Gender number (%) women 15 (50%) 16 (52%) 0.90 BMI (kg/m) 2 mean ± SD 29.6 ± 4.5 29.5 ± 5.1 0.78 Aerobic capacity (ml O 2 /kg x min) mean ± SD 25.9 ± 6.4 25.2 ± 4.9 0.66 KOOS* pain 60 ± 18 64 ± 19 0.38 KOOS* symptoms 63 ± 20 66 ± 18 0.67 KOOS* ADL 69 ± 18 71 ± 21 0.76 KOOS* sport & recreation 34 ± 31 37 ± 29 0.54 KOOS* QOL 40 ± 15 46 ± 21 0.31 Knee Injury and Osteoarthritis Outcome Score [ 18 , 19 ] Score from 0–100, worst to best.
BODY.RESULTS.COMPLIANCE:
The total number of performed supervised exercise sessions by the 28 patients available for follow-up in the intervention group was 302/336 (89.9%). Patients participated on average in 11 out of 12 possible exercise classes (12 classes (n = 11), 11 (n = 9), 10 (n = 6), 9 (n = 1), 2 (n = 1)). The most common reason for absence was illness not related to knee osteoarthritis, and work-related lack of time.
BODY.RESULTS.BETWEEN-GROUP DIFFERENCES:
There was no difference between groups in pain or self-estimated function at either 6 week or 6 month follow-up. Quality of life improved significantly in the exercise group compared to the control group at 6 weeks (4.0 vs. -0.7, p = 0.05) and the results persisted at 6 months (5.1 vs. -2.3, p = 0.02, Table 2) Table 2 Comparisons of change in Knee injury and Osteoarthritis Outcome Score (KOOS) ‡ [ 18 , 19 ] subscales between exercise and control group KOOS Subscales Exercise group Control group Change in KOOS score* 95 % CI Change in KOOS score* 95 % CI p † Pain 6 w 1.8 -3.2 – 6.8 -0.3 -6.2 – 5.7 0.49 6 m 3.1 -1.9 – 8.2 -1.1 -6.6 – 4.4 0.32 Symptom 6 w 0.2 -5.1 – 5.6 -3.8 -7.7 – 0.0 0.07 6 m 1.0 -3.8 – 5.8 -3.4 -8.8 – 1.9 0.31 ADL 6 w 2.0 -2.3 – 6.3 -0.6 -7.0 – 5.8 0.96 6 m 0.9 -3.8 – 5.6 -1.9 -7.7 – 3.9 0.61 SportRec 6 w 1.2 -7.9 – 10.4 -4.4 -12.6 – 3.7 0.22 6 m 0.5 -10.1 – 11.2 -8.3 -19.5 – 2.8 0.32 QOL 6 w 4.0 -0.4 – 8.5 -0.7 -5.6 – 4.3 0.05 6 m 5.1 -0.7 – 11.0 -2.3 -9.5 – 4.9 0.02 * negative = worsening, positive = improvement † p-value for between group differences in change over time ‡ [ 18 , 19 ] The individual differences ranged from clinically significant improvement of at least 10 points to clinically significant deterioration in all KOOS subscales and in both the exercise and control group (Figure 3). Figure 3Change in KOOS pain score at six weeks. The individual change in KOOS pain at 6 weeks compared to baseline ranged from improvement to worsening, in both exercise and control group. A change of 10 points or more is considered clinically significant [20]. A similar pattern was seen for all KOOS and SF-36 subscales.
BODY.RESULTS.BETWEEN-GROUP DIFFERENCES.SECONDARY OUTCOMES:
A significant improvement was found in the exercise group compared to the control group at six weeks with regard to the SF-36 Mental Component Summary scale (MCS) (2.1 vs -1.6, p = 0.04). At six months follow-up this difference was no longer persistent (Table 3). Table 3 Comparisons of change in SF-36 Physical and Mental Components Summaries (PCS and MCS) [ 23 ] between exercise and control group. Short Form-36 item (SF-36) [22] Exercise group Control group mean 95%CI mean 95%CI p* Physical Component Summary (PCS) Baseline 42.5 24.4 – 57.5 43.8 24.2 – 57.3 0.49 Change at 6 weeks 3.0 -5.9 – 13.4 0.3 -15.2 – 12.6 0.13 Change at 6 months 3.0 -5.9 – 16.3 -0.7 -14.8 – 9.8 0.09 Mental Component Summary (MCS) Baseline 55.6 40.2 – 66.2 56.3 37.0 – 67.0 0.63 Change at 6 weeks 1.6 -10.6 – 15.0 -2.1 -16.9 – 11.5 0.04 Change at 6 months 0.7 -18.1 – 13.2 -0.7 -16.8 – 12.8 0.40 * Comparison between groups Improvements in functional performance of 0–20 % were seen in both groups at six weeks and six months. There was no difference in improvement between exercisers and controls (p = 0.08–0.9). See additional file 2 for the change in functional performance.
BODY.DISCUSSION.MAIN MESSAGE:
Six weeks of intensive exercise had no effect on self-reported pain or function in middle-aged patients with symptomatic and moderate-severe radiographic knee osteoarthritis.
BODY.DISCUSSION.COMPARISONS WITH OTHER STUDIES:
Quite opposite to previously published studies on exercise in knee osteoarthritis we found no improvement in pain or function. Possible reasons for this include our study group having moderate to severe osteoarthritis compared with mild to moderate in most previous studies, being younger than previously studied groups and the intervention being of comparably high intensity. It has been suggested that the responsiveness to exercise is modified by the loss of joint space width [31]. The homogeneity of this study population, with regard to radiographic changes, provided us the possibility to study the effects of exercise on patients with moderate to severe radiographic knee osteoarthritis. Can significant improvements of pain or self-reported function be expected in patients with radiographic knee osteoarthritis corresponding to Kellgren & Lawrence grade 3 or more? In this study, no improvements were seen on group level in pain or function. However, regular exercise in general is important to prevent diseases caused by inactivity [6], and thus patients with knee osteoarthritis should be encouraged to exercise. In clinical practice, patients with severe knee osteoarthritis should have treatments based on individual preferences and different stages of motivation [32]. It can be argued that the exercise intensity was too high for this group with moderate to severe knee osteoarthritis. Even though the intensity of each exercise was individually adapted, all individuals exercised at a minimum of 60% of HR max. It has been suggested that pain during exercise might be a protective mechanism in knee osteoarthritis, i.e. an increase in pain from too intensive exercises may restrain patients from further joint loading, which otherwise could cause further cartilage damage [33]. Patients in the current study were told to reduce the exercise intensity if pain during exercise was perceived as worse than 'acceptable', or persisted more than 24 hours. It is suggested that the different degrees of varus-valgus laxity should be taken into account in exercise interventions, to enhance the functional outcome [34,35]. Severe knee osteoarthritis is associated with a hip-knee-ankle malalignment and an increase in varus-valgus laxity compared to healthy knees [36]. It is possible that varus-valgus laxity mediated the effect of exercise on pain since all patients had radiographic changes corresponding to Kellgren and Lawrence grade III or more. Malalignment may cause increased joint loads, and greater quadriceps strength might further increase joint load by the muscles compressing the articular surfaces [37]. Younger patients are usually more physically active than elderly [38], and have higher demands on level of physical function and physical performance at work or leisure time. Thus, moderate to severe knee osteoarthritis might be perceived as more disabling by younger individuals compared to elderly. Our study population was younger (<65 years) and comprised more men (49%) than most other populations with knee osteoarthritis described in randomized controlled trials of exercise [13-15,39,40], which might have reduced the effect on self-reported function in the present study. This study showed no significant differences on self-reported pain and function either between or within groups. A post-hoc analysis was performed to study the possibility that the benefit from exercise was larger in subjects with worse pain at baseline. Fifteen patients in the exercise group were compared to 13 from the control group who had worse than total group median pain score (KOOS Pain 58 on a 0–100, worst to best scale) at baseline. The groups had comparable patient characteristics. The changes seen in these subgroups were however not different from the changes seen in the total groups. A possible limitation could be lack of power. A post-hoc analysis was performed to estimate the number of patients needed to show a clinically significant difference of 11 ± 15 KOOS-points [20]. The standard deviation of 15 is supported by results from randomized controlled trials of glucosamine supplementation [41] and a nutritional supplement [42] for knee osteoarthritis, where significant group differences were found in KOOS pain and ADL subscales. The number of subjects in each treatment arm in these RCT:s ranged from 15 to 27. The standard deviations in KOOS subscales have not previously been determined in exercise interventions. Only one of the five KOOS subscales showed a statistical significant improvement, and it can not be excluded that this result could be due to chance. The improvement of the KOOS subscale Quality Of Life in the exercise group was of doubtful clinical significance, however the improvement persisted over time, and is in accordance with previous findings of impact from exercise on mental health aspects in patients with knee osteoarthritis [31,43,44]. Group dynamics, support, or attention received may possibly have influenced the quality of life more than the exercise itself in the present study. Psychosocial factors are important determinants of physical function [45], and our results suggest that supervised exercises and follow-up are important, and that quality of life should be evaluated in osteoarthritis interventions.
BODY.CONCLUSION:
A six-week high-intensive exercise program had no effect on pain or function in middle-aged patients with moderate to severe radiographic knee OA. Some effect was seen on quality of life in the exercise group compared to the control group.
BODY.COMPETING INTERESTS:
The author(s) declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
CT participated in design, exercise intervention, assessments and follow-ups, statistical analyses and writing. ER participated in design, analysis and interpretation of the data, and critically revised the article. IP participated in design and interpretation of the data and critically revised the article. CE initiated and obtained necessary permissions for the study, arranged the initial funding, and participated in the analyses, interpretation and revision of the manuscript. All authors read and approved the final manuscript.
BODY.PRE-PUBLICATION HISTORY:
The pre-publication history for this paper can be accessed here:
BODY.SUPPLEMENTARY MATERIAL:
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TITLE: Short-term comparative study of high frequency chest wall oscillation and European airway clearance techniques in patients with cystic fibrosis
ABSTRACT.BACKGROUND:
High frequency chest wall oscillation (HFCWO) is standard treatment for airway clearance in the USA and has recently been introduced in the UK and Europe. There is little published research comparing HFCWO with airway clearance techniques (ACTs) frequently used in the UK and Europe. The aim of this study was to compare the short-term effects of HFCWO with usual ACTs in patients with cystic fibrosis hospitalised with an infective pulmonary exacerbation.
ABSTRACT.METHODS:
A 4-day randomised crossover design was used. Patients received either HFCWO on days 1 and 3 and usual ACTs on days 2 and 4 or vice versa. Wet weight of sputum, spirometry and oxygen saturation were measured. Perceived efficacy, comfort, incidence of urinary leakage and preference were assessed. Data were analysed by mixed model analysis.
ABSTRACT.RESULTS:
29 patients (72% male) of mean (SD) age 29.4 (8.4) years and mean (SD) forced expiratory volume in 1 s (FEV1) percentage predicted (FEV1%) 38 (16.7) completed the study. Significantly more sputum was expectorated during a single treatment session and over a 24 h period (mean difference 4.4 g and 6.9 g, respectively) with usual ACTs than with HFCWO (p<0.001). No statistically significant change in FEV1% or oxygen saturation was observed after either HFCWO or usual ACTs compared with baseline. 17 patients (55%) expressed a preference for their usual ACT.
ABSTRACT.CONCLUSIONS:
During both a finite treatment period and over 24 h, less sputum was cleared using HFCWO than usual ACT. HFCWO does not appear to cause any adverse physiological effects and may influence adherence.
BODY.INTRODUCTION:
The last four decades have seen improved survival in patients with cystic fibrosis (CF). The latest figures estimate the median life expectancy of individuals with CF born in 2000–3 to be approximately 40 years.1 Respiratory failure is the major cause of morbidity and mortality in those with CF.2 Accumulation of secretions in the CF airway precipitates chronic infection, causing a progressive deterioration in lung function and eventually respiratory failure and death.3 Airway clearance techniques (ACTs) are an essential component of the management of patients with CF and are considered standard care.4 There is a range of ACTs which augment the normal mucus clearance mechanisms of the lung to facilitate expectoration. These techniques generally aim to promote secretion clearance by altering airflow and mucus viscosity. Typically, high frequency chest wall oscillation (HFCWO) produces compression of the chest wall via an inflatable jacket linked to an air pulse generator. The generator delivers an intermittent flow of air into the jacket which rapidly compresses and releases the chest wall at a variety of frequencies. Consequently, an oscillation in airflow within the airways is achieved. HFCWO has been shown to enhance central and peripheral mucus clearance.5 A number of underlying mechanisms have been hypothesised including increased airflow-mucus interaction causing a reduction in viscolelasticity, production of an expiratory airflow bias which promotes a cephalad movement of mucus and the enhancement and stimulation of ciliary activity.6 7 Published short-term evidence has demonstrated increased sputum clearance and improved pulmonary function with HFCWO compared with no treatment.8 This and other studies have also compared HFCWO with alternative ACTs. Some have demonstrated increased sputum clearance with HFCWO compared with postural drainage and percussion (PD&P).9–11 Others found no significant difference in sputum clearance between HFCWO and PD&P,8 12 13 positive expiratory pressure (PEP),8 high frequency oral oscillation13 or intrapulmonary percussive ventilation.14 Furthermore, some of these studies found no differences in efficacy related to pulmonary function between HFCWO and PD&P,8 12 13 PEP,8 15 oscillating positive expiratory pressure (Flutter, manufactured by Axcan Scandipharm Inc, Birmingham, AL, USA)16 and high frequency oral oscillation.13 One study reported an improved outcome in forced expiratory volume in 1 s (FEV1) in the longer term using HFCWO compared with PD&P.17 Few trials have compared HFCWO with alternative ACTs which are commonly used in the UK and Europe by individuals with CF. Phillips et al18 compared HFCWO (using the Hayek Cuirass) with the active cycle of breathing techniques (ACBT) in hospitalised paediatric patients. Significantly more sputum was cleared with the ACBT. The authors concluded that HFCWO was not an effective airway clearance treatment for children with CF. It is difficult to compare this study directly with those above, as the Hayek Cuirass machine has a different operating mode to the inflatable vest system. A series of Cochrane systematic reviews have found that no one ACT is superior in terms of respiratory function and efficacy.19 Of a number of published studies on HFCWO, only two were deemed of sufficient quality to be included in these randomised control trial systematic reviews.8 12 HFCWO is widely used in the USA where it is considered standard care in CF.20 It has recently been introduced to the UK and Europe, where the mainstay of care for airway clearance in CF is the ACBT, autogenic drainage (AD) and other airway clearance regimens using small devices.4 In the USA these techniques and devices tend to be considered adjuncts, with PD&P and HFCWO remaining the most common ACTs.20 While there is a body of evidence which equates HFCWO and PD&P, there is a need for further trials to compare HFCWO with alternative ACTs to provide a more relevant evidence base for HFCWO in the UK and Europe. The aim of the present study was to compare the short-term effects of HFCWO with patients' usual ACTs in those with CF admitted to hospital with an acute exacerbation of pulmonary infection. The hypothesis was that HFCWO was superior to patients' usual ACTs.
BODY.METHODS.STUDY PARTICIPANTS:
All patients admitted to hospital who met the entry criteria were invited to participate in the study. The inclusion criteria were a diagnosis of CF (established by genotype or sweat sodium >70 mmol/l or sweat chloride of >60 mmol/l), FEV1 ≥ 20% predicted, age ≥16 years and an infective pulmonary exacerbation as defined by Thornton et al.21 Exclusion criteria were current severe haemoptysis, rib fractures, pregnancy, inability to give consent and those whose usual ACT was HFCWO. Informed written consent was obtained for all patients and the study was approved by Brompton Harefield and National Heart and Lung Institute research ethics committee.
BODY.METHODS.STUDY DESIGN:
A randomised crossover design was used to compare HFCWO with patients' usual ACTs, which allowed within-patient variability to be controlled. Over four consecutive days, patients received either HFCWO therapy on days 1 and 3 and their normal ACT on days 2 and 4 or vice versa. Allocation to HFCWO or usual ACT on day 1 was determined using a computer-generated randomisation table.
BODY.METHODS.PROTOCOLS:
Patients performed their usual ACT or received HFCWO two times daily at the same time. Before starting the study, each patient's usual ACT was reviewed by an experienced senior respiratory physiotherapist. In addition, patients were familiarised with HFCWO (The Vest). This involved the patients using The Vest for a trial period the day before the start of the study, during which time they were given the opportunity to experience all three protocol frequencies at a variety of pressures. Each airway clearance treatment session lasted 30 min and was supervised by the same physiotherapist to ensure optimisation and standardisation of usual ACT and HFCWO performance. All nebulised and inhaled medications were taken before each treatment session in accordance with the patients' individual regimens.
BODY.METHODS.HIGH FREQUENCY CHEST WALL OSCILLATION:
The following regimen was identified as current best practice following an in-depth review of the literature and discussion with clinical experts in the USA. Using The Vest Airway Clearance System Model 4 (Hill-Rom UK Ltd, Leicestershire, UK), each patient was fitted with an appropriately-sized, full torso, inflatable, disposable vest connected to the air pulse generator via two flexible tubes. Patients remained in an upright sitting position throughout the 30 min treatment session. HFCWO was applied for 8 min at each of three frequencies in sequence (10, 13 and 15 Hz) with each frequency followed by a 2 min rest period. The pulse pressure was set according to individual patient's reported comfort at all three frequency settings. During both the HFCWO and rest periods, patients were instructed to huff or cough as they felt necessary in order to expectorate loosened bronchial secretions.
BODY.METHODS.USUAL ACT:
Usual ACTs were in accordance with the guidelines of the International Physiotherapy Group for Cystic Fibrosis.22 Patients performed their usual ACT for 30 min, and for patients practising an assisted ACT, the physiotherapist provided percussion. Patients were allowed to perform combined ACTs where this was their usual practice. This reflected current international practice more accurately and recommendations that ACTs be adapted on an individual basis.23
BODY.METHODS.OUTCOME MEASURES:
The primary outcome measure was wet weight of sputum expectorated during a treatment session. Patients were instructed to expectorate all sputum into a preweighed pot during and for 30 min following each treatment session. They were also instructed to collect sputum expectorated at all other times during each 24 h period. All sputum collected was weighed immediately following collection on weighing scales with an accuracy of 0.01 g (BL310; Sartorious UK Ltd, Epsom, UK). FEV1 was measured using a hand-held spirometer (2120; Vitalograph Ltd, Buckingham, UK) in accordance with internationally agreed standards.24 Measurements were taken immediately before and after a 30 min period following each treatment session. Data were analysed using Spirotrac IV Version 4.30 software (Vitalograph Ltd). Pulsed arterial oxygen saturation (SpO2) was measured transcutaneously at rest, for 5 min immediately before, 30 min during and 30 min immediately following each session. SpO2 was measured with a fingertip pulse oximeter (Konica-Minolta Pulsox-300i; Stowood Scientific Instruments, Oxford, UK). The data were analysed using Download 2001 Version 2.8.0 software (Stowood Scientific Instruments Ltd). The perceived efficacy and comfort of each ACT and the incidence of urinary leakage during treatment were measured using 10 cm visual analogue scales (VAS). Each day, after the last treatment session, patients completed three 10 cm VAS with reference to the ACT used that day. On the VAS used, 0 represented not at all effective/comfortable or no urinary leakage and 10 represented extremely effective/comfortable or a lot of urinary leakage. On the fourth and final day, participants were also asked to indicate which ACT they would prefer. An independent observer, blind to the daily method of airway clearance used, performed the spirometry, weighed the sputum samples and collected the 10 cm VAS throughout the study.
BODY.METHODS.STATISTICAL ANALYSIS:
A sample size calculation determined the number of patients required to test for superiority of HFCWO. This was based on a difference of 4 g of sputum between the usual ACT and HFCWO during a single treatment session. A square-root of within SEM of 4 g at the 5% significance level would require 24 patients to achieve 90% power. Data are presented as mean (SD), median (IQR) or n (%) as appropriate. Continuous variables were analysed using a mixed-effects linear regression model. This was to allow the results to be adjusted for a number of factors which are inherent to the design of a crossover trial. The order of treatment randomisation and the day and time of treatment were all entered into the model and their effect on the outcomes was tested. For this trial, the results were also adjusted for the method and position of treatment in the ACT session. In these models, patients were entered as random effects since it was not of interest to quantify the differences between individual patients, but it was important to account for the repeated measurements on each patient. The estimates of the fixed effect of ACT versus HFCWO are presented as mean (95% CI). A p value of 0.05 was taken to be statistically significant. All analyses were conducted using Stata 9.2 (StataCorp).
BODY.RESULTS.PARTICIPANTS:
Fifty patients were invited to participate in the study, 20 declined, 29 patients completed the study and 1 patient was withdrawn due to a hypoglycaemic episode. Table 1 shows demographic and baseline characteristics of the patients who completed the study. Table 1 Patient demographics and baseline characteristics (n=29) Age (years) 29.4 (8.4) Male (%) 21 (72%) Height (cm) 171 (9) Weight (kg) 60 (11) BMI (kg/m 2 ) 20.4 (2.6) FEV 1 (l) 1.46 (0.72) FEV 1 % predicted 38 (16.7) SpO 2 (%) 94.3 (2.1) Data are presented as mean (SD) or n (%) as appropriate. BMI, body mass index; FEV 1 , forced expiratory volume in 1 s; SpO 2 , pulsed arterial oxygen saturation. Twenty-nine patients were treated with intravenous antibiotics as part of their medical management. All participants received two treatment sessions on each study day and all treatment sessions were 30 min in duration. The mean (SD) length of stay for patients was 14 (5) days and the mean day of entry to the study was day 8 (3) days.
BODY.RESULTS.USUAL ACT:
Usual ACTs included the ACBT with modified PD&P (41%; n=12) and with modified PD alone (7%; n=2), AD in sitting (28%; n=8) and with modified PD (7%; n=2), PEP (7%; n=2) and Flutter (10%; n=3).
BODY.RESULTS.SPUTUM WEIGHT:
The wet weight of sputum expectorated with usual ACT compared with HFCWO is shown in table 2. The mean weight of sputum expectorated during a single treatment session and over a 24 h period was significantly greater with usual ACT than with HFCWO. The mean difference in wet weight of sputum expectorated during a treatment session was 4.4 g (p<0.001) and the mean difference in wet weight of sputum expectorated over a 24 h period was 6.9 g (p<0.001). These findings were not affected by order, time, day or position of treatment. Table 2 Wet weight of sputum expectorated: HFCWO compared with usual ACT Period of sputum collection Expectorated sputum wet weight (g) Usual ACT HFCWO Mean difference p Value Mean (SD) Median (IQR) Mean (SD) Median (IQR) Single treatment session 9.1 (7.9) 7.2 (3.0–14.2) 4.6 (4.1) 3.4 (1.5–6.7) 4.4 (3.5 to 5.4) <0.001 24 h (excluding treatment) * 22.4 (26.8) 12.9 (4.0–29.9) 24.9 (25.8) 15.3 (3.9–40.1) −1.5 (−4.6 to 1.6) 0.352 24 h (including treatment) 39.8 (36.3) 25.5 (14.0–57.1) 34.3 (30.7) 26.3 (12.1–46.0) 6.9 (3.1 to 10.8) <0.001 Data are presented as mean (SD) or (95% CI) or median (IQR) as appropriate. Data are adjusted for randomisation, day, time and position of treatment using a mixed effects linear regression model. * Of 116 24-h sputum samples collected, two were discarded as they were incomplete. ACT, airway clearance technique; HFCWO, high frequency chest wall oscillation. No statistically significant difference was observed in the amount of sputum expectorated when using HFCWO or usual ACT between treatments in a 24 h period.
BODY.RESULTS.PHYSIOLOGICAL MEASURES:
FEV1 and SpO2 measured before, during and after usual ACT and HFCWO treatment sessions are shown in table 3. Table 3 Forced expiratory volume in 1 s and pulsed arterial oxygen saturation at baseline, during and after treatment with usual airway clearance technique and HFCWO Usual ACT HFCWO Baseline During treatment 30 min after treatment Baseline During treatment 30 min after treatment FEV 1 % predicted 39.1 (16.9) NA 38.9 (17.1) 38.9 (16.8) NA 39.2 (16.7) SpO 2 (%) 94.4 (2.0) 94.4 (1.9) 93.9 (1.6) 94.5 (1.8) 95.0 (1.7) 94.3 (1.7) Data are presented as mean (SD). ACT, airway clearance technique; FEV 1 , forced expiratory volume in 1 s; HFCWO, high frequency chest wall oscillation; NA, not applicable; SpO 2 , pulsed arterial oxygen saturation.
BODY.RESULTS.COMFORT, EFFICACY AND PREFERENCE:
The VAS scores for comfort, efficacy and urinary leakage during usual ACT compared with HFCWO are shown in table 4. No significant differences were observed in VAS scores for comfort or urinary leakage between HFCWO and usual ACT. Patients scored the efficacy of their usual ACT significantly higher than for HFCWO (mean difference 14 mm; p=0.002). This was not affected by the order or day of treatment. Of those patients who completed the study, 17 (55%) expressed a preference for their usual ACT over HFCWO. Preference was not predicted by the amount of sputum expectorated. Table 4 Comfort, efficacy and urinary leakage: HFCWO compared with usual ACT Self reported measure Visual analogue scale score (mm) Usual ACT HFCWO Mean difference p Value Comfort 69 (23) 70 (22) −1 (−9 to 7) 0.784 Efficacy 68 (21) 54 (26) 14 (6 to 23) 0.002 Urinary leakage 0 (1) 0 (1) −0.05 (−0.3 to 0.4) 0.791 Data are presented as mean (SD) or (95% CI) as appropriate. Data are adjusted for randomisation, day of treatment and time of treatment using a mixed effects linear regression model. ACT, airway clearance technique; HFCWO, high frequency chest wall oscillation.
BODY.DISCUSSION:
There have been few published comparisons between HFCWO using a vest system with the ACTs of the ACBT and AD. This short-term study, carried out in individuals with CF admitted to hospital with an acute infective pulmonary exacerbation, showed that significantly more sputum was expectorated during a single treatment session and over a 24 h period using the patient's usual ACT than with HFCWO. In addition, slightly less sputum was expectorated at all other times (excluding treatment sessions) on usual ACT days compared with HFCWO, but this trend was not statistically significant. These findings were independent of order, time or day and position of treatment. Neither HFCWO nor any of the usual ACTs were associated with any adverse clinical events. A possible factor contributing to the difference in sputum clearance between HFCWO and usual ACT may have been the number and frequency of forced expiratory manoeuvres (FEMs) and the more gentle expiratory manoeuvres of the AD breath that were performed with the usual ACTs. Some studies have standardised the number of coughs and FEMs that patients performed; however, at the time of designing the protocol, the aim was to compare the regimens as currently practised internationally and the frequency of coughs and FEMs was neither standardised nor counted. In retrospect, it would have been of value to have counted the number of coughs and FEMs undertaken during each regimen, but it had not been anticipated that any differences between HFCWO and usual ACTs may be a consequence of the number of FEMs or AD breaths. Theoretically, during the three 8 min periods of HFCWO, fewer FEMs, coughs or AD breaths would be undertaken than during an equivalent period of the ACBT, AD, PEP or Flutter (all of which inherently include FEMs or AD breaths at regular intervals). This difference was supported by observations of the investigators. However, manual cough counts are subject to observer error. Objective cough monitoring using the Leicester Cough Monitor has only recently been validated and should be considered for use in further studies.25 Components of patient satisfaction include efficacy, comfort and convenience. Some studies have formally evaluated patient satisfaction and compliance. One study reported that 50% of subjects chose HFCWO compared with the Flutter, and efficacy was the most frequently cited reason for this choice.16 A later study reported that HFCWO was not preferred over PD&P and intrapulmonary percussive ventilation; furthermore, there was no significant correlation between treatment preference and sputum weight.14 The current study found that patients perceived the efficacy of HFCWO to be statistically significantly less than that of their usual ACT. However, nearly half (45%) of patients expressed a preference for HFCWO. Preference may have been affected by the novelty of a new treatment and it is unknown whether this would continue in the long term. There is no one recommended protocol for the application of HFCWO in the literature. Published studies describe differing numbers and duration of frequencies, length of treatment and airway clearance. Frequencies of 10, 13 and 15 Hz were chosen as it has been reported that maximum mucus transport occurs between 11 and 15 Hz with a peak at 13 Hz.5 6 In addition, the highest oscillated tidal volume flow (peak airflow) occurred between 10 and15 Hz in patients with CF.26 More recent research recommends an individual "tuning" method to identify optimum treatment frequencies. These have been shown to vary among individuals and the oscillation waveform,27 but it is unknown whether "tuning" increases efficacy. It is possible that a practice effect could have occurred as all patients were new to HFCWO. However, the protocol used in this study did not require the patient to perform any newly learnt physical technique. In addition, the statistical analysis ensured data were adjusted for day of treatment and found no effect. Alternatively, patients' familiarity with their usual ACT may also have had an effect on outcomes. This study was powered to detect a difference of 4 g of sputum expectorated during a single treatment session. Other studies have been based on a difference of 3–3.5 g, which is generally accepted as a clinically important difference.28 29 Wet weight sputum was felt to be an appropriate primary outcome measure in this short-term study in an acute environment. Previous work has found wet weight to be proportional to dry weight sputum.28 30 Emerging non-invasive means of measuring airway clearance may be more sensitive indicators in the future (eg, lung clearance index and electrical impedance tomography). Considering the cost benefit of HFCWO compared with other ACTs and the differing healthcare systems in the USA and the UK, it is unlikely that HFCWO will become the first choice ACT for most individuals in the UK. Further work needs to be undertaken to identify the place of HFCWO in Europe. Patient preference for a treatment regimen may positively influence adherence to treatment in the short term, and nearly half the patients who participated in this study preferred HFCWO to their usual ACT. HFCWO is a safe treatment that facilitates airway clearance in CF but, when compared with patients' usual ACTs, HFCWO led to the clearance of significantly less sputum during a single treatment session and over a 24 h period. | 2,922,723 | {
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TITLE: Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: A placebo-controlled double-blind trial
ABSTRACT.BACKGROUND:
The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD.
ABSTRACT.METHODS:
In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations.
ABSTRACT.RESULTS:
Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups.
ABSTRACT.CONCLUSION:
Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane.
ABSTRACT.TRIAL REGISTRATION:
ISRCTN07600011
BODY.INTRODUCTION:
Chronic obstructive pulmonary disease (COPD) is considered to be a multi-component disease comprising structural and functional changes inside and outside the lungs. Effective medications for COPD are available and can reduce or prevent symptoms, increase exercise capacity, reduce the number and severity of exacerbations and improve health status. In common clinical use are bronchodilators as β-agonists, anticholinergic drugs and methylxanthines as well as glucocorticosteroids. The clinical effectiveness of these drugs has been shown in many controlled clinical studies [1-7]. Airway inflammation and mucociliary dysfunction in COPD patients have direct clinical consequences on the decline of lung function. As a consequence of cigarette smoking the ciliated epithelium is damaged and the mucus membrane becomes inflamed, resulting in decreased mucociliary transport leading to an accumulation of mucus within the airway so that the likelihood of recurrent respiratory infection is increased. Cineole has positive effects on the beat frequency of the cilias in the mucus membrane and has bronchodilating and anti-inflammatory effects. Therefore, it is appropriate to postulate that cineole will show positive influence on the exacerbations as well as on the lung function in COPD patients – even as concomitant therapy [8-13]. We conducted a randomised, placebo-controlled multi-center trial with the concomitant prescription of cineole – the main constituent of eucalyptus oil – in patients with stable COPD. The primary hypothesis was that cineole would decrease the number, severity and duration of exacerbations. Secondary outcome measures were lung function, severity of dyspnea and quality of life as well as relevant adverse effects.
BODY.MATERIALS AND METHODS.ENROLMENT OF PARTICIPANTS:
Participants were recruited in the offices of 4 general practitioners and 7 specialists in pneumology in Germany. The study was carried out during the winter seasons 2003/2004 and 2004/2005 over a treatment period of 6 months in the winter and starting the enrolment in September at the earliest. The participants were 40 to 80 years of age and had airflow limitation with FEV1 of less than 70% and more than 30% of the predicted value (moderate to severe COPD; according to GOLD classification stages 2 and 3 of COPD) [14]. Patients with an increase of more than 15% and more than 200 ml in FEV1 after inhalation of β-agonists (at least 200 μg Salbutamol or equivalent) were excluded according to the definition of COPD of the German Airway-League. [15]. All patients were current smokers or ex-smokers with at least 10 pack years. Patients were excluded if they had severe medical conditions such as bronchial carcinoma, myocardial infarction, alcoholism, heart failure. All randomised patients provided written informed consent and the protocol was approved by the local Ethics Committees at each of the 11 participating centres.
BODY.MATERIALS AND METHODS.TREATMENT GROUPS:
242 patients were randomly assigned to one of the two treatment groups with stratification according to the clinical centres. All patients were given the necessary dose of capsules each containing 100 mg cineole or no active ingredient. For each group 2 capsules 3 times daily were prescribed resulting in a dose of 600 mg per day for the cineole or no cineole for the placebo group as concomitant therapy. Patients were instructed to take the capsules half an hour before meal so that they could not recognize the smell of cineole. Capsules with active substance and placebo looked absolutely identical and were sealed in blister stripes. The diagnosis of COPD was confirmed according to the current guidelines of "Global Initiative for Chronic Obstructive Lung Disease" (GOLD). Frequency, duration, severity and symptoms of exacerbations were defined according to the literature [16-18]. An exacerbation was documented when the duration was more than 3 days or a complex of at least 2 respiratory adverse events with a duration of more than 3 days occurred. Exacerbation severity was defined as: mild (Score = 1, increased need for basic medication of COPD which the individual can manage in its own normal environment), moderate (score = 2, increased need for medication and he/she feels the need to seek additional medical assistance) and severe (score = 3, patient recognise obvious and/or rapid deterioration in conditions requiring hospitalisation). Details for the number, duration and severity as well as treatment and symptoms of exacerbations were recorded in the patient's diary for each day. Since the most relevant differentiation for exacerbations are frequency, duration and severity, the multiple criteria were combined as primary outcome measures for the statistical evaluation. Secondary outcome measures were the single parameters of the exacerbation as well as lung function, symptoms and quality of life. Spirometric measurements were carried out before the beginning of the study determining reversibility of the airflow limitation by inhalation of short acting β2-agonists to assure that the reversibility of lung function was less than 200 ml or 15%. Spirometric measurement included determination of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and vital capacity (VC) at the beginning and after 3 and 6 months. Additionally, symptoms score were determined for dyspnea (scores: 0 = caused no problems, 1 = caused occasionally problems, 2 = caused a lot of problems, 3 = the most important problem the patient had), weekly frequency of dyspnea (scores: 0 = no day was good, 1 = 1–2 days were good, 2 = 3–4 days were good, 3 = nearly every day was good, 4 = every day was good), general conditions (scores: 0 = good, 1 = impaired, 2 = bad, 3 = very bad, 4 = unbearable), cough (scores: 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often, 5 = nearly continuously). Diagnosis-related quality of life was determined according to the "St. George's Respiratory Questionnaire" [19].
BODY.MATERIALS AND METHODS.VISITS AND RANDOMIZATION:
Before randomisation we ascertained the patients' eligibility and conducted spirometry. After the randomisation the following parameters were recorded: height, weight, age, time since first symptoms for the diagnosis of COPD, documentation of allergies, concomitant disease, smoking habits (documentation of pack years), number of exacerbations in the year before during winter time, determination of quality of life and current maintenance therapy. The following control visits were carried out after 1, 2, 3, 4, 5 and 6 months recording exacerbations since last visit, frequency of dyspnea, characterisation of dyspnea, hypersecretion and cough as well as adverse events, compliance and change of therapy. Spirometry was carried out at the beginning of the study as well as after 3 and 6 months of treatment. Quality of life was determined at the beginning and at the end of the study.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
The proposed sample size for the present trial was 240 patients for both treatment groups. The sample size was chosen to detect a minimum difference of 15% of exacerbations after 6 months of treatment. Analysis of efficacy was performed with the intention-to-treat-population including all eligible patients who received at least one dose of medication and had at least one follow-up visit. The number of all exacerbations, duration of exacerbations, degree of severity of exacerbation recorded in patients diary during the 6 months treatment period were summarised and the sums compared according to Wei-Lachin's directional test of multiple criteria (equally weighted) [20]. Additionally, single parameters characterising the exacerbations and dyspnea were analyzed exploratory as secondary outcome measures at multiple endpoints according to Wei-Lachin validating the sum-formation. The Wilcoxon-Mann-Whitney-U Test was used for all other secondary outcome measures. Data are expressed as mean values (with SD) and all tests were two-tailed. P-values of 0.05 or less were considered to indicate statistical significance.
BODY.RESULTS:
A total of 242 patients were randomised and received at least one dose of study medication. 22 patients were excluded from the statistical analysis of efficacy because they did not meet the requirements of the GOLD guidelines since FEV1/VC was > 0.7. 220 patients were eligible according to the GOLD guidelines having COPD of stage II and III. The two treatment groups were well matched with respect to baseline characteristics (table 1). The mean age of the participants at entry was 62 years in both groups. The mean duration of COPD of 13 years as well as 31 pack-years and the basic medication (i.e. ICS, β-agonists, anticholinergics and theophylline) were balanced between the two groups (table 2). Medication was not changed during the treatment period except in occurrence of exacerbations. The baseline lung function and reversibility in both groups were comparable. Treatment compliance was determined by counting the study medication at each visit and was found high and comparable across the treatment groups. Table 1 Base Line Characteristics of the Patients* CHARACTERISTIC PLACEBO (N = 110) CINEOLE (N = 110) Age – yr Mean 62.5 ± 10.2 62.2 ± 9.1 Range 40 – 79 41 – 79 Sex – M/F 75/35 66/44 Weight – kg Mean 79 ± 16 79 ± 14 Range 48 – 120 52 – 113 Height – m Mean 1.71 ± 8.8 1.70 ± 8.0 Range 1.48 – 1.90 1.54 – 1.92 Years since appearance of COPD Mean 12.8 ± 9.7 13.6 ± 10.9 Range 1 – 56 1 – 59 Severity of COPD [number of patients] Moderate COPD (II) 69 68 Severe COPD (III) 41 42 FEV 1 /VC [%] 58.0 58.7 FEV 1 [l] 1.61 ± 0.5 1.62 ± 0.5 FEV 1 % predicted value 54.4 54.9 Reversibility (increase of FEV 1 after inhalation of β-agonist) [%] 5.5 4.5 Allergies (number) 10 9 Pack years 31.5 ± 19 31.3 ± 16 * Plus – minus values are means ± SD. Table 2 Constant concomitant therapy THERAPY PLACEBO (N = 110) CINEOLE (N = 110) Inhaled β-agonists* (LABA and SABA) 83 88 Inhaled anticholinergics 29 35 Inhaled corticosteroids (ICS) 27 25 Theophylline 38 32 * including combinations
BODY.RESULTS.PRIMARY OUTCOME MEASURES.EXACERBATIONS:
At baseline the mean exacerbation rate was 3.2 in both groups during the previous year. The number of patients with exacerbations during the treatment period in the cineole group was 31 patients (28.2%) and 50 patients (45.5%) in the placebo group. As primary outcome measure the sum of exacerbations for frequency, duration and severity at all 6 following visits as composite endpoint (equally weighted) were calculated according to the Wei-Lachin Test procedure for multiple criteria and showed a statistically significant difference for the primary outcome measure between both treatment groups (p = 0.0120) Table 3. Calculating these single parameters alone exploratory according to Mann-Whitney-U it could be proven that they were statistically significant too (i.e. for frequency 0.0069 an, duration 0.0210 and for severity 0.0240). Validating these results by Wei-Lachin-Test procedure for multiple endpoints for the number, the degree and the severity of exacerbations, the degree during the 6-month treatment the differences between both treatment groups were statistically significant (p = 0.0016, 0.0031 and 0.0025) which underlines higher sensitivity of this test-procedure. Medication of the exacerbations with additionally applied corticosteroids occurred in 17 cases in the cineole and in 25 cases in the placebo group which was not statistically significant different. Table 3 Mean of sum of number, duration and severity of exacerbations during 6 months of treatment with cineole or placebo* PLACEBO CINEOLE SCORE SCORE P VALUE† Sum of exacerbations (number)# 0.9 ± 1.46 0.4 ± 0.82 0.0069 Sum of duration (days)# 5.7 ± 8.9 4.0 ± 10.9 0.0210 Sum of severity (score)# 1.4 ± 2.2 0.8 ± 1.5 0.0242 Summarized parameter (directional test) 0.0120 * Plus – minus values are means ± SD. † P-Values are for the comparison between the two groups. # The sum of the exacerbation parameters is calculated by addition of the documented parameters at all visits.
BODY.RESULTS.SECONDARY OUTCOME MEASURES.LUNG FUNCTION:
Patients only discontinued inhaled β2-agonist prior to spirometry testing. After inhalation of a β2-agonist the reversibility of lung obstruction (increase of FEV1) at the start of the study was 4.5% in the cineole group and 5.5% in the placebo group (table 1). After 6 months of treatment the mean FEV1 increased by 78 ml (4.7%) in the cineole group (table 4). The mean differences between both groups were not statistically significant (p = 0.0627). After 6 months of treatment an increase of FVC by 62 ml (2.7%) after cineole therapy and a decline of 25 ml (1.1%) after treatment with placebo was determined. The difference concerning change of FVC and VC between both treatment groups was not clinically relevant. Table 4 Secondary outcome measures during 6 months Of treatment with cineole or placebo for change of lung function and dyspnea symptoms * LUNG FUNCTION AND SYMPTOMS PLACEBO CINEOLE BASE LINE 3 MONTHS 6 MONTHS BASE LINE 3 MONTHS 6 MONTHS p-Value FEV 1 [l] 1.61 ± 0.5 1.62 ± 0.5 1.61 ± 0.5 1.62 ± 0.5 1.67 ± 0.5 1.70 ± 0.6 0.0627 † FVC [l] 2.23 ± 0.8 2.25 ± 0.8 2.22 ± 0.7 2.33 ± 0.8 2.36 ± 0.9 2.36 ± 0.9 0.2409 † VC [l] 2.81 ± 0.8 2.71 ± 0.7 2.68 ± 0.8 2.80 ± 0.8 2.73 ± 0.8 2.72 ± 0.9 0.2060 † Trouble in breathing # 1.8 ± 0.9 2.1 ± 0.9 2.2 ± 1.0 1.9 ± 0.9 2.4 ± 1.0 2.5 ± 1.1 0.0103 & Dyspnea in the morning $ 1.1 ± 0.7 0.9 ± 0.7 0.7 ± 0.7 1.1 ± 0.8 0.7 ± 0.7 0.5 ± 0.6 0.0466 & Dyspnea at rest $ 0.7 ± 0.7 0.4 ± 0.6 0.4 ± 0.6 0.6 ± 0.6 0.3 ± 0.5 0.3 ± 0.5 0.0156 & Dyspnea during exercise $ 2.0 ± 0.6 1.8 ± 0.7 1.7 ± 0.8 2.0 ± 0.6 1.7 ± 0.7 1.5 ± 0.9 0.1252 & * Plus – minus values are means ± SD. Higher scores on the symptoms-sum-score indicate more disease activity. † P-Values are for the comparison of the changes from base line to 6 months between the two groups. & P-Values for the comparison are calculated by the multiple criteria calculation of 6 visits by Wei-Lachin between the two groups. # Scores: 0 = no day was good, 1 = 1–3 days were good, 2 = nearly every day was good, 3 = every day was good in a week. $ Scores: 0 = did not cause any problems, 1 = sometimes caused problems, 2 = caused a lot of problems, 3 = the most important problem the patient had
BODY.RESULTS.SECONDARY OUTCOME MEASURES.DYSPNEA:
The differences between both groups after 6 months of treatment are summarised in table 4. The baseline dyspnea scores in the morning, trouble in breathing, dyspnea at rest and dyspnea during exercise were similar in both groups, indicating a moderate level of a dyspnea for most patients at the beginning of the treatment period. Calculating the values at all 6 visits at multiple endpoints the difference between both treatment groups were statistically significant for trouble in breathing, dyspnea in the morning and dyspnea at rest. Dyspnea during exercise did not show a statistically significant difference between treatment groups.
BODY.RESULTS.SECONDARY OUTCOME MEASURES.QUALITY OF LIFE:
At 6 months the mean improvement of SGRQ total symptom score was -9.1 after treatment with cineole and -4.1 after treatment with placebo (table 5). The difference between treatment groups was not statistically significant (p = 0.0630). The improvement of the symptom score was statistically significant (p = 0.0224). The differences of changes of activity score and impact score were not statistically significant between the two groups. Table 5 Secondary outcome measures for saint george's respiratory questionnaire (sgrq): Change of total symptom score, symptom score, activity score and impact score During 6 months of treatment with cineole or placebo* SGRQ SCORES PLACEBO CINEOLE P VALUE † BASE LINE 6 MONTHS BASE LINE 6 MONTHS Symptom score 57.4 ± 20.2 48.5 ± 24.9 57.3 ± 20.4 43.8 ± 24.3 0.0224 Activity score 53.4 ± 21.9 50.0 ± 24.8 52.1 ± 20.5 43.5 ± 22.4 0.2032 Impact score 37.2 ± 20.9 33.9 ± 23.3 35.8 ± 20.2 27.4 ± 19.2 0.1126 TOTAL SYMPTOM SCORE 45.6 ± 18.9 41.3 ± 22.5 44.4 ± 17.8 34.5 ± 18.9 0.0630 * Plus – minus values are means ± SD. Lower scores on the scores indicate higher quality of life. † P-Values are for the comparison of the changes in scores from base line to 6 months treatment between the two groups.
BODY.RESULTS.MULTIPLE CRITERIA:
Symptomatic of COPD patients is characterized by lung function, dyspnea and quality of life. In order to include these relevant secondary outcome measures together we used these parameters equally weighted as multiple criteria. The increase of FEV1, amelioration of dyspnea and improvement of total score of "SGRQ" were calculated according to the Wei-Lachin Test procedure for multiple criteria and showed a statistically significant difference for the relevant secondary outcome measure between both treatment groups (p = 0.0024).
BODY.RESULTS.MULTIPLE CRITERIA.OTHER FINDINGS:
Concomitant therapy with β-agonists and anticholinergics, corticosteroids or combinations and methylxanthines in both groups were comparable (table 2). The global assessment of efficacy showed a significant difference, which correlated with the amelioration of clinical findings after treatment with cineole.
BODY.RESULTS.SIDE EFFECTS:
All patients receiving the study medication (including those with FEV1/VC > 0.7) were included in the safety examination. During treatment side effects were seen in 22 patients whereas in 17 cases adverse events were not related to the study medication. In the placebo group 11 adverse events were estimated not being related to the study medication whereas 2 cases were interpreted as being related to the study medication (heartburn). During treatment with cineole 9 cases of adverse events were reported whereas 6 adverse events were reported not being related to the study medication. In 3 patients (nausea, diarrhoea, heartburn) the adverse events were estimated being related to the study medication. The difference between the two treatment groups was neither clinically relevant nor statistically significant. Safety examinations of the global assessment showed no difference between the two treatment groups. During the 6 months of treatment compliance was good in all patients.
BODY.DISCUSSION:
Patients with COPD experience exertional breathlessness caused by bronchoconstriction, mucous secretion, edema of the airway wall and loss of attachments to the terminal airways [14]. Hence pharmacological therapy has focused on the treatment of airway obstruction and inflammation to improve symptoms primarily dyspnea as well as health status. Bronchodilators are the mainstay of pharmacotherapy for patients with COPD. On the other hand it is well known that mucociliary dysfunction has direct clinical implications. Mucus is beneficial in normal quantities but in case of mucus hypersecretion when cilia fail, the mucus pool allows bacterial colonisation. The presence of pooled bacteria results in the release of bacterially-derived toxins that destroy the underlying epithelium and trigger a neutrophilic response [21]. Taking into account the known pharmacological effects of the defined natural product cineole it was assumed that this compound might be beneficial for patients with COPD. Exacerbations have been shown to be reduced in various studies evaluating treatment with inhaled β-agonists or corticosteroids or combinations. The major finding of the present study is that cineole provides a significantly greater reduction of frequency, duration and severity of exacerbations than placebo. The exacerbations were analyzed as multiple criteria for the relevant specifications frequency, duration and severity. The result for the primary outcome measure could be validated exploratory for the single parameters showing a statistical significant difference too. Therefore, both testing procedures are valid whereas the testing multiple criteria is more sensitive. This proof of efficacy is an important contribution to the known pharmacological properties of cineole which therefore is not a mucolytic agent only. The result of this study suggests important new evidence of superior therapeutic efficacy of additional therapy with cineole to better control COPD exacerbations compared to the currently recommended combined therapy with ICS and LABA. Furthermore, additional therapy with cineole may positively interact with anti-inflammatory activity of recommended airway therapies in COPD and may serve to protect airways from other environmental agents. In general, quality of life deteriorates slowly in patients with COPD. During the period of 6 months treatment of this study we observed a decrease of the scores of SGRQ in both treatment groups. The reason for this finding in the placebo group, too, seems to be due to patients receiving better medical attention when involved in clinical trials. The higher rate of exacerbations in the winter before the study began in both treatment groups is due to the same reason. Our present data with cineole therapy underline a greater improvement than after treatment with placebo. Differences in change of FEV1 were not statistically significant (p = 0.0627). These findings correlate with a decline of FEV1 in the placebo group of 0.4% and an increase of 4.8% in the cineole group. This value is nearly identical with the increase of FEV1 after the inhalation of β-agonists, when testing the reversibility, before concomitant therapy with cineole started for six months.
BODY.CONCLUSION:
These collective findings underline that cineole not only reduces exacerbation rate but also provides clinical benefits as manifested by improved airflow obstruction, reduced severity of dyspnea and improvement of health status. Therefore, cineole can provide a useful treatment option for symptomatic patients with COPD in addition to treatment according to the guidelines. These results have to be seen in context with socio-economic aspects. As COPD is an extremely costly disease and a cause of major financial and social burden concomitant therapy with cineole can be recommended, especially due to the lack of relevant side effects and relatively low cost. The results of our study provide good evidence that cineole will show benefits as additional therapeutic regimen in patients with COPD. These findings correspond to the interpretation of the efficacy-study with Carbocysteine but not with Acetylcysteine, because this medication did not show a significant reduction of exacerbations [22,23].
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
The study was designed and the protocol developed by HW, C S and UD. CS worked as principal investigator. Statistical analysis was carried out by UD. The results were interpreted by HW, CS and UD. All authors gave substantial critical input in revising the manuscript. | 2,720,945 | {
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TITLE: Cervical ripening with prostaglandin gel and hygroscopic dilators.
ABSTRACT:
OBJECTIVE: To study the effectiveness and morbidity of adding hygroscopic cervical dilators to prostaglandin gel for cervical ripening and labor induction. STUDY DESIGN: Patients of at least 34 weeks' gestation with a medical indication for induction of labor and with a modified Bishop score of 5 or less were randomized to receive either prostaglandin gel or prostaglandin gel with hygroscopic cervical dilators. Primary outcomes were time to delivery, change in cervical score, and infection. Secondary outcomes included cesarean delivery rate and deliveries before 24 hours of induction. Continuous variables were analyzed by Wilcoxon sum rank test and categorical data by chi-square or Fisher exact test, with P < 0.05 being significant. RESULTS: Seventeen patients were randomized to intracervical prostaglandin alone and 23 patients received intracervical prostaglandin plus hygroscopic dilators. No demographic differences were noted between the groups. After six hours of ripening, the combined group achieved a greater change in Bishop score (3.6 vs. 2.1, P = 0.007) and tended to have a shorter induction time (21.7 vs. 26.4 hours, P = 0.085). The combined therapy group had a higher infection rate than the prostaglandin-only group (59% vs. 12%, P = 0.003). CONCLUSION: Combining cervical dilators with prostaglandin gel provides more effective cervical ripening and a more rapid induction to delivery interval than prostaglandin alone but with a significant and prohibitive rate of infection. | 1,784,771 | {
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TITLE: Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial
ABSTRACT.INTRODUCTION:
Experimental research has demonstrated that the level of neuroprotection conferred by the various barbiturates is not equal. Until now no controlled studies have been conducted to compare their effectiveness, even though the Brain Trauma Foundation Guidelines recommend that such studies be undertaken. The objectives of the present study were to assess the effectiveness of pentobarbital and thiopental in terms of controlling refractory intracranial hypertension in patients with severe traumatic brain injury, and to evaluate the adverse effects of treatment.
ABSTRACT.METHODS:
This was a prospective, randomized, cohort study comparing two treatments: pentobarbital and thiopental. Patients who had suffered a severe traumatic brain injury (Glasgow Coma Scale score after resuscitation ≤ 8 points or neurological deterioration during the first week after trauma) and with refractory intracranial hypertension (intracranial pressure > 20 mmHg) first-tier measures, in accordance with the Brain Trauma Foundation Guidelines.
ABSTRACT.RESULTS:
A total of 44 patients (22 in each group) were included over a 5-year period. There were no statistically significant differences in ' baseline characteristics, except for admission computed cranial tomography characteristics, using the Traumatic Coma Data Bank classification. Uncontrollable intracranial pressure occurred in 11 patients (50%) in the thiopental treatment group and in 18 patients (82%) in the pentobarbital group (P = 0.03). Under logistic regression analysis – undertaken in an effort to adjust for the cranial tomography characteristics, which were unfavourable for pentobarbital – thiopental was more effective than pentobarbital in terms of controlling intracranial pressure (odds ratio = 5.1, 95% confidence interval 1.2 to 21.9; P = 0.027). There were no significant differences between the two groups with respect to the incidence of arterial hypotension or infection.
ABSTRACT.CONCLUSIONS:
Thiopental appeared to be more effective than pentobarbital in controlling intracranial hypertension refractory to first-tier measures. These findings should be interpreted with caution because of the imbalance in cranial tomography characteristics and the different dosages employed in the two arms of the study. The incidence of adverse effects was similar in both groups.
ABSTRACT.TRIAL REGISTRATION:
(Trial registration: US Clinical Trials registry NCT00622570.)
BODY.INTRODUCTION:
High dosages of barbiturates are used in patients with severe traumatic brain injury (TBI) who present with refractory intracranial hypertension (ICH) after medical and surgical treatment. This practice is recommended in the Brain Trauma Foundation (BTF) Guidelines, because this is the only second-level measure for which there is class II evidence that it can reduce intracranial pressure (ICP) [1]. Nevertheless, its effect on outcome is unproven [2], mainly because of severe medical complications. Within the family of barbiturates the oxibarbiturates and thiobarbiturates stand out, their primary representatives being pentobarbital and thiopental. Until now no controlled studies have been reported that compare the effectiveness of pentobarbital and thiopental in controlling ICH. At the experimental level, research has demonstrated that mechanisms of action and levels of neuroprotection differ between these agents [3-6]. For this reason, research is needed to compare the effectiveness of these two drugs in terms of controlling refractory ICH in patients with severe TBI. Based on various studies conducted in laboratory animals [3-6], suggesting that the neuroprotective capacity of thiopental is superior, our working hypothesis was that thiopental is more effective than pentobarbital in controlling ICP in patients with severe TBI, with a similar incidence of adverse side effects. In support of our work in the present study, the BTF Guidelines recommend that studies be undertaken to compare the effectiveness of the different barbiturates that are currently used in TBI patients [1].
BODY.MATERIALS AND METHODS:
We conducted a prospective, randomized cohort study comparing two treatments: pentobarbital and thiopental. Our primary objective was to compare the effectiveness of these agents in controlling refractory ICH in patients with severe TBI. Secondary objectives were to compare the incidence of secondary effects, especially arterial hypotension, which was defined as the presence of mean arterial pressure (MAP) under 80 mmHg at any point during barbiturate therapy. This study was conducted at Son Dureta University Hospital (Palma de Mallorca, Spain) and was approved by the Ethics Committee of the Balearic Islands on 31 March 2002. It is registered with the US Clinical Trials Registry, with the number NCT00622570. In all cases, the patient's closest relative, legal representative, or guardian gave written informed consent for their inclusion in the study.
BODY.MATERIALS AND METHODS.INCLUSION CRITERIA:
Patients admitted to our intensive care unit (ICU) between May 2002 and July 2007 with a severe TBI (Glasgow Coma Scale [GCS] score after nonsurgical resuscitation ≤ 8) and presenting with refractory ICH (ICP > 20 mmHg), and who underwent first-level measures in accordance with the BTF Guidelines [7], were included. Refractory ICH was defined as follows: ICP 21 to 29 mmHg for 30 minutes or more, ICP of 30 to 39 mmHg for 15 minutes or more, or ICP greater than 40 mmHg for more than 1 minute, in the absence of external interventions. Included patients were required to be haemodynamically stable at the point of inclusion in the study; haemodynamic stability was defined as systolic blood pressure of 100 mmHg or greater.
BODY.MATERIALS AND METHODS.EXCLUSION CRITERIA:
We did not include in the study patients who were younger than 15 or older than 76 years; patients with a GCS score of 3 upon admission and neurological signs of brain death (bilateral arreactive midryasis and loss of brainstem reflexes); and patients who were pregnant, had barbiturate allergy or intolerance, or had a history of severe cardiac ventricular dysfunction with an ejection fraction under 35%.
BODY.MATERIALS AND METHODS.GENERAL THERAPEUTIC PROTOCOL:
All patients with severe TBI underwent cranial computed tomography (CT) upon admission and were categorized in accordance with the classification proposed by the Traumatic Coma Data Bank [8]. We also recorded findings of CTs conducted before inclusion of the patients in the study. The CT findings on inclusion were regarded to be the worst of the hospital stay; the prognostic value of such CT findings have been described by other authors [9]. CTs were independently reviewed and categorized by two neurosurgeons (JI and MB) who were unaware of the treatment group to which the patients had been assigned. In cases of disagreement between these investigators, a third investigator reviewed the CT images. All patients' ICP was monitored using an intraparenchymal Camino catheter (Integra Neurosciences, Plainsboro, NJ, USA). The ICP catheter was placed in the frontal region of the hemisphere with more radiological lesions on the CT. The systemic monitoring of these patients included invasive blood pressure, pulse oximetry, and a pulmonary artery thermodilution catheter. The ICP, MAP and cerebral perfusion pressure data were gathered on an hourly basis (one value every full hour) throughout the study using the Care Vue® clinical monitoring system (Phillips, Eindhoven, The Netherlands). The general treatment objectives in patients with severe TBI were to maintain MAP above 80 mmHg, ICP below 20 mmHg, and cerebral perfusion pressure above 60 mmHg. To achieve these objectives, we used liquids and/or vasoactive support with norepinephrine (noradrenaline). In patients with ICP greater than 20 mmHg, initial treatment included elevation of the head of the bed, keeping the neck straight, appropriate sedation, muscular paralysis, ventricular drainage (if the patient had visible ventricles on the CT), 20% mannitol (0.25 to 0.75 mg/kg), 7.5% hypertonic saline (2 ml/kg) and moderate hyperventilation (partial carbon dioxide tension of 30 to 35 mmHg). Neurosurgical interventions were undertaken when necessary to evacuate surgical lesions. This approach can be considered conventional treatment and is included in the BTF Guidelines as first-tier therapy [7]. Patients whose ICP remained high with conventional treatment were included in the study. Before randomization of the patient to a study group, we required that patient to have received maximal medical treatment (first-level measures). In addition, we required a CT to have been conducted within 24 hours before inclusion of the patient in the study; intravenous administration of 0.7 g/kg mannitol 1 hour before randomization; or a plasmatic osmolarity measurement above 320 mOsm/kg, in order to ensure that hyperosmolar therapy had been optimized before inclusion.
BODY.MATERIALS AND METHODS.RANDOMISATION:
Randomization was based on a computer-generated list that intercollated the two drugs. Allocation was done by the intensive care unit physician who was on duty, once the patient had been found to meet the inclusion criteria and none of the exclusion criteria. Data collection and patient follow up were conducted by the same investigator (JPB).
BODY.MATERIALS AND METHODS.BLINDING OF TREATMENT GROUPS:
The study was not blinded because it was difficult for us to mask treatment; thiopental is liophylized for administration and pentobarbital is not.
BODY.MATERIALS AND METHODS.ADMINISTRATION OF BARBITURATES AND MONITORING OF EFFECTS:
Pentobarbital was administered in accordance with the protocol established by Eisenberg and coworkers [10], using a loading dose of 10 mg/kg over 30 minutes followed by a continuous perfusion of 5 mg/kg per hour for 3 hours. This was followed by a maintenance dosage of 1 mg/kg per hour. Thiopental was administered in the form of a 2 mg/kg bolus administered over 20 seconds. If the ICP was not lowered to below 20 mmHg, then the protocol permitted a second bolus of 3 mg/kg, which could be readministered at 5 mg/kg if necessary to reduce persistently elevated ICP. The maintenance dosage was an infusion of thiopental at a rate of 3 mg/kg per hour. In both treatment groups, for cases in which the maintenance dosage did not achieve the reduction in ICP to below the 20 mmHg threshold, the maintenance dosage for both drugs could be increased by 1 mg/kg per hour, while looking for electroencephalographic burst suppression or even the flat pattern, in order to ensure that different doses of the two barbiturates were equipotent. Electroencephalography was conducted daily in a noncontinuous manner (Nicolet; Viasys Healthcare, Verona Road, Madison, WI, USA). Results were analyzed by an experienced neurologist who was blinded to the treatment of the patients. In those patients in whom barbiturate coma did not control ICP, we used decompressive craniotomy and/or external lumbar drainage, in accordance with the Munch criteria, as life-saving measures [11,12].
BODY.MATERIALS AND METHODS.EFFECTIVENESS CRITERIA:
Adequate response to treatment was defined as a decrease in ICP to below 20 mmHg, and maintenance below this threshold for at least 48 hours. To describe the ICP, we also followed the criteria previously employed by Stocchetti and coworkers [13]; the arithmetic mean of ICP data recorded during every 24-hour period, after filtering to exclude inaccurate readings, was calculated and expressed as 'mean ICP'. Three ICP blocks were considered for further analysis: less than 20 mmHg, 20 to 30 mmHg, and more than 30 mmHg. Uncontrollable ICP was defined as follows: ICP of 21 to 35 mmHg for 4 hours, ICP of 36 to 40 mmHg for 1 hour, or ICP above 41 mmHg for 5 minutes, in the absence of external interventions. We also defined as unresponsive to treatment those cases in which, because of refractory ICP, the patient needed some other treatment (surgery and/or lumbar drainage) and cases in which the patient progressed to brain death. Although it was not a main objective of the study, patients were evaluated 6 months after injury using the Glasgow Outcome Scale [14].
BODY.MATERIALS AND METHODS.WITHDRAWAL OF TREATMENT:
When ICP was controlled (<20 mmHg for 48 hours), we conducted a step-wise reduction in the barbiturate coma in steps that reduced the dosage by 50% every 24 hours until the infusion was suspended. In the event of ICP values rising to the study's inclusion values during the withdrawal of barbiturate treatment, the perfusion dosage was once again increased to achieve control of the patient's ICP.
BODY.MATERIALS AND METHODS.SAMPLE SIZE:
Accepting an α error of 0.05 and a β error of 0.2 in a bilateral hypothesis contrast, we estimated that 47 patients were needed in each group to detect differences of 30% or greater in the control of ICH. To calculate sample size, we assumed that the therapeutic response rate in the pentobarbital group would be 50%, excluding patients lost to follow up.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Quantitative variables are expressed as the mean and standard deviation from the mean (SD) in normal distributions, and as median and interquartile range in cases that were not normally distributed. Qualitative variables are expressed as percentages, along with 95% confidence interval (CI). To determine whether variables followed a normal distribution, we used the Shapiro Wilks test. For the comparison of quantitative variables, Student's t-test was used if the variable followed a normal distribution. In other cases, we used the Mann-Whitney U-test. For the comparison of qualitative variables, we used χ2 or Fisher's exact test, as appropriate. Given that the randomization did not create groups that were similar in terms of types of intracranial lesions shown on the CT results, which is a prognostic variable that influences the effectiveness of barbiturate treatment in controlling ICP, we conducted a multivariate analysis using binary logistic regression, so that we would include the prognostic variables with the most plausible association with the dependent variable 'uncontrollable ICP'. These are variables such as age, GCS score at admission, and the worst CT obtained within 24 hours before inclusion of the patient in the study, as well as the type of barbiturate administered. To achieve this multivariate analysis, and given the small number of cases in each of the five groups in Marshall's classification, the CT data were grouped into focal and diffuse lesions. We also included in the model the minimum daily MAP during barbiturate treatment, given that in the second and third days of treatment there were statistically significant differences between the groups in the univariate analysis. The significant variables identified by the 'likelihood ratio' ≤ 0.1 test were used, along with those whose inclusion affected the calculation of the effect of the 'treatment group' variable. Both treatment groups were very similar in terms of other known prognostic variables, such as the presence of hypoxia, hypotension before hospital admission and pupil reactivity, and the univariate analysis did not identify differences between them, so these were not included in the multivariate analysis. To analyze the variable ICP, which was determined on an hourly basis, we calculated the area under the curve (AUC) at 24, 48 and 72 hours, and also standardized by time [15]. For all comparisons, we considered statistical significance to have been achieved if the two-tailed α error probability was 5% or less (P ≤ 0.05). Statistical analyses were conducted using SPSS version 15 (SPSS Inc., Chicago, IL, USA).
BODY.RESULTS:
Preliminary results for the first 20 patients have already been published elsewhere [16]. From May 2002 to July 2007, 480 TBI patients were admitted to the intensive care unit of the Son Dureta University Hospital. Of these 480 patients, 71 (14.8%) presented with ICH refractory to first-level measures, of whom 44 were included in the study. The study was concluded prematurely because of the unexpected and slow inclusion rate; this could have modified some uncontrollable environmental factors that may affect results. The reasons for not including the remaining 27 refractory ICH cases were as follows: 13 patients were included in other studies, six were older than 76 years, five were admitted with nonreacting midriatic pupils and with clinical evidence of brain death, two presented with haemodynamic instability at the time of randomization, and one patient was transferred to a different hospital during the first 24 hours of admission, which excluded that patient from follow-up analysis. On average, the barbiturate coma was initiated in the thiopental group at 89 ± 15.5 hours after admission and in the pentobarbital group at 61 ± 14.3 hours after admission (P = 0.33). The baseline characteristics of the 44 patients included in the study, 22 randomized to each group, are presented in Table 1. There were no statistically significant differences with respect to epidemiological data, co-morbidity (data not shown) or lesions associated with TBI, although there were differences in the CT classification. Table 1 Baseline characteristics of patient population Characteristic Thiopental (n = 22) Pentobarbital (n = 22) P Sex (male; n) 19 19 1 Age (years) 26 (20 to 41) 32 (22 to 43) 0.45 ISS 25 (24 to 34) 25 (25 to 38) 0.77 SAPS II 42 (28 to 54) 43 (38 to 46) 0.95 APACHE II 23 (15 to 25) 20 (18 to 26) 0.27 APACHE III 60 (38 to 73) 52 (32 to 76) 0.41 Associated lesion (n) Thoracic injury 7 2 0.13 Abdominal injury 4 1 0.34 Extremities injury 9 5 0.20 Admission CT (n) Diffuse injury without brain swelling 12 4 0.046 Diffuse bilateral brain swelling 6 12 Diffuse unilateral brain swelling with midline shift 1 0 Any mass lesion > 25 ml 3 6 Age, ISS, SAPS II, APACHE II and APACHE III are expressed as median and interquartile range. APACHE, Acute Physiology and Chronic Health Evaluation; admission CT, admission computed tomography (according to the Traumatic Coma Data Bank); ISS, Injury Severity Score; SAPS, Simplified Acute Physiology. The summary of prognostic variables for the 44 patients is shown in Table 2. As in Table 1 the characteristics of the worst CT conducted before inclusion in the study differed between the two groups. Table 2 Prognostic variables of patient population Variable Thiopental (n = 22) Pentobarbital (n = 22) P Admission GCS score 6.5 (3.0 to 7.2) 7 (4.7 to 10.0) 0.38 Out-of-hospital hypoxia (n) 5 7 0.63 Out-of-hospital hypotension (n) 5 4 1 Pupillary reactivity (n) a One reacting 3 5 0.66 Both reacting b 12 14 Pre-enrolment CT (n) Diffuse injury without brain swelling 8 5 0.04 Diffuse bilateral brain swelling 1 8 Diffuse injury unilateral brain swelling with midline shift 5 1 Any mass lesion evacuated 7 5 Nonevacuated mass lesion 1 3 Admission GCS is expressed as median (interquartile range). a Pupillary reactivity at hospital admission. b Miotic pupils were considered as reactive. CT, computed tomography; GCS, Glasgow Coma Scale.
BODY.RESULTS.EFFECTIVENESS CRITERION: CONTROL OF INTRACRANIAL PRESSURE:
The distribution of the ICP during the first 3 days of treatment, according to Stocchetti's criteria, is summarized in Table 3. The missing cases during these 3 days were due to brain deaths or to receipt of rescue treatment for uncontrollable ICP. Finally ICP was uncontrollable in 11 cases (50%) in the thiopental group and in 18 patients (82%) in the pentobarbital group (P = 0.03). In nonresponding patients, we chose to place a lumbar drainage in five, in three we opted for surgical treatment, and in three other patients we combined both treatments, drainage and surgery. Surgical decompression was conducted in four patients in the thiopental group and in two of the patients in the pentobarbital group. The number of hyperosmolar treatments administered (manitol and/or hypertonic saline) during the barbiturate coma was similar in both groups: 16.5 (8.0 to 24.2) in the thiopental group and 16.5 (3.0 to 21.5) in the pentobarbital group (P = 0.9). The mean ± SD duration of the barbiturate coma was 156 ± 60 hours for thiopental and 108 ± 100 hours for pentobarbital (P = 0.06). Seven (31.8%) patients presented an ICP rebound with thiopental and six (27.3%) with pentobarbital (P = 0.74) during treatment withdrawal. Table 3 Mean ICP recorded per day during the first 3 days of barbiturate coma Drug Day Mean ICP (n[%]) <20 mmHg 20 to 30 mmHg >30 mmHg Thiopental 1 10 46 11 50 1 5 2 15 71 4 19 2 10 3 12 63 6 32 1 5 Pentobarbital 1 9 41 8 36 5 23 2 8 38 9 43 4 19 3 6 43 8 57 0 0 Mean intracranial pressure (ICP) is the arithmetic mean of ICP data recorded during every 24-hour period, according to Stocchetti's criteria [ 13 ]. Data are presented as number of cases and as a percentage of the total number of cases each day. Figure 1 presents the AUC for ICP above 20 mmHg, standardized over time, as follows. The ICP value of AUC0–24 h was 458.00 mmHg·hour (95% CI = 421.84 to 494.16) in the thiopental group and 550.63 mmHg·hour (95% CI = 411.31 to 689.95) in the pentobarbital group. The AUC0–48 h was 913.18 mmHg·hour (95% CI = 814.08 to 1,012.27) in the thiopental group and 997.27 mmHg·hour (95% CI = 757.10 to 1,237.43) in the pentobarbital group. The AUC0–72 h in the thiopental group was 1,291.69 mmHg·hour (95% CI = 1,172.27 to 1,411.12) and 1,399.73 mmHg·hour (95% CI = 1,291.11 to 1,508.35) in the pentobarbital group. Standardized over time, the AUC per hour in the thiopental group was 23.90 mmHg (95% CI = 22.00 to 25.81) and in the pentobarbital group it was 29.39 mmHg (95% CI = 23.20 to 35.59). Figure 1AUC of ICP data. Presented are areas under the curve (AUCs) of the intracranial pressure (ICP) data, standardized by time, with a base value of 20 mmHg. Both treatment groups were similar in terms of known prognostic variables, such as presence of hypoxia, hypotension before hospital admission and pupil reactivity, and the univariate analysis did not identify differences between them. Therefore, these were not included in the multivariate analysis. The logistic regression analysis showed that, after adjusting for the worst CT and the type of barbiturate used, thiopental was five times more likely than pentobarbital to control ICP (odds ratio = 5.1, 95% CI = 1.2 to 21.9; P = 0.027). The Hosmer-Lemeshow test indicated that the fit of the model was good (P = 0.799). The association of focal lesions in the pre-inclusion CT with ICP control was 3.6 times higher than that for the diffuse lesions. The relative risk for good control of ICP in the thiopental versus pentobarbital group was 2.26 for patients with focal lesions and 3.52 for those who presented with diffuse lesions. The other variables analyzed did not exhibit a significant relationship to ICP control, and did not modify the effect of the barbiturate treatment, including the third day minimum MAP, which was significantly different between the two treatments (data not shown).
BODY.RESULTS.ADVERSE SIDE EFFECTS DURING THE BARBITURATE COMA:
The secondary effects during the barbiturate coma are presented in Table 4. In both groups almost all patients presented with at least one MAP measurement below 80 mmHg. There were no differences between groups with respect to the incidence of infections, Sepsis related Organ-Failure Assessment (SOFA) scores before initiation of treatment, or the maximum SOFA value [17] during the entire period of barbiturate coma. Table 4 Adverse events during barbiturate coma Adverse event Thiopental (n = 22) Pentobarbital (n = 22) P Hypotension a 21 20 1 Respiratory infection b 18 17 1 Urinary infection c 0 2 0.49 Positive blood culture 4 1 0.34 ICP catheter colonization 7 5 0.5 CNS infection (CSF) d 3 0 0.23 SOFA pre e 7 (4.5 to 9.5) 8.0 (5.5 to 9.0) 0.57 SOFA maximum f 11 (10 to 12) 11 (10 to 12) 0.94 a Hypotension is defined as detection of a medium arterial blood pressure below 80 mmHg at any time during barbiturate coma. b Respiratory infection: presence of a positive sputum culture. c Urinary infection: presence of a positive urine culture. d Central nervous system infection (CNS) infection (cerebrospinal fluid [CSF]): infection of the CNS with a positive culture in the CSF. e SOFA pre: value of the Sepsis related Organ-Failure Assessment (SOFA) score before the beginning of the barbiturate coma. f SOFA maximum: maximum value of the SOFA during the barbiturate coma, according the indication by Moreno and coworkers [ 16 ]. A thermodilution catheter was placed in 42 patients to facilitate haemodynamic control. The haemodynamic changes produced during the barbiturate coma are presented in Table 5. Differences of note include the minimum MAP, the pulmonary wedge pressure value, and the maximum norepinephrine dosage on days 2 and 3. Table 5 Systemic changes during barbiturate coma Parameter Pretreatment 1st day 2nd day 3rd day 4rd day Cardiac output (l/minute) a Thiopental 6.8 ± 1.4 6.4 ± 1.5 6.0 ± 1.4 6.7 ± 1.5 6.6 ± 1.8 Pentobarbital 7.4 ± 2.2 7.1 ± 1.9 6.5 ± 2.0 7 ± 1.4 6.1 ± 1.3 Cardiac index (l/minute per m 2 ) Thiopental 3.6 ± 0.6 3.4 ± 0.6 3.1 ± 0.6 3.6 ± 1.6 3.5 ± 0.9 Pentobarbital 3.8 ± 1.2 3.8 ± 0.8 3.4 ± 0.8 3.6 ± 0.7 3.2 ± 0.6 Peripheral venous resistance (dines/m 2 ) Thiopental 1,015 ± 325 1,022 ± 347 1,140 ± 429 1,089 ± 289 1,029 ± 253 Pentobarbital 952 ± 257 893 ± 210 1,003 ± 322 939 ± 261 914 ± 188 Pulmonary artery wedge pressure (mmHg) Thiopental 10.4 ± 4.5 9.6 ± 3.6 10.1 ± 4.1* 10.9 ± 4.6* 11.4 ± 3.5* Pentobarbital 11.6 ± 4.0 11.4 ± 3.1 12.8 ± 3.1 13.2 ± 2.1 13.9 ± 3.1 mBP (mmHg) b Thiopental 92 ± 11 75 ± 7 76 ± 9* 76 ± 6* 76 ± 8 Pentobarbital 94 ± 10 74 ± 1 68 ± 10 70 ± 1 70 ± 10 NAD (μg/kg per minute) c Thiopental 0.18 ± 0.33 0.28 ± 0.27 0.37 ± 0.3* 0.46 ± 0.39 0.56 ± 0.63 Pentobarbital 0.19 ± 0.18 0.55 ± 0.68 0.73 ± 0.69 0.60 ± 0.44 0.96 ± 0.79 P O 2 /Fi O 2 d Thiopental 284 ± 130 300 ± 139 293 ± 132 285 ± 138 254 ± 119 Pentobarbital 317 ± 127 304 ± 116 262 ± 125 211 ± 77 184 ± 92 Haemoglobin Thiopental 10.9 ± 1.6 10.7 ± 1.3 11 ± 1.2 10.8 ± 0.9 10.7 ± 1.4 Pentobarbital 10.6 ± 1.2 10.1 ± 1.0 10.4 ± 1.1 10.5 ± 1.1 10.2 ± 1.2 Temperature (°C) e Thiopental 35.8 ± 0.5 34.6 ± 1.3 34.6 ± 3.4 34.9 ± 1.0 34.9 ± 1.0 Pentobarbital 35.7 ± 1.0 34.6 ± 1.2 34.3 ± 1.3 34.4 ± 1.3 34.2 ± 1.1 a Cardiac output, cardiac index, peripheral venous resistance and pulmonary artery wedge pressure: the values are the mean values over 24 hours. b mBP: minimum value of the medium blood pressure during the day. c NAD: maximum dose of Noradrenaline bitartrate during the day. d P O 2 /Fis O 2 : ratio of partial oxygen tension to inspired fractional oxygen tension at 8:00 am. e Temperature: value of the minimum central temperature. * P < 0.05.
BODY.RESULTS.SIX-MONTH OUTCOMES:
In the thiopental group, the neurological outcomes at 6 months (in accordance with Glasgow Outcome Scale score) were as follows: death in nine patients, vegetative state in two, severe disability in two, moderate disability in four and good recovery in four. In the pentobarbital group, the 6-month outcome was death in 16 patients, vegetative state in one, moderate disability in two and good recovery in two. In both groups one case was missing from the 6-month follow up analysis
BODY.DISCUSSION:
The results of this study indicate that thiopental is five times more effective than pentobarbital in controlling refractory ICH. However, these findings must be interpreted with caution, given the small sample size and the fact that the study was unable to mask assignment to treatment groups. Barbiturate coma is at present the only therapy for which we have class II evidence, under BTF Guidelines [1], of efficacy in treating refractory ICH. Hence, it is perhaps the case that barbiturate coma is the most used second-level measure, with a usage frequency reported in the literature that varies from 13% to 56% [18,19]. Therefore, it is important to test the effectiveness of the various barbiturates available for controlling ICP refractory to first-level measures.
BODY.DISCUSSION.DIFFERENCES BETWEEN OXIBARBITURATES AND THIOBARBITURATES:
The pharmacokinetic characteristics of thiopental and pentobarbital are different because their protein binding, distribution volume and clearance differ [20]. Nevertheless, the mean half life (thiopental 6 to 46 hours and pentobarbital 15 and 48 hours), which is the fundamental pharmacological parameter, differs little between the two agents. It therefore does not appear that these pharmacokinetic differences have clinical repercussions. One difference between these two groups of barbiturates is the presence of active metabolites. Thiopental has five metabolites, of which four are inactive and one (pentobarbital, or pentobarbitone) is active. Therefore, pentobarbital is an active metabolite of thiopental. This fact, along with the great intra-individual and inter-individual variability in the metabolism of these agents (caused by the existence of enzymatic induction phenomena associated with hepatic cytochrome P450), results in a weak correlation between serum concentrations and pharmacological effect. For this reason, monitoring this treatment with electroencephalography is strongly recommended. At the experimental level, various studies have compared these two medications. Hatano and coworkers [21], in a study conducted in a dog model, concluded that thiobarbiturates provoke cerebral vasoconstriction, which could help to redistribute cerebral blood flow toward ischaemic zones. Cole and colleagues [4] demonstrated that thiopental reduced the size of the ischaemic area more than did pentobarbital, even though both drugs achieved electroencephalographic burst suppression patterns. Shibuta [5] observed that thiopental, but not pentobarbital, was capable of limiting the cytotoxic damage caused by nitric oxide. Almaas and coworkers [3] observed that the different barbiturates had different neuroprotective effects with respect to oxygen and glucose deprivation in a model using human neurone cultures. Thiopental exhibited a neuroprotective effect at all the dosages studied, whereas pentobarbital was neuroprotective only at elevated dosages. Finally, in an in vitro study, Smith and colleagues [6] demonstrated that although thiopental provoked 96% inhibition of lipid peroxidation, pentobarbital had almost no effect. These experimental studies demonstrate that not all barbiturates are equal and that their neuroprotective capacity and effectiveness may differ [22]. Therefore, despite the unavoidable methodological limitations of the present study, we believe that our results may have clinical relevance.
BODY.DISCUSSION.SECONDARY EFFECTS OF BARBITURATE COMA:
The most frequently detected secondary effect in our study, as might be expected, was arterial hypotension, which occurred in 21 patients in the thiopental group and 20 patients in the pentobarbital group. Although this incidence may be greater than that in previous studies [10], we attribute this to the definition of hypotension used (detection at any time in the barbiturate coma of MAP < 80 mmHg), which did not take the 'time' variable into account. For that reason, we collected data on other variables, such as maximum daily norepinephrine dosage and minimum daily MAP. Nearly all patients were monitored using a pulmonary artery thermodilution catheter, and arterial hypotension episodes were rigorously managed with fluid therapy and vasoactive drugs. We would note that the changes produced by pentobarbital at the cardiac and respiratory level were, in general terms, greater than those produced by thiopental. This is because (as shown in Table 5) cardiac output, cardiac index, and partial oxygen tension/fraction of inspired oxygen ratio exhibited greater changes during treatment with pentobarbital than with thiopental. This observation contrasts with the findings of previous experimental studies [23], in which it appeared that at high doses pentobarbital was safer and better tolerated than thiopental. Other complications (mostly infections) and the incidence of multiple organ dysfunction (identified using maximum SOFA) were similar in the two groups.
BODY.DISCUSSION.LIMITATIONS OF THE STUDY:
As previously noted, this study has two important limitations. First, it was not a blinded study because the pentobarbital was not liophylized and thiopental was. Second, the sample size was small, so that small changes in the principal variable studied, namely ICP control, could significantly affect the statistical analysis. The classical view is that ICP response to barbiturates varies from 30% to 50%, and so it is possible that part of the difference found between drugs is due to poor response by the pentobarbital group as a result of any confounding bias. The randomization process is a potent mechanism that tends to eliminate bias by randomly distributing the values of all of the variables to the experimental groups. Nonetheless, the tool is not perfect and the groups frequently exhibit an imbalance in some confounding variable, especially when working with samples that are not very large. For this reason, in this study we used logistic regression analysis to eliminate any possible bias, and separate, independent analyses of the CT data were also conducted by two investigators who did not know the experimental group to which the patients belonged. Another limitation is that the dosages in the two groups were not the same. This leaves the possibility that the reason for the difference between agents that we identified is inadequate pentobarbital dose. Although in the two groups barbiturates were used with the end-point of ICP control, in this type of patient we also employ daily noncontinuous electroencephalographic monitoring. In this way, we believe that – despite different doses – the effect of the two barbiturates can be considered as equipotent because we looked for burst suppression or even the flat electroencephalographic pattern if the ICP was not controlled and the patients remained haemodynamically stable.
BODY.CONCLUSION:
In this patient sample, thiopental appeared to be more effective than pentobarbital in controlling ICH refractory to first-level measures, according to the BTF Guidelines. Nevertheless, these findings should be interpreted with caution because of the imbalance in CT characteristics and the different dosages employed in the two arms of the study. However, the present study is useful as a hypothesis testing exercise and will help to inform the design of future studies. These findings corroborate experimental evidence suggesting that there are differences in the neuroprotective mechanism between the two treatments, and this study may be a first step toward translating evidence from animal models to clinical disease. The incidence of secondary effects during treatment was similar between groups.
BODY.KEY MESSAGES:
• High doses of barbiturates are used in those patients with severe TBI who present with refractory ICH, and this recommendation is included in the BTF Guidelines. • Until now no controlled studies have been conducted to compare the effectiveness of pentobarbital and thiopental in controlling refractory ICH. Nevertheless, at the experimental level, research has demonstrated that their mechanisms and levels of neuroprotection differ. • Thiopental appeared to be more effective than pentobarbital in controlling ICH refractory to first-tier measures, although these results should be interpreted with caution because of the imbalance in CT characteristics and other limitations of the study.
BODY.ABBREVIATIONS:
AUC: area under the curve; BTF: Brain Trauma Foundation; CI: confidence interval; ICH: intracranial hypertension; ICP: intracranial pressure; MAP: mean arterial pressure; SD: standard deviation; SOFA: Sepsis related Organ-Failure Assessment; TBI: traumatic brain injury.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
JPB was responsible for study design, acquisition of data, analysis and interpretation of data, and writing of the manuscript. JALP was responsible for acquisition of data and patient randomization. JH acquired data and conducted patient randomization. JMA acquired data and conducted patient randomization. JMR conducted statistical analyses. GF conducted statistical analyses. MB was responsible for designing the study and reviewing CT findings. JI was responsible for designing the study and reviewing CT findings. JI revised the article critically and gave final approval to the version to be published. | 2,575,601 | {
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TITLE: Repair of Giant Midline Abdominal Wall Hernias: “Components Separation Technique” versus Prosthetic Repair
ABSTRACT.BACKGROUND:
Reconstruction of giant midline abdominal wall hernias is difficult, and no data are available to decide which technique should be used. It was the aim of this study to compare the "components separation technique" (CST) versus prosthetic repair with e-PTFE patch (PR).
ABSTRACT.METHOD:
Patients with giant midline abdominal wall hernias were randomized for CST or PR. Patients underwent operation following standard procedures. Postoperative morbidity was scored on a standard form, and patients were followed for 36 months after operation for recurrent hernia.
ABSTRACT.RESULTS:
Between November 1999 and June 2001, 39 patients were randomized for the study, 19 for CST and 18 for PR. Two patients were excluded perioperatively because of gross contamination of the operative field. No differences were found between the groups at baseline with respect to demographic details, co-morbidity, and size of the defect. There was no in-hospital mortality. Wound complications were found in 10 of 19 patients after CST and 13 of 18 patients after PR. Seroma was found more frequently after PR. In 7 of 18 patients after PR, the prosthesis had to be removed as a consequence of early or late infection. Reherniation occurred in 10 patients after CST and in 4 patients after PR.
ABSTRACT.CONCLUSIONS:
Repair of abdominal wall hernias with the component separation technique compares favorably with prosthetic repair. Although the reherniation rate after CST is relatively high, the consequences of wound healing disturbances in the presence of e-PTFE patch are far-reaching, often resulting in loss of the prosthesis.
BODY:
Reconstruction of giant midline abdominal wall hernias that cannot be closed primarily is a technical challenge to a surgeon. Many surgeons discourage abdominal wall reconstruction because of the technical difficulties, the high morbidity, and the relatively high recurrence rate associated with these procedures. However, many patients with large hernias have invalidating complaints such as bulging of the abdominal wall, chronic wounds, immobility, and back pain, necessitating surgical treatment. The lack of sufficient tissue requires the insertion of prosthetic material or transposition of autologous material to bridge the fascial gap. Reconstruction using pre-peritoneally placed prosthetic material is still the most frequently applied method of reconstruction.1 The increased risk of infection in case of wound complications is a relative contraindication against the use of prosthetic materials. Moreover, interposition of either peritoneum or greater omentum between the bowel and the prosthesis is often impossible, which is another reason to avoid the use of prosthetic material. In 1990 Ramirez, Ruas, and Dellon introduced the "components separation technique (CST)" to bridge the fascial gap without the use of prosthetic material.2 The technique is based on enlargement of the abdominal wall surface by separation and advancement of the muscular layers. In this way, defects of up to 20 cm at the waistline can be bridged. Retrospective series report promising results, but no prospective study has been published until now.3–12 It was the aim of this prospective study to compare the results of prosthetic repair with CST in patients with giant abdominal wall hernias that cannot be closed primarily. The primary endpoint of the study was reherniation; secondary endpoints were operation time and postoperative wound complications. In the present report the results of an interim analysis are presented.
BODY.PATIENTS AND METHODS:
Adult patients (18–80 years) with an incisional hernia after midline laparotomy with a craniocaudal length of at least 20 cm that could not be closed primarily, in whom the repair could be performed under clean or clean-contaminated conditions, and who were not using corticosteroid therapy were asked to participate in the study. Patients with perioperative gross contamination of the operative field were excluded from the study. After written informed consent the patients were randomized between CST and prosthetic repair by the data center of the Radboud University Nijmegen Medical Centre using envelope, the day before operation. Fully trained abdominal wall surgeons who had done at least five procedures of both techniques before the start of the study performed the operations. H.v.G. and R.P.B. performed supervision in centers not having this expertise. Before each procedure, a preoperative chest x-ray was made. Demographic data, co-morbidity (COPD, cardiovascular disease, or diabetes), body mass index, condition of the skin, size of the hernia at the time of the operative procedure, kind of anesthesia, operation time, perioperative blood loss, postoperative ICU stay, analgesia use, complications, hospital stay, and follow-up were recorded on a standard form. The study protocol was reviewed and approved by the institutional ethics commissions of all the participating hospitals. All patients gave written informed consent after receiving a thorough explanation of the study.
BODY.PATIENTS AND METHODS.OPERATIVE TECHNIQUE:
Standard thrombosis (Nadroparine 2,850 IE) and antibiotic prophylaxis (cefazoline 3 × 1 g and metronidazole 3 × 500 mg) were started preoperatively. After induction of anesthesia (combined general and epidural, if possible) and disinfection of the skin with iodine tincture, an adhesive drape was applied on the skin, if possible. The abdomen was entered via a midline laparotomy or at the lateral edge of the graft if the bowels were covered with a split skin graft. Adhesions between the ventral abdominal wall and the intra-abdominal viscera were cut, after which the length and width of the defect were measured.
BODY.PATIENTS AND METHODS.COMPONENTS SEPARATION TECHNIQUE (CST GROUP):
The component separation technique was performed as described in detail in former publications.2,12,13 Briefly, the skin and subcutaneous fat are dissected free from the anterior rectus sheath and the aponeurosis of the external oblique muscle (Figure 1A). The aponeurosis of the external oblique muscle is transected longitudinally about 2 cm lateral from the rectus sheath, including the muscular part that inserts on the thoracic wall, which extends at least 5–7 cm cranially of the costal margin (Figure 1B). The external oblique muscle is separated from the internal oblique muscle as far laterally as possible (Figure 1B). The posterior rectal sheath is separated from the rectus abdominis muscle if tension-free closure is impossible (Figure 1C). The fascia is closed in the midline with a running polydioxanone suture (PDS-loop, Johnson & Johnson, Ltd.) of at least 4 times the length of the incision. The skin is closed over at least two closed suction drains.
Figure 1.Operative technique of the "components separation technique." 1 = rectus abdominis muscle; 2 = external oblique muscle; 3 = internal oblique muscle; 4 = transversus abdominis muscle; 5 = posterior rectal sheath. A. Dissection of skin and subcutaneous fat. B. Transaction of aponeurosis of external oblique muscle and separation of internal oblique muscle. C. Mobilization of posterior rectal sheath and closure in the midline. Adapted from Bleichrodt et al.13, with permission of Elsevier.
BODY.PATIENTS AND METHODS.PROSTHETIC REPAIR (E-PTFE GROUP):
The skin and subcutaneous tissue are mobilized from the underlying fascia of the rectus abdominis muscle. As a consequence all epigastric perforating arteries supplying the overlying skin are separated. After adhesiolysis , a 20 × 30 cm, 1.5-mm-thick e-PTFE patch (Gore-Tex dual mesh plus with holes, W. L. Gore and associates Inc., Flagstaff, AZ, USA) is shaped in size and implanted intra-abdominally as underlay with an overlap of at least 4 cm to the aponeurosis, as described elsewhere.14 The mesh is placed intra-abdominally as an underlay and is sutured under slight tension to the ventral abdominal wall using a double row of interrupted sutures of e-PTFE 1/0 (Gore-Tex 1/0, W. L. Gore and associates Inc., Flagstaff, AZ, USA) that passed the rectus abdominis muscle. The prosthesis is implanted with the microporous side facing the intra-abdominal viscera and the macroporous side facing the fascia. (As a consequence of the large size of the hernias, the fascia could not be closed over the prosthesis in any of the patients in our series.) After implantation, the skin is closed over at least two closed suction drains.
BODY.PATIENTS AND METHODS.POSTOPERATIVE CARE:
Antibiotic prophylaxis, cefazoline 3 × 1 g and metronidazole 3 × 500 mg was started preoperatively and continued for the first 24 h postoperatively. All patients have epidural anesthesia if possible. Wounds were inspected on a daily basis with respect to hematoma, seroma, skin necrosis, and wound infection. Hematoma was defined as an accumulation of blood in the operative field for which a surgical intervention (puncture or drainage) was needed; seroma as an accumulation of fluid in the operative field for which an intervention (puncture or drainage) was needed in case of mechanical or physical limitations. Skin edge necrosis was defined as necrotic loss of full thickness skin for which surgical intervention was needed. The wound was scored on a daily basis according to CDC criteria, as follows15: grade 1: normal wound, grade 2: erythema and swelling, grade 3: purulent effluent; or grade 4: open wound. Drains were removed after 5 days or if production was less than 50 ml/24 h. The thorax was examined daily by physical examination, and a routine x-ray of the thorax was performed on the second and seventh days after the operation, to detect pneumonia and atelectasis. No specific instructions were given to the patients after operation and patients had no restriction of physical activity except heavy lifting. Follow-up was done in the outpatient clinic at 3, 6, 12, 24, and 36 months after operation. At each visit a physical examination was done to diagnose recurrent hernia. Ultrasonography or computed tomography (CT) scanning was performed on indication, especially to detect small recurrences.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS:
Patients were analyzed as per intention to treat. Hernia recurrence-free survival was compared using the Kaplan-Meier methods according to the intention-to-treat principle.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS.POWER ANALYSIS:
Type I and II errors were set to 0.05 and 0.1, respectively. The minimum relevant difference in reherniation between groups was set to 30%, in advantage of CST. Accordingly, a minimum of 84 patients was required (two groups of 42 patients). An interim analysis was planned to evaluate the results of the trial after inclusion of 40 patients. Differences between groups were analyzed using the Fisher exact test for demographic data, preoperative and perioperative data, wound complications, reoperation, and reherniation (Table 1).
Table 1.Study characteristic of patients with prosthetic repair or components separation techniqueGroup 1: prosthetic repairGroup 2: components separation techniqueSignificance(t-test)Age (mean)58.7 (range: 42–82)53.9 (range: 33–37)NS(Fisher exact test)Gender (women/men)6/126/13NS(t-test)BMI28.7 (range: 21.5–39.6)28.2 (range: 23.9–38.7)NSDefect (median) (cm)(t-test)Length25 (range: 20–30)25 (range: 20–33)NSWidth17 (range: 9–30)15 (range: 7–25)NSSkin (n)(t-test) Intact, full thickness1412NS Intact, split skin47NSAnesthesia (n)(Fisher exact test) General35NS Epidural and general1514NS(t-test)Operative time (min)183 (range 135–254)113 (range 63–175)p < 0.001(t-test)Blood loss (ml)420 (range 100–900)289 (range 50–1000)NSICU stay(Mann-Whitney U-test) Patients (n)63NS Time (days)2 (range: 1–6)5 (range: 1–10)NS(t-test)Pulmonary complications (n)24NS Pneumonia21NS Atelectasis03NSAnalgesia(t-test) Epidural (days)2.4 (range: 0–5)2.4 (range: 0–6)NS Morphine (days)3.3 (range: 0–8)3.6 (range: 0–10)NS(Fisher exact test)Wound complication (n)11NS Hematoma74NS Seroma32NS Skin necrosis23NSInfected mesh (n)70(t-test)Reoperation (in OR) for wound complications (n)72p = 0.05Recurrence (n)1110NSBMI: body mass index; ICU: intensive care unit; NS: not statistically significant; OR: Operation room.
BODY.RESULTS:
Between November 1999 and June 2001, 39 patients were included in the study and were operated on by one of 5 surgeons. Two patients were excluded from the study because of gross contamination during operation. Nineteen patients, 6 women and 13 men, were randomized to the CST group: reconstruction using the components separation technique. The mean age of these 19 patients was 53.9 years (range: 33–73 years). Eighteen patients, 6 women and 12 men, were randomized to the e-PTFE group (prosthetic repair). Their mean age was 58.7 years (range: 42–82 years). In the CST group, closure of the fascia was accomplished in 18 of the 19 patients (Figure 2). In one patient the abdominal wall hernia was too large and had to be repaired using a combination of the CST and prosthetic repair. In the e-PTFE group the procedure was successful in 17 of the 18 patients. In one patient the abdominal wall hernia was too large and was reconstructed using a combination of prosthetic repair and CST. No differences were found between the groups with respect to demographic data (Table 1), co-morbidity, length and width of the defect, skin coverage, anesthesia, blood loss, and ICU stay (Table 1). All operations were performed without major intraoperative complications, except for the two excluded patients with gross perioperative contamination. The operation time for prosthetic repair was significantly longer as compared with the components separation technique (p < 0.001, Fisher exact test) (Table 1). This is mainly due to the time-consuming fixation of the patch to the fascia with a double row of single sutures.
Figure 2.A. Preoperative view of a giant abdominal wall hernia covered with a split skin. B. Postoperative view of the same abdominal wall after reconstruction using the components separation technique.
BODY.RESULTS.POSTOPERATIVE MORTALITY AND MORBIDITY:
There was no 30-day mortality. Major wound complications were found in 10 of the 19 patients in the CST group: wound infection (n = 3), skin necrosis (n = 2), hematoma (n = 1). Four patients developed seroma; these were not associated with the aforementioned complications. Major wound complications were found in 13 of the 18 patients in the e-PTFE group: wound infection (n = 2), skin necrosis (n = 3), hematoma (n = 1). Both wound infection and skin necrosis ultimately resulted in loss of the prosthesis (Table 1). Seven patients developed a seroma. In two of these patients seroma puncture was performed to prevent spontaneous evacuation via the midline wound; this resulted in infection and, ultimately, loss of the patch. Seven patches were removed after a median period of 94 days (range: 30–262 days). In the cases where the prosthesis was removed, the abdominal wall defect was reconstructed using CST. Pulmonary complications were found in 4 patients in the CST group and 2 in the e-PTFE group (not significant, Fisher exact test) (Table 1).
BODY.RESULTS.REHERNIATION:
Follow-up was complete in all patients. Four patients in the CST group died before the end of the follow-up period 5, 9, 10, and 12 months after the operation from unrelated causes. Two had a reherniation at the time of death. Of the remaining 15 patients, 8 had a reherniation. Recurrences occurred after a mean period of 7 months (range: 0.5–12 months). Recurrences were all located in the midline in the upper abdomen and were small. Two patients underwent reconstruction of their recurrence. One patient in whom the reconstruction was performed with a combination of CST and prosthetic bridging had a recurrent hernia at the edge of the prosthesis (Figure 3).
Figure 3.Kaplan-Meier for recurrent hernia after prosthetic repair (n = 18) and components separation technique (n = 19). Seven of 18 prostheses were removed during the first 7 months after implantation. Reherniation rates after 36 months are similar in both groups.
BODY.RESULTS.PROSTHETIC REPAIR:
One patient in the e-PTFE group died 6 months after the operation from an unrelated cause. Of the remaining 17 patients, 7 had an infected prosthesis that had to be removed. The abdominal wall defect was then reconstructed using CST repair. Four other patients had a small recurrent hernia after prosthetic repair, without complaints. Recurrences occurred after a mean period of 22 months (range: 6–36 months). None of these four patients underwent reoperation for their recurrence (Figure 3).
BODY.DISCUSSION:
The present study is the first randomized controlled trial comparing different techniques to repair giant midline hernias and the first prospective trial regarding the "component separation technique." Although our series is relatively small, the results suggest that repair of giant abdominal wall defects with the component separation technique compares favourably with prosthetic repair, because wound infection in patients in whom a prosthetic repair was performed had major consequences, resulting in removal of the prosthesis in 7, whereas wound infection in patients after CST had only minor consequences. Disturbed wound healing frequently complicates repair of large abdominal wall hernias. Wound complications such as hematoma, seroma, skin necrosis, and infection are reported in 12%–67% of patients after CST2–5,7–12,16 and in 12%–27% after prosthetic repair. Wound complications are associated with the extensive dissection needed in both procedures, which are often performed after intra-abdominal catastrophes. The risk is further increased by the long duration of the operative procedure and the need to mobilize the skin in dividing the epigastric perforating arteries (Figure 4). This endangers the blood supply of the skin, because then it solely depends on the intercostal arteries, which may have been damaged during former operations by introduction of drains, or by stoma construction and other procedures needed in patients with intra-abdominal sepsis.17–19 Wound complications in our series were rather frequent. Although they are mentioned in most other publications about CST, the method of follow-up is mentioned in only one other study from our own group.12Figure 4.The operation wound after performing a components separation technique for abdominal wall reconstruction, showing the large wound surface and the extensive skin dissection needed. Loss of the prosthesis may also be associated with the choice of the prosthetic material used. Several materials have been developed for hernia repair. In the present series only patients with giant and often complex hernias were included. In the majority of these patients the peritoneum or greater omentum was not available to interpose between the prosthesis and the intra-abdominal viscera. Therefore, an e-PTFE dual patch was used to bridge the fascial gap. The expanded-PTFE dual patch has significantly better mechanical properties than polypropylene-mesh. It is a soft pliable microporous material that causes no mechanical trauma to the viscera. The micropores on both sides of the patch are too small to allow ingrowth of fibrocollagenous tissue, thus preventing fibrous adhesions on the visceral side of the patch. Lack of ingrowth results in insufficient anchorage of the patch to the adjacent fascia, however, and this is a major disadvantage of e-PTFE patches.14,20,21 The patch should be placed as underlay with an overlap of at least 4 cm and fixed to the aponeurosis with a double row of single sutures.14 The e-PTFE patch is prone to infection because of its hydrophobic characteristics. To reduce the infection risk, the e-PTFE patch used is impregnated with silver salts and chlorhexidine, which both have anti-microbial properties and work synergistically.22 Moreover, antibiotic prophylaxis was given to all patients and an adhesive drape was applied to the skin. Nevertheless, 40% of our patients had an early or late infection resulting in removal of the patch. In a recent experimental study in rats with a large abdominal wall defect, it was found that impregnation with silver salts resulted in an aggravated inflammatory response around the patch and an increased reherniation rate.23 This observation may explain the increased risk for seroma formation, which is associated with prosthetic loss in this study. Some patients (n = 3, 16%) were operated under clean-contaminated condition, which means they had an accidental bowel lesion during adhesiolysis without gross contamination. We suspect that most surgeons still place a prosthetic patch for abdominal wall reconstruction in these situations, which is supported by some small series in the literature.24,25 In our opinion polypropylene, which is still the most widely used material for hernia repair, is contraindicated because of its propensity for inducing extensive visceral adhesions and occasional fistula formation.26–28 If large areas of polypropylene mesh are exposed, scar contraction will result in wrinkling of the polypropylene mesh, causing mechanical irritation, which promotes infection and carries the risk of mesh erosion into the skin or the intestine.29 If the polypropylene mesh cannot be covered with full-thickness skin, chronic infection and sinus formation will ultimately result in loss of the mesh.27 Therefore the results probably would not have been better if polypropylene mesh or polypropylene mesh based prosthesis was used. Recurrent hernia still is a major problem The only randomized controlled trial comparing open suture and mesh repair of small ventral hernias was reported by Luijendijk et al. reporting recurrence rates of 46% and 23%, respectively, after a follow-up of 36 months and 63% and 32%, respectively, after a follow-up of 75 months.1,30 In retrospective studies recurrence rates of 25%–63% in suture repair and 8%–25% in mesh repair are reported. Tension-free repair of incisional hernia is a prerequisite to prevent recurrence. In CST a tension-free repair was accomplished. In the literature recurrence rates of 0%–28% have been reported for CST, although how follow-up was accomplished is not well documented in most series.2–12 But it seems impossible to have a reherniation rate, in series of large abdominal wall defects, that is far below the reherniation rate of reconstruction of small abdominal wall defects in a well performed randomized controlled trial.1,30 Despite the high recurrence rate in the present study and our retrospective study, CST remains an attractive technique for repair of giant ventral hernias. Most recurrent hernias are small and asymptomatic and need no further treatment. In addition, the functional and cosmetic results are good and patients were satisfied. In a recent other study in 39 patients undergoing CST repair for heavily contaminated abdominal wall defects, similar results were found with respect to complications and reherniation rate (36%).31 All but one patient indicated satisfaction with the result when compared to their situation before operation. In that study, postoperative quality of life was assessed using the SF 36 questionnaire. When compared to the general population, patients had an average score or higher on pain, vitality, social functioning, and role limitations (emotional problems); the score was below average on physical functioning, role limitations (physical problems), in general health perception, and in mental health.31 On the basis of the interim analysis, the trial was discontinued because the frequency of wound complications resulting in subsequent prosthetic loss was unacceptably high. Because underlay repair necessitates transection of the perforating epigastric arteries in patient with prosthetic repair it was expected that this complication could not be prevented, whereas CST remains possible if the epigastric perforators are spared. Impregnation of the e-PTFE patch with silver salts and chlorhexidine might have contributed to this.23 Recently, a prospective randomized controlled trial has started comparing CST with CST + preperitoneal polypropylene mesh support, combining the advantages of CST and prosthetic repair. | 1,913,177 | {
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TITLE: Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]
ABSTRACT.BACKGROUND:
Topical NSAIDs have been proven to relieve the symptoms of osteoarthritis (OA) in short-term studies (2 weeks). To justify its chronic use, efficacy of a topical NSAID over a longer term of study should be demonstrated. The efficacy and safety of a topical diclofenac solution over a 6-week treatment course in symptomatic primary OA of the knee was investigated.
ABSTRACT.METHODS:
216 men and women, age 40–85 years, with radiologically confirmed primary OA of the knee and a flare of pain at baseline following discontinuation of prior therapy were enrolled into this double-blind study. Participants applied either a topical diclofenac solution (Pennsaid®) or vehicle control solution (carrier with no diclofenac); 40 drops 4 times daily directly to the painful knee(s), without massage, for 6 weeks. Pre-planned primary efficacy outcome measures included the core continuous variables pain relief and improved physical function measured by the Western Ontario and McMaster Universities (WOMAC) LK3.1 OA Index, and improved patient global assessment (PGA). Secondary efficacy measure was reduced stiffness. Safety assessments included adverse events and vital signs.
ABSTRACT.RESULTS:
The topical diclofenac group had a significantly greater mean change in score (final minus baseline) compared to the vehicle control group for pain (-5.2 vs. -3.3, p = 0.003), physical function (-13.4 vs. -6.9, p = 0.001), PGA (-1.3 vs. -0.7, p = 0.0001) and stiffness (-1.8 vs. -0.9, p = 0.002). The mean difference between treatment arms (95% confidence interval [CI]) was 1.9 (0.7 to 3.2), 6.5 (2.5 to 10.5), 0.6 (0.2 to 0.9), and 0.9 (0.3 to 1.4), respectively. Safety analyses showed that topical diclofenac caused skin irritation, mostly minor local skin dryness, in 42/107 (39%), leading to discontinuation of treatment in 5/107 (5%) participants.
ABSTRACT.CONCLUSION:
This topical diclofenac solution demonstrated relief at 6 weeks of the symptoms of primary osteoarthritis of the knee.
BODY.BACKGROUND:
Meta-analysis of previous trials of topical non-steroidal anti-inflammatory drugs (NSAIDs) concluded that they effectively treat the pain of acute soft tissue injuries [1] and chronic musculoskeletal conditions [2,3]. Current evidence-based recommendations for the management of osteoarthritis (OA) support the use of topical NSAIDs and rubefacients [4-6] as a therapeutic option potentially with fewer gastrointestinal risks than oral NSAIDs [7]. However, a recent critical meta-analysis concluded that claims of pain relief in OA by currently available topical NSAIDs are supported by only a limited number of randomised controlled trials of small size and brief duration, with no data demonstrating efficacy beyond 2 weeks [8]. In this report, we present the efficacy and safety results from a 6-week controlled trial using a newer topical diclofenac solution in knee OA. Effect size data and number-needed-to-treat (NNT) are presented, facilitating comparison with the previously reviewed data.
BODY.METHODS.PARTICIPANTS AND INCLUSION/EXCLUSION CRITERIA:
This study was conducted from November 1999 to August 2000, at 17 medical centres across central Canada, following approval by a central ethics review board (Integrated Research Incorporated, Ethics Review Committee, Montreal, QC). Participants were recruited from the physician's private practice or the surrounding community. At the screening visit, after providing written, informed consent, each participant underwent a screening interview and was eligible to proceed to washout if all inclusion criteria and no exclusion criteria were met. Inclusion criteria specified men and non-pregnant women, age 40–85 years, with primary OA of at least one knee, and a flare of pain after withdrawal of prior therapy with either an oral NSAID or acetaminophen (used at least 3 days per week during the previous month). Primary OA was defined by deterioration and abrasion of articular cartilage (joint space narrowing) or formation of new bone (osteophytes) at the joint surface of the knee (medial tibio-femoral, lateral tibio-femoral or patello-femoral), demonstrated on a radiological examination carried out within the previous 3 months [9]. Pain was measured by the Western Ontario and McMaster Universities LK3.1 OA Index (WOMAC) 5-item pain subscale, each item scored on a 5-point Likert scale (none = 0; mild = 1; moderate = 2; severe = 3; extreme = 4) [10]. Pain was scored at the screening visit, following which prior therapy was withdrawn. The patient scored the pain again at the baseline visit. A flare was defined as an increase in total pain subscale score of at least 2 and at least 25%, with a baseline total pain score of at least 6 (out of a possible 20), and a score of ≥2 (out of a possible 4) on at least one of the 5 items in the WOMAC pain subscale. Participants were excluded if they had secondary arthritis related to systemic inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis, post-infectious arthritis and metabolic arthritis, traumatic arthritis or surgical joint replacement); corticosteroid use: (a) oral corticosteroid within the previous 14 days, or (b) intramuscular corticosteroid within 30 days, or (c) intra-articular corticosteroid into the study knee within 90 days, or (d) intra-articular corticosteroid into any other joint within 30 days, or (e) topical corticosteroid at the site of application within 14 days; intra-articular viscosupplementation (e.g., Synvisc®) into the study knee in the preceding 90 days; ongoing use of prohibited medication including NSAID, other oral analgesic, muscle relaxant, or low-dose antidepressant for any chronic pain management; ongoing use of glucosamine or chondroitin (unless used continuously for 90 days prior to study entry); sensitivity to diclofenac, acetylsalicylic acid (ASA) or any other NSAID, acetaminophen, dimethyl sulphoxide, propylene glycol, glycerine or ethanol; clinically-active renal, hepatic or peptic ulcer disease; history of alcohol or drug abuse; lactation; concomitant skin disease at the application site; current application for disability benefits on the basis of knee osteoarthritis; fibromyalgia; other painful or disabling condition affecting the knee; or participation in another investigational drug trial in the previous 30 days.
BODY.METHODS.INTERVENTIONS:
At the baseline visit, all patients that met the final entry criterion of a flare of pain were randomly assigned to receive one of two treatments: (a) topical diclofenac solution (Pennsaid®; Dimethaid Research Inc.), consisting of 1.5% (w/w) diclofenac sodium in a patented carrier containing dimethyl sulphoxide (45.5%, w/w), propylene glycol, glycerine, ethanol and water, or (b) vehicle control solution, consisting of the complete carrier (including dimethyl sulphoxide, 45.5% w/w) but no diclofenac. Participants applied a dose of 40 drops of study solution (about 1.3 mL) to the affected knee 4 times daily for up to 6 weeks. The participant was instructed to apply 10 drops of solution to each side of the knee (front, back, medial and lateral) either dripped directly onto the knee or first into the hand, and then spread over the site without massage. Compliance was verified by weighing the solution bottles at each visit. If the other knee was painful at any time during the study, it was treated and evaluated for safety, but efficacy analysis was performed on only the study knee – the one with the greater baseline pain score (or the dominant knee if both had the same score). Consumption of acetaminophen (up to four 325-mg tablets per day) was permitted for residual knee or other body pain throughout the treatment period, but not during the washout period prior to baseline assessment or during the week prior to final assessment at week 6. ASA (≤ 325 mg/day) was permitted for cardiovascular prophylaxis.
BODY.METHODS.OUTCOME MEASURES:
The primary outcome measures were defined as the change from baseline to final assessment of the study knee in the 3 core continuous variables [11] pain and physical function, assessed using the WOMAC subscales, and patient global assessment (PGA). There was no intermediate assessment of efficacy. The WOMAC is a validated questionnaire [12] consisting of 24 questions (5 on pain, 17 on physical function and 2 on stiffness), each scored on a 5-point Likert scale (see Participants). The PGA question asked: "How has the osteoarthritis in your study joint been over the last 48 hours?" and was scored on a Likert scale (very good = 0; good = 1; fair = 2; poor = 3; very poor = 4). This question focuses on the treated site, unlike a PGA in an oral NSAID trial that can probe the non-signal joints. Secondary measure was change in stiffness. Ancillary measures defined a posteriori were pain on walking – the first question of the WOMAC pain subscale (referred to as 'use-related pain' [13]) – and the following dichotomous variables: 50% improvement in pain [3]; final PGA score of "good" or "very good" [3]; and response based on OMERACT-OARSI responder criteria [14] (a responder is defined as a participant with ≥ 50% improvement in pain or function that was ≥ 20% of the scale, or ≥ 20% improvement in at least two of pain, function or PGA that was ≥ 10% of the scale).
BODY.METHODS.SAFETY ANALYSES:
Safety was assessed during all clinic visits (weeks 3 and 6) and telephone 'visits' (weeks 1 and 5). Safety variables included adverse events, application-site dermatological reactions and vital signs. Adverse events were identified using open-ended questions and a checklist covering common oral NSAID side effects. Dermatological assessment of the knee was based on a standard scale [15] and any abnormality was recorded as an adverse event. All adverse events were categorised according to Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) [16]. Laboratory assessment was not done.
BODY.METHODS.SAMPLE SIZE:
Based on a power of 80% and a Type I error rate of α = 0.052-tailed, a sample size of 80 participants per group was required to detect an estimated important difference of 2 between the treatment arms, in the change in WOMAC pain dimension score from baseline to final (with standard deviation of 4.5). A total sample size of 200 participants (100 per treatment group) was specified in the protocol, which allowed for a non-evaluable rate of up to 20%.
BODY.METHODS.RANDOMISATION AND BLINDING:
The study kits were prepared, labelled and numbered according to a computer-generated randomisation schedule created by an outside consultant using a randomly chosen block size of 4 or 6. They were shipped to the sites in multiples of complete blocks to ensure that a balanced number of participants was assigned to the two treatment arms within each site. As a participant qualified for study entry at the baseline visit, the investigator assigned him/her the next randomisation number in a sequential manner. The randomisation schedule was concealed from the investigators, their support staff, study participants and the sponsor's clinical research personnel, until final data lock. Except for the individual participant identification number on the label, the two study solutions were identical clear, colourless liquids packaged in opaque bottles.
BODY.METHODS.STATISTICAL ANALYSIS:
Safety analyses were performed on all randomised participants who received at least one dose of study solution. There was no imputation of missing safety data. Efficacy analyses were performed on an intent-to-treat (ITT) group, defined as a subset of all randomised participants who met critical inclusion criteria (primary OA by history, an abnormal radiological study, and any degree of knee pain), as per ICH guidelines [17]. For any missing efficacy data in the ITT analysis, the last observation was carried forward. A per-protocol group was defined based on stricter adherence to study conduct, including requirement for a moderate flare of knee pain (see Participants) and treatment continuing for at least 40 days. Baseline demographic and clinical variables were analysed by Chi-square or Student's t-Test. Adverse event incidence was analysed by Chi-square or Fisher's Exact Test. Continuous variables (WOMAC dimensions, PGA and pain on walking) were analysed by ANCOVA with baseline score as the covariate without adjustment for testing secondary/alternative objectives. The dichotomous variables were analysed by Chi-square test. All statistical tests were two-sided and were performed at the 0.05 level of significance.
BODY.RESULTS.PARTICIPANT FLOW:
Two hundred and sixteen participants were randomised to treatment with either topical diclofenac (n = 107) or vehicle control (n = 109). All participants received their allocated intervention. More participants in the topical diclofenac group (86 [80%]) completed the entire 6-week treatment period compared to the vehicle control group (70 [64%]; p = 0.008). Discontinuation rate due to an adverse event was similar in both groups. Dropout due to lack of effect was lower for topical diclofenac (8 [7.5%]) compared to vehicle control (18 [16.5%]; p = 0.041). No participant was lost to follow-up (Fig. 1). Figure 1Flow of participants.
BODY.RESULTS.BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS:
No significant difference was found between treatment groups in baseline demographic and clinical characteristics (Table 1). The mean (SD) screening and baseline pain scores were 8.2 (2.7) and 13.0 (3.2) in the topical diclofenac group versus 8.3 (3.0) and 12.8 (3.1) in the vehicle control group (12.9 [3.2] overall). Most participants treated both knees, either from baseline or by the end of the trial. Table 1 Baseline demographic and clinical characteristics of treatment groups Topical diclofenac (n = 107) Vehicle control (n = 109) Age (years) 65.0 (11.0) 64.6 (10.9) Women, number (%) 56 (52.3) 66 (60.6) Race/ethnicity, number (%) White 88 (82.2) 91 (83.5) Black 8 (7.5) 3 (2.8) Oriental 3 (2.8) 2 (1.8) Other 8 (7.5) 13 (11.9) Weight (kg) 89.9 (18.1) 86.5 (17.3) Height (m) 1.65 (0.11) 1.65 (0.10) Heart rate (bpm) 74.1 (10.0) 74.3 (9.1) Systolic blood pressure (mm Hg) 137.6 (16.3) 133.6 (15.6) Diastolic blood pressure (mm Hg) 81.4 (9.1) 79.7 (8.7) Total x-ray score* 7.7 (5.4) 7.0 (5.0) Screening pain score 8.2 (2.7) 8.3 (3.0) Baseline † pain score 13.0 (3.2) 12.8 (3.1) Baseline † physical function score 40.7 (11.9) 40.4 (11.2) Baseline † stiffness score 5.2 (1.5) 5.2 (1.5) Patient global assessment score‡ 3.1 (0.8) 3.2 (0.8) Participants treating two knees at baseline, number (%) 64 (59.8) 70 (64.2) Participants treating two knees at final, number (%) 84 (78.5) 89 (81.7) Data are presented as mean (SD) unless otherwise indicated. *Total score of joint space narrowing, marginal osteophytes formation and subchondrial sclerosis for each knee compartment (medial, lateral, patello-femoral); maximum score possible was 27. †After washout of prior therapy; pain scale ranged from 0 (no pain) to 20 (extreme pain); physical function scale ranged from 0 (no difficulty) to 68 (extreme difficulty); stiffness scale ranged from 0 (no stiffness) to 8 (extreme stiffness). ‡Patient global assessment was measured using a Likert scale, ranging from 0 (very good) to 4 (very poor). Mean (SD) duration of treatment in the topical diclofenac group was 38.2 (9.9) days versus 34.4 (12.5) days in the vehicle control group (p = 0.013). Compliance with the dosing regime was 83.1 % and 84.5% for the topical diclofenac and vehicle control groups, respectively. No significant difference was noted in the mean (SD) consumption of rescue acetaminophen tablets per day between the topical diclofenac (0.9 [0.9]) and vehicle control groups (1.1 [1.0]; p = 0.079).
BODY.RESULTS.EFFICACY ANALYSES:
Four of 216 randomized participants were not included in the ITT analysis group because they violated major entry criteria: 2 participants lacked radiological confirmation of OA (no radiological examination for one participant and a normal examination for the other), and 2 participants had secondary OA (related to osteochondroma). Inclusion of these participants yielded the same results in a subsequent re-analysis (data not shown).
BODY.RESULTS.EFFICACY ANALYSES.PLANNED ANALYSES:
There was a significantly greater improvement in score with topical diclofenac compared to vehicle control (Table 2) for pain (-5.2 vs. -3.3; p = 0.003,), physical function (-13.4 vs. -6.9; p = 0.001), PGA (-1.3 vs. -0.7; p = 0.0001) and stiffness (-1.8 vs. -0. 9; p = 0.002) Analysis of the per protocol group of 128 participants confirmed the statistical superiority of topical diclofenac over vehicle control for the primary and secondary outcome measures (p < 0.01; data not shown). Table 2 Efficacy evaluation of the continuous variables Efficacy variable Treatment group N Baseline score, mean (SD) Change in score mean (SD) Mean difference in change (95% CI) P-value Effect size (95% CI) Pain Topical diclofenac 105 13.0 (3.1) -5.2 (5.0) 1.9 (0.7 to 3.2) 0.003 0.41 (0.14 to 0.68) Vehicle control 107 12.7 (3.2) -3.3 (4.3) Physical function Topical diclofenac 105 40.9 (11.9) -13.4 (16.3) 6.5 (2.5 to 10.5) 0.001 0.44 (0.16 to 0.71) Vehicle control 107 40.3 (11.3) -6.9 (13.2) Patient global assessment Topical diclofenac 105 3.1 (0.8) -1.3 (1.3) 0.6 (0.2 to 0.9) 0.0001 0.47 (0.19 to 0.74) Vehicle control 107 3.2 (0.7) -0.7 (1.1) Stiffness Topical diclofenac 105 5.3 (1.4) -1.8 (2.1) 0.9 (0.3 to 1.4) 0.002 0.43 (0.15 to 0.70) Vehicle control 107 5.2 (1.5) -0.9 (2.0) Pain on walking Topical diclofenac 105 2.7 (0.8) -1.2 (1.2) 0.4 (0.1 to 0.7) 0.014 0.34 (0.07 to 0.61) Vehicle control 107 2.7 (0.8) -0.8 (1.1)
BODY.RESULTS.EFFICACY ANALYSES.A POSTERIORI ANALYSES:
There was a significantly greater improvement in score with topical diclofenac compared to vehicle control (Table 2) for pain on walking (-1.2 vs. -0.8; p = 0.014). The response rate for at least a 50% reduction in pain (Table 3) was significantly greater following topical diclofenac treatment compared to vehicle control (46/105 [43.8%] vs. 27/107 [25.2%]; p = 0.004). The topical diclofenac group had a significantly greater number of participants with good or very good PGA response (43.8% vs. 16.8%; p <0.0001) compared to the vehicle control group and of OMERACT-OARSI responders (65.7% vs. 49.5%; p = 0.017). Table 3 Efficacy evaluation of the dichotomous variables Efficacy variables Treatment group N Number (%) of participants p-value Number-needed-to-treat (95% CI) 50% reduction in pain Topical diclofenac 105 46 (43.8) 0.004 5 (3–17) Vehicle control 107 27 (25.2) OMERACT-OARSI responder* Topical diclofenac 105 69 (65.7) 0.017 6 (3–33) Vehicle control 107 53 (49.5) Good or very good PGA response Topical diclofenac 105 46 (43.8) <0.0001 4 (3–7) Vehicle control 107 18 (16.8) *A responder is defined as a participant with ≥ 50% improvement in pain or function that was ≥ 20% of the scale, or ≥ 20% improvement in at least two of pain, function or patient global assessment that was ≥ 10% of the scale.
BODY.RESULTS.ADVERSE EVENTS:
The major adverse effect reported was dry skin at the application site, occurring in 42/107 (39.3%) and 23/109 (21.1%; p = 0.004) of topical diclofenac and vehicle control participants, respectively (Table 4). A skin-related adverse event led to discontinuation of only 5 participants in the topical diclofenac group. All skin reactions resolved promptly upon withdrawal of treatment. Abdominal pain and dyspepsia each were reported in 4 [3.7%] participants in the topical diclofenac group compared to 1 [0.9%] participant in the vehicle control group, but this difference was not significant (p = 0.21). Table 4 Number (%) of adverse events Adverse Event Topical diclofenac (n = 107) Vehicle control (n = 109) Gastrointestinal reaction Abdominal pain 4 (3.7) 1 (0.9) Constipation 1 (0.9) 1 (0.9) Diarrhea 1 (0.9) 0 Dyspepsia 4 (3.7) 1 (0.9) Gastritis 1 (0.9) 0 Melena 0 1 (0.9) Nausea 1 (0.9) 2 (1.8) Application-site skin reaction Dry skin 42 (39.3)* 23 (21.1) Rash 2 (1.9) 4 (3.7) Paresthesia 2 (1.9) 2 (1.8) Pruritus 0 2 (1.8) Other reaction Headache 6 (5.6) 10 (9.2) Halitosis 2 (1.9) 0 Taste Perversion 4 (3.7) 2 (1.8) *p < 0.01 vs. vehicle control
BODY.DISCUSSION:
Published guidelines have incorporated topical NSAIDs as recommended treatment for OA of the knee [4-6]. However, there has been controversy surrounding the adequacy of data supporting their benefit beyond 2 weeks [2,3,8,18]. Moreover, the studies identified in these meta-analyses generally did not conform to current standards for OA trial design [11,19]. In contrast, the present trial utilized standardized radiological and clinical entry criteria and measured efficacy with validated outcome measures. Baseline pain score was substantial; mean (SD) score was 12.9 (3.2) out of a maximum of 20, indicating a flare of pain following withdrawal of prior therapy. Analysis of all of the primary and secondary measures demonstrated that treatment with this topical diclofenac solution relieved the symptoms of primary knee OA at 6 weeks in this study population. Two other recently published trials using this topical diclofenac solution showed it to be superior to vehicle control and/or placebo; a 4-week, non-flare trial of 248 participants [20] and a 12-week, flare trial of 326 participants [21]. As with most NSAID trials, the subject population in this study was selected by the inclusion criterion of a flare of pain, which demonstrates the potential to respond to NSAID/analgesic. In clinical practice, an individual not taking an analgesic may have considered previous NSAID therapy ineffective, in which case s/he would not be expected to respond to topical diclofenac. However, where an individual is intolerant to oral NSAID, one may consider topical diclofenac as a treatment option. Comparison of efficacy results from independent trials with various treatments is facilitated by the introduction of benchmark determinants that are mathematically derived from the experimental raw data, such as effect size [22] for improvement of a continuous variable (e.g. "How much did the patient's pain improve, relative to placebo?"). We calculated an effect size (95% CI) of 0.41 (0.14 to 0.68) for pain relief, 0.44 (0.16 to 0.71) for improved physical function and 0.34–0.47 for improved measures of PGA, stiffness and pain on walking (Table 2). In contrast, Lin et al. [8] calculated a pooled effect size for pain relief of 0.04 (essentially no effect) in 3 placebo-controlled topical NSAID trials of 4 weeks duration. A meta-analysis of 23 oral NSAID trials for OA knee, lasting 2–13 weeks, reported a pooled effect size of 0.32 for pain reduction and 0.29 for improving physical function [23]. Another meta-analysis of 14 OA trials found a pooled effect size of 0.37 for pain reduction with oral NSAIDs and 0.44 for coxibs [24]. Zhang et al. [25], using data from 2 oral NSAID studies of 6–12 weeks duration, calculated a pooled effect size for OA pain reduction of 0.34. Efficacy of a treatment is being expressed increasingly as a dichotomous result, e.g. "Did the patient's pain improve by 50%; yes or no?". We derived the response rate for each dichotomous variable from our raw data, and demonstrated the superiority of topical diclofenac over vehicle control for 50% reduction in pain, achieving a good or very good final PGA response, and 'response' by OMERACT-OARSI criteria (Table 3). The benchmark determinant for comparing dichotomous efficacy results of various treatments is the number-needed-to-treat (NNT) [26]. We calculated a NNT between 4 and 6, depending upon the variable (Table 3). In their meta-analysis of topical NSAIDs, Mason et al. [3] cited 5 placebo-controlled trials of short duration for OA knee pain – 8 days (1 trial), 14 days (3 trials), and 28 days (1 trial). Their definition of clinical success, representing approximately a 50% reduction of pain, was estimated using patient or physician global assessment as the outcome measure (4 trials and 1 trial, respectively). They calculated a NNT of 5.3. Few oral NSAID studies have reported dichotomous data. Osiri et al. [26] reported a NNT for pain improvement of 4.4 with etodolac and 3.8 with tenoxicam. Defining improvement as an increase of at least 2 grades (on a 0–5 scale) in the patient's global rating of arthritis, Edwards et al. [27] reported a NNT of 11–13 for valdecoxib treatment of OA. The OMERACT-OARSI initiative used a consensus approach to derive dichotomous 'responder' criteria [14]. Through their vast meta-analysis of suitable trials, the authors found that for trials of oral NSAIDs vs. placebo the responder rates were 65.4% and 45.9% respectively. Responder rates of 60–65% have been reported for 13-week treatment of OA with celecoxib and lumiracoxib, with placebo responder rates of 49–53% [28,29]. The OMERACT-OARSI initiative did not look at topicals but we applied its criteria to this study and found a responder rate for topical diclofenac of 65.7% with a placebo responder rate of 49.5%, similar to their oral NSAID data. A caveat in the application of the mathematical benchmarks, effect size and NNT, is the influence of trial design, outcome measures and patient population on the apparent magnitude of response to a given treatment. Because the trials with topical diclofenac were designed according to the OARSI guidelines, like most recent NSAID and cyclooxygenase-2 (COX-2) inhibitor studies, such comparison of results is reasonable [19]. Although the data observed for topical diclofenac in this trial are comparable to other NSAID trials, a direct head-to-head comparison trial is required to prove equivalency of two treatments. A previously published 12-week comparative trial of 622 participants with OA knee confirmed the clinical equivalence between topical diclofenac solution and oral diclofenac [30]. Safety analysis revealed no serious clinical adverse effects and only minor application-site skin reactions, mostly skin dryness, following treatment with topical diclofenac. While dimethyl sulphoxide in the carrier acts as a penetrant [31], it also dissolves normal surface oils and leaves the skin dry. Common skin lubricants may prevent most application site reactions and any related discontinued therapy, but such products were not permitted in this trial in order to detect the maximum potential side effect profile of the study solutions. The low dropout rate due to skin reactions (5/107 [4.7%] for topical diclofenac) suggests patient acceptance of the overall topical treatment regime. The use of a checklist to prompt the patient about possible adverse events likely yielded a high estimate of the true incidence of gastrointestinal adverse reactions caused by topical diclofenac. The report of abdominal pain and dyspepsia each in 3.7% of patients is consistent with what was seen in other published trials of this topical diclofenac [20,21] and much lower than commonly experienced with oral NSAIDs or COX-2s [30]. Those other trials included results of laboratory testing and found minor abnormality of liver enzymes in 2–5%, creatinine in 1% and haemoglobin in 2% of patients, significantly lower than with oral diclofenac [30]. This safety profile can be predicted from the low systemic availability of topically applied diclofenac. Although the patient applies a daily dose (40 drops, 4 times a day) of 86 mg of diclofenac to the knee, the blood level is only 12 ng/mL [31]. The level reported after oral administration of 50 mg Voltaren® is 1500 ng/mL [32]. Similar improved safety with topical NSAIDs has been reported previously [33].
BODY.CONCLUSION:
Topical diclofenac solution provides 6-week relief of the symptoms of knee OA. The data in this and previous reports provide substantial evidence for the efficacy and safety of topical diclofenac solution in chronic OA.
BODY.COMPETING INTERESTS:
LMT and ZS are employees of Dimethaid Research Inc. PAB was a principal investigator in the trial, and was remunerated for his participation.
BODY.AUTHORS' CONTRIBUTIONS:
PAB was a major investigator in the trial and was involved in data interpretation. LMT was involved in analysis and interpretation of the data and writing of the manuscript. ZS was involved in trial design and conduct, data review and writing of the manuscript. All authors reviewed and approved the final draft of the manuscript.
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TITLE: An Open Label, Randomised Trial of Artesunate+Amodiaquine, Artesunate+Chlorproguanil-Dapsone and Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria
ABSTRACT.BACKGROUND:
Artesunate+amodiaquine (AS+AQ) and artemether-lumefantrine (AL) are now the most frequently recommended first line treatments for uncomplicated malaria in Africa. Artesunate+chlorproguanil-dapsone (AS+CD) was a potential alternative for treatment of uncomplicated malaria. A comparison of the efficacy and safety of these three drug combinations was necessary to make evidence based drug treatment policies.
ABSTRACT.METHODS:
Five hundred and thirty-four, glucose-6-phosphate dehydrogenase (G6PD) normal children were randomised in blocks of 15 to the AS+AQ, AL or AS+CD groups. Administration of study drugs was supervised by project staff and the children were followed up at r home on days 1,2,3,7,14 and 28 post treatment. Parasitological and clinical failures and adverse events were compared between the study groups.
ABSTRACT.MAIN FINDINGS:
In a per-protocol analysis, the parasitological and clinical failure rate at day 28 post treatment (PCF28) was lower in the AS+AQ group compared to the AL or AS+CD groups (corrected for re-infections: 6.6% vs 13.8% and 13.8% respectively, p = 0.08; uncorrected: 14.6% vs 27.6% and 28.1% respectively, p = 0.005). In the intention to treat analysis, the rate of early treatment failure was high in all three groups (AS+AQ 13.3%; AL 15.2%; and AS+CD 9.3%, p = 0.2) primarily due to vomiting. However, the PCF28 corrected for re-infection was lower, though not significantly, in the AS+AQ group compared to the AL or the AS+CD groups (AS+AQ 18.3%; AL 24.2%; AS+CD 20.8%, p = 0.4) The incidence of adverse events was comparable between the groups.
ABSTRACT.CONCLUSIONS:
AS+AQ is an appropriate first line treatment for uncomplicated malaria in Ghana and possibly in the neighbouring countries in West Africa. The effectiveness of AL in routine programme conditions needs to be studied further in West Africa.
ABSTRACT.TRIAL REGISTRATION:
ClinicalTrials.gov NCT00119145
BODY.INTRODUCTION:
There is now widespread acceptance that combination therapy (≥2 antimalarial drugs with different modes of action) is a better option than monotherapy for the treatment of uncomplicated malaria and artemisinin based combination therapy (ACT) is advocated as a way forward.[1] The WHO recommends artesunate+amodiaquine (AS+AQ), artemether-lumefantrine (AL) or artesunate+sulphadoxine-pyremethamine (AS+SP) as the first line treatment for uncomplicated malaria in Africa.[2] By November 2006, most malaria endemic countries in Africa (33/42) had adopted ACT as the first line treatment for uncomplicated malaria.[3] In 2002, Ghana adopted AS+AQ as first line treatment based on the evidence of its efficacy and safety observed elsewhere in Africa and on account of its potential for production by local manufacturers.[4] Randomised controlled efficacy trials in Zanzibar,[5] Uganda[6] and Angola[7] had shown that polymerase chain reaction ( PCR) corrected adequate clinical response rates at day 28 post treatment (ACPR28) were very high for both AS+AQ (94–100%) and AL (97–100%). In 2003, a four arm comparative efficacy trial in Ghana showed that the ACPR28 was 100% (n = 51) for AL and 97.5% (n = 54) for AS+AQ.[8] However, a randomised trial of the effectiveness of AS+AQ and AL in Tanzania showed that the parasitological failure at day 28 was 2.6 fold (95% CI 1.9–3.4) higher in the AS+AQ group (40%) compared to the AL group (21%).[9] Artesunate+chlorproguanil-dapsone (AS+CD) is another potential alternative for AS+AQ because chlorproguanil-dapsone has been shown to be efficacious in areas with high SP and chloroquine resistance.[10] Clinical trials of AS+CD have been carried out in several countries in Africa (www.ispub.com/ostia/index.phpxmlFilePathjournals/ijid/vol4n2/cda.xml) but the development of AS+CD was abandoned recently due to safety concerns in glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. There has been no comparative studies of the efficacy and safety of AS+CD versus AS+AQ or AL. Even though most countries in Africa have adopted ACT as first line treatment, antimalarial monotherapy is still common and this can undermine the efficacy of ACT. Furthermore high levels of resistance to AQ already exists in many parts of Africa.[9] Thus, it is important to evaluate the efficacy of ACTs particularly that of AS+AQ periodically. In this paper, we report the results of a randomised trial that compared the efficacy and safety of AS+AQ, AL and AS+CD in children in Ghana.
BODY.METHODS:
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see checklist S1 and Protocol S1.
BODY.METHODS.PARTICIPANTS:
The study was conducted in Kintampo district hospital, Brong-Ahafo region, Ghana. Malaria transmission in this forest region of Ghana is perennial but peaks in July–August and the entomological inoculation rate is high, about 270 infective bites per person per year. Although the study area has high transmission, malaria is common in older children and therefore the study included children up to 10 years of age. From June 2005 to May 2006, 1718 children aged 6 months to 10 years who attended the study hospital's outpatient department with a history of fever or an axillary temperature ≥37.5°C were examined for malaria parasitaemia and screened for their eligibility for enrolment in this study after written, informed consent had been obtained from their caretakers (Figure 1). Children who had a body weight ≤5 kg, Hb <7 g/dL, malaria parasitaemia <2000 or >200000 parasites/μL, danger signs (unable to drink, history of repeated vomiting, convulsions or other signs of severe malaria, or any other concomitant febrile disease were excluded from the study but offered standard care according to Ministry of Health guidelines. Children were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency before randomisation (the G6PD test took about 1hour). A total of 630 children were eligible; 534 were G6PD normal and 96 were G6PD deficient. The G6PD normal children were randomly assigned to the AL, AS+AQ, or AS+CD groups. The G6PD deficient children were randomised to the AS+AQ or AL group only because the Ghana Ministry of Health Ethical Committee expressed concern about the possibility of haemolysis associated with chlorproguanil-dapsone treatment in G6PD deficient children. 10.1371/journal.pone.0002530.g001Figure 1Enrolment and Follow up profile.
BODY.METHODS.PROCEDURES:
Administration of the first dose of study drugs was supervised by a study nurse and the administration of subsequent doses was supervised by study field workers. All children were given iron along with antimalarials according to national treatment guidelines. Caretakers of children in the AL group were told about the need to give a fatty meal along with the drug. Children were actively followed up at their homes by 10 field workers on days 1, 2, 3, 7, 14 and 28 post treatment to solicit adverse events. Finger prick blood samples for parasitological observations were obtained on days 3, 7, 14, 28, for haematological measurements on days 1, 2, 3, 7, 28 and for biochemical assessments on days 2, 7, 28 (0.7ml of capillary blood) after the start of treatment. Blood samples were collected from children who attended the study clinic for suspected malaria on any other day outside the scheduled days of follow up. There were 77 unscheduled visits and those who had a positive blood slide on these unscheduled visits (n = 15) were treated with quinine and classified as treatment failures.
BODY.METHODS.RANDOMISATION:
Randomisation was done using Microsoft Excel 2003© randomisation generator. G6PD normal children were randomised in blocks of 15 to the AL, AS-AQ, or AS+CD group. G6PD deficient children were randomised in blocks of 10 to AL or AS-AQ group. Co-blistered packs of artesunate and amodiaquine (Arsucam,® Sanofi-Aventis), artemether-lumefantrine (Coartem,© Novartis) and chlorproguanil-dapsone (Lapdap,TM GlaxoSmithKline) were obtained from the respective local suppliers.
BODY.METHODS.STATISTICAL METHODS:
Data were double-entered, and validated using Visual Foxpro© 6.0.and the analysis was done using StataTM 9.1. Per protocol analysis included patients who were properly randomised, had received the study drugs according to the protocol, and for whom data were available on the primary end point (ACPR28). Intention to treat (ITT) analysis involved all randomised patients irrespective of how many doses of the study drugs had been given but excluded all major day 0 protocol violations. All statistical tests were two-sided and an α-level <0.05 was considered a statistically significant result. For comparisons of continuous variables between groups, the t-test was used and for comparisons between more than two groups, one-way analysis of variance was used after assuring normality and homogeneity of variances assumptions were satisfied. For comparison of categorical variables, the chi-square test was used with the exact extension invoked when there were small numbers in the cells. A survival analysis using the life table method was done on the cumulative proportion of children having treatment failure at different time points during the post treatment period in each of the arms of the study. The end points were any of the following: failure to take the drug on any of the first three days, parasitaemia on day 2 greater than that on day 0, presence of parasitaemia on day 7, diagnosis of severe malaria at any point after day 0, recurrent parasitaemia after day 7 up to day 28. The likelihood-ratio test statistic of homogeneity and the logrank tests of homogeneity of arm were also carried out.
BODY.METHODS.SAMPLE SIZE:
The primary endpoint was PCR corrected ACPR by day 28. A sample size of 510 children was chosen on the basis of the following assumptions: (1) the efficacy of AL would be 95%; (2) the study would have 80% power at 95% significance level to detect a 10% difference in efficacy as measured by the parasitological failure at day 28 post-treatment in the AS+AQ, and AS+CD groups compared with the AL group; (3) loss to follow up by day 28 post treatment would be <5%.
BODY.METHODS.LABORATORY PROCEDURES:
At least 200 oil immersion fields of thick blood films stained with Giemsa stain were examined for malaria parasites before a blood film was considered negative. The parasite density per micro-litre was estimated by multiplying the number of parasites per 200 leukocytes by a factor of 40, assuming a white blood cell count of 8,000/μl. Each blood slide was read by two microscopists. If the difference in the parasite density estimated by the two microscopists was <50%, the mean of the two readings was defined as the true parasite density. If the disagreement between the two readings was ≥50%, a third microscopist examined the slide and the mean of the two closest readings was deemed to be the true parasite density. To distinguish between recrudescent and new infections, parasites identified on Days 14 and 28 were compared to those identified at enrolment using PCR amplification of msp2 P. falciparum genes. Full blood count and biochemical tests were done by calibrated automated ABX MICROS 60 (Horiba ABX, France) and Selectra E Clinical Chemistry Analyzer (Vital Scientific N.V, Netherlands) respectively. Quantitative G6PD phenotype analysis was conducted using Randox method with Humalyser Junior (Human, Germany). Plasma ALT, AST, Total Bilirubin, Creatinine and Urea were measured on the Selectra E Clinical Chemistry analyzer (Vital Scientific, The Netherlands) using reagents from Elitech Diagnostics (Sees, France). ALT and AST were measured using the kinetic, UV, IFCC method without pyridoxal phosphate, total bilirubin with the modified Evelyn-Malloy method, creatinine with the kinetic Jaffe method and urea with the kinetic urease method. Glucose-6-phosphate dehydrogenase (G6PD) activity was measured using a quantitative UV G6PD kit from Randox (Antrium, UK). The enzyme activity was determined by the measurement of the rate of absorbance change at 340 nm due to the reduction of NADP+.
BODY.METHODS.ETHICS:
The study protocol was approved by the ethics committees of the Kintmapo Health Research Centre, Ghana Ministry of Health and the London School of Hygiene & Tropical Medicine. The study is registered at the United States National Institute of Health clinical trials register; the registration number is NCT00119145 and the URL:https://clinicaltrials.gov/ct2/show/NCT00119145/
BODY.RESULTS.G6PD NORMAL CHILDREN:
There were no statistically significant differences in the demographic or baseline haematological characteristics between the three treatment groups at enrolment (Table 1). 10.1371/journal.pone.0002530.t001 Table 1 Demographic and haematological characteristics at enrolment in G6PD normal children. Characteristics AS+AQ [N = 178] AL [N = 177] AS+CD [N = 178] P n (%) n (%) n (%)
Age (months)
6–11 26 (14.6) 25 (14.0) 22 (12.4) 1.0 12–59 119 (66.9) 120 (67.4) 122 (68.5) 60+ 32 (18.0) 33 (18.5) 34 (19.1) Mean (SD) 37.6 (24.3) 36.8 (26.2) 39.4 (25.0) 0.6
Gender
Male 83 (46.9) 94 (52.8) 92 (51.7) 0.5 Female 94 (52.8) 84 (47.2) 86 (48.3)
Weight (Kg)
<9.9 50 (28.1) 54 (30.3) 46 (25.8) 0.8 10.0–19.9 117 (65.7) 112 (62.9) 118 (66.3) 20.0+ 10 (5.6) 12 (6.7) 14 (7.9) Mean (SD) 12.6 (4.3) 12.4 (4.5) 12.6 (4.3) 0.9
Temperature (°C)
≥37.5 106 (59.6) 107 (60.1) 97 (54.5) 0.5 Mean (SD) 37.9 (1.1) 39.9 (1.1) 37.7 (1.1) 0.3
Parasite Density/μL
<2500 39 (21.9) 31 (17.4) 32 (18.0) 0.2 2500-<10000 42 (23.6) 28 (15.7) 36 (20.2) ≥10000 96 (53.9) 119 (66.9) 110 (61.8) Geometric mean (range) 12507 (1000, 198520) 16521 (1000, 197360) 13820 (1000,199280) Gametocytaemia 10 (5.6) 11 (6.2) 16 (9.0) 0.4
Haemoglobin (g/dL)
6-<11 163 (91.6) 167 (93.8) 165 (92.7) 0.8 11+ 14 (7.9) 11 (6.2) 13 (7.3) Mean (SD) 9.1 (1.4) 8.9 (1.3) 8.9 (1.4) 0.3 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone In the per-protocol (PP) analyses there were no statistically significant differences in the rates of early treatment, late treatment, parasitological or clinical failures at day 14 between the three groups (Table 2). Survival analysis showed that there was no statistically significant differences in treatment failure at different time points during the 28 day post treatment period between the three groups (Figure 2). However, the parasitological and clinical failure rate at day 28 (PCF28) uncorrected for re-infections was significantly lower in the AS+AQ group (14.6%) compared to the AL (27.6%) or AS+CD (28.1%) groups (Table 2). The PCF28 corrected for re-infection was also lower in the AS+AQ group (6.6%) than in the AL (13.8%) or AS+CD (13.8%) groups but this difference was not statistically significant. PCF28 uncorrected for re-infection was nearly 50% less in the AS+AQ group compared to AL and AS+CD groups (Table 3). PCF28 corrected for new infections was significantly lower in the AS+AQ group compared to AS+CD group (RR 0.43; 95% CI 0.20, 0.89). There was no significant difference in the PCF28 between AL and AS+CD groups (Table 3). 10.1371/journal.pone.0002530.g002Figure 2Proportion of children having treatment failures at different time points during the post treatment period Per protocol analysis of G6PD normal children. 10.1371/journal.pone.0002530.t002 Table 2 Treatment outcomes (per protocol analysis). Outcomes AS+AQ [N = 151] AL [N = 152] AS+CD [N = 160] P *
n (%) n (%) n (%) Early treatment failure 1 (0.7) 5 (3.3) 3 (1.9) 0.257 Late treatment failure 6 (4.0) 7 (4.6) 7 (4.4) 0.960 Parasitological or clinical failure by day 14 8 (5.3) 13 (8.6) 13 (8.1) 0.482 Parasitological or clinical failure by day 28 (PCR uncorrected) 22 (14.6) 42 (27.6) 45 (28.1) 0.005 Parasitological or clinical failure by day 28 (PCR corrected) 10 (6.6) 21 (13.8) 22 (13.8) 0.083 Missing PCR by day 28 (excluded) 3 (2.0) 9 (5.9) 13 (8.1) - Gametocytaemia by day 7 3 (2.0) 0 (0) 6 (3.8) 0.043 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone *
exact P values
10.1371/journal.pone.0002530.t003 Table 3 Comparison of treatment outcomes between groups (per protocol analysis). Outcomes AS+AQ vs AL P *
AS+AQ vs AS+CD P *
AS+CD vs AL P *
RR (95% CI) RR (95% CI) RR (95% CI) Parasitological or clinical failure by day 14 0.69 (0.28,1.63) 0.4 0.67 (0.27,1.55) 0.4 1.08 (0.49,2.22) 0.8 Parasitological of clinical failure by day 28 (PCR uncorrected) 0.53 (0.32,0.85) 0.007 0.51 (0.30,0.81) 0.004 1.01 (0.68,1.41) 1.0 Parasitological of clinical failure by day 28 (PCR corrected) 0.48 (0.23,0.98) 0.044 0.43 (0.20,0.89) 0.023 1.03 (0.57,1.47) 0.9 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone *
since there are three comparisons Bonfferroni correction is applied; the P value has to <0.017 to be statistically significant
In the intention to treat analyses, the rate of early treatment failure was high in all three groups (13.3% in AS+AQ, 15.2% in AL, and 9.3% in AS+CD groups respectively) but this was primarily due to vomiting twice or more within half an hour of administration of the study drugs. Among the early treatment failures, 22/23 in AS+AQ, 22/27 in AL, and 13/16 in AS+CD groups were due to repeated vomiting of study drugs. In the intention to treat analyses the relative risk (RR) of parasitological and clinical failure by day 28 corrected for reinfection was lower, though not statistically significantly, in the AS+AQ group compared to the AL group (RR 0.75; 95% CI 0.48, 1.14) or to the AS+CD group (RR 0.81; 95% CI 0.5, 1.27). The relative risk of parasitological and clinical failure corrected for reinfection was lower in the AS+AQ group compared to the AL (RR 0.68, 95% CI 0.47, 0.94) or AS+CD group (RR 0.72, 95% CI 0.49, 1.01). There was a drop in mean Hb concentration on day 2 post treatment compared to day 0 in each of the three groups (Table 4). The mean drop in Hb on day 2 ranged from 0.8 g/dl in the AS+CD group to 0.4 g/dl in the AL group. By day 7 post treatment, the mean Hb concentration had recovered to the day 0 levels in the AS+AQ and AL groups and by day 28 the mean Hb was higher than the day 0 in all three groups. The rate of recovery of Hb was slightly slower in the AS+CD group compared to the other two groups. 10.1371/journal.pone.0002530.t004 Table 4 Haemoglobin concentration during the post treatment period in the study groups. Post treatment day AS+AQ (n = 151) AL (n = 152) AS+CD (n = 160) P *
Mean Hb g/dl (SD) Mean Hb g/dl (SD) Mean Hb g/dl (SD) 0 9.0 (1.3) 9.2 (1.4) 8.9 (1.3) 0.2 1 8.5 (1.6) 8.7 (1.6) 8.3 (1.4) 0.08 2 8.3 (1.7) 8.8 (1.7) 8.1 (1.6) 0.002 3 8.8 (1.8) 8.9 (1.6) 8.4 (1.5) 0.045 7 9.0 (1.7) 9.3 (1.6) 8.6 (1.5) 0.001 28 9.9 (1.7) 10.0 (1.6) 9.7 (1.6) 0.3 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone SD = standard deviation *
since there are five time points compared against the baseline (day 0), Bonfferroni correction is applied; the P value has to <0.008 to be statistically significant
The reported incidences of solicited adverse events during the 7 days post treatment are shown in Table 5. The incidence of solicited adverse events was comparable between the three groups. A history of body pain was more frequent in the AS+AQ group than the other two groups (Table 5). 10.1371/journal.pone.0002530.t005 Table 5 Distribution of solicited adverse events during the 7-day post treatment period. Reported symptoms AS+AQ (n = 178) AL (n = 177) AS+CD (n = 178) P *
(Adverse events) n (%) n (%) n (%) Unable to suck/drink 8 (4.5) 5 (2.8) 2 (1.1) 0.11 Fever 0 (0) 0 (0) 0 (0) - Runny nose 29 (16.3) 30 (17.0) 14 (7.9) 0.03 Cough 33 (18.5) 23 (13.0) 21(11.8) 0.30 Difficulty in breathing 3 (1.7) 4 (2.3) 2 (1.1) 0.48 Diarrhoea 13 (7.3) 19(10.7) 11(6.2) 0.44 Vomiting 8(4.5) 6(3.4) 12 (6.7) 0.58 Itching/pruritus 13 (7.3) 10 (5.7) 10 (5.6) 0.93 Loss of appetite 61 (34.3) 44 (24.9) 50 (28.1) 0.29 Nausea 2 (1.1) 0 (0.0) 5 (2.8) 0.17 Abdominal pain 31 (17.4) 19 (10.7) 28 (15.7) 0.34 Body pain 25 (14.0) 10 (5.7) 9 (5.1) 0.01 Difficulty in sleeping 2 (12.4) 23 (13.0) 16 (9.0) 0.75 Joint pain 4 (2.3) 1 (0.6) 0 (0.0) 0.28 Palpitation 3 (1.7) 4 (2.6) 5 (2.8) 0.89 Rash 2 (1.1) 3 (1.7) 2 (1.1) 0.97 Ulcers in mouth/tongue 15 (8.4) 12 (6.8) 10 (5.6) 0.82 Yellow eyes 4 (2.3) 3 (1.7) 4 (2.3) 1.00 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone *
exact P values
BODY.RESULTS.G6PD DEFICIENT CHILDREN:
There was no statistically significant differences in the parasitological or clinical failure rates by day 14 or day 28 between the AS+AQ and AL groups (Table 6). The drop in mean Hb by day 3 post treatment and the recovery in Hb by day 28 were comparable between AS+AQ and AL groups and there was no apparent difference in the distribution of Hb concentrations following treatment between the G6PD normal and deficient children (data not shown). 10.1371/journal.pone.0002530.t006 Table 6 Treatment outcomes in G6PD deficient children (Per protocol analysis) Outcomes AS+AQ [N = 44] AL [N = 42] P *
n (%) n (%) Early treatment failure 1 (2.3) 0 (0.0) 0.3 Late treatment failure 1 (2.3) 2 (4.8) 0.5 Parasitological or clinical failure by day 14 3 (6.8) 2 (4.8) 0.7 Parasitological or clinical failure by day 28 (PCR uncorrected) 11 (25.0) 11 (26.2) 0.9 Parasitological or clinical failure by day 28 (PCR corrected) 6/43 (14.0) 4/42 (9.5) 0.5 Missing PCR by day 28 (excluded) 1 (2.3) 0 0.3 AS = artesunate; AQ = amodiaquine; AL = artemether-lumefantrine; CD = chlorproguanil-dapsone *
exact P values
BODY.DISCUSSION:
In our study population, the parasitological and clinical failure at day 28 was lower in the AS+AQ group than in AL group. Our PCR corrected parasitological failure rate at day 28 is higher than that previously reported from Ghana[8] for AS+AQ (6.6% vs 2.5%) and remarkably higher for AL (13.8% vs 0%). The reason for the substantially higher parasitological failure at day 28 for AL compared to the results of a previous study in Ghana[8] and elsewhere[9] is unclear. Dietary differences between our population and the previously studied populations is a possible explanation for this difference; poor absorption of AL leading to a higher parasitological failure compared to that reported from elsewhere. We did not follow the recommended practice of administering AL with a fatty diet in a clinical trial; instead we only advised caretakers to give fatty food at the time of drug administration. This was a pragmatic decision because in routine health care setting one can only advise a caretaker to administer AL with a fatty meal. Thus, the observed higher treatment failure of AL observed in our study compared with others may have been due to the lack of intake of fat along with AL, as is likely to happen frequently in routine clinical practice. Although there was a significant difference in the parasitological failure rate (both recrudescence and re-infections) at day 28 between AL and AS+AQ, there was no difference in the clinical failure between the two groups, perhaps because both combinations contain a fast acting artemisinin. The parasitological or clinical failure of AS+CD by day 14 was 8% and by day 28 (PCR corrected) was 13.8% in our study population. There are no other published studies of efficacy of AS+CD with which to compare these results. An earlier multicountry trial of CD monotherapy showed a parasitological or clinical failure rate of 5% by day 14 in Nigeria.[10] Our study suggests that adding AS to CD may have little value in West Africa given that the PCR corrected failure rate by day 28 has already reached 13.8%. Surprisingly, the PCR corrected failure rate by day 28 for AL was also 13.8% and this suggests that introducing AL as a replacement for AS+AQ needs to considered with caution. More evidence on the efficacy of AL in Ghana is needed urgently. In the AL group, all children who had gametocytes on day 0 (n = 11) had cleared gametocytes by day 3 post treatment; gametocytes appeared in the blood of two children between day 14 and 28. In children in the AS+AQ group who had gametocytes on day 0 (n = 10) only one child had gametocytes on day 3 and 7. Two more children developed gametocytaemia by day 7 but all children cleared gametocytes by day 14. In children in the AS+CD group who had gametocytes on day 0 (n = 16) 4 children had gametocytes on day 3 and one child had gametocytes on day 7 Gametocytes appeared in a further child by day 7 but all children had cleared gametocytes by day 14; two children had developed gametocytes between day 14 an 28. It appears that all three ACTs tested in this study are effective at clearing gametocytes and this property of ACTs should have an effect on the transmission of malaria. A slight reduction in the Hb concentration occured during the early post treatment period in all three treatment groups. Although differences were not remarkable, the recovery of Hb was slowest following treatment with AS+CD. There was no difference in the risk of haemolysis between the three ACTs in G6PD normal children. However, we cannot comment about the potential risk of haemolysis associated with AS+CD in an unselected population because G6PD deficient children were not included in the AS+CD arm. Results from recently completed multicentre trials indicate that coformulated AS+CD can cause serious haemolysis in children who are G6PD deficient so further development of this drug combination has been halted. Our study results supports the current policy of AS+AQ as first line treatment for uncomplicated malaria in Ghana. However, the slightly higher incidence of adverse events, particularly vomiting and body pain, associated with use of AS+AQ is a concern. If these adverse events are common in adults as well then they might reduce adherence to a full course of the treatment. There were some reports of adverse events of AQ in the Ghanaian mass media and this has lead to the general public being reluctant to accept AS+AQ combination therapy. Although the overall incidence of adverse events related to AS+AQ group is reasonable, in order to achieve a good compliance an appropriate communication strategy is needed in addition to the introduction of the new fixed combinations of artesunate plus amodiaquine that are currently being developed. We conclude that AS+AQ is an appropriate first line treatment for uncomplicated malaria in Ghana and possibly in neighbouring countries in West Africa. However, the deployment of AS+AQ should be linked to a clear information strategy regarding the potential mild adverse events for health care providers and the general public. The efficacy and safety of AL when given in the context of routine care need to be further studied in Ghana and elsewhere in West Africa.
BODY.SUPPORTING INFORMATION:
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TITLE: Efficacy and safety of collagenase clostridium histolyticum for Dupuytren disease nodules: a randomized controlled trial
ABSTRACT.BACKGROUND:
To determine the safety and efficacy of collagenase clostridium histolyticum (CCH) injection for the treatment of palmar Dupuytren disease nodules.
ABSTRACT.METHODS:
In this 8-week, double-blind trial, palpable palmar nodules on one hand of adults with Dupuytren disease were selected for treatment. Patients were randomly assigned using an interactive web response system to receive a dose of 0.25 mg, 0.40 mg, or 0.60 mg (1:1:1 ratio) and then allocated to active treatment (CCH) or placebo (4:1 ratio). All patients and investigators were blinded to treatment. One injection was made in the selected nodule on Day 1. Caliper measurements of nodule length and width were performed at screening and at Weeks 4 and 8. Investigator-reported nodular consistency and hardness were evaluated at baseline and Weeks 1, 4, and 8. Investigator-rated patient improvement (1 [very much improved] to 7 [very much worse]) and patient satisfaction were assessed at study end.
ABSTRACT.RESULTS:
In the efficacy population (n = 74), percentage changes in area were significantly greater with CCH 0.40 mg (−80.1%, P = 0.0002) and CCH 0.60 mg (−78.2%, P = 0.0003), but not CCH 0.25 mg (−58.3%, P = 0.079), versus placebo (−42.2%) at post-treatment Week 8. Mean change in nodular consistency and hardness were significantly improved with CCH versus placebo at Weeks 4 and 8 (P ≤ 0.0139 for all). At Week 8, investigator global assessment of improvement was significantly greater with CCH 0.40 mg and 0.60 mg (P ≤ 0.0014) but not statistically significant with CCH 0.25 mg versus placebo (P = 0.13). Most patients were "very satisfied" or "quite satisfied" with CCH 0.40 mg and 0.60 mg. Contusion/bruising (50.0% to 59.1%) was the most common adverse event with CCH treatment.
ABSTRACT.CONCLUSION:
In patients with Dupuytren disease, a single CCH injection significantly improved palmar nodule size and hardness. The safety of CCH was similar to that observed previously in patients with Dupuytren contracture.
ABSTRACT.TRIAL REGISTRATION:
ClinicalTrials.gov identifier: NCT02193828. Date of trial registration: July 2, 2014 to December 5, 2014
BODY.BACKGROUND:
Dupuytren disease is a common fibroproliferative disease of the palmar fascia [1] that is reported to affect between 1% and 32% of individuals in Western countries [2, 3]. It is characterized by the formation of thick collagen nodules that can progress to fibrous cords capable of producing digital flexion contractures and reducing hand function [4]. Dupuytren disease exhibits three clinical phases known as the proliferative, contractile, and residual phases [5]. In the early proliferative phase, nodules form as myofibroblasts and proliferate around microvessels [5]. This myofibroblast proliferation may lead to vessel occlusion and hypoxia, and signal infiltration of immune cells [5]. Expression of inflammatory signals and growth factors (eg, transforming growth factor-β) by immune cells may stimulate myofibroblast differentiation [6] and contraction [7] and augment the production of extracellular matrix proteins, such as fibronectin and collagen within nodules [8, 9]. In the contractile phase, nodules are reduced in size and myofibroblasts become arranged around the major areas of stress within the nodule, forming a cord [4]. Myofibroblasts also continue to produce collagen, particularly Type III, as well as fibronectin [4]. In the residual phase, nodules have been replaced by fibrous cords, which can shorten and cause further contracture [4]. Currently, no treatment has been approved for nodules associated with Dupuytren disease, although many nodules are symptomatic when pressure is applied to the palm and many will progress to cords with resultant contracture [10]. When treatment (eg, the injection of collagenase clostridium histolyticum [CCH] or surgery) is considered appropriate, it is generally applied during the contractile and residual phases once cords have developed. However, given that collagen augments the disease process and decreases with disease progression [4, 11, 12], earlier treatment with agents that disrupt collagen formation (eg, CCH) is thought to potentially alter disease progression and reduce nodule size, symptoms, and clinical impact [13, 14]. The CCH formulation Xiaflex® (Endo Pharmaceuticals Inc., Malvern, PA, USA) is a combination of two Clostridium histolyticum collagenases (AUX-I and AUX-II) that is currently approved in the United States, Europe, and Australia for the treatment of adult patients with Dupuytren contracture with a palpable cord [1]. These enzymes hydrolyze type I and type III collagen into smaller peptides, which may then be degraded by endogenous human collagenases [1]. In two phase 3 trials (Collagenase Option for the Reduction of Dupuytren [CORD I and CORD II]), injection of CCH into the cords of patients with Dupuytren contracture reduced joint contraction to 0–5° of full extension within 30 days of the last injection in a significantly greater percentage of joints versus placebo injection (CORD I: 64.0% with CCH vs 6.8% with placebo; CORD II: 44.4% vs 4.8%; P < 0.001 for both) [13, 14]. This phase 2a study evaluated the safety and efficacy of multiple doses of CCH injections for the treatment of palmar Dupuytren disease nodules.
BODY.METHODS.PATIENT POPULATION:
Patients ≥18 years of age with Dupuytren disease who had ≥1 palpable palmar nodule that was not associated with a cord and measured between 0.5 cm and 2.0 cm in length and between 0.5 cm and 2.0 cm in width were eligible for inclusion in the study. Patients who had received steroid injections or collagenase treatment (including Santyl® ointment, Smith & Nephew, Inc., Fort Worth, TX, USA) for the treatment of the selected nodule within the past 30 days or surgery on the selected hand within 3 months were excluded. Patients were also ineligible if they had a chronic hand-related muscular, neurologic, or neuromuscular condition, had received or were planning to receive anticoagulant medication within 7 days of study initiation, or had a recent history of stroke or bleeding. All patients included in the study received injection of either CCH or placebo.
BODY.METHODS.CLINICAL STUDY DESIGN:
This 8-week, double-blind, placebo-controlled, exploratory phase 2a study (ClinicalTrials.gov identifier: NCT02193828) was conducted between July 2, 2014, and December 5, 2014 at 11 centers in the United States and Australia. During the screening visit, a palpable palmar nodule on one hand was selected to receive treatment for each eligible patient. On Day 1, patients were randomly assigned to a dose group (based on doses of CCH evaluated in the study) in a 1:1:1 ratio and then further randomly assigned to active treatment [CCH] or placebo in a 4:1 ratio using an interactive web response system. All patients and study site personnel involved in patient evaluation, including the investigators, were blinded to treatment throughout the study. Both CCH and placebo were reconstituted in a solution containing 0.9% NaCl and 0.03% CaCl. Patients received CCH 0.25 mg, 0.40 mg, or 0.60 mg (plus Tris-HCl and sucrose) in a 0.11-, 0.17-, or 0.21-mL total injection volume, respectively, or volume-matched placebo (Tris-HCl and sucrose). Different injection volumes for each treatment group were necessary to ensure delivery of the appropriate concentration of CCH. Patients received a single injection directly into the selected hand nodule using a 26- or 27-gauge, 13-mm needle. The needle was inserted horizontally along the length of the nodule but did not penetrate the opposite side of the nodule. Treatment volume was dispensed as the needle was withdrawn to ensure complete deposition within the nodule. Patients were monitored for immediate immunologic adverse events (AEs) for 20 min post-injection. Follow-up visits occurred at post-injection Week 1, Week 4, and Week 8. Starting at Week 1, all patients were instructed to massage the nodule (massage for 30 s, rest for 30 s, and repeat) twice daily until Week 4. The study was approved by central or local institutional review boards at each participating center within Australia and the United States and followed Good Clinical Practice and principles expressed in the Declaration of Helsinki. All patients provided written informed consent.
BODY.METHODS.STUDY ASSESSMENTS:
The size of the selected nodule was measured at screening, Week 4, and Week 8 using hand-held calipers (for length and width), and at screening and Week 8 using ultrasonography (for length, width, and depth). Nodular consistency was rated by the investigator on a 5-point scale (5 [hard/solid], 4 [firm throughout], 3 [moderate firmness], 2 [soft], or 1 [non-palpable]) after palpation of the selected nodule on Day 1 (the day of injection) and at Weeks 1, 4 and 8. Nodule hardness and pain were assessed on Day 1 and at Weeks 1, 4 and 8. A durometer was used to assess the hardness of the selected nodule with a range of 0–100. Nodular pain was induced using a dynamometer (by applying direct pressure to the nodule) and was then measured on a visual analog scale from 0 (no pain or discomfort) to 10 (extreme pain or discomfort). Investigators rated patient improvement from screening to Week 8 on a scale from 1 (very much improved) to 7 (very much worse). Patient satisfaction with treatment was assessed at Week 8 using a 5-point scale: 1 (very satisfied), 2 (quite satisfied), 3 (neither satisfied nor dissatisfied), 4 (quite dissatisfied), and 5 (very dissatisfied). Treatment-emergent AEs were monitored and vital signs were collected throughout the study. Serum samples for the determination of AUX-I and AUX-II antibodies were collected at screening and the final visit (Week 8).
BODY.METHODS.STATISTICAL ANALYSIS:
Sample size was estimated assuming response rates of 15% for all placebo groups, 50% for CCH 0.60-mg, 40% for CCH 0.40-mg, and 35% for CCH 0.25-mg groups. Thus, a sample size of 80 patients would be required to achieve ≥85% power to detect differences between placebo and CCH 0.60 mg or CCH 0.40 mg. Assuming a common dropout rate (10%), 90 patients were determined to be sufficient for enrollment. The safety population included any patients who received an injection of the study drug. All patients in the safety population who also had pre- and post-injection nodule measurements were included in the efficacy population. The primary end point was the percentage change from baseline in surface area, as measured by calipers, of the treated nodule at Week 8. Secondary end points included percent change from baseline in surface area (as measured by ultrasound) of the treated nodule at Week 8, change from baseline in consistency and hardness of the treated nodule at Week 8, change in nodule pain from baseline to Week 8, investigator global assessment of improvement and patient satisfaction at Week 8, and composite responder analysis at Week 8. Patients who reported being satisfied with treatment (ie, responded very satisfied [1] or quite satisfied [2]) and reported improvement according to investigator assessment (ie, very much improved [1], much improved [2], or minimally improved [3]) were considered composite responders. Between-group differences in categorical variables other than the composite responder end point (ie, investigator global assessment of improvement, patient satisfaction, nodular consistency, change from baseline in nodular consistency) were analyzed using a Kruskal-Wallis test. Differences between each CCH-dose group and placebo were compared using a Mann-Whitney test. For the composite responder end point, the Fisher's exact test was used to analyze between-group comparisons. One-way analysis of variance was used to assess between-group differences in continuous variables (percent change in area [using caliper or ultrasound measurement], nodular hardness, and change in nodular pain). Pairwise comparisons were performed to compare each CCH dose and placebo. Occurrences of AEs were reported using descriptive statistics. The overall count and percentage of patients with AUX-I and AUX-II antibodies were summarized as categorical variables. Log-transformed AUX-I and AUX-II titer values and vital sign measurements were summarized as continuous variables.
BODY.RESULTS.STUDY POPULATION:
Of 84 patients screened, 76 patients met eligibility criteria and were randomly assigned to treatment. Of those, 75 patients were included in the safety population (1 patient withdrew consent before treatment administration; Fig. 1). Demographics and baseline characteristics for the safety population (n = 75) were similar among groups (Table 1). Seventy patients overall (86.4% to 100.0% of patients in each treatment group) had not received previous treatment for Dupuytren disease. One patient in the safety population received study medication but did not complete any post-treatment efficacy evaluations; therefore, only 74 patients were included in the efficacy analyses (Fig. 1).Fig. 1Patient disposition. One patient withdrew consent before receiving study drug on Day 1 and was excluded from all analyses (safety and efficacy). CCH, collagenase clostridium histolyticum
Table 1Demographic and Baseline Characteristicsa
ParameterCCH 0.25 mg(n = 22)CCH 0.40 mg(n = 18)CCH 0.60 mg(n = 18)Placebo(n = 17)Mean age, y (SD)57.9 (10.0)58.1 (12.4)60.0 (10.2)59.9 (8.8)Sex, n (%) Female11 (50.0)10 (55.6)6 (33.3)7 (41.2) Male11 (50.0)8 (44.4)12 (66.7)10 (58.8)Race, n (%) White22 (100.0)17 (94.4)18 (100.0)17 (100.0) Other01 (5.6)00Mean age at Dupuytren disease onset, y (SD)51.6 (13.5)50.4 (13.8)55.8 (8.3)54.7 (11.2)Nodules on selected hand, n (%) 19 (40.9)9 (50.0)10 (55.6)6 (35.3) 26 (27.3)3 (16.7)4 (22.2)5 (29.4) ≥ 37 (31.8)6 (33.3)4 (22.2)6 (35.3)Mean nodule areab, cm2 (SD)0.7 (0.3)0.7 (0.4)0.7 (0.3)0.8 (0.4)Prior Dupuytren disease treatments None19 (86.4)18 (100.0)16 (88.9)17 (100.0) Fasciectomy2 (9.1)000 Needle aponeurotomy001 (5.6)0 CCH1 (4.5)02 (11.1)0
aSafety population (n = 75)
bMeasured using calipers. Calculated as 0.79 × length × width
CCH collagenase clostridium histolyticum, SD standard deviation
BODY.RESULTS.EFFICACY:
In the efficacy population at Week 4, improvements in caliper-measured nodular surface area (change from baseline: CCH 0.25 mg, −0.30 cm2; CCH 0.40 mg, −0.49 cm2; CCH 0.60 mg, −0.50 cm2) were numerically greater in all CCH groups versus placebo (−0.21 cm2). Percentage reductions in area at Week 4 were significantly greater with CCH 0.40 mg (−58.8%, P = 0.0109) and CCH 0.60 mg (−72.4%, P = 0.0003) versus placebo (−27.9%), but not with CCH 0.25 mg (−41.4%; P = 0.24). At Week 8, significant differences versus placebo were observed in caliper-measured nodular surface area for CCH 0.60 mg (P = 0.0003) and CCH 0.40 mg (P = 0.0002), but not with CCH 0.25 mg (P = 0.08; Fig. 2) Ultrasound measurements of nodule size did not correlate with direct caliper measurements and were, therefore, considered an unreliable assessment of treatment efficacy and not reported for this study. Nodular consistency and hardness improved from baseline to Week 1, with significant improvements in all CCH groups versus placebo at Weeks 4 and 8 (Table 2). At Week 8, soft or non-palpable nodules were observed in 8 (36.4%) of 22 nodules in the 0.25-mg group, 12 (70.6%) of 17 nodules in the CCH 0.40-mg group, and 12 (75.0%) of 16 nodules in the CCH 0.60-mg group. Baseline median pain scores were low for all treatment groups (placebo and CCH 0.25 mg [2.0], CCH 0.40 mg [0.5], CCH 0.60 mg [0.0]), illustrating that most patients had little to no nodular pain at study initiation. Significant improvement in nodular pain from baseline was not observed between any CCH group and placebo at any time point. Investigator global assessment of improvement and patient satisfaction at Week 8 were significantly greater in the 0.60-mg and 0.40-mg CCH groups versus placebo (Fig. 3a). A significantly greater percentage of patients in the higher CCH-dose groups were composite responders (CCH 0.40 mg, 88.9%, P = 0.003; CCH 0.60 mg, 77.8%, P = 0.03) compared with those in the placebo group (37.5%; Fig. 3b). Although the percentage of responders in the 0.25-mg group (54.5%) was numerically greater than that reported for placebo responders (37.5%), this difference was not statistically significant (P = 0.34).Fig. 2Nodular area at baseline and Week 8. Error bars represent standard deviations. *
P ≤ 0.0003 vs placebo. CCH, collagenase clostridium histolyticum
Table 2Nodule Consistency and HardnessParameterCCH 0.25 mg(n = 22)CCH 0.40 mg(n = 18)CCH 0.60 mg(n = 18)Placebo(n = 16)Nodule Consistency Scorea
Baseline, mean (SD)4.2 (0.7)4.1 (0.7)4.1 (0.5)3.7 (0.6)Week 1b
Mean (SD)3.1 (0.8)2.7 (0.8)2.6 (0.8)3.6 (0.7) Mean change from baseline (SD)−1.0 (0.8)−1.4 (0.6)−1.4 (0.9)−0.1 (0.7)Week 4 Mean (SD)3.1 (0.8)2.4 (1.0)c
2.0 (0.8)d
3.5 (0.8) Mean change from baseline (SD)−1.1 (0.9)c
−1.7 (0.8)d
−2.1 (0.9)d
−0.2 (0.8)Week 8 Mean (SD)3.0 (1.1)2.2 (1.0)c
2.1 (0.8)d
3.4 (1.0) Mean change from baseline (SD)−1.2 (1.1)c
−1.9 (1.1)d
−1.9 (0.9)d
−0.3 (1.0)Nodule Hardness Scoree
Baseline, mean (SD)68.7 (12.5)67.0 (8.8)68.2 (8.0)63.0 (10.0)Week 1b,f
Mean (SD)58.3 (12.8)52.8 (8.6)55.0 (10.4)65.3 (10.6) Mean change from baseline (SD)−10.4 (13.3)−14.2 (12.5)−13.2 (11.8)2.3 (12.6)Week 4g
Mean (SD)56.4 (10.9)54.7 (9.3)55.6 (12.6)63.1 (11.6) Mean change from baseline (SD)−12.0c (11.3)−12.3 (10.6)c
−13.1 (14.3)c
0.3 (12.6)Week 8h
Mean (SD)55.9 (15.2)46.9 (17.8)56.4 (10.9)64.3 (10.4) Mean change from baseline (SD)−12.8 (14.9)c
−19.6 (14.4)d
−12.1 (11.8)c
1.5 (12.5)
aNodular consistency was rated as 5 (hard/solid), 4 (firm throughout), 3 (moderate firmness), 2 (soft), or 1 (non-palpable). Negative percentage change indicates improvement
bStatistical analyses were not performed on Week 1 data
c
P < 0.02 vs placebo
d
P < 0.001 vs placebo
eHardness of the nodule was assessed using a durometer on a scale of 0–100
fPlacebo, n = 16; CCH 0.25 mg, n = 22; CCH 0.40 mg, n = 18; CCH 0.60 mg, n = 18
gPlacebo, n = 15; CCH 0.25 mg, n = 21; CCH 0.40 mg, n = 18; CCH 0.60 mg, n = 17
hPlacebo, n = 15; CCH 0.25 mg, n = 22; CCH 0.40 mg, n = 17; CCH 0.60 mg, n = 16
CCH collagenase clostridium histolyticum, SD standard deviation
Fig. 3Investigator- and patient-reported assessments at Week 8. Investigator-reported improvement (rating: 1 [very much improved] to 7 [very much worse]) and patient-reported satisfaction (rating: 1 [very satisfied] to 5 [very dissatisfied]) (a) and percentage of composite responders (b). Error bars represent standard deviations. *
P ≤ 0.03 vs placebo. CCH, collagenase clostridium histolyticum
BODY.RESULTS.SAFETY:
The most common AEs in the CCH groups were contusion/bruising, extremity pain, and localized swelling (Table 3). There were no trends for increased AE occurrence with increasing CCH dose, except for injection-site bruising and localized swelling. Most AEs in all CCH groups were mild (84.5% with 0.25 mg, 69.1% with 0.40 mg, and 84.2% with 0.60 mg) or moderate (15.5%, 30.9%, 14.0%, with CCH 0.25 mg, 0.40 mg, and 0.60 mg, respectively). Severe treatment-related injection-site pain was reported in one patient receiving CCH 0.60 mg. No clinically meaningful changes in vital signs were observed. No deaths or patient discontinuations because of a treatment-emergent AE were reported. At Week 8, most patients in all CCH groups (86.4–100.0%) tested positive for antibodies against AUX-I and AUX-II; however, mean log antibody titers were low (ie, <3.2).Table 3Adverse Events Reported by ≥2 Patients in Any Treatment Group (Safety Population)a
AE, n (%)CCH 0.25 mg(n = 22)CCH 0.40 mg(n = 18)CCH 0.60 mg(n = 18)Placebo(n = 17)Any AE21 (95.5)18 (100.0)17 (94.4)7 (41.2) Discontinuations due to AEs0000 Any serious AE0000 Contusion/bruising13 (59.1)9 (50.0)9 (50.0)1 (5.9) Extremity pain10 (45.5)10 (55.6)7 (38.9)1 (5.9) Local swelling8 (36.4)7 (38.9)10 (55.6)3 (17.6) Injection-site bruising5 (22.7)4 (22.2)6 (33.3)0 Axillary pain6 (27.3)1 (5.6)4 (22.2)0 Injection-site pain4 (18.2)4 (22.2)2 (11.1)0 Injection-site swelling5 (22.7)4 (22.2)00 Injection-site pruritus2 (9.1)3 (16.7)2 (11.1)1 (5.9) Injection-site edema2 (9.1)02 (11.1)0 Pruritus2 (9.1)2 (11.1)1 (5.6)0 Injection-site hemorrhage2 (9.1)01 (5.6)0
aPresented in order of occurrence in the active treatment groups
AE adverse event, CCH collagenase clostridium histolyticum
BODY.DISCUSSION:
Currently, no treatments have been approved for Dupuytren nodules, although a retrospective chart review by Reilly et al. showed that 51% of patients with nodules who returned for follow-up (mean time between diagnosis and follow-up: 8.7 years, range, 6–15 years) had developed a cord and 8% had progressed to full contracture [10]. In addition, nodules may be painful in some patients and impair their ability to grip objects or use their hands successfully. Although the pathophysiology underlying Dupuytren disease remains a controversial topic, inflammatory and growth factor signals likely play a role through the augmentation of specific aspects of the disease (eg, myoblast proliferation and collagen production) [5, 6, 8, 9]. Dupuytren nodules are rich in collagen type I and III (ie, the substrates for CCH) [15] and in vitro, CCH has been shown to reduce the expression of extracellular matrix components, cytokines, and growth factors that may contribute to nodule formation and progression [15]. Thus, the properties of CCH at the site of local injection suggest CCH as a possible treatment option for nodules. The results of the current phase 2a, dose-ranging study support continued investigation into the efficacy and safety of CCH for the treatment of Dupuytren nodules. Despite a greater than expected improvement in caliper-measured nodular surface area from baseline to Week 8 in the placebo group (42.2%), improvement was only significantly greater with CCH 0.40 mg (80.1%, P = 0.0002) and 0.60 mg (78.2%, P = 0.0003). Improvement in the lowest CCH-dose group (0.25 mg: 58.3%) was numerically greater than that observed with placebo (42.2%); however, the difference did not reach statistical significance (ie, P > 0.05). Significant improvements from baseline versus placebo were observed in the CCH 0.25-mg group for nodule hardness and consistency. However, greater improvement was observed at the two higher CCH doses (0.40 mg and 0.60 mg), with little apparent increase in the incidence of AEs. Furthermore, investigators noted "very much" or "much" improvement in most (83.3% with CCH 0.40 mg and 88.9% with CCH 0.60 mg) patients who received the two higher doses of CCH. Most patients also expressed a high degree of satisfaction with CCH treatment, indicating that they were "very satisfied" or "quite satisfied" with the two higher CCH doses. Based on these data, CCH doses greater than 0.25 mg appear to be more effective than lower doses for the treatment of Dupuytren nodules and warrant further investigation. Clinical trials have demonstrated the beneficial effect of CCH for the treatment of Dupuytren contracture [13, 14]. During these trials, joints with low baseline contracture severity had greater reduction in contracture to 0–5° of normal (primary end point) 30 days post-injection than joints with more severe contracture [13, 14], implying that earlier treatment may have an effect on the potential response to CCH. However, the current medical literature for the pharmacologic treatment of Dupuytren nodules is limited. In a 4-year study of patients with Dupuytren nodules (n = 75 hands), injection of triamcinolone acetonide (a corticosteroid) flattened and softened the injected nodules in most (97%) hands. However, multiple injections per site were performed (mean number of injections, 3.2), and the authors concluded that the initial injection of corticosteroids was more of a "priming" than a therapeutic dose [16]. The current study demonstrated that injection of CCH into nodules significantly improved nodule consistency and reduced hardness versus placebo within 4 weeks after a single injection. The overall safety profile of CCH was similar to that reported in phase 3 clinical trials of CCH for treatment of Dupuytren contracture [13, 14]. The most commonly reported AEs (ie, contusion/bruising, extremity pain, and local swelling) with the injection of CCH into nodules were similar to those previously reported with CCH injection for the treatment of Dupuytren contracture [13, 14]. Most patients (86.4–100.0%) had antibodies against AUX-I and AUX-II, which was consistent with the rate reported for patients receiving injection into a Dupuytren cord (82–95.2%) [13, 14]. Research has also shown that the presence of AUX-I and AUX-II antibodies has no impact on the efficacy or safety of later injections [17–19]. The current study is limited by its small sample size per treatment group, the administration of only one injection, the limited follow-up duration, and an inability to quantify changes in nodules accurately using ultrasound. Discordance between caliper and ultrasound measurements of nodule size was related to extreme outliers and lack of convergent validity with other efficacy measures. This was likely because of a lack of existing standards for use of ultrasound to measure nodules. Similar patterns of results were observed for both caliper and ultrasound measurements, with the CCH 0.40-mg and 0.60-mg groups showing greater reduction in nodule size compared with placebo, but the wide variability in the ultrasound measurements prevented computation of any significant treatment effect. Thus, we recommend that standard measurement rules be pre-specified in future studies using ultrasound measurements of nodules, and that personnel conducting ultrasound assessments undergo training to maximize measurement consistency. Some improvement was noted in the placebo group for all efficacy end points, which suggests that factors other than active treatment (eg, local injection of anesthesia, nodular massage alone, or patient expectation [placebo response effect]) may have impacted the results. However, the fact that significant improvements with CCH treatment were observed despite the high placebo rate may indicate that benefits of CCH are potentially greater than what has been reported in the current study. In addition, ratings of nodule consistency, nodule pain, and patient satisfaction were subjective; and although both the patient and investigators were blinded to treatment, it is possible that these end points were affected by individuals' desire for or anticipation of improvement. However, the consistency of the improvement observed among all subjective and non-subjective assessments (eg, nodule size as measured with calipers and durometer measurements of hardness) suggests the subjective measurements used in the current study accurately assessed an effect of treatment. Finally, practical use of a dynamometer to potentiate pressure on the affected nodule and then measure nodule pain had not been previously studied in this type of clinical scenario with Dupuytren disease. The positioning of the dynamometer against the nodule was not standardized; thus, patients may not have applied direct pressure to the nodule if it was painful. This variation to avoid pain may explain why no significant improvements in pain were observed with CCH versus placebo. Despite these issues, CCH treatment improved nodular pain by the end of the study and a treatment effect was observed in a post hoc analysis of patients with baseline pain scores ≥3.
BODY.CONCLUSION:
This phase 2a, dose-ranging study demonstrated that a single injection of CCH 0.40 mg or 0.60 mg significantly decreased the size and hardness of palmar nodules in patients with Dupuytren disease and displayed a tolerable safety profile, similar to that reported with CCH treatment for Dupuytren contracture. Additional studies are needed to confirm these initial results and evaluate the long-term efficacy and safety of CCH for palmar nodules. | 5,577,662 | {
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TITLE: The effect of uphill stride manipulation on race walking gait
ABSTRACT:
Stride length analysis represents an easy method for assessing race walking kinematics. However, the stride parameters emerging from such an analysis have never been used to design a training protocol aimed at increasing stride length. With this aim, we investigated the effects of stride frequency manipulation during three weeks of uphill (2%) training on stride length at iso-efficiency speed. Twelve male race walkers were randomly allocated to one of two training groups: stride frequency manipulation (RWM, n=6) and free stride frequency (RWF, n=6). Results. Kinematic parameters measured before and after the 3-week training in RWM showed increased stride length (4.54%; p<0.0001) and contact time (4.58%; p<0.001); inversely, a decreased stride frequency (4.44%; p<0.0001) and internal work (7.09%; p<0.05) were found. In RWF the effect of the training showed a decrease in stride length (1.18%; p<0.0001) and contact time (<1%; p<0.0001) with respect to baseline conditions and an increased stride frequency and internal work of 1.19% (p<0.0001). These results suggest that using slopes (2%) as RWM could help coaches to provide some training methods that would improve an athlete's performance, through increasing stride length without altering his or her race walking technique or metabolic demands.
BODY.INTRODUCTION:
Olympic race walking (RW) is an historical competition, even though only a small number of athletes participate; indeed, race walking has been investigated more often in the laboratory than during competition [1]. An increasing interest in race walking competitions can be seen in the research [2–5]. Moreover, numerous factors have been shown to influence RW performance, including metabolic demand [4, 5], stride technique [2, 3, 6] and nutritional factors [7]. Indeed, race walkers require considerable training and preparation [8]. The importance of investigating various critical aspects involved in RW competitions [2, 3], such as energy cost [9], has become evident in recent years. In particular, researchers have taken a strong interest in training studies in order to understand how energetic cost in high level race walkers can be optimized [10, 11]. Within RW races there are variations in the track terrain, in which small differences in the slope that can influence the mechanics of RW are often present [12]. During a longer competition, such as the 50 km race, top level race walkers usually take approximately 52,600 strides [6], and stride length can decrease by 4% between the start and the end of the race [3]. Therefore, increases in stride length could be advantageous, because this would allow for the same speed to have a lower stride frequency and a better mechanical efficiency [13]. According to this hypothesis, focusing on stride parameters which change the individual stride frequency [6] is desirable in training for improving the stride length, as demonstrated in marathon runners [14]. Usually, uphill RW is used to improve race walking gait [6, 13], but its chronic effects are unknown. Furthermore, it can be stated that uphill RW alone does not help to improve stride length [6]. Indeed, a recent study has shown that even at low speeds on small slopes (2%), RW energy cost increased by 0.30 J/(kg · m) [15] over the energy cost at 0%, while the stride length decreased by ∼4% at both constant and low speed with respect to the level gradient [6]. Therefore, it may be useful to perform race walking on a slope at iso-efficiency speed (decreasing the velocity) [13], without increasing the metabolic demand, as well as on the level, as demonstrated in running [16], but manipulating stride frequency. In addition, considering that during uphill RW stride length decreases [6], it is important to decrease the speed to allow race walkers to adequately modify stride parameters during uphill RW training. In the current study, we hypothesize that manipulating the stride frequency in uphill training will prove advantageous to stride length during level RW. Therefore, the aim of this study was to investigate the effects of the stride frequency manipulation (same stride length on level gradient) vs. free stride frequency during training on a slope (2%) at iso-efficiency speed [13] in national race walkers.
BODY.MATERIALS AND METHODS.PARTICIPANTS:
Twelve male race walkers (Senior's category) were selected for this study following the approval of the University Ethical Committee. All the subjects were randomly assigned to one [17] of the two groups: stride frequency manipulation (RWM= 6, age 24.8±7.4 years, height 1.77±0.08 m, weight 60±6.32 kg, body mass index (BMI) 19.14±0.72 kg · m−2) and free stride frequency (RWF= 6, age 24.2±5.7 years, height 1.78±0.05 m, weight 61.85±4.74 kg, BMI 19.44±1.16 kg · m−2). The inclusion criterion was: high skill with more than six years of training (all were ranked at the national level in their category). None of the athletes suffered from nutritional disturbances, none had any musculoskeletal injuries, and no medications or drugs expected to affect their physical performance were taken during the course of this investigation. In order to make the group homogeneous with regard to the training conditions, none of the subjects performed any strenuous endurance activity and/or resistance training outside of their normal endurance training protocol. The diet control was designed to eliminate the risk of any differences in the total consumption of proteins, carbohydrates and of saturated and unsaturated fats; all the athletes lived together and followed the recommendations of the same sports nutritionist. The TCU Institutional Review Board for the use of Human Subjects approved the details of this study, as well as all related informational and consent documentation, before any data collection was performed. After being informed of the procedures, methods, benefits and possible risks involved in the study, each subject reviewed and signed an informed consent form prior to participation in the study, in accordance with the ethical standards.
BODY.MATERIALS AND METHODS.PROCEDURES:
All subjects were tested before (double check for the reliability of the measures) and after the training intervention in the Human Performance Laboratory. All the tests were carried out in a climate-controlled laboratory: average temperature 23.5°C (min 23°C, max 24°C), between 4:00 p.m. and 7:00 p.m. to control for circadian variation [18]. Riley et al. (2008) reported a high correlation (r=0.93) between over-ground and treadmill walking [19]. All the subjects wore RW shoes (Category A2, 135 g) and performed a standardized 15-min warm-up, consisting of RW at 9 km · h−1, in order to familiarize themselves with the treadmill [20] (Run Race Technogym Run 500, Gambettola Italy [21]). The subjects performed 5 min of dynamic muscular stretching [22] prior to performing the treadmill test for kinematic analysis. The treadmill was calibrated and checked before and after each test, according to the instructions of the manufacturer [20]. Percent grade (%) was expressed as being equal to the tangent [theta] × 100 [20]. The speed at "0" level (mean ± SD) for the 5-min duration was set at 1 km · h−1 less than the best mean speed performed by each participant for 10,000 m (IES0) corresponding to 12.83±0.60 km · h−1 [13]. Previous studies have found that this corresponds to ∼50% (estimate) maximal oxygen consumption (VO2max) [23] and requires an energy cost (Cw) of 5.0 J · (kg · m) −1 [9, 23]. Furthermore, according to the previous data [15] the increase in Cw as a result of a level gradient is:Cwi=0.15×slopei(%)+Cw0, where Cw0 is the Cw at a level gradient (0%). As mentioned above, oxygen consumption (VO2) is proportional to the energetic cost and velocity, so for each gradient the velocity (IESi) at which the VO2 was equal to level RW was calculated by taking VO2= [(Cw0 / (21 (J · min−1)) × ((IES0 / 0.06 (m · min−1)))], where 21 (J · min−1) and 0.06 (m · min−1) are constant values. This leads to the equation:IESi(km·h−1)=[(VO2(kJ/min/kg)×21(J/l)×0.06(m/min))/(0.15×slopei(%)+Cw0)].
BODY.MATERIALS AND METHODS.KINEMATIC ANALYSES:
Pre- and post-training two-dimensional (2D) video data of the subjects' RW on the treadmill were collected using a high-speed (210 Hz) camera (Casio Exilim FH20, Japan). In accordance with previous studies [13, 14, 24], considering that the treadmill device was 50 cm high, the camera was positioned on a 1.5 m high tripod standing 6 m from the participant, and was located perpendicular to the plane of motion and the participant's sagittal plane [25] as standard calibration. The film sequences were analyzed off-line using Dartfish 5.5-Pro motion analysis software (Dartfish, Fribourg, CH). The following kinematic variables were studied: (i) contact time (ms), (ii) stride length (m), and (iii) stride frequency (Hz); 100 strides were sampled [26] within the 5-min duration of the test. Stride frequency was freely chosen within the pre and post-test training. Since the velocity of the treadmill was known, both stride length (left/right, SL) and stride frequency (SF) could be calculated. The contact time (CT) was calculated for both the left and the right foot [27]. The CT was defined and calculated as the time between initial contact (rear foot) with the ground and the last frame of contact before toe-off (forefoot). Initial contact and toe-off were visually detected. According to previous studies [6, 13, 16, 28], SF was calculated as SF= [1000/CT)]; alternatively, SL was calculated with the following equation: SL= [(speed/3.6)/SF].
BODY.MATERIALS AND METHODS.INTERNAL WORK:
We calculated the internal work (WINT) with the Nardello equation [29]WINT=SF·v·(1+(DF·(1-DF)-1)2)·q, where SF is the stride frequency (Hz), v is the speed (m · s−1), DF is the duty factor – i.e. deflection of the duration of stride period when each foot is on the ground (%) and q the value of 0.1 referring to the inertial properties of the oscillating limbs.
BODY.MATERIALS AND METHODS.TRAINING ON A SLOPE:
Slope training was carried out on the treadmill (Run Race Technogym Run 500, Gambettola Italy) over three weeks, with two training sessions per week (Monday and Friday), in accordance with a previous study [14]. All the participants wore RW shoes (Category A2) and performed a standardized 15-min warm-up, consisting of RW at 9 km · h−1 on a treadmill at a level gradient and following 3 min of RW on a 2% slope before each set. The RWM group performed the following training procedure on the treadmill: 5 sets of 5-min RW at a 2% gradient at IES (IES2) with a manipulated individualized stride frequency. Between each set 5 min of active recovery was performed, which consisted of RW at 0% gradient and speed corresponding to IES2 minus 1.5 km · h−1. IES2 and stride frequency were 12.08±0.59 km · h−1 and 3.07±0.25 Hz, respectively. Manipulated stride frequency on a slope was predetermined. SF was calculated in order to replicate the same stride length elicited during level RW at IES, in accordance with the training equation [6]. The athletes were requested to count their strides and to replicate the number each minute (visual counter each 30 s with treadmill display, with an error of one stride). Training equation for slope= [(speed (km · h−1) / 3.6 (m · s−1)) during slope / SL (m) during level × 60 (min)] [6]. The RWF group performed the following training procedure on the treadmill: 5 sets of 5-min RW at 2% gradient at IES2 with a freely chosen stride frequency. IES2 and stride frequency were 12.13±0.58 km · h−1 and 2.92±0.15 Hz, respectively. Between each set, 5 min of active recovery was performed, which consisted of RW at 0% gradient and speed corresponding to IES2 minus 1.5 km · h−1. To balance the training load, both groups (RWM-RWF) during the training weeks (4 days per week) performed the same normal training programme on a level gradient (based on ∼14.5 km per day).
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Data are reported as mean ± SD. The kinematic variables (i) contact time, (ii) stride length, (iii) stride frequency and (iv) internal work were analysed using a separated two-way ANOVA with repeated measures and Bonferroni post-hoc tests. The effect size (η2) was calculated for all variables between pre- and post-testing. For testing the repeatability of the measure [30], we first calculated the intra-class correlation coefficient (ICC) for each variable measured. Assumption of normality was verified using the Shapiro-Wilk W. Test. The within factor was time with two levels (pre- and post-training) and the between factor was the training with at two levels (RWM and RWF). Furthermore, a t-test was used to compare pre- and post-training in different groups for: (i) contact time, (ii) stride length, and (iii) stride frequency. Then, a pair-wise comparison was performed when the main effect was significant, and the significance level was set at p<0.05. Statistical analysis was performed using SigmaPlot software 11.0 (Systat Software, Tulsa, OK).
BODY.RESULTS:
There were no differences between the two groups at baseline conditions for age, height, weight, training experience or RW velocity on both the level and a slope (2%). The test-retest reliability of this testing procedure was demonstrated through an ICC and standard error of measurements (SEM) for the following variables: stride length (ICC: 0.97–0.98, SEM: 0.03–0.07 m), contact time (ICC: 0.96–0.98, SEM: 9–11 ms) and stride frequency (ICC: 0.95–0.98, SEM: 0.8–0.11 Hz). Repeated measures ANOVA showed significant differences between the two training groups in CT: F(1,10)= 32.856, p<0.0001 (η2= 0.767) and the interaction training type × time F(1,10)= 94.776, p<0.0001 (η2= 0.905). Significant differences were also found for SF: F(1,10)= 24.038, p<0.001 (η2= 0.706) and the interaction training type × time F(1,10)= 71.022, p<0.0001 (η2= 0.877). Similarly, significant differences were found for the SL: F(1,10)= 40.941, p<0.0001 (η2= 0.804) and the interaction training type × time F(1,10)= 120.115, p<0.0001 (η2= 0.923). WINT showed significant differences: F(1,10)= 5.784, p=0.037 (η2= 0.584) and the interaction training type × time F(1,10)= 11.372, p=0.007 (η2= 0.859). With regard to the two training strategies, within the RWM group the CT significantly increased by 4.58% (p<0.001), as did SL (4.54% with p<0.0001) between pre- and post-training (Table 1). SF and WINT (Figure 1) also significantly decreased by 4.44% and 7.09% (p<0.0001 with p=0.03), respectively, within the RWM. Conversely, in RWF the SL and CT decreased by 1.18% with p<0.0001 and <1% with p<0.0001, respectively, between pre- and post-training, while the SF and WINT increased (1.19% with p<0.0001) respectively. FIG. 1Changes in the WINT variable (means and SE) for the stride frequency manipulation (RWM) and free stride frequency groups (RWF) depending on the time (pre- and post-training). "†" represents significant (p<0.0001) training × time interaction; "*" p<0.05 and "**" p<0.01 represent significant differences between pre- and post-training. TABLE 1 Effects of uphill race walking training on step analysis. BASELINE RWM RWF Contact time (ms) 311 ± 16.89 324 ± 22.96* 308 ± 7.56† Step frequency (Hz) 3.23 ± 0.18 3.10 ± 0.23† 3.25 ± 0.08† Stride length (m) 1.11 ± 0.09 1.15 ± 0.12† 1.10 ± 0.07† Note: Kinematic variables in the step frequency manipulation group (RWM) and the free step frequency group (RWF) between post-training and the baseline conditions with “*” p<0.001, or “†” p<0.0001.
BODY.DISCUSSION:
The current study shows for the first time the effect of stride frequency manipulation on kinematic parameters during uphill training in national race walkers. The study investigated the effects of two types of uphill RW training – RWM and RWF. The uphill training aimed to reproduce the same stride length that was elicited during RW on a level gradient. Uphill RW speed was therefore slower compared to level RW, 12.11±0.56 km · h−1 and 12.83±0.59 km · h−1, respectively. The previous research that carried out RW training programmes used greater slopes, which produced higher speeds [6]. Such conditions would produce unnatural conditions for race walkers [31, 32]. This would presumably increase the energy cost of RW [15, 33] and lead to improvements in the cardiovascular system. Within the current study, the aim was to look at kinematic parameters and maintain a similar metabolic cost; due to this, IES was used [13]. In the present study the reduction in speed [13] allowed for effective stride frequency manipulation. Research suggests that race walkers often unconsciously select a stride frequency which minimizes injury and energy expenditure [8, 23] and is modulated by the central pattern generators [34], as in running [24]. Due to this notion, race walkers within the RWM group found it problematic during the first training session to alter their stride pattern. The RWF group, however, did not have such issues, as stride frequency was freely chosen. The results following six uphill training sessions (over 3 weeks) suggest that the RWM group elicited kinematic improvements. Conversely, the RWF group did not show any significant kinematic improvements. Some researchers suggest that successful running race performances are characterized by increased stride length, increased cadence becomes more important at greater speeds [35, 36] and contact times are shorter. Our results support this approach, and following training the RWM group increased SL by 4.54% with p<0.0001 related to decreased WINT (7.05% p<0.05; Figure 1). During training the RWM group subjects were required to reduce their mechanical pattern in order to reduce their stride frequency (∼5%). Changes in CT were also evident: RWM increased by 4.58% (p<0.001), but only a <1% decrease was found for the RWF group. The decreases in CT may have produced greater peak vertical force [37], thus providing longer stride lengths. This was supported within the RWM group in the current study. The kinematic adaptations elicited by the RWM group were characteristic of better race walkers, as energy efficient performances are. Longer contact times and smaller stride frequencies are associated with energy efficiency [13, 38]. A particular limitation of this study, concerning the low sample size, can be explained considering the kind of discipline involved: in the last 30 years the mean number of subjects studied in the laboratory was very low (male, n=7±4.5; female n=4±2.7 [1]), due to the specificity of the RW technique.
BODY.CONCLUSIONS:
In conclusion, this study showed how the stride frequency manipulation during uphill RW training alters subsequent level RW kinematics, and presumably aids efficient RW performance. The increase in SL could provide an advantageous alteration to kinematics. Because of the direct positive relationship between SL and speed, increasing SL could significantly increase the speed (which is the race walker's aim), assuming that the foot does not advance too far ahead of the centre of mass, providing a braking effect [39]. Considering that the RW race (50 km) record is 3 h 32 min 33 s [40], and the stride length decrease is 4% [3], this study could be useful in closing this gap with the training method of increasing athletes' stride length, leading to the first time an athlete could complete a race under 3 h 30 min The same training protocol could also be applied for a middle distance race (20 km), where a decrease of stride length by 2.4 and 2.7% was observed in males and females respectively between the last and first kilometres [12]. An uphill race walking protocol (changing stride frequency) could be useful to diversify athletes' common training protocol without stressing their current metabolic demand. In addition, given that several physiological systems are involved during RW, the possible effect of combining different training strategies, shown to be effective in isolation, warrants future studies. | 4,577,567 | {
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TITLE: The effects of multi-strain probiotic compound on symptoms and quality-of-life in patients with irritable bowel syndrome: A randomized placebo-controlled trial
ABSTRACT.BACKGROUND::
Evidence has shown beneficial effects of probiotics in the treatment of irritable bowel syndrome (IBS); however, there is still a lack of data in this regard. We evaluated the efficacy of a multi-strain probiotic compound on IBS symptoms and quality-of-life (QOL).
ABSTRACT.MATERIALS AND METHODS::
Adult IBS patients (n = 132) were randomized to receive a probiotic compound containing seven bacteria species including Lactobacillus strains, Bifidobacterium strains and Streptococcus thermophiles or similar placebo, twice daily after a meal for 14 consecutive days. Improvement of IBS symptoms was assessed in categories of abdominal pain and distension and improvement of bowel habit. Improvement in patients QOL was assessed by the IBS-QOL instrument. Patients were evaluated for symptoms and QOL at baseline and then 1 month after completion of the treatment.
ABSTRACT.RESULTS::
After treatment, there was a decrease in abdominal pain and distension severity in both probiotic and the placebo groups (P<0.001), but there was no difference between the two groups in this regard (P>0.05). Improvement in bowel habit was observed in 33.3% of the probiotic and 36.5% of the placebo group (P = 0.910). There was no significant difference between the two groups in QOL after the treatment (P >0.05).
ABSTRACT.CONCLUSIONS::
We found no beneficial effects over placebo for a 2-week treatment with the above mentioned multi-strain probiotic compound in the treatment of IBS. Further, trials are yet required before a clear conclusion in this regards.
BODY.INTRODUCTION:
Irritable bowel syndrome (IBS) is the most common functional bowel disorder characterized by abdominal pain/discomfort accompanying with disturbed bowel habits. It is estimated that 3-15% of the general population have IBS world-wide, modestly more prevalent in women than in men.[1] IBS possesses a chronic nature and affects patients physically, psychologically and economically and therefore, it is associated with impaired quality-of-life (QOL) and causes a major economic burden.[2] The pathophysiology of IBS is still not completely understood. Studies have shown that the etiology is most likely multifactorial and abnormal brain-gut interaction, food intolerance; altered microflora, post-infectious or inflammatory changes and genetic and psychological factors contribute to the pathogenesis of IBS.[34] Heterogeneous pathophysiology and nature of IBS has a substantial impact on the efficacy of therapies for IBS. Only few therapies have been found to be effective in IBS treatment and treatments are not satisfactory in about half of the patients.[5] The role of altered gut microbiota in the pathogenesis of IBS is highlighted by evidences showing changes in fecal and mucosa associated microflora, post-infectious IBS phenomenon and the link with intestinal bacterial overgrowth and dysregulation of mucosal immune system. Therefore, investigators have tried to see the effects of alterations in the intestinal microflora on IBS symptoms.[6] In this regard, the role of probiotics for intestinal functions and altered bowel microbiota, found in patients with IBS, has drawn attention toward these agents. Previous studies have shown beneficial effects of probiotics in the treatment of IBS and their safety has also contributed in to their popularity.[789] However, the benefits are likely to be strain-specific[10] and Bifidobacterium infantis has resulted in significant improvement in almost all IBS symptoms.[9] Based on some evidence, a mixture of probiotics that contains several species of bacteria could be more effective than a single species of bacteria in the treatment of some gastrointestinal diseases. It is assumed that multi-strain probiotics have synergistic effects that increase their effectiveness.[1112] However, whether a probiotic mixture is more effective than a single agent in treatment of IBS is remained un-answered yet. Another remained concern is the world-wide generalizability of current studies results. Almost all clinical studies with microbial therapies are carried out with people from developed countries.[789] Since, there is a variety in gut flora between different world's regions[1314] the efficacy of probiotics may be affected by different ethnic groups of patients from different countries. There is no published report about probiotics efficacy on IBS treatment in Iran yet. Moreover, most of the previous studies are limited by small sample size.[15] Considering the above mentioned questions and lack of qualified studies, the purpose of our study was to evaluate the efficacy of a multi-strain probiotic compound, Balance® (Protexin Co., Somerset, UK), in the treatment of Iranian IBS patients. Balance® contains seven species of bacteria including Lactobacillus and Bifidobacterium species that separately have been shown helpful for treatment of IBS.[916] We hypothesized that this probiotic compound would decrease symptoms of IBS and increase the QOL.
BODY.MATERIALS AND METHODS.PATIENTS AND SETTING:
This randomized placebo-controlled triple-blinded study was conducted on adult patients with IBS referred to gastroenterology clinics of Alzahra University Hospital in Isfahan City (central Iran). IBS was diagnosed by a single gastroenterologist according to the Rome II criteria (reference is needed). Patients with symptoms presented at least for 2 days/week in the preceding 2 weeks were included. Those with any infectious diseases before or during the study that need antibiotic therapy, immune-deficient disease, history of surgery on the gastrointestinal tract and history of using antibiotics or probiotics within 4 weeks before the study were not included. Considering type I error = 0.05, study power = 0.8 and expecting 10 point increase in the QOL score,[17] the study sample size was calculated as 66 cases per group. The study was approved by the Ethics Committee of Isfahan University of Medical Sciences and registered in the U.S. National Institutes of Health Protocol Registration System (available at clinicaltrials.gov NCT01837472). Informed consent was obtained from all patients after full explanation of the study aim and protocol.
BODY.MATERIALS AND METHODS.INTERVENTION:
Patients were randomized into probiotic and placebo groups based on random table list. Patients in the probiotic group received the probiotic compound Balance® (Protexin Co., Somerset, UK), twice daily after a meal for 14 consecutive days. Balance® capsules contain seven bacteria species including Lactobacillus strains (Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus acidophilus and Lactobacillus bulgaricus), Bifidobacterium strains (Bifidobacterium breve and Bifidobacterium longum) and Streptococcus thermophiles. Total viable count is 1 × 108 CFU/per capsule. Other Ingredients are Fructo-oligosaccharide as prebiotic, magnesium stearate and hydroxypropyl methyl cellulose. Those in the placebo group received placebo capsules with the same order as probiotic group. No other treatment was prescribed for patients during the study period.
BODY.MATERIALS AND METHODS.ASSESSMENTS:
Primary outcome of this study was improvement of IBS symptoms that was assessed in categories of abdominal pain and distension (from 0: No symptom to 3: Severe symptom) and improvement of bowel habit (get worse, no change, get better). Secondary outcome was improvement in patients QOL that was assessed by applying the IBS-QOL instrument. The IBS-QOL is a reliable and valid instrument for the assessment of IBS patients' QOL. It contains 34 items with 5-point response scale (1: No problem to 5: Extreme problem). The total score is converted into 0-100 points for better interpretation.[17] The Persian version of the IBS-QOL with sufficient psychometric properties was used in this study.[18] Patients were evaluated for symptoms and QOL at baseline and then 1 month after completion of the treatment.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSES:
This study was designed as a triple-blind study and attending physicians, patients, principal investigators as well as data analyzer were all unaware about the treatment arms and drug codes. A third colleague who coded the probiotic and placebo capsules clarified the codes after data analyses. Data were analyzed using the SPSS software for windows version 16.0. Quantitative data and qualitative data were compared between the two groups with independent sample t-test and Chi-square/Mann-Whitney U tests, respectively. Paired t-test and Wilcoxon test were applied to assess changes in QOL score and symptoms severity within each group, respectively. A P value of less than 0.05 was considered as indicating a statistical significant difference in all analyses.
BODY.RESULTS:
A total of 160 patients were evaluated during the study period. Twenty eight patients were not included owing to unwillingness to participate, receiving antibiotics or probiotics at the time of the study. Thus, 132 patients were randomized into the probiotic and placebo groups. Three patients from the placebo group did not come for follow-up evaluations, not due to drug side effects. Thus, 129 patients completed the trial; 66 patients in the probiotic and 63 ones in the placebo group. Mean age was 36.2 ± 9.3 years and 85 (65.9%) cases were female. The two groups were similar regarding demographic and baseline clinical characteristics [Table 1]. Table 1 Comparison of the two groups with regards to demographic and baseline clinical characteristics After the treatment period, there was a significant decrease in abdominal pain severity in both the probiotic (P < 0.001) and the placebo (P = 0.001) groups. There was no difference between the two groups in this regard (P = 0.558). Furthermore, distension severity decreased significantly in both probiotic (P < 0.001) and the placebo (P < 0.001) groups, but no difference was observed between the two groups in this regard (P = 0.673). Improvement in bowel habit was observed in 33.3% of the probiotic and 36.5% of the placebo group (P = 0.910). With regard to QOL, an improvement was observed in the probiotic (P = 0.008), but not in the placebo group (P = 0.175); though, there was no significant difference between the two groups in this regard (P = 0.372), Table 2. Further analysis in each subgroup of bowel habit did not change these results. Table 2 Comparison of the two groups with regards to symptoms and quality-of-life after treatment In the probiotic group, three patients experienced mild abdominal pain and nausea at the beginning of therapy, which disappeared by continuing the drug. No specific side-effect was reported in the placebo group.
BODY.DISCUSSION:
The aim of the present study was to evaluate the efficacy of a multi-strain probiotic compound, which contains seven species of bacteria including Lactobacillus and Bifidobacterium species in the treatment of Iranian IBS patients. We found no beneficial effects for this probiotic compound over placebo in reliving IBS symptoms. Although there was a statistically significant improvement in QOL score in the probiotic group, this change was not clinically important, which might be due to short duration of the study. Previous studies on the efficacy of multi-strain probiotic compounds in the treatment of IBS have provided different results. Two small studies by Kim et al. on a probiotic compound containing Bifidobacterium, Lactobacillus and Streptococcus salivarius species for 4-8 weeks found beneficial effects of these probiotics over placebo only for bloating and flatulence symptoms.[1920] Ki Cha et al. have evaluated a probiotic mixture containing Lactobacillus and Bifidobacterium and S. thermophilus for 8 weeks and found an overall response rate of 48% versus 12% with placebo; though, it had no significant effect on individual symptoms.[21] The study by Williams et al. on a combination of Lactobacillus and Bifidobacterium species also found greater improvement in IBS symptom severity and also in QOL compared with placebo over the 8-week intervention period.[22] Two other studies by Kajander et al. showed that a probiotic mixture of Lactobacillus and Bifidobacterium species for 5 months can stabilize the intestinal microbiota and alleviate IBS symptoms.[2324] In contrast to these reports, the study by Søndergaard on a probiotic fermented milk containing Lactobacillus and Bifidobacterium species has found no special effect over acidified milk for 8 weeks.[25] A similar study by Simrén et al. also found no positive effect of such treatment.[26] Our study also found no beneficial effects of multi-strain probiotic over placebo in the treatment of IBS. According to systematic reviews and meta-analyses on this subject, there is a considerable heterogeneity among previous clinical trials regarding study design, which prevent a clear conclusion. Studies are different considering the duration of treatment (2 weeks to 5 months), outcome assessments and the type and amount (drug dose) of intervention. A publication bias toward positive results also should be considered.[9] Future studies should follow Rome Committee recommendations for appropriate design of clinical trials in this field.[27] There are some limitations for this study. We assessed abdominal pain, the most important IBS symptom for patients as well as other symptoms with a Likert scale. This type of assessment is based on clinical importance of change; however, it might not detect small changes. Therefore, it is better for future studies to apply more comprehensive evaluation of symptoms.[28] Furthermore, the IBS-QOL evaluates QOL of the patient in the preceding 30 days; thus, 1 month was not an appropriate interval for expecting change in QOL and the study needed longer follow-up for evaluation of changes in QOL.
BODY.CONCLUSIONS:
We found no beneficial effects for a 2-weeks treatment with a multi-strain probiotic compound containing Lactobacillus and Bifidobacterium species over placebo in the treatment of Iranian IBS patients. Further trials with longer duration of treatment and follow-ups are yet required before a clear conclusion in this regards. Such research should also focus on the type, optimal dose of probiotics and the subgroups of patients who are likely to benefit the most. | 4,139,977 | {
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TITLE: Behavioural recovery after treatment for varicose veins
ABSTRACT.BACKGROUND:
The aim of this study was to assess behavioural recovery from the patient's perspective as a prespecified secondary outcome in a multicentre parallel‐group randomized clinical trial comparing ultrasound‐guided foam sclerotherapy (UGFS), endovenous laser ablation (EVLA) and surgery for the treatment of primary varicose veins.
ABSTRACT.METHODS:
Participants were recruited from 11 UK sites as part of the CLASS trial, a randomized trial of UGFS, EVLA or surgery for varicose veins. Patients were followed up 6 weeks after treatment and asked to complete the Behavioural Recovery After treatment for Varicose Veins (BRAVVO) questionnaire. This is a 15‐item instrument that covers eight activity behaviours (tasks or actions an individual is capable of doing in an idealized situation) and seven participation behaviours (what the individual does in an everyday, real‐world situation) that were identified to be important from the patient's perspective.
ABSTRACT.RESULTS:
A total of 798 participants were recruited. Both UGFS and EVLA resulted in a significantly quicker recovery compared with surgery for 13 of the 15 behaviours assessed. UGFS was superior to EVLA in terms of return to full‐time work (hazard ratio 1·43, 95 per cent c.i. 1·11 to 1·85), looking after children (1·45, 1·04 to 2·02) and walks of short (1·48, 1·19 to 1·84) and longer (1·32, 1·05 to 1·66) duration.
ABSTRACT.CONCLUSION:
Both UGFS and EVLA resulted in more rapid recovery than surgery, and UGFS was superior to EVLA for one‐quarter of the behaviours assessed. The BRAVVO questionnaire has the potential to provide important meaningful information to patients about their early recovery and what they may expect to be able to achieve after treatment.
BODY.INTRODUCTION:
Minimally invasive treatments for varicose veins such as ultrasound‐guided foam sclerotherapy (UGFS) and thermal ablation techniques have become widely used alternatives to surgery for the treatment of varicose veins. One of the advantages of these techniques is the reported quicker return to normal activities, particularly following UGFS1, 2, 3. However, it is unclear whether thermal ablation, in particular endovenous laser ablation (EVLA), is also associated with a clinically significant quicker return to normal activities compared with surgery; some studies4, 5 have shown an earlier return and others2, 6, 7, 8 no difference. Until recently, there was no standard means of assessing recovery from the patient's perspective. This led to the use of varying definitions such as return to 'normal activities', 'full activity', 'daily activity' or 'basic physical activities' and/or 'return to work' in previous studies. This lack of standardization led the authors to develop a 15‐item questionnaire to assess distinct aspects of normal activities that were identified as important by patients9 – the Behavioural Recovery After treatment for Varicose Veins (BRAVVO) questionnaire. This paper reports behavioural recovery results from a multicentre parallel‐group randomized clinical trial (CLASS, Comparison of LAser, Surgery and foam Sclerotherapy) that compared the clinical efficacy and cost‐effectiveness of three treatment modalities: UGFS, EVLA with delayed foam sclerotherapy to residual varicosities if required, and surgery. Behavioural recovery was one of the prespecified secondary outcomes of the CLASS trial. The clinical and cost‐effectiveness results have been reported elsewhere10, 11.
BODY.METHODS:
Patients were recruited from 11 centres in the UK between November 2008 and October 2012. This study (ISRCTN51995477) had research ethics committee and Medicines and Healthcare products Regulatory Authority approval. Eight centres randomized participants to one of three treatment options, and three centres offered only UGFS and surgery. Participants were randomized between the treatments with even allocation, using a minimization algorithm that included centre, age (less than 50 years, 50 years or more), sex, great saphenous vein (GSV) or small saphenous vein (SSV) reflux, and unilateral or bilateral disease. Inclusion criteria were: age over 18 years; primary unilateral or bilateral symptomatic varicose veins (Clinical Etiologic Anatomic Pathophysiological (CEAP) grade C2 or above); GSV and/or SSV involvement; and reflux exceeding 1 s on duplex ultrasonography. Exclusion criteria were: current deep vein thrombosis; acute superficial vein thrombosis; a GSV or SSV diameter smaller than 3 mm or larger than 15 mm; tortuous veins considered unsuitable for EVLA or stripping; and contraindications to UGFS or to general/regional anaesthesia that would be required for surgery.
BODY.METHODS.TREATMENTS:
The treatments have been described in detail elsewhere9, 10. For UGFS, foam was produced using the Tessari technique12 using a ratio of 0·5 ml sodium tetradecyl sulphate to 1·5 ml air (3 per cent for GSV/SSV truncal veins, 1 per cent for varicosities; maximum 12 ml foam per session). EVLA of GSVs/SSVs was performed under local anaesthetic, and patients were offered UGFS to any residual varicosities at 6‐week follow‐up if required, with the exception of one centre that performed concurrent phlebectomies. Surgery in the form of proximal GSV/SSV ligation and stripping (all GSV) and concurrent phlebectomies was performed under general or regional anaesthetic as a day‐case procedure. Compression stockings were applied after all three treatments.
BODY.METHODS.POST‐TREATMENT ACTIVITY:
All participants were given a study patient information leaflet (PIL), which recommended a return to all normal activities as soon as they were able, but that strenuous activity/contact sport should be avoided for 1–2 weeks. The PIL specifically stated that following EVLA or UGFS 'most people are able to return to work within 2–3 days of treatment, but some people go back the following day or even the same day', and that following surgery 'people can return to office or sedentary work after 2–3 days; and that most people will be back at work within a week after surgery to one leg and 2 weeks after surgery to both legs; but there is no reason to remain off work as long if it can be managed with reasonable comfort'. Participants undergoing UGFS or EVLA were advised to wear compression stocking for 10 days constantly (day and night). Those in the surgery group were advised that bandages would be removed the day after operation, following which they should wear a stocking for 10 days, but that it was reasonable to remove the stocking after 4 or 5 days, providing that they were active.
BODY.METHODS.DATA COLLECTION:
The participants were asked to complete the BRAVVO questionnaire along with other study questionnaires (Aberdeen Varicose Vein Questionnaire, EQ‐5DTM (EuroQoL, Rotterdam, The Netherlands) and Short Form 36 (QualityMetric, Lincoln, Rhode Island, USA)) at the 6‐week follow‐up appointment. Participants who failed to attend the 6‐week appointment were sent the questionnaire to complete at home. The BRAVVO questionnaire was developed as an instrument to assess the activity and participation components of the World Health Organization International Classification of Disability and Function model13. Variation in activity and participation is not fully explained by impairment and so these constructs are important additional indicators of health outcome. An interview study involving 17 patients who had recently undergone varicose vein treatment was carried out to identify normal activities and 'milestone' behaviours to incorporate into the questionnaire. In addition to sampling from the three treatment options, diversity sampling was used in an attempt to gain a mix of sex, age and rural–urban location. Seventeen interview transcripts were content‐analysed in four stages to identify appropriate items to include in a questionnaire. Full details of this process have been published previously9. The BRAVVO questionnaire assesses the time taken for patients to return to performing 15 behaviours: eight 'activity' behaviours (tasks or actions an individual is capable of doing in an idealized situation) and seven 'participation' behaviours (what the individual does in an everyday, real‐world situation) that were identified to be important from the patient's perspective9. Fig. 1 shows the question layout. Figure 1Question layoutBJS-10081-FIG-0001-c
BODY.METHODS.STATISTICAL ANALYSIS:
Data from the BRAVVO questionnaire were analysed within an interval‐censored time‐to‐event framework using flexible parametric survival models14. For each behaviour item, each participant's response was converted into the number of days to return to that behaviour. If a participant indicated that return to the behaviour was on the day of the procedure, this was assumed to be interval‐censored between day 0 and day 1. If a participant indicated return to the behaviour was after a number of weeks, not days, this was assumed to be interval‐censored between the previous week and the week indicated. For example, if a participant reported 5 weeks, it was assumed that the return to the behaviour took place between 28 and 35 days. A participant who indicated that they had not returned to a behaviour that they usually performed was right‐censored at 42 days. Participants who indicated that they did not normally perform a specific behaviour were not included in analysis of that behaviour. No missing data were imputed. Data are reported as the number of days for 50 and 90 per cent of participants to return to each behaviour, estimated from the parametric survival models (the 50 per cent value represents the median time to return to this behaviour). Extrapolation beyond the 42‐day cut‐off was performed for behaviours where 90 per cent of participants had not returned to the behaviour by 42 days. Treatment effects are presented as hazard ratios with associated 95 per cent c.i. All analyses were carried out in Stata® 1215. Flexible parametric survival models were fitted using the stpm package16.
BODY.RESULTS:
Seven hundred and ninety‐eight participants were recruited, of whom 13 were ineligible (for example because they had recurrent veins or veins larger than 15 mm in diameter) after randomization and were considered postrandomization exclusions (Fig.
2). The groups were well balanced in terms of demographic characteristics at baseline, but there was an increased incidence of deep venous reflux in the foam group compared with the surgery group (P = 0·005) (Table
1). Of the 670 participants who completed the 6‐week questionnaire, 655 completed at least one of the BRAVVO questions. Completion rates were slightly lower for the questions about going out socially (74·8 per cent) and sporting activity (66·0 per cent), which may not have been relevant to all participants. For all behaviours, except wearing clothes that show the leg, going out socially and sporting activities, over 95 per cent of participants had returned to normal behaviour within 6 weeks of intervention. Figure 2CONSORT diagram for the trial. Reasons for postrandomization exclusion included: recurrent varicose veins and veins larger than 15 mm. Reasons for withdrawal from follow‐up included: patient decided not to proceed with treatment (and also declined follow‐up), declined follow‐up after treatment or did not wish to complete questionnaires. UGFS, ultrasound‐guided foam sclerotherapy; EVLA, endovenous laser ablationBJS-10081-FIG-0002-c Table 1 Demographic details at recruitment EVLA UGFS Surgery ( n = 210) ( n = 286) ( n = 289) Age (years) *
49·7 (18–80) 49·0 (19–78) 49·2 (22–85) Sex ratio (F : M) 120 : 90 162 : 124 163 : 126 Body mass index (kg/m 2 ) *
27·0 (17–42) 27·1 (17–44) 27·7 (17–44) Unilateral disease 153 (72·9) 215 (75·2) 196 (67·8) Employment status Self‐employed 21 (10·2) 37 (13·0) 29 (10·3) Employed 120 (58·3) 169 (59·3) 179 (63·5) Other 65 (31·6) 79 (27·7) 74 (26·2) Unknown 4 1 7 Saphenous vein involvement Great saphenous 182 (86·7) 232 (81·1) 239 (82·7) Small saphenous 14 (6·7) 21 (7·3) 21 (7·3) Great and small saphenous 14 (6·7) 33 (11·5) 29 (10·0) Deep vein reflux 28 of 205 (13·7) 47 of 280 (16·8) 25 of 282 (8·9) CEAP classification C2, varicose veins over 3 mm 113 (54·1) 169 (59·1) 147 (51·2) C3, oedema 28 (13·4) 35 (12·2) 39 (13·6) C4, skin/subcutaneous changes 56 (26·8) 74 (25·9) 90 (31·4) C5/C6, healed/active venous ulcer 12 (5·7) 8 (2·8) 11 (3·8) Unknown 1 0 2 Values in parentheses are percentages unless indicated otherwise; * values are mean (range). EVLA, endovenous laser ablation; UGFS, ultrasound‐guided foam sclerotherapy; CEAP, Clinical Etiologic Anatomic Pathophysiologic.
BODY.RESULTS.ULTRASOUND‐GUIDED FOAM SCLEROTHERAPY :
Participants randomized to UGFS recalled being able to carry out 13 of the 15 behaviours significantly more quickly than those randomized to surgery (Table
2
). The two behaviours for which there was no evidence of a difference in the time to recover between the trial arms were 'having a bath or shower' and 'wearing clothes that show the legs'. In general, the median time to return to the activity behaviours was 5 days or less for those randomized to UGFS and up to 9 days for those randomized to surgery. In both groups, there was greater variation in the median time to return to the participation behaviours than the activity behaviours. Table 2 Behavioural recovery: ultrasound‐guided foam sclerotherapy versus surgery Proportion carrying out behaviour (%) Time until specified proportion of participants could carry out behaviour (days) *
Hazard ratio †
UGFS Surgery Activity items Bending the legs without discomfort 50 3·0 4·6 1·38 (1·14, 1·67) 90 14·1 21·3 Lifting heavy objects without discomfort 50 4·8 9·8 1·97 (1·59, 2·44) 90 16·9 34·5 Moving from standing to sitting without discomfort 50 1·9 3·7 1·63 (1·35, 1·97) 90 9·3 17·5 Standing still for a long time (> 15 min ) without discomfort 50 3·9 7·1 1·67 (1·36, 2·05) 90 15·8 28·7 Walking short distances (< 20 min ) without discomfort 50 1·9 4·4 2·00 (1·65, 2·42) 90 8·2 19·1 Walking long distances (> 20 min) 50 4·5 8·0 1·76 (1·45, 2·14) 90 15·2 27·1 Having a bath or shower 50 5·4 4·9 0·85 (0·70, 1·03) 90 11·4 10·3 Driving a car 50 4·1 7·0 1·78 (1·45, 2·19) 90 12·4 21·1 Participation items Doing housework 50 2·1 4·5 2·10 (1·72, 2·56) 90 7·3 15·7 Looking after children 50 1·2 3·5 2·20 (1·61, 3·00) 90 6·2 17·9 Wearing clothes that show the legs 50 12·4 12·8 1·03 (0·78, 1·35) 90 56·6 58·7 Partial return to normal work/employment 50 4·4 9·9 2·16 (1·72, 2·72) 90 15·4 34·2 Full return to normal work/employment 50 4·8 11·7 2·56 (2·05, 3·21) 90 14·9 36·2 Going out socially 50 7·1 9·3 1·29 (1·06, 1·57) 90 25·8 34·0 Sporting activity or exercise 50 15·7 21·8 1·33 (1·05, 1·68) 90 62·6 86·7 Values in parentheses are 95 per cent c.i. * The 50 per cent value is equivalent to the median time to return to the behaviour. † A hazard ratio greater than 1·00 shows that return to the behaviour took longer in the surgery arm. UGFS, ultrasound‐guided foam sclerotherapy.
BODY.RESULTS.ENDOVENOUS LASER ABLATION :
Participants randomized to EVLA recalled being able to carry out 13 of the 15 behaviours significantly more quickly than those randomized to surgery (Table
3). Return to 'having a bath or shower' was quicker after surgery than after EVLA. There was no difference in time to return to the participation behaviour of 'wearing clothes that show the legs'. Table 3 Behavioural recovery: endovenous laser ablation versus surgery Proportion carrying out behaviour (%) Time until specified proportion of participants could carry out behaviour (days) *
Hazard ratio †
EVLA Surgery Activity items Bending the legs without discomfort 50 2·7 4·6 1·49 (1·19, 1·75) 90 12·6 21·3 Lifting heavy objects without discomfort 50 5·9 9·8 1·79 (1·39, 2·27) 90 20·5 34·5 Moving from standing to sitting without discomfort 50 2·2 3·7 1·56 (1·27, 1·96) 90 10·4 17·5 Standing still for a long time (> 15 min) without discomfort 50 4·8 7·1 1·41 (1·11, 1·79) 90 20·0 28·7 Walking short distances (< 20 min) without discomfort 50 3·0 4·4 1·30 (1·04, 1·61) 90 13·2 19·1 Walking long distances (> 20 min) 50 5·6 8·0 1·53 (1·06, 1·67) 90 19·8 27·1 Having a bath or shower 50 5·5 4·9 0·74 (0·59, 0·93) 90 12·8 10·3 Driving a car 50 4·4 7·0 1·82 (1·43, 2·33) 90 12·7 21·1 Participation items Doing housework 50 2·5 4·5 1·89 (1·49, 2·38) 90 8·4 15·7 Looking after children 50 1·9 3·5 1·61 (1·15, 2·27) 90 8·8 17·9 Wearing clothes that show the legs 50 14·6 12·8 0·97 (0·69, 1·35) 90 75·1 58·7 Partial return to normal work/employment 50 6·3 9·9 1·75 (1·33, 2·27) 90 21·1 34·2 Full return to normal work/employment 50 7·7 11·7 1·79 (1·37, 2·27) 90 23·5 36·2 Going out socially 50 6·9 9·3 1·41 (1·12, 1·75) 90 23·9 34·0 Sporting activity or exercise 50 14·2 21·8 1·47 (1·12, 1·92) 90 55·5 86·7 Values in parentheses are 95 per cent c.i. * The 50 per cent value is equivalent to the median time to return to the behaviour. † A hazard ratio greater than 1·00 shows that return to the behaviour took longer in the surgery arm. EVLA, endovenous laser ablation. There were no differences in the time taken to return to 11 of the 15 behaviours between participants randomized to EVLA and those randomized to UGFS (Table
4). Return to 'walking short distances without discomfort', 'walking long distances', 'looking after children' and 'full return to normal work/employment' took longer for the EVLA group than the UGFS group. Following UGFS or EVLA only one‐third of the specific behaviours could be carried out by 50 per cent of participants by 3 days after treatment. Table 4 Behavioural recovery: endovenous laser ablation versus ultrasound‐guided foam sclerotherapy Proportion carrying out behaviour (%) Time until specified proportion of participants can carry out behaviour (days) *
Hazard ratio †
EVLA UGFS Activity items Bending the legs without discomfort 50 2·7 3·0 0·94 (0·75, 1·17) 90 12·6 14·1 Lifting heavy objects without discomfort 50 5·9 4·8 1·11 (0·87, 1·42) 90 20·5 16·9 Moving from standing to sitting without discomfort 50 2·2 1·9 1·12 (0·90, 1·40) 90 10·4 9·3 Standing still for a long time (> 15 min) without discomfort 50 4·8 3·9 1·14 (0·90, 1·44) 90 20·0 15·8 Walking short distances (< 20 min) without discomfort 50 3·0 1·9 1·48 (1·19, 1·84) 90 13·2 8·2 Walking long distances (> 20 min) 50 5·6 4·5 1·32 (1·05, 1·66) 90 19·8 15·2 Having a bath or shower 50 5·5 5·4 1·19 (0·96, 1·48) 90 12·8 11·4 Driving a car 50 4·4 4·1 0·95 (0·74, 1·21) 90 12·7 12·4 Participation items Doing housework 50 2·5 2·1 1·03 (0·82, 1·29) 90 8·4 7·3 Looking after children 50 1·9 1·2 1·45 (1·04, 2·02) 90 8·8 6·2 Wearing clothes that show the legs 50 14·6 12·4 1·17 (0·83, 1·64) 90 75·1 56·6 Partial return to normal work/employment 50 6·3 4·4 1·17 (0·89, 1·52) 90 21·1 15·4 Full return to normal work/employment 50 7·7 4·8 1·43 (1·11, 1·85) 90 23·5 14·9 Going out socially 50 6·9 7·1 0·88 (0·70, 1·10) 90 23·9 25·8 Sporting activity or exercise 50 14·2 15·7 0·80 (0·61, 1·04) 90 55·5 62·6 Values in parentheses are 95 per cent c.i. * The 50 per cent value is equivalent to the median time to return to the behaviour. † A hazard ratio greater than 1·00 shows that return to the behaviour took longer in the endovenous laser ablation (EVLA) arm. UGFS, ultrasound‐guided foam sclerotherapy.
BODY.DISCUSSION:
This study showed that both UGFS and EVLA resulted in a more rapid recovery compared with surgery for 13 of the 15 behaviours. UGFS was superior to EVLA in terms of return to full time work, looking after children and walking (both short and long distances). Importantly, the specific behaviours assessed were shown to have a range of different recovery trajectories. Previous randomized clinical trials showed behavioural recovery to be more rapid following UGFS compared with surgery1, 2, but the benefit of EVLA over surgery was less clear2, 4, 8 . In this study, for all but two behaviours (wearing clothes that showed the legs and showering/bathing) the recovery was quicker following UGFS or EVLA compared with surgery. These findings may have arisen as a result of information contained in the study PIL, which recommended that compression hosiery was worn continuously for 10 days following UGFS or EVLA but for 4–5 days routinely after surgery. In the comparison between UGFS and EVLA, behavioural recovery was faster following UGFS for four of the 15 behaviours; there was no difference between the groups for the other behaviours. Two previous randomized trials2, 3 showed earlier return to 'normal activities' in patients undergoing UGFS compared with EVLA. Specifically, the present study showed a quicker return to full‐time work following UGFS, similar to the findings of Rasmussen and colleagues2. The median time taken to return to work following EVLA (7·7 days) was within the ranges reported2, 4, 5, 6, 7, 8. However, Rasmussen and colleagues2 reported earlier return to work after UGFS compared with the present study (median 2·9 versus 4·8 days respectively). A partial explanation of the difference between the two studies may be that, unlike the previous study, the present analysis did not correct for weekends. For other behaviours, the recalled recovery times following both UGFS and EVLA were longer than might be expected from the literature2, 3, 4, 5, 8. This may be explained by the timing of the questionnaire at 6 weeks, and thus it is the nature of the differences between treatment groups rather than the absolute timings taken to return to these activities that the authors wish to highlight in this paper. The extent of this overall delay in recovery is hard to justify, particularly in light of the standard information and advice given in the study PIL. There may have been a number of external influences affecting participants' recollection of their recovery, including misinformation and fear. Although attitudes to recovery and return to normal behaviours have changed in secondary care, this may not have filtered into primary care or 'public knowledge'. Fear of activity or fear of pain caused by activity has been documented following surgery for other conditions17, 18. It is possible that some people undergoing treatment for varicose veins experience similar fears, and this may limit or restrict their activity following treatment. With regard to return to work, there are clearly a number of additional factors that might play a role, such as a person's employment status (employed or self‐employed), the sickness benefits they are entitled to, the type of work they are employed to do, how long they are 'signed off' by the doctor, and the views of their employer on return to work after an operation. It should be noted that this study distinguished between partial and full return to work, and that no difference was noted in partial return to work following UGFS and EVLA. This finding may be of substantial importance to patients, their employers and the economy as a whole. The main strength of this study is that the behaviours investigated were based on systematic investigation of the recovery milestones that are important to patients following treatment for varicose veins. Hence, the findings are of personal importance from a patient perspective. Distinguishing between the behaviours that contribute to 'normal activity' helps build a profile of recovery that may be particularly useful for patients preparing for, or recovering from, treatment. Furthermore, the methodology used to develop the BRAVVO questionnaire could be used in other conditions to provide normative information about behavioural recovery that is relevant to patients. The BRAVVO questionnaire was pilot tested and found to be acceptable to patients, comprehensible and appropriate for self‐completion. Despite this, a potential weakness of the study is that the level of missing data in the BRAVVO questionnaire was higher for two of the questions. Further work to reformat or rephrase the questions or response options may help minimize levels of missing data. A further potential weakness is the choice of assessment time point (6 weeks after treatment). This may have compromised recall, particularly for behaviours that participants were able to return to a short time after treatment; however, any compromise in recall is likely to have affected the three treatment groups equally. Other study outcomes were assessed at 6 weeks, and behavioural recovery was assessed at the same time point to minimize participant burden. Further work is required to determine the optimal timing(s) of this questionnaire. Given that the median time to return to the behaviour was less than 14 days for 13 of the behaviours, and up to 22 days for the other two (wearing clothes that show the legs, sporting activity or exercise), the use of the questionnaire at approximately 2–3 weeks would seem appropriate. | 4,819,709 | {
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17579
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1,
1,
1
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"In Abstract": [
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true,
true
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-1,
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-1,
13146
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"<td align=\"left\" colspan=\"1\" rowspan=\"2\" style=\"padding-left:10%\" valign=\"top\">Lifting heavy objects without discomfort</td><td align=\"center\" colspan=\"1\" rowspan=\"1\" valign=\"top\">50</td><td align=\"center\" colspan=\"1\" rowspan=\"1\" valign=\"top\">4·8</td><td align=\"center\" colspan=\"1\" rowspan=\"1\" valign=\"top\">9·8</td><td align=\"center\" colspan=\"1\" rowspan=\"2\" valign=\"top\">1·97 (1·59, 2·44)</td>",
"Table 2\n\n\n\n\n\n\n\n\nBehavioural recovery: ultrasound�?guided foam sclerotherapy versus surgery",
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12797
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13146
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"Participants randomized to UGFS recalled being able to carry out 13 of the 15 behaviours significantly more quickly than those randomized to surgery (Table \n\n\n\n2\n\n\n\n)",
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1
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1
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true
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4819709
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1
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4819709
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1
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true
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4819709
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1,
1
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true,
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12797
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13146
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} |
TITLE: Physiological-dose steroid therapy in sepsis [ISRCTN36253388]
ABSTRACT.INTRODUCTION:
The aim of the study was to assess the prognostic importance of basal cortisol concentrations and cortisol response to corticotropin, and to determine the effects of physiological dose steroid therapy on mortality in patients with sepsis.
ABSTRACT.METHODS:
Basal cortisol level and corticotropin stimulation test were performed within 24 hours in all patients. One group (20 patients) received standard therapy for sepsis and physiological-dose steroid therapy for 10 days; the other group (20 patients) received only standard therapy for sepsis. Basal cortisol level was measured on the 14th day in patients who recovered. The outcome of sepsis was compared.
ABSTRACT.RESULTS:
Only Sequential Organ Failure Assessment (SOFA) score was found related to mortality, independent from other factors in multivariate analysis. No significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group and the standard therapy group in survivors, nor between the groups in basal and peak cortisol levels, cortisol response to corticotropin test and mortality. The mortality rates among patients with occult adrenal insufficiencies were 40% in the steroid therapy group and 55.6% in the standard therapy group.
ABSTRACT.DISCUSSION:
There was a trend towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy. In the advancing process from sepsis to septic shock, adrenal insufficiency was not frequent as supposed. There was a trend (that did not reach significance) towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy.
BODY.INTRODUCTION:
This paper was presented at the 10th European Congress of Clinical Microbiology and Infectious Diseases (28–31 May 2000, Stockholm, Sweden). Sepsis can be defined as a systemic response to infection [1]. The incidence of sepsis worldwide is on the increase. Sepsis and its sequels are the leading causes of death in intensive care units. Mortality rates are higher for patients with pre-existing disease, medical conditions, care in the intensive care unit, and multiple organ failure [2,3]. Despite steady improvements in antibiotic therapy and intensive care management during the past decade, mortality has remained close to 50%. This high mortality rate has continued to stimulate interest in pharmacological agents that might reduce morbidity and mortality [4,5,6,7]. Steroid therapy in patients with sepsis is still controversial. In the 1960s, stress doses of hydrocortisone for the treatment of sepsis were investigated, but no advantages could be shown in a double-blind multicenter study [8]. This led to the discontinuation of steroid replacement therapy for sepsis. In the 1970s, therapy with pharmacological doses of glucocorticoids was widely used in patients with sepsis and septic shock. The most compelling evidence in favor of corticosteroid treatment was reported by Schumer [9] in his prospective randomized study of steroid administration to patients with septic shock. These data indicate that methylprednisolone (30 mg/kg) or dexamethasone (3 mg/kg) reduced the mortality rate from 38.4% to 10.5%. However, later in the mid-1980s, pharmacological doses of glucocorticoids for the treatment of sepsis were investigated extensively until several clinical trials gave negative results [10,11,12]. Moreover, there is some evidence that the use of high-dose glucocorticoids in sepsis might be harmful [11]. Many studies have demonstrated that elevated cortisol levels in sepsis and the degree of elevation are related to the severity of illness [13]. Basal and corticotropin (ACTH)-stimulated cortisol levels correlate with the severity of illness, and very high cortisol levels often signify a poor prognosis [14]. In sepsis, the hypothalamic–pituitary–adrenal axis is activated through systemic and neural pathways. Circulating cytokines such as tumor necrosis factor α, interleukin-1 and interleukin-6 activate the hypothalamic–pituitary–adrenal axis independently and, when combined, have synergistic effects [15]. Sepsis can also cause adrenal insufficiency (AI), which is associated with increased mortality [16]. In recent years, several authors have proposed a syndrome of occult AI in septic shock in the presence of normal or even elevated serum cortisol concentrations. This hypothesis is based on many studies investigating the adrenocortical response of patients with septic shock to 0.25 mg of ACTH. Up to 28% of seriously ill patients have been suggested to have occult or unrecognized AI [14]. The prevalence of occult AI (a cortisol increment after a short ACTH test of less than 9 mg/dl) in severe sepsis was estimated at about 50% and the 28-day mortality rate at about 75% [17]. A few studies have indicated that stress doses of hydrocortisone improve hemody-namics in patients with hyperdynamic septic shock, which is unresponsive to conventional therapy [18,19]. However, the use of a physiological dose of steroid in patients with sepsis, severe sepsis, and septic shock has not yet been completely evaluated. We therefore performed a placebo-controlled, randomized, double-blind, single-center study. The aim of this study was to assess basal cortisol concentrations and the cortisol response to ACTH stimulation as well as their prognostic importance, and also to determine the effects of the physiological-dose steroid therapy on mortality in patients with sepsis.
BODY.METHODS.STUDY DESIGN:
The study protocol was approved by the Institutional Review Board of Erciyes University and informed consent was obtained from the patients' relatives. This placebo-controlled, randomized, double-blind, single-center study was performed at the Department of Medical Intensive Care Unit and the Department of Infectious Diseases of Erciyes University Medical School during a 2-year period (from May 1997 to April 1999).
BODY.METHODS.PATIENT SELECTION:
Patients over 17 years old and diagnosed with sepsis were included consecutively in the study. The diagnosis of sepsis was based on the definition of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Report [1]. The severity of illness was classified according to this definition (Table 1). Table 1 Consensus conference group definitions of the stages of sepsis [ 1 ] I. Systemic inflammatory response syndrome (SIRS) Two or more of the following: Temperature of more than 38°C or less than 36°C Heart rate of more than 90/min Respiratory rate of more than 20/min White blood cell count of more than 12,000/mm 3 or less than 4000/mm 3 or more than 10% immature forms (bands) II. Sepsis Systemic inflammatory response syndrome plus a culture-documented infection III. Severe sepsis Sepsis plus organ dysfunction, hypotension, or hypoperfusion (including but not limited to lactic acidosis, oliguria, or acute alteration in mental status) IV. Septic shock Hypotension (despite fluid resuscitation) plus hypoperfusion abnormalities Criteria for exclusion from the study were as follows: already known pre-existing adrenal disease or adrenalectomy, known malignancies, tuberculosis that might have involved the adrenal gland, and administration of steroids within the 3 months before the admission. In addition, patients with burns, hemorrhagic shock or those who had suffered myocar-dial infarction were not included.
BODY.METHODS.TREATMENT PROTOCOL:
Patients enrolled in the study were treated with standard therapy used in the treatment of sepsis and septic shock. This therapy could include the following: administration of antibiotics, fluid replacement, vasoactive drugs, mechanical ventila-tory support, and any other form of supportive therapy deemed necessary by the primary physicians. Soon after the presumptive diagnosis of severe sepsis, initial laboratory specimens were obtained and within 2 hours the patients were randomized to treatment with prednisolone or placebo groups. The treatment groups were determined by a computer-generated randomization procedure. The steroid therapy group received prednisolone at a physiological dose. Prednisolone was given intravenously at 06.00 (5 mg) and 18.00 (2.5 mg) for 10 days. The standard therapy group received a placebo infusion containing physiological saline solution in an identical manner. Patients and their primary physicians were blinded as to which therapy was administered.
BODY.METHODS.DATA COLLECTION:
An ACTH stimulation test was performed with 250 g of tetracosactrin (synacthene; Ciba Geigy, Germany) given intravenously. Blood samples were taken immediately before the test and at 30 and 60 minutes afterwards. After centrifugation, plasma samples were stored at -20°C until assayed. ACTH stimulation test was repeated on the 14th day in the patients who survived. Plasma cortisol concentrations were determined by radioimmunoassay with a commercially available kit (ICN Biomedicals, Inc, Costa Mesa, California, USA). Intra-assay coefficients of variation were for control A 7.0%, control B 5.8%, and control C 5.1%. Inter-assay coefficients of variation were for control A 7.9%, control B 6.5%, control C 6.0%. The cortisol response was defined as the difference between the basal and peak cortisol concentrations. Normal adrenal function was defined as a plasma cortisol level (before or at 30 or 60 minutes after the injection of ACTH) above 20 μg/dl. The cases with peak cortisol levels lower than 20 μg/dl were considered to be AI [13,20,21,22]. Occult AI was defined as an increase in cortisol after a ACTH test of less than 9 g/dl (a cortisol response of no more than 9 μg/dl) [17,23,24]. Community-acquired sepsis had its onset within 72 hours of the patients' admission to the hospital, whereas hospital-acquired sepsis began 72 hours or later after admission. The estimated prognosis of any pre-existing underlying diseases had been classified according to the classification of McCabe and Jackson [25]. Observed initial findings that related to disseminated intravas-cular coagulation, respiratory insufficiency, altered mental status, and renal, cardiac, and liver failure were noted [26,27]. The severity of the illness was assessed with the Acute Physiology and Chronic Health Evaluation II (APACHEII) scoring system [28]. The Sequential Organ Failure Assessment (SOFA) score [29] was added to the study protocol by amendment and retrospectively from the raw data. Infections were diagnosed according to clinical and microbiological criteria. Blood samples for cultures were obtained by the same investigator (O Yildiz) and inoculated into a standard culture medium (BACTEC 9240). Patients were evaluated at enrollment and at the 24th hour, and on the 3rd, 7th, 10th, 14th, 21st, and 28th days, and followed for 1 month after discharge from hospital. Body temperature, respiratory rate, heart rate, blood pressure, the use of vasopressor drugs, urine output, complete blood counts, urinalysis with microscopic examination, erythrocytes sedimentation rate, blood chemistry, prothrombin time, partial thromboplastin time, fibrinogen, fibrin debranch-ing product, blood gases, electrocardiogram, and chest roentgenogram were recorded for each patient individually.
BODY.METHODS.STUDY ENDPOINTS:
The primary endpoint of the study was 28-day mortality from all causes. The secondary endpoint consisted of adverse occurrences including possible complications of drug therapy and morbid events such as the progression of initial infection and the development of secondary infection. Secondary infection was defined as the identification of a new site of infection or the emergence of a different organism at the same site, generally requiring a change in antibiotic management. All medications given to the patients, any complications, the duration of hospitalization, the mortality rate, and the causes of death were recorded and compared between the groups. We also compared average values of basal cortisol, peak cortisol and cortisol responses to ACTH between survivors and non-survivors on the first day. Moreover, basal cortisol levels on the 1st and 14th days were compared in patients who recovered in each group.
BODY.METHODS.STATISTICAL ANALYSIS:
Student's t-test and the Mann-Whitney U multivariate analysis test were used for continuous variables, χ2 and Fisher's χ2 tests were used for proportions, and logistic regression was used for effects of factors on mortality. Values are expressed as means ± SD, odds ratio (OR) and 95% confidence interval (CI) or proportion.
BODY.RESULTS.DESCRIPTION OF STUDY POPULATION:
Forty patients with sepsis, severe sepsis and septic shock were included in this study. The mean age of patients was 56.5 ± 16.4 years in the standard therapy group and 57.8 ± 17.7 years in the steroid therapy group. There was no significant difference in demographic characteristics, the severity of underlying diseases, the APACHE II and SOFA scores, the median time to hospital and median time to death, the acquisition of infection, and the sepsis categories between the groups (Table 2). Table 2 Characteristics of patients Variable Steroid therapy group Standard therapy group Total χ 2 P All patients 20 (50%) 20 (50%) 40 0.417 0.748 Female 7 (43.8%) 9 (56.3%) 16 Male 13 (54.2%) 11 (45.8%) 24 Mean age (years) (mean ± SD) 57.8 ± 17.7 56.5 ± 16.4 57.1 ± 16.9 0.818 Underlying diseases 11 (40.7%) 16 (59.3%) 27 2.849 0.176 Rapidly fatal - - - Ultimately fatal 2 (50%) 2 (50%) 4 Nonfatal 9 (39.1%) 14 (60.9%) 23 No underlying diseases 9 (69.2%) 4 (30.8%) 13 APACHE II (mean ± SD) 15.4 ± 5.5 17.9 ± 8.0 16.6 ± 6.9 0.249 Maximum SOFA (mean ± SD) 7.8 ± 3.9 9.3 ± 4.0 8.5 ± 4.0 0.257 Acquisition of infection 0.143 1.000 Community 16 (51.6%) 15 (48.4%) 31 Hospital 4 (44.4%) 5 (55.6%) 9 Sepsis categories 0.456 0.531 Sepsis 8 (57.1%) 6 (42.9%) 14 Severe sepsis 8 (47.1%) 9 (52.9%) 17 Septic shock 4 (44.4%) 5 (55.6%) 9 Positive cultures 2.345 >0.05 Gram-negative infection 4 (36.4%) 7 (63.6%) 11 Gram-positive infection 10 (66.7%) 5 (33.3%) 15 Candida infection 1 (33.3%) 2 (66.7%) 3 Polymicrobial infection 3 (60.0%) 2 (40.0%) 5 Negative cultures 6 (46.2%) 7 (53.8%) 13 Organ failure 16 (47.1%) 18 (52.9%) 34 DIC 5 (45.5%) 6 (54.5%) 11 Laboratory measurements (mean ± SD) Leukocytes (/mm 3 ) 16,057 ± 12,568 14,781 ± 7,317 0.697 Platelets (/mm 3 ) 183,050 ± 137,983 192,800 ± 127,157 0.324 ESR (mm/h) 69 ± 36 49 ± 33 0.081 CRP (mg/l) 67 ± 16 67 ± 24 0.981 Fibrinogen (mg/dl) 814 ± 394 434 ± 198 0.002 Median stay in hospital (days) 14 (95% CI 11.09–20.08) 13 (95% CI 10.13–16.37) 0.406 Median time to death (days) 5 (95% CI, 2.55–8.20) 5.5 (95% CI, 2.19–13) 0.496 Non-survivors 8 (40%) 12 (60%) 20 1.600 * 0.343 Survivors 12 (60%) 8 (40%) 20 * Fisher's χ 2 test. CI, confidence interval; DIC, disseminated intravascular coagulation; ESR, erythrocytes sedimentation rate.
BODY.RESULTS.THE 28-DAY MORTALITY:
There were eight deaths (40%) in the steroid therapy group and 12 (60%) deaths in the standard therapy group (P = 0.343). The mortality rate in the patients with hospital-acquired sepsis was higher than that in the patients with community-acquired sepsis in both groups, but this difference was not statistically significant. The relationship between mortality and age, the presence of an underlying disease, vasopressor and steroid therapy, and APACHE II and SOFA scores was assessed. Age, the presence of an underlying disease, steroid therapy, basal plasma cortisol levels, and cortisol response to ACTH below 9 g/dl were not associated with mortality. Although a univariate analysis found vasopressor therapy (OR 4.64, 95% CI 1.02–21.00), APACHE II (OR 1.18, 95% CI 1.04–1.34) and maximum SOFA (OR 1.63, 95% CI 1.23–2.16) to be effective on mortality, only the SOFA score was found related to mortality, independently of other factors (OR 2.09, 95% CI 1.01–4.30) in a multivariate analysis (Fig. 1 and Table 3). Figure 1Comparison of mortality rates for (a) basal cortisol (μg/dl), (b) cortisol response to ACTH (μg/dl), (c) APACHE II and (d) maximum SOFA scores in both groups. Table 3 Average values (means ± SD) of basal cortisol, peak cortisol, cortisol responses to corticotropin, APACHE II and maximum SOFA scores according to survivors and non-survivors in both groups on the first day Steroid therapy group Standard therapy group Variable Non-survivors ( n = 8) Survivors ( n = 12) P Non-survivors ( n = 12) Survivors ( n = 8) P Basal cortisol level (μg/dl) 44.4 ± 24.8 52.5 ± 30.5 0.536 60.5 ± 34.7 40.3 ± 19.9 0.154 Peak cortisol level (μg/dl) 73.1 ± 35.1 79.2 ± 33.5 0.699 80.7 ± 45.9 60.1 ± 25.7 0.265 Cortisol response (μg/dl) 28.7 ± 22.1 21.2 ± 32.7 0.579 16.3 ± 24.6 18.2 ± 16.3 0.835 APACHE II score 17.6 ± 4.5 13.8 ± 5.8 0.130 21 ± 7.9 13.3 ± 6 0.024 Maximum SOFA score 10.6 ± 3.2 5.9 ± 3.3 0.009 11.4 ± 2.9 6 ± 3.3 0.003 APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment.
BODY.RESULTS.VARIATIONS OF TREATMENT EFFECTS ON THE 28-DAY MORTALITY AMONG SUBGROUPS:
The mortality rates among patients with a cortisol level over 60 μg/dl were 29% (2 of 7) in the steroid therapy group and 78% (7 of 9) in the standard therapy group (χ2 = 3.874, P = 0.126). Although there was an increase in the level of basal cortisol in patients with sepsis, 14 of 40 patients (35%) had occult AI. The mortality rates in patients with occult AI were 40% (2 of 5) in the steroid therapy group and 55.6% (5 of 9) in the standard therapy group, respectively (χ2 = 0.311, P = 1). Only one patient had both basal and peak cortisol levels lower than 20 g/dl; this patient was in the standard therapy group and died on the 7th day of treatment. This case was accepted as adrenal failure. A comparison of mortality rates for basal cortisol and cortisol responses to ACTH in both groups is shown in Figure 1. The median time to death was 5 days (95% CI 2.55–8.20) in the steroid therapy group and 5.5 days (95% CI 2.19–13) in the standard therapy group (P = 0.496). The reason for death in all patients was attributed to sepsis. The median stay in hospital was 14 days (95% CI 11.09–20.08) in the steroid therapy group and 13 days (95% CI 10.13–16.37) in the standard therapy group (P = 0.406).
BODY.RESULTS.SEPSIS-RELATED ORGAN DYSFUNCTION:
Organ dysfunction and failure rates of the patients on admission were 40% and 45% in the steroid therapy and the standard therapy groups, respectively (Table 4). No statistically significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group (43.1 ± 26.5%) and the standard therapy group (45.4 ± 12.7%) in survivors (P = 0.624). Table 4 Organ failure in groups at baseline Condition Steroid therapy group Standard therapy group Total Renal failure 6 (50%) 6 (50%) 12 Liver failure 9 (52.9%) 8 (47.1%) 17 Altered mental status 10 (38.5%) 16 (61.5%) 26 DIC 5 (45.5%) 6 (54.5%) 11 Cardiac failure 0 (0%) 2 (100%) 2 Respiratory failure 2 (28.6%) 5 (71.4%) 7 DIC, disseminated intravascular coagulation.
BODY.RESULTS.CORTISOL LEVELS AND CORTISOL RESPONSES TO ACTH:
Basal and peak cortisol levels and cortisol responses to ACTH in the steroid therapy group were not significantly different from those in the standard therapy group (Table 5). The average values of basal cortisol, peak cortisol and cortisol responses to ACTH in survivors and non-survivors in both groups for the first day are shown in Table 3. There was no significant difference between the values for survivors and non-survivors. The mean basal cortisol level was 47.6 ± 26.9 g/dl on the first day in all survivors and 17.2 ± 8.6 g/dl on the 14th day in patients who recovered (P = 0.0003). In the steroid therapy group, the mean basal cortisol level was 52.5 ± 30.5 g/dl on the first day and 17.6 ± 10.3 g/dl on the 14th day (P = 0.003). In the standard therapy group, the mean basal cortisol level was 40.3 ± 19.9 g/dl on the first day and 16.4 ± 4.6 g/dl on the 14th day (P = 0.028) (Table 6). Table 5 Average values (means ± SD) of basal cortisol, peak cortisol and cortisol responses of all patients on the first day Variable Steroid therapy group ( n = 20) Standard therapy group ( n = 20) P Basal cortisol level (μg/dl) 49.3 ± 28 52.4 ± 30.8 0.737 Peak cortisol level (μg/dl) 76.8 ± 33. 3 72.5 ± 39.6 0.712 Cortisol response (μg/dl) 24.2 ± 28.5 17.1 ± 21.2 0.376 Table 6 Comparison of basal cortisol levels (μg/dl; means ± SD) on the 1st and 14th days in recovering patients Steroid therapy group Standard therapy group Total 1st day 14th day P 1st day 14th day P 1st day 14th day P Cortisol 52.5 ± 30.5 17.6 ± 10.3 0.003 40.3 ± 19.9 16.4 ± 4.6 0.028 47.6 ± 26.9 17.2 ± 8.6 0.0003
BODY.RESULTS.ADVERSE EVENTS:
There were no adverse effects due to steroid therapy. Only one patient, in the standard therapy group, had a secondary infection.
BODY.DISCUSSION:
Sepsis is a severe and life-threatening disease. Septic shock is associated with a mortality rate of more than 50%. Despite improvements in the overall management of such patients, including intensive fluid resuscitation, broad-spectrum antibiotic therapy, and life-support devices, mortality rates have not improved during the past decade [4]. In this randomized, double-blind study of the physiological dose of intravenous prednisolone or placebo in the treatment of sepsis, we observed an important difference in mortality rates between both groups. The mortality rates were 40% in the steroid therapy group and 60% in the standard treatment group. There was a trend towards a decrease in the mortality rate of the patients with sepsis who received physiological-dose steroid therapy. However, the differences were not statisti-μ cally significant (P = 0.343). Several factors were suspected to be associated with mortality in sepsis [30,31]. Annane et al. [17] reported that SOFA score, high plasma cortisol levels and weak response of cortisol to ACTH were also associated with mortality. However, we found that only SOFA score was related to mortality, independently of other factors (OR 2.07, 95% CI 1.02–4.22) in the multivariate analysis. Briegel et al. [19] showed that stress doses of hydrocorti-sone reduce the time for the reversal of shock, the number of organ system failures, and the length of mechanical ventilation in patients with septic shock. This finding underlines the fact that an impaired adrenocortical function contributes to vascular hyporesponsiveness in septic shock. In contrast to other studies, our study was performed in patients with sepsis, severe sepsis and septic shock with the use of physiological-dose prednisolone with or without vasopressor support. Because the administration of prednisolone does not affect the circadian adrenocortical patterns and the results of an ACTH stimulation test in adults, we preferred to use this drug [32]. In this study we did not completely evaluate the effect of the steroid on patients with vasopressor-dependent septic shock. However, in a few patients, a physiological dose of prednisolone reduces the time for the reversal of shock as defined by the cessation of vasopressor therapy. It is known that the plasma cortisol level increases in critical illnesses and that basal cortisol levels have a positive correlation with severity of illness and prognosis. However, some investigators [16,23,33,34,35] showed that patients with sepsis and high baseline cortisol levels had a lower cortisol response to the ACTH stimulation test. Our entire study group had higher mean random basal and stimulated cortisol levels than those seen in outpatients. The difference between the basal cortisol levels on the 1st and 14th days in patients who recovered was statistically significant (P < 0.0001) (Table 5). We have also shown that basal cortisol levels correlate with the severity of the illness, and that very high corti-sol levels signify a poor prognosis in the standard therapy group (Fig. 1). Clinically significant AI is unusual in outpatients. The studies of adrenal function in critically ill patients report conflicting incidences of AI ranging from 0% to 28% [35,36,37]. Our results show a low incidence of AI in septic patients. One of our 40 patients had abnormal basal and peak cortisol levels (less than 20 g/dl) and died. This condition was evaluated as AI. In the advancing process from sepsis to septic shock, we concluded that AI was not so frequent as supposed. In recent years, several authors have proposed a syndrome of occult AI in septic shock in the presence of normal or even elevated serum cortisol concentrations. Annane et al. [17] reported that 50% of patients with severe sepsis had occult AI. In the present study, 14 (35%) of the 40 patients had a subnormal cortisol response (occult AI). Five patients in the steroid treatment group had an inadequate cortisol response; two of them died. However, five of nine patients in the standard treatment group who showed inadequate cortisol response died. No statistical differences were observed in mortality rates between the patients who had occult AI (χ2 = 0.311, P = 1) (Fig. 1). In conclusion, a physiological dose of intravenous pred-nisolone had a tendency towards a decrease in mortality in the patients with sepsis, but the difference between the two groups was not significant. Because our study had a small sample size and showed heterogeneity in population in terms of clinical severity, treatment with physiological-dose steroid in sepsis should be evaluated in a larger group of patients.
BODY.KEY MESSAGES:
· There was an increase in the level of basal cortisol in patients with sepsis. · In the advancing process from sepsis to septic shock, adrenal insufficiency was not so frequent as supposed. · Sepsis can cause occult adrenal insufficiency in the presence of normal or even elevated serum cortisol concentrations. · Physiological-dose prednisolone therapy had a tendency towards a decrease in mortality in the patients with sepsis.
BODY.COMPETING INTERESTS:
None declared.
BODY.ABBREVIATIONS:
AI = adrenal insufficiency; APACHE = Acute Physiology and Chronic Health Evaluation; ACTH = corticotropin; CI = confidence interval; OR = odds ratio; SOFA = Sequential Organ Failure Assessment. | 125,315 | {
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TITLE: Lay support for pregnant women with social risk: a randomised controlled trial
ABSTRACT.OBJECTIVES:
We sought evidence of effectiveness of lay support to improve maternal and child outcomes in disadvantaged families.
ABSTRACT.DESIGN:
Prospective, pragmatic, individually randomised controlled trial.
ABSTRACT.SETTING:
3 Maternity Trusts in West Midlands, UK.
ABSTRACT.PARTICIPANTS:
Following routine midwife systematic assessment of social risk factors, 1324 nulliparous women were assigned, using telephone randomisation, to standard maternity care, or addition of referral to a Pregnancy Outreach Worker (POW) service. Those under 16 years and teenagers recruited to the Family Nurse Partnership trial were excluded.
ABSTRACT.INTERVENTIONS:
POWs were trained to provide individual support and case management for the women including home visiting from randomisation to 6 weeks after birth. Standard maternity care (control) included provision for referring women with social risk factors to specialist midwifery services, available to both arms.
ABSTRACT.MAIN OUTCOME MEASURES:
Primary outcomes were antenatal visits attended and Edinburgh Postnatal Depression Scale (EPDS) 8–12 weeks postpartum. Prespecified, powered, subgroup comparison was among women with 2 or more social risks. Secondary outcomes included maternal and neonatal birth outcomes; maternal self-efficacy, and mother-to-infant bonding at 8–12 weeks; child development assessment at 6 weeks, breastfeeding at 6 weeks, and immunisation uptake at 4 months, all collected from routine child health systems.
ABSTRACT.RESULTS:
Antenatal attendances were high in the standard care control and did not increase further with addition of the POW intervention (10.1 vs 10.1 (mean difference; MD) −0.00, 95% CI (95% CI −0.37 to 0.37)). In the powered subgroup of women with 2 or more social risk factors, mean EPDS (MD −0.79 (95% CI −1.56 to −0.02) was significantly better, although for all women recruited, no significant differences were seen (MD −0.59 (95% CI −1.24 to 0.06). Mother-to-infant bonding was significantly better in the intervention group for all women (MD −0.30 (95% CI −0.61 to −0.00) p=0.05), and there were no differences in other secondary outcomes.
ABSTRACT.CONCLUSIONS:
This trial demonstrates differences in depressive symptomatology with addition of the POW service in the powered subgroup of women with 2 or more social risk factors. Addition to existing evidence indicates benefit from lay interventions in preventing postnatal depression. This finding is important for women and their families given the known effect of maternal depression on longer term childhood outcomes.
ABSTRACT.TRIAL REGISTRATION NUMBER:
ISRCTN35027323; Results.
BODY:
Strengths and limitations of this studyLarge, robust, individual, randomised controlled trial to evaluate a real National Health Service service demonstrating differences in aspects of maternal psychological health from the addition of lay workers.Achieved excellent follow-up of both primary outcomes in intervention and control arms which is unusual in studies of women with social disadvantage.Baseline Edinburgh Postnatal Depression Scale scores not feasible in real service pragmatic trial, so change in score not obtained, but routine baseline data on current or previous mental health problem was the same across trial arms.Set within the UK maternity care system where standard care includes specialist midwife referral for women with some social risks, so effect of intervention may be greater in maternity systems without this.
BODY.BACKGROUND:
Postnatal depression is a major public health issue, with lasting effects on the child,1–3 and meta-analyses have reported prevalences of 13% and 19%.4–6 Women with antenatal depression, or with a previous history, are at higher risk,7 but most pregnant women who go on to have postnatal depression do not have these risk factors. It is known that postnatal depression is associated with social isolation and inadequate support.8 Many of the factors considered to be indicators of increased risk of adverse perinatal morbidity and mortality are also surrogates for social isolation, including teenage pregnancy,9 minority ethnic group,10
11 experience of domestic violence,12 asylum seekers and refugees,13 and homelessness.14 A Cochrane review15 showed that taken as a group, psychosocial and psychological interventions were more effective in preventing postnatal depression than usual care, but there is little evidence regarding lay support except among women screened positive for possible depression. A recent synthesis of barriers to engagement with maternity services in women with social disadvantage16 suggested that lay workers providing non-judgemental support, working in conjunction with antenatal services, would be well received by women, however, evidence on effectiveness is lacking. The need to provide additional lay support (in this instance Pregnancy Outreach Workers, POWs) to women with identified social risk factors had been recognised in the West Midlands, and a service developed. The hypothesis was that this might improve engagement with maternity services (and thereby improve maternal and neonatal birth outcomes), and reduce postnatal depression, and we undertook a pragmatic randomised controlled trial to evaluate this.
BODY.METHODS.DESIGN:
The study was a pragmatic, individually randomised, controlled trial across a UK geographical area containing three maternity units, where social risk factors are systematically identified at routine midwife antenatal booking. Nulliparous women under 28 weeks gestation, with social risk factors, were eligible. Exclusions were women under 16 years of age and teenagers already recruited to the Family Nurse Partnership Trial. Multiparous women were not included since some social support was already available for this group which could have masked a trial effect. Potentially eligible women (ie, nulliparous women with one or more social risk factor) were identified at midwife antenatal booking and given information about the trial. Following agreement, they were referred to specifically trained midwives who obtained informed consent, and randomised women. Randomisation to standard maternity care, or addition of the POW service was by telephone using a registered trials unit. Randomisation lists were computer generated (by trial statistician) using random block sizes (4–12) and stratified for Maternity Trust. POWs were trained to provide individual case management for the women including home visits, and were integrated into the community midwifery teams. Objectives were to encourage women to attend antenatal appointments, make healthy lifestyle choices, to provide social/emotional support, and help ensure benefits, housing difficulties and mental health problems were managed. In the postnatal period (to 6 weeks postpartum), POWs also provided breast feeding and advice about infant care. The POW service was developed before the trial began, but not available outside the trial, and was provided by an independent organisation, who had access to supervision from experts with specific skills and knowledge. Standard UK maternity care (control) included provision for referring women with social risk factors to specialist midwives or directing them to other agencies but did not include the offer of the POW service.
BODY.METHODS.OUTCOME MEASURES, DATA COLLECTION AND FOLLOW-UP:
The two primary outcomes were engagement with antenatal care and maternal postnatal depression 8–12 weeks after birth. Antenatal attendance was assessed by number of antenatal visits attended, including all visits with a healthcare professional (midwife, obstetrician, mental health specialist) in hospital or community except for routine dating and abnormality scans. Maternal depression was assessed using the Edinburgh Postnatal Depression Scale17 (EPDS) at 8–12 weeks postpartum by postal/telephone questionnaire. We chose EPDS as it is the most commonly used validated instrument to assess postpartum symptoms. The original Cox publication17 quotes a cut-off score as ≥13, so we present data for that.
BODY.METHODS.SECONDARY OUTCOMES:
Maternal and neonatal birth outcomes included routinely collected birth outcome data detailed in online supplementary material. Data to evaluate other maternal psychological outcomes (self-efficacy and bonding) were collected using validated tools 8–12 weeks postpartum (Pearlin and Schooler Mastery Scale18 and Mother-to-infant Bonding Scale19). Longer term infant outcomes: attendance at child development assessments and breastfeeding at 6 weeks and immunisation uptake at 4 months were collected from routine child health systems (detailed in see online supplementary information). 10.1136/bmjopen-2015-009203.supp1Supplementary data
BODY.METHODS.DATA COLLECTION:
Collection of demographic data, gestation, ethnicity, medical history at booking and systematically assessed social risk factors (table 1) were part of midwife routine antenatal booking information and available for trial use. Blinding of women and caregivers was not possible, but those who collected/entered data remained blind to allocation. Table 1 Baseline characteristics and description of social risk factors identified at randomisation Baseline characteristics POW n=662 Standard care n=662 Maternal age (years) median, IQR 21.8 (19.0, 25.5) 21.5 (18.8, 24.6) Gestation at recruitment Median, IQR 12.9 (9.9, 17.3) 12.7 (9.9, 18.0) Under 12 weeks 288 (43) 283 (43) 12–19+6 weeks 266 (40) 252 (38) ≥20 weeks 108 (16) 127 (19) Ethnicity Africa (North Africa, sub-Sahara, other) 41 (6) 46 (8) Asia Pakistan 100 (15) 107 (16) India 26 (4) 27 (4) Bangladesh 24 (4) 19 (3) Other 22 (3) 16 (2) Caribbean 24 (4) 45 (7) European Britain 320 (48) 315 (48) Eastern Europe 23 (4) 20 (3) Other 6 (1) 6 (1) Middle East 23 (4) 19 (3) Other 53 (8) 42 (6) Index of multiple deprivation from postcode at recruitment Quintile 1 494 (75) 488 (74) Quintile 2 99 (15) 110 (17) Quintile 3 51 (8) 49 (7) Quintile 4 15 (2) 13 (2) Quintile 5 3 (<1) 2 (<1) Medical history noted at booking 320 (48) 301 (45) Social risk factor Housing problems such as rent arrears, temporary accommodation registered with National Asylum Support Service (NASS) or of No Fixed Abode (NFA) 282 (43) 262 (40) Teen parent (under 20 years old) 230 (35) 249 (38) Smoking 192 (29) 183 (28) Difficulty with the English language both spoken and written 176 (27) 169 (26) Identified benefit problem 154 (23) 160 (24) UK resident for under a year 116 (18) 93 (14) Clinical diagnosis of past or present mental illness 100 (15) 96 (15) No support from either partner or family or friend 63 (10) 80 (12) Body mass index ≥35 34 (5) 33 (5) Body mass index ≤18 32 (5) 26 (4) Late booking (defined as booking after 18 weeks gestation) 28 (4) 31 (5) Woman/household member in receipt of social services support, including child protection 24 (4) 34 (5) Drug misuse including other's in the household 19 (3) 17 (3) Domestic abuse 13 (2) 19 (3) Alcohol misuse 6 (1) 7 (1) DNA 2 or more antenatal appointments (under 28 weeks gestation) 5 (1) 8 (1) Number of social risk factors identified 1 social risk factor 174 (26) 194 (29) 2 social risk factors 269 (41) 247 (37) 3 social risk factors 141 (21) 145 (22) 4 or more social risk factors 78 (12) 76 (11) Values are numbers (percentages) unless otherwise stated. POW, Pregnancy Outreach Worker. Maternal and neonatal birth outcome data were obtained from hospital systems. Number of antenatal contacts was not recorded electronically, so was collected by hand-abstraction from notes. Maternal psychological outcomes were obtained from a postal questionnaire sent at 8–12 weeks postpartum using methods shown to maximise response rates.20 Women could opt to complete the questionnaire by phone, and interpreters were available. Details of these and the data quality checks are given in online supplementary material. Data on POW contacts, collected by the independent service and checked by the researchers, are shown in the online supplementary material.
BODY.METHODS.STUDY OVERSIGHT:
The trial was not registered with the controlled trials register until after first patient recruitment. The trial was a pragmatic one to evaluate a real-time National Health Service implementation, so evaluation had to take place urgently, otherwise trial design would have been compromised. We were informed at that time that only CTIMP trials required trial registration prior to first patient enrolment. Our trial documentation is available for scrutiny, which provides evidence that this did not compromise our research probity.
BODY.METHODS.SAMPLE SIZE JUSTIFICATION:
The sample size was 421 women per arm to provide 90% power (5% significance level) to detect 1.5 mean EPDS score reduction (SD 6), and provide greater than 90% power to detect 1.5–2 increased antenatal contacts (SD 6) allowing for 20% drop-out or loss to follow-up (detailed sample size rationale in published protocol).21 Prior to the trial, data was not available on numbers of social risk factors women had. Following a successful initial 6 months pilot where 475 women were recruited, it was observed that 64% had two or more social risk factors, and it was agreed to increase the sample size to allow power to detect differences in primary outcomes in the prespecified subgroup of women with two or more social risk factors, that is, so that the required sample size of 421 would be recruited within this subgroup. This powered subgroup gave a sample size of 658 women per arm.
BODY.METHODS.STATISTICAL ANALYSIS:
Baseline characteristics were summarised by control and intervention arms using means and SDs, medians and inter-quartile ranges, or numbers and percentages, as appropriate. For continuous outcomes, we reported mean (SE) in each arm, and mean difference. For continuous variables, statistical significance was assessed using two sample t tests assuming equal variances, or a Mann-Whitney U test, as appropriate. For binary outcomes, we reported the number (percentage) in each arm, along with relative risk (RR) and number needed to treat, calculated as 1 divided by risk difference; and also the risk difference (RD). For RRs, we calculated 95% CIs using standard normal approximation methods, and tested for statistical significance using χ2 test. Analyses were carried out in Stata V.12, according to intention to treat principles, and included women for whom outcomes could be collected. Analyses of primary outcomes were replicated independently. We undertook additional analysis of EPDS score ≥13 as a binary outcome17 to enable comparisons with other trials.
BODY.RESULTS.WOMEN AND FOLLOW-UP:
Between July 2010 and October 2011, 1324 nulliparous women with identified social risk factors were randomised, 662 to standard maternity care and 662 to addition of the POW service. Follow-up data collection, which included both postal questionnaire and longer term infant outcomes data were completed by September 2013. Baseline characteristics were similar between groups including identified social risk factors (Table 1). Of women allocated standard care, 49 were not included in analyses (39 had subsequent miscarriage/termination, so no outcomes), and in those allocated POW service, 62 women were not included (30 had subsequent miscarriage/termination) (figure 1). Analyses, therefore, included 613 women allocated standard care, and 600 allocated the POW service. Primary outcome data regarding antenatal contacts were available for 99% of women in the standard care, and 100% in the POW service arms. Data from the questionnaire on EPDS 8–12 weeks postpartum was available for 85% and 82% of groups, respectively: 180 women completed the questionnaire via an interpreter, and 146 in English by phone as requested by the women. Figure 1Consort diagram. EPDS, Edinburgh Postnatal Depression Scale. Baseline characteristics of responders and non-responders to the postnatal questionnaire were broadly similar although marginally more non-responders were younger, recruited at earlier gestation, had housing problems, or were smokers (table 2). Table 2 Baseline characteristics for responders and non-responders to the questionnaire Responders n=1008 (83%) Non-responders n=205 (17%) Maternal age (years) median, IQR 21.0 (21.98, 22.58) 19.0 (20.48, 21.70) Gestation at recruitment Median, IQR 13.2 (14.05, 14.78) 12.6 (13.18, 14.59) Under 12 weeks 421 (41) 92 (45) 12–19+6 weeks 387 (38) 84 (41) ≥20 weeks 200 (20) 29 (14) Ethnicity Africa (North Africa, sub-Sahara, other) 68 (7) 12 (6) Asia Pakistan 163 (16) 26 (13) India 41 (4) 4 (2) Bangladesh 34 (3) 5 (2) Other 34 (3) 2 (1) Caribbean 53 (5) 12 (6) European Britain 475 (47) 110 (54) Eastern Europe 35 (3) 5 (2) Other 9 (0.9) 1 (1) Middle East 30 (3) 6 (3) Other 66 (7) 21 (10) Index of multiple deprivation from postcode at recruitment Quintile 1 750 (74) 143 (70) Quintile 2 151 (15) 40 (20) Quintile 3 81 (8) 17 (8) Quintile 4 22 (2) 5 (2) Quintile 5 4 (<0.5) NA Medical history noted at booking 687 (68) 140 (68) Social risk factors Housing problems such as rent arrears, temporary accommodation registered with National Asylum Support Service (NASS) or of No Fixed Abode (NFA) 392 (39) 107 (52) Teen parent (under 20 years old) 339 (34) 105 (51) Smoking 269 (27) 75 (37) Difficulty with the English language both spoken and written 277 (28) 40 (20) Identified benefit problem 244 (24) 51 (25) UK resident for under a year 166 (17) 24 (12) Clinical diagnosis of past or present mental illness 152 (15) 30 (15) No support from either partner or family or friend 99 (10) 28 (14) Body mass index ≥35 514 (5) 11 (5) Body mass index ≤18 46 (5) 10 (5) Late booking (defined as booking after 18 weeks gestation) 52 (5) 7 (3) Woman/household member in receipt of social services support, including child protection 37 (4) 16 (8) Drug misuse including other's in the household 23 (2) 9 (4) Domestic abuse 27 (3) 5 (2) Alcohol misuse 11 (1) 1 (0.5) DNA 2 or more antenatal appointments (under 28 weeks gestation) 7 (0.7) 5 (2) Social risk identified 0 social risk factor 1 (<0.5) NA 1 social risk factor 258 (26) 55 (27) 2 social risk factors 384 (38) 70 (34) 3 social risk factors 229 (23) 50 (24) 4 or more social risk factors 136 (14) 30 (15) Values are numbers (percentages) unless otherwise stated. NA, not applicable.
BODY.RESULTS.PRIMARY OUTCOMES AND PRESPECIFIED SUBGROUP COMPARISONS:
Antenatal attendance: No difference was seen between groups, either for all women or for women with two or more social risk factors (table 3). Table 3 Primary outcomes and prespecified subgroup analysis Antenatal attendance POW n=599 Standard care n=604 Mean difference (95% CI) p Value Number of contacts, mean (SE) 10.1 (0.14) 10.1 (0.13) −0.00 (−0.37 to 0.37) 0.99 Number with ≥10 contacts 322 (54.3) 320 (53.5) RR=1.01 (0.91 to 1.13) 0.78 Number of social risk factors 1 social risk factor 9.9 (0.27) n=152 10.0 (0.23) n=173 −0.19 (−0.89 to 0.51) 0.59 2 or more social risk factors 10.2 (0.16) n=440 10.1 (0.15) n=425 0.06 (−0.37 to 0.50) 0.82 EPDS POW n=489 (49) Standard Care n=519 (51) Mean Difference (95% CI) p Value NNT Mean, SE 6.76 (0.23) 7.35 (0.24) −0.59 (−1.24 to 0.06) 0.08 EPDS≥13 61 (12) 87 (17) RR=0.74 (0.55 to 1.01) 0.05 23 Number of social risk factors 1 social risk factor n=128 n=159 Mean, SE 6.8 (0.48) 6.9 (0.42) −0.14 (−1.38 to 1.10) 0.82 EPDS≥13 13 (10) 24 (15) RR=0.67 (0.36 to 1.27) 0.21 20 2 or more social risk factors n=361 n=360 Mean, SE 6.8 (0.27) 7.6 (0.29) −0.79 (−1.56 to −0.02) 0.05 EPDS≥13 48 (13) 63 (18) RR=0.76 (0.54, 1.07) 0.12 24 Values are numbers (%) unless otherwise stated. EPDS, Edinburgh Postnatal Depression Scale; NNT, number to treat; POW, pregnancy outreach worker. Postnatal depression: The prespecified comparison for women with two or more social risk factors showed a statistically significant reduction in mean EPDS (MD −0.79 (95% CI −1.56 to −0.02) p=0.05), although no significant differences were seen in the mean EPDS (mean difference (MD) −0.59 (95% CI −1.24 to 0.06)) for all the women recruited. The additional analysis of EPDS as a binary outcome showed a relative risk reduction of 26% for those with an EPDS ≥13 (RR 0.74 (95% CI 0.55 to 1.01) p=0.05), which equates to a reduction of five percentage points (17% vs 12%, RD 0.04 (95% CI −0.00 to 0.09)). In the group with two or more social risk factors, there was a reduction of five percentage points for EPDS ≥13 (18% vs 13%), giving an RD −0.04 (95% CI −0.09 to 0.01) and RR 0.76 (95% CI 0.54 to 1.07).
BODY.RESULTS.SECONDARY OUTCOMES.MATERNAL AND INFANT OUTCOME DATA:
No differences were seen in any secondary maternal or neonatal birth outcomes, including the adverse perinatal composite outcome (see online supplementary tables S1 and S2). 10.1136/bmjopen-2015-009203.supp2Supplementary tables Mother-to-infant bonding was significantly better in the intervention group for all women (MD −0.30 (95% CI −0.61 to 0.00) p=0.05), but did not achieve statistical significance for those with two or more social risk factors (MD −0.35 (95% CI −0.72 to 0.01) p=0.06). Maternal self-efficacy was higher, but not significantly so, in both the intervention group overall (MD 0.43 (95% CI −0.06 to 0.91) p=0.08) and in the group with two or more social risks (MD 0.48 (95% CI −0.08 to 1.04) p=0.09) (see online supplementary table S3). Routine child assessment attendance, primary immunisation uptake, and breastfeeding at 6–8 weeks did not differ between groups (see online supplementary table S4).
BODY.RESULTS.SECONDARY OUTCOMES.DESCRIPTION OF POW SERVICE:
Data on intensity of the POW service showed over 17 000 contacts between POWs and women, 27% of which were face to face, with half of them lasting 1–2 h (see online supplementary table S5). Most contacts took place antenatally (77%). The most common type of support recorded as given by the POWs (see online supplementary table S6) were finance/legal/benefits (19%), emotional and health matters (17%) and housing (15%). Additional social risk factors were disclosed to the POWs after recruitment by 83 women, most commonly; social service/child protection 35; domestic abuse 30; housing problems 21.
BODY.DISCUSSION:
Despite prior indication of local low engagement with maternity care services in disadvantaged women, no difference in antenatal contacts was identified between trial groups. This was at the UK recommended level of 1022 visits in both groups. Various other initiatives to encourage antenatal attendance and engagement had already occurred, thereby reducing potential for further improvement. Since antenatal attendance was unaffected, it is not surprising that maternal and neonatal birth outcomes were no different between trial groups. This trial, however, provides some evidence of a benefit of lay support to maternal depression in women with social risk factors relative to similar controls: while there was no significant difference in mean EPDS for the intervention group as a whole, there was a significant difference in the powered subgroup of women with two or more social risk factors, and mother-to-infant bonding scores were better than among controls overall. Systematic reviews show that children of depressed mothers are more likely to suffer insecure attachment, behavioural problems, cognitive developmental deficits and difficulties in emotional functioning, with impaired bonding between mother and child.23 The implications of a reduction in maternal depression are likely to be of lasting importance to the child, family and more generally to society. The strengths of this trial are that it was an evaluation of an existing service using highest quality methodology with excellent balance between groups, including social risks, and it achieved excellent retention and follow-up which is uncommon among disadvantaged women. A possible limitation is that EPDS was not administered at baseline, but this was not feasible as a pragmatic trial evaluating a real service with inclusion based on routine maternity booking information. The difference in maternal depression we have seen might have been influenced by baseline differences in previous or current mental health problems, but prevalence of this was the same at 15% in the trial groups. Our results could also have been influenced by the fact that 25 women recruited to the intervention group subsequently withdrew relative to only two in the control group, however, this was almost entirely a result of the women deciding that they did not want to continue with the POW service after meeting their POW, and not unsurprising within a real service situation. Improvements in aspects of maternal psychological health in women who received support from the POWs are plausible. For any service-level intervention to be effective it must be implemented and must show impact on the short-term factors that mediate improved long-term outcomes on the service user.24 In the case of the POW service, we have evidence that the service was implemented with commitment: there was an average of over six face-to-face contacts per woman, over half of which exceeded 1 h, and an overall average of more than 24 total contacts per woman. The ingredients shown in the literature to characterise an effective service, practical and emotional support,25 were also provided, and evidence that the POWs achieved positive relationships with women comes from the observation that many divulged sensitive information, for example, domestic abuse. The Cochrane review of 'Psychosocial and psychological interventions for preventing postpartum depression'15 identified 28 trials, involving almost 17 000 women with types of intervention divided into psychological (eg, debriefing, cognitive behavioural therapy) and psychosocial interventions (eg, antenatal/postnatal groups, professional/lay home visits). The review concluded that as a group these interventions significantly reduced the development of postpartum depression. However, only seven trials were of lay interventions, three of which recruited women screened positive for probable depression, and none of the remaining four trials were effective in preventing postnatal depression. No difference in mean depression scores at final study assessment overall was seen in the lay support trials (MD −10 (−0.20 to 0.01)), and the review recommended further trials of support by lay individuals. Addition of data from our trial to this meta-analysis indicates a significant reduction in mean depression scores MD −0.10 (−0.18 to −0.03) in lay support trials (figure 2). Before our trial, therefore, evidence was inconclusive on whether postnatal depression could be prevented through a lay-based intervention, except among women already exhibiting possible depression. Figure 2Forest plot of difference in mean depression scores at final study assessment in lay-based interventions. Two of the seven lay worker trials in the Cochrane review did not report mean depression score at final study assessment. One small trial (n=65) of women screened positive for probable depression reported depression diagnosis and showed a reduction with lay support, and the other in India (n=468) reported depressive symptomatology and showed no difference. Given that UK standard maternity care routinely provides some specialist services to support women with social risks, in international contexts where such standard services are lacking, benefit from a similar POW service might be greater than evidenced here. Moreover, this trial only included nulliparous women, and it is plausible that the effect of the service may be greater in multiparous women, likely to have more social risks. This trial provides evidence that a lay support service targeted to women with two or more social risk factors improves aspects of maternal psychological health relative to controls; such improvements are likely to be of lasting impact due to the known effect of maternal depression and poor attachment on longer term childhood outcomes. This, together with the relatively low costs of the service (approximately £500 000 for 1000 women annually), means that consideration should be given by policymakers to introduction of a lay support service. | 4,785,315 | {
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TITLE: A randomized trial of artemether-lumefantrine
ABSTRACT.BACKGROUND:
The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border.
ABSTRACT.METHODS:
The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis.
ABSTRACT.RESULTS:
In 2001–2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination.
ABSTRACT.CONCLUSION:
Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.
BODY.INTRODUCTION:
Multi-drug resistance of Plasmodium falciparum is a major health problem in many countries and the number of drugs available, effective and affordable is very limited [1]. Along the Thai-Myanmar border, P. falciparum has developed resistance to almost all available antimalarials [2]. As in tuberculosis and HIV where resistance to drugs is a serious issue, combination therapy has been applied to malaria treatment [3]. The use of antimalarial drug combinations with artemisinin derivatives has been advocated and is now implemented in many countries [4]. An extensive amount of information on efficacy and safety of mefloquine has been reported and reviewed [5]. Artemisinin or Qinghaosu is an extract of the medical plant Qinghao (Artemisia annua), which together with its derivatives, artesunate and artemether are the most active antimalarial compounds to date [6]. The artemisinin derivatives have a rapid onset of therapeutic effect, where a single dose can reduce the parasite biomass by a factor of approximately 104 every 48 hours. In addition, they have a very short terminal elimination half-life of less than 2 hours [7]. Previous studies showed that once-daily administration with artemisinin derivatives produced equivalent cure rates to more frequent administration [8]. A three-day course of artesunate combined with high dose mefloquine has become the standard treatment combination for P. falciparum infections in Thailand [9]. Oral artesunate-mefloquine is the most widely used combination. More recently, a fixed combination of oral artemether-lumefantrine (formerly known as benflumetol) has become available. Artemether is a methyl-ether derivative of artemisinin. Lumefantrine is a racemic fluorine derivative with high blood schizontocidal activity [10]. Both artemisinin combination therapies (ACT) are highly effective and well tolerated [11]. However, resistance to mefloquine and/or to lumefantrine, would compromise both combinations. Therefore it is important to monitor the therapeutic efficacy and thus provide advance warning in case of change. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine combination given over three days for the treatment of uncomplicated P. falciparum infections in adults and children on the western border of Thailand.
BODY.PATIENTS AND METHODS:
This study was conducted in the Maela and Mawker Tai malaria clinics of the Shoklo Malaria Research Unit (Mae Sot, Thailand)between July 2001 and June 2002. Patients were recruited from two populations: displaced people of the Karen ethnic minority and migrant workers living on the western border of Thailand. This is an area of low and unstable transmission of Plasmodium vivax and multi-drug-resistant P. falciparum [12]. The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine andmefloquine-artesunate. This study was approved by the Ethical and Scientific Committees of the Faculty of Tropical Medicine, Mahidol University.
BODY.PATIENTS AND METHODS.PROCEDURES:
Patients >10 kg in weight who had slide-confirmed acute P. falciparum malaria were included in the study, provided that they or their guardians gave fully informed written consent intheir own language, they were not pregnant, they had not received mefloquine in the previous 63 days and there were no other clinical or laboratory signs of severe illness and/or severe and complicated malaria [13]. If they gave written informed consent, they were allocated randomly to receive either the six-dose regimen of artemether-lumefantrine (Coartem® 20/120, Novartis Pharma AG, Basel, Switzerland) or mefloquine (Lariam®, Hoffman-La Roche, Basel, Switzerland) plus artesunate (Guilin Pharmaceutical Factory No.1, Guilin, China). At enrolment (Day 0), a medical history was obtained, a full physical examination was performed and blood was taken for quantitative parasite counts and routine haematology (finger prick blood sample for malaria smear and haematocrit). All information was recorded on a standard case record form. All patients were examined and blood smears were taken daily until they became aparasitaemic, and then weekly for 6 weeks. At each visit a questionnaire on adverse events was completed. A blood smear was also taken from any patient complaining of fever or symptoms compatible with malaria during the follow-up period. Parasite counts were determined on Giemsa-stained thick and thin blood films. The person-gametocyte-weeks were calculated per 1,000 person-weeks after excluding the episodes on admission and during treatment.
BODY.PATIENTS AND METHODS.DRUG REGIMENS:
Computerized randomization was in blocks of ten. Patients allocated to artemether-lumefantrine group (ALN) received the tablets at 0 and 8 hours and twice daily for the following 2 days. Artemether-lumefantrine was dispensed as a fixed dose combination tablet. Each tablet contained 20 mg of artemether and 120 mg of lumefantrine. The number of tablets was given according to the body weight. The minimum dosage for patients weighing less than 15 kg was one tablet per dose; patients between 15 and 24 kg received two tablets, those between 25 and 34 kg received three tablets and patients 35 kg and above were treated with four tablets per dose. Patients allocated to artesunate-mefloquine group (MAS3) received artesunate, 4 mg/kg oncedaily for 3 days (day 0 was the first day of treatment), plus mefloquine, 15 mg/kg on day 1 and 10 mg/kg on day 2. Each patient was given antipyretics and cooled by tepid sponging if the tympanic temperature was equal or above 37.5°C before drug administration. Drug administration was observed in all patients and if vomiting occurred in less than 30 min, administration of the full dose was repeated, if vomiting occurred between 30 and 60 min, half the dose was repeated. Patients treated with artemether-lumefantrine were given a glass of chocolate milk (200 ml) with each dose to increase absorption [14].
BODY.PATIENTS AND METHODS.OUTCOME MEASURES:
The primary therapeutic outcome measure in this study was the incidence of microscopically and genotypically confirmedrecrudescent infections in both treatment groups by day 42. Parasite genotyping by the polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. P. falciparum infections were genotyped for allelic variation in three polymorphic antigen loci, merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) and glutamate rich protein (GLURP), on admission and in case of parasite reappearance [15,16]. Secondary measures were the immediate treatment responses: parasite clearance, fever clearance, incidence of adverse events, and degree of anaemia. The sample size was calculated to detect a difference in failure rates of 7 % between the two regimens with 90% CI and 80 % power assuming a 20% drop out.
BODY.PATIENTS AND METHODS.ADVERSE EVENTS:
Adverse events were symptoms or signs that were not presenton admission and that developed after the start of treatment. All adverse events, including those probably related to malaria, were recording and compared among treatment groups. The rates of early vomiting (<1 h) after each dose and for each drug wererecorded and compared among the groups in the analysis.
BODY.PATIENTS AND METHODS.MANAGEMENT OF RECRUDESCENT INFECTIONS:
Patients with uncomplicated recrudescent infections were re-treated with artesunate, 2 mg/kg/day for 7 days; patients >8 years oldalso received doxycycline, 4 mg/kg/day for 7 days.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS:
Data were analysed using SPSS for Windows, version 11. Categorical data were compared using the Chi-square test with Yates' correction or by Fisher's exact test, as appropriate. Continuous variables conforming to a normal distribution were compared using Student's t test. Data not normally distributed were log-transformed or compared using the Mann-Whitney U test. The relative risks were calculated using cross-tabulations. The rates of adverse events at three different periods (days 1–2, days 3–7 and days 14–42) were compared among treatment groups. For each of the three periods, the events were counted only once (e.g., if a patient vomited on day one and day two, this was counted as one adverse event). The PCR-adjusted cure rates were evaluated by survival analysis and compared using the log-rank test. Patients for whom PCR genotyping was either inconclusive or missing were censored in the survival analysis on the day of parasite reappearance. For all statistical tests the significance level (p) was set at 0.05.
BODY.RESULTS:
Four hundred and ninety patients with uncomplicated P. falciparum infections were enrolled between July 2001 and May 2002. The artesunate-mefloquine and artemether-lumefantrine groups included 245 patients each, the age range for all patients was 2–72 years. Baseline characteristics were similar in both groups (Table 1). In total, 484 patients (242 each group) were included in the final evaluation. Six patients (three in each group) were excluded for the following reasons; withdrew consent (1), non-compliance e.g. failure to complete trial treatment course (4), failure to meet protocol criteria (1). Overall compliance was good; around 99% of the patients in the study (481 of 484) were seen at the day seven scheduled visit, 96.1% (465 patients) were seen at day 28 and 93.4% (452 patients) were seen at day 42. Table 1 Demographic and baseline characteristics ALN* (n = 245) MAS3** (n = 245) Maela 100 100 Mawker Tai 145 145 Males, no. (%) 172 (70) 164 (67) Age, years Mean (SD) 23.2 (14.6) 23.6 (15.1) Range 3–70 2–72 Age group, no. (%) <5 10 (4.1) 8 (3.3) 5–14 81 (33.1) 75 (30.6) >14 154 (62.9) 162 (66.1) Weight, kg Mean (SD) 42.4 (14.5) 42.3 (15.0) Range 10–77 10–78 Temperature, °C Mean (SD) 37.7 (1.0) 37.8 (1.1) Range 35.6–40.5 35.9–41.0 Fever a , no (%) 136 (55.5) 142 (58.0) Haematocrit, % Mean (SD) 36.7 (5.9) 36.4 (5.8) Range 21–52 20–51 Geometric mean (range) 8,047 7,570 parasite count (μl -1 ) (32–198,789) (16–198,789) Hepatomegaly, no (%) 48 (19.6) 50 (20.4) Splenomegaly, no (%) 70 (28.6) 57 (23.3) * ALN = artemether-lumefantrine, ** MAS3 = artesunate-mefloquine a Tympanic temperature ≥ 37.5°C
BODY.RESULTS.CLINICAL AND PARASITOLOGICAL FINDINGS:
The initial responses to the two treatment groups were similar. None of the patients developed severe malaria. On admission, 55.0% (133/242) of the patients on ALN and 57.9% (140/242) of the patients in the MAS3 group had a tympanic temperature ≥ 37.5°C. All except three patients had a normal temperature on day 3 (2 in ALN and 1 in MAS3). There was no difference in fever clearance times between the two treatment groups (Figure 1). Parasite clearance times were short and most patients cleared their parasitaemia by day two. Figure 2 shows the percentage of patients with positive slide for asexual P. falciparum in both groups. By day three, four (1.8%) of 227 patients in the artemether-lumefantrine recipients and three (1.3%) of 238 artesunate-mefloquine recipients still had a positive blood film (P > 0.05). Overall, 12.3 % of patients were anaemic (haematocrit <30%) on admission, 10.8% in ALN group and 13.8% in MAS3 group (P = 0.33). The mean (SD) decrease in haematocrit value at day seven from baseline was greater in the group receiving MAS3 than in the ALN group: 9.3% (SD,11.5%; 95% CI, 7.7% to 10.9%) compared with 6.7% (SD, 11.4%; 95% CI, 5.1 to 8.3%) respectively (P = 0.023). Figure 1Percentage of patients with fever (temperature > 37.5°C). Figure 2Percentage of patients with positive slide for asexual P. falciparum forms. During the 42-day follow-up period, 27 new P. falciparum infections occurred among artemether-lumefantrine and 24 among artesunate-mefloquine recipients (P > 0.05) (Table 2). The PCR-adjusted cure rates by day 42 were 98.8% (95% CI, 96.4% to 99.6%) in the ALN group and 96.3% (95% CI, 93.1% to 98.0%) in the MAS3 group (P = 0.08). PCR confirmed treatment failures were more likely in children aged below 15 years than in adults (RR, 5.1; 95% CI, 1.4–18.7; P = 0.006). The mean age was 13.6 years (n = 12; SD = 8.5) in patients with treatment failure and 23.7 years (n = 438; SD = 15.2) in successfully treated patients. In this trial, only age group was independently associated with treatment failure, but not other factors e.g. higher parasitaemia (>10,000/μL); anaemia (haematocrit <30%); fever (tympanic temp ≥ 37.5°C) on admission; sites; treatment groups; early vomiting (within one hour following drug administration). The mediantime to recrudescence was comparable for MAS3 group (21 days; n = 9; range, 14–28 days) and ALN group (28 days; n = 3; range, 21–42 days; P > 0.05).
BODY.RESULTS.OTHER PARASITOLOGICAL FINDINGS:
Of 452 patients, 119 (26.3%) had P. vivax parasitaemia detected during follow up. There were significantly fewer cases of vivax malaria in the MAS3 group (29 of 227) than in the ALN group (90 of 225) (P < 0.001). The median time to appearance of P. vivax parasitaemia was longer in the MAS3 group (40 days; range, 13–43 days) than in the ALN group (28 days; range, 14–43 days; P < 0.001). Twenty patients (8.3%) in the artemether-lumefantrine group and 19 (7.9%) in the artesunate-mefloquine group had gametocytes detected during the first 3 days. All except one patient in ALN group cleared gametocytes within first week after start of treatment. After excluding these, gametocytes developed (between day 7 and 42) in 1.2% (3/241) of ALN group and 1.3 (3/240) of MAS3 group. The person-gametocyte weeks were low and similar: 2.7 (95% CI, 0.6–7.8) per 1000 person-weeks for both groups.
BODY.RESULTS.ADVERSE EVENTS:
Both treatment regimens were well tolerated. No serious adverse events were reported. Overall, 5/242(2.1%) of the patients vomited one or more doses of medication in the ALN group and 2/242(0.8%) of the MAS3 treated patients (RR, 2.5; 95% CI, 0.5–12.7; P = 0.45). The rates of early vomiting (within one hour) of the drugs were very low (around 2%) and did not differ among groups (one in each group on day 2). The most commonly reported and possibly drug-related adverse events to both combination therapies were effects on the gastrointestinal (abdominal pain, anorexia, nausea, diarrhoea and late vomiting e.g. >1 h after administration of treatment) and central nervous system (headache, dizziness). Figure 3 shows the proportions of possibly drug-related adverse events of those who did not have those symptoms at admission during follow-up in both groups. Overall, there were less adverse events in ALN group compared to MAS3, though the differences were not statistically significant. Figure 3Possibly drug-related adverse events (day 1 – day 42).
BODY.DISCUSSION:
The loss of affordable effective antimalarial drugs to resistance represents a major threat to the people of malaria endemic countries [1]. Using ineffective drugs with high failure rates kills many and is unacceptable. A clear treatment policy and readiness to use the new, more effective artemisinin-based combination therapies (ACT) are crucial [17]. Along the north-western border of Thailand, where highly multi-drug resistant isolates of P. falciparum are found, artesunate-mefloquine combination therapy (MAS3) is the standard treatment regimen for uncomplicated falciparum malaria [9]. Early diagnosis and treatment with an artemisinin-based drug combination of very high efficacy that reduces gametocyte carriage, has led to a marked decline in the incidence of falciparum malaria and a reversal of the previous trend toward increasing mefloquine resistance [18]. Artemisinin derivatives will ensure rapid clinical and parasitological responses and are remarkably effective, hence clinical deterioration is extremely unusual. To optimize therapy, combination with a slower-acting antimalarial drug is required. Systematic use of ACT would help to delay the emergence of resistance if the drug was used widely. However, the continued use of mefloquine monotherapy or with only 2 days of artesunate in this region, provides persistent selective pressure to continue the evolution of mefloquine resistance, which could diminish the efficacy of the artesunate-mefloquine combination and that of artemether-lumefantrine. Artemether-lumefantrine has been introduced recently for oral treatment of uncomplicated falciparum malaria. In Thailand, several trials have been conducted with this combination. The six-dose schedule provides sustained blood lumefantrine levels and thus improved cure rates [11]. Lumefantrine is highly lipophilic and the oral bioavailability varies considerably between individuals and increases greatly if the drug is administered after a meal rich in fat [19]. The present trial reconfirmed the efficacy of the six-dose regimen of artemether-lumefantrine given over three days [20]. Both treatments in this study cleared fever and parasitaemia promptly and reliably. Both treatments were well tolerated and highly effective. Importantly 2/3 less P. vivax infections and 12 days longer median time to appearance of P. vivax parasitaemia in the MAS3 group were most probably due to the longer terminal half-life of mefloquine compared to lumefantrine [21,22]. More data on the safety and efficacy of artemether-lumefantrine in very small children and pregnant women are needed.
BODY.AUTHORS' CONTRIBUTIONS:
RH carried out the study and analyzed the data. RH, EAA, RMG, PS, TJ, NJW, FN conceived the study, participated in its design and co-ordination and contributed to draft the manuscript. LP, KLT assisted in collection of data. AB performed the PCR experiments. All authors read and approved the final manuscript. Table 2 Treatment response. Treatment group ALN* (n = 245) MAS3** (n = 245) Compliance, no. (%) Completed day 7 241 (99.6%) 240 (99.2%) Completed day 28 232 (95.9%) 233 (96.3%) Completed day 42 225 (93.0%) 227 (93.4%) Cumulative proportion of patients with clinical failure, no (%) Day 7 0 (0) 0 (0) Day 28 13 (5.6) 14 (6.0) Day 42 27 (12.0) 24 (10.6) PCR, no. Novel 23 14 Recrudescent 2 8 Novel + recrudescent 1 1 Indeterminate/missing 1 1 PCR-adjusted cure rates, no. (%) Day 7 0 (100) 0 (100) Day 28 2 (99.1) 9(96.1) Day 42 3 (98.8) 9 (96.3) * ALN = artemether-lumefantrine, ** MAS3 = artesunate-mefloquine | 1,261,533 | {
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TITLE: OA01.06. A clinical evaluation of langlimool (gloriosa superba) on inderlupta w.s.r. to alopacia areata
ABSTRACT.PURPOSE::
Beauty has very important role in our life. Hair plays very vital role in our beauty. A human body without hair would be seen just as a tree without leaves. So everyone has an ambition that his/her hair should be long, black and thick. In Ayurveda there are many synonyms for Hair loss as Inderlupta, KhaIitya, rujya etc. Indralupta is a unique, idiopathic, non-cictricial, non-inflammatory alopecia, presents as discoid areas of hair loss.
ABSTRACT.METHOD::
Therapeutic assessment of lepa of sodhita langalimoola was carried out on the patient of Indralupta. Lepa of the fine powder of langali moola was made with madhu. External application was done twice a day for a period of 60 days. Selection of Cases Source: For the present study, patients with Indralupta were screened out from OPD & IPD of NIA, Jaipur. Number of cases: 30 Patients were registered from OPD & IPD of NIA Jaipur. Grouping of Patients: Selected patients were randomly divided into two groups. Group A: This group of 15 patients was treated with Gomutra sodhit Langali moola with honey for external application. Group B: This group of 15 patients was treated with Godugdha sodhit Langali moola with honey for external application.
ABSTRACT.RESULT ::
It was observed that after 60 days of treatment with Gomutrashodhit Langlimool in Group A there was reduction in Hair fall which is statistically highly significant (P<0.001) and highly significant improvement was observed in reducing dandruff.(p<0.001). Where as in Group B Godugdashodhit Langlimool application reduced the hair fall to statistically significant level (p<0.01) and statistically significant in reducing the dandruff in patient with Indralupta (P<0.01).
ABSTRACT.CONCLUSION::
Gomutrasodhit Langali moola churna was highly effective in the management of Indralupta. | 3,800,940 | {
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TITLE: Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial
ABSTRACT.INTRODUCTION:
Although exercise is therapeutic for adults with fibromyalgia (FM), its symptoms often create obstacles that discourage exercise. We evaluated the effects of accumulating at least 30 minutes of self-selected lifestyle physical activity (LPA) on perceived physical function, pain, fatigue, body mass index, depression, tenderness, and the six-minute walk test in adults with FM.
ABSTRACT.METHODS:
Eighty-four minimally active adults with FM were randomized to either LPA or a FM education control (FME) group. LPA participants worked toward accumulating 30 minutes of self-selected moderate-intensity LPA, five to seven days per week, while the FME participants received information and support.
ABSTRACT.RESULTS:
Seventy-three of the 84 participants (87%) completed the 12-week trial. The LPA group increased their average daily steps by 54%. Compared to FME, the LPA group reported significantly less perceived functional deficits (P = .032) and less pain (P = .006). There were no differences between the groups on the six-minute walk test (P = .067), fatigue, depression, body mass index, or tenderness.
ABSTRACT.CONCLUSIONS:
Accumulating 30 minutes of LPA throughout the day produces clinically relevant changes in perceived physical function and pain in previously minimally active adults with FM.
ABSTRACT.TRIAL REGISTRATION:
clinicaltrials.gov NCT00383084
BODY.INTRODUCTION:
Fibromyalgia (FM) is a chronic, multidimensional disorder characterized by persistent, widespread body pain and tenderness [1]. FM is estimated to occur in 2% of the U.S. general population, affecting about eight times more women than men [2,3]. Symptoms associated with FM include body pain, fatigue, sleep disruption, headache, memory or concentration problems, mood disturbances, and irritable bowel syndrome [4]. FM often substantially hampers day-to-day functioning and is a primary cause of disability [5]. Even with the recent Food and Drug Administration approval of medications to treat FM, pharmacotherapy generally produces modest and inconsistent benefits on symptoms, functioning, and quality of life [6]. As such, nonpharmacologic treatments, such as exercise and cognitive-behavioral interventions, are recommended to assist people with FM to better manage the array of symptoms and functional deficits [6]. Although exercise has been shown to be beneficial [for example, [7]], the symptoms of FM often create obstacles that deter many from exercising consistently enough to derive benefits [8]. Thus, finding new ways to promote increased physical activity in persons with FM that can be sustained overtime is important. One promising approach is to ask people with FM to increase their lifestyle physical activity (LPA). LPA involves working toward meeting the U.S. Surgeon General's 1996 Physical Activity Recommendations of accumulating at least 30 minutes, above one's usual activity, of moderate-intensity physical activity five to seven days a week by integrating short bouts of activity into the day, such as increasing the amount of walking, performing more yard work, using the stairs and so on [9-11]. Although it is unclear whether a continuous 30 minute bout of physical activity is superior to accumulating smaller (10- to 15-minute) bouts of activity with regard to health outcomes, asking people with FM to accumulate small bouts of physical activity throughout the day, as opposed to being active for 30 consecutive minutes, might be less taxing and therefore easier to initiate and sustain over time. In a pilot study [12], we found that small bouts of LPA promoted a 70% increase in physical activity in FM. However, in that small study LPA did not produce significant benefits on pain, fatigue, or perceived physical function compared to controls. As part of an ongoing randomized trial designed to investigate the effects of LPA on ambulatory reports of physical activity, pain and fatigue, as well as measures of fitness, pain threshold and pain tolerance, we also collected questionnaire-based data on these variables. This paper presents the results on questionnaire-based assessments of perceived physical function, pain, fatigue and depression, as well as tenderness and aerobic endurance after 12 weeks of LPA in minimally active adults with FM.
BODY.MATERIALS AND METHODS.PARTICIPANTS:
Participants were 92 adults (88 women and 4 men) aged 18 years or older who met American College of Rheumatology diagnostic criteria for FM [13]. The mean (SD) age of participants was 47.7 ± 10.7 years and 80% were white. The mean duration of FM was 7.5 ± 6.2 years. At enrollment, participants were not meeting the US Surgeon General's 1996 recommendation for physical activity [11] for the previous six months (that is, not engaging in either moderate-intensity physical activity for ≥ 30 minutes on ≥ five days per week or vigorous physical activity ≥ three times per week for ≥ 20 minutes each time during the previous month). Persons with acute or chronic medical conditions that could preclude active participation (for example, cancer, coronary artery disease) were excluded from the trial. We also excluded those who intended to change medications that might affect mood, those who intended to seek professional treatment for anxiety or depression during the study period, and those who were unwilling to make the required time commitment. Participants were recruited from the Johns Hopkins Arthritis Center, affiliated Johns Hopkins Rheumatology clinics, by advertisements in the Arthritis Foundation Maryland Chapter newsletter, newspaper advertisements, and via clinical trial recruitment websites, including clinicaltrials.gov. All participants completed baseline testing which included a series of questionnaires, a tender point examination, and a six-minute walk test. At baseline, participants also wore a waist-mounted pedometer (AccuSplit Eagle 1020, Livermore, CA, USA) for seven days (recalibrating it each morning) and recorded their daily step count. These data were used to calculate the mean steps per day as an estimate of physical activity. This study was approved by the Institutional Review Board of Johns Hopkins University School of Medicine, and all participants gave written informed consent.
BODY.MATERIALS AND METHODS.STUDY PROCEDURES:
Participants were randomized via a coin flip at a 1:1 allocation ratio to each of the two groups. The group meetings for LPA and FME were held on different days to avoid contact between participants assigned to the different conditions. The interventions did not replace usual medical care and the participants had comparable durations of contact time with study staff (Table 1 summarizes the LPA and FME conditions). Table 1 Description of lifestyle physical activity (LPA) and fibromyalgia education (FME) protocols* Component LPA FME Three, two-hour FM education and support meetings NO YES Physical activity intervention delivered in six, one-hour meetings YES NO Wear pedometer and keep a physical activity log YES NO Prescribed physical activity YES NO Approximately six hours of face-to-face contact time YES YES Topics Covered During the Meetings LPA FME "Physical Activity & FM" Described FM (symptoms, diagnosis, treatment)/benefits of physical activity/demonstrated moderate-intensity LE/prescribed LE and self-monitoring/identified and addressed barriers to physical activity (Sessions 1 & 2) "FM: What is it and how is it diagnosed?" Presented general information on the symptoms of FM and how it is diagnosed; Discussion and social gathering (Session 1) "How to Keep Moving" Discussed progress, effect on symptoms, goal setting, problem solving, importance of self-monitoring, provided feedback, and troubleshooting (Sessions 3 & 4) "What causes FM?" Presented the latest information on the causes and consequences of FM; Discussion and social gathering (Session 2) "Now It's Up To You" Planned for setbacks & developed strategies to overcome them, set long-term goals, self-monitoring over the long-term (Sessions 5 & 6) "Treating FM" Discussed of medical and non-medical approaches, including exercise, to treating FM; Discussion and social gathering (Session 3) LPA Accumulate ≥ 30 minutes of self-selected physical activity five to seven days per week FME Did not alter their characteristic level of physical activity *FM, fibromyalgia; FME = fibromyalgia education; LPA, lifestyle physical activity
BODY.MATERIALS AND METHODS.LIFESTYLE PHYSICAL ACTIVITY (LPA):
Participants assigned to LPA attended six, 60-minute group sessions over 12 weeks. Delivered by one of the authors (KRF), the LPA protocol was identical to the one developed for our pilot study [12] and was loosely based on Active Living Every Day, a cognitive-behavioral physical activity promotion program developed by Dr. Steven Blair and colleagues at the Cooper Aerobics Center [14]. The LPA protocol addressed FM-specific challenges to becoming more physically active (that is, dealing with pain and fatigue, fear that physical activity will promote a flare) and discussed how LPA successfully addresses them. The goal of the LPA intervention was to increase moderate-intensity physical activity by helping participants find ways to accumulate short bouts of physical activity throughout the day. Participants were asked to gradually work their way up to meeting the Surgeon General's 1996 recommendation of accumulating 30 minutes, above usual activity, of moderate-intensity LPA five to seven days each week. At the first session, participants were taught how to perform their LPA at moderate-intensity (that is, you will be breathing heavily but not so heavily that you could not hold a conversation). They were also prescribed 15 minutes, above usual level, of accumulated moderate-intensity LPA five to seven days a week, and asked to increase the daily duration of LPA by five minutes each week. The five-minute increase in the daily duration of LPA was based on findings from our pilot study [12] and was well-tolerated by the majority of participants. Thus, by Week 5, most participants were accumulating 30 minutes, above their usual level, of LPA five to seven days a week. Participants were free to accumulate more than 30 minutes of LPA five to seven days per week, if desired. During subsequent sessions participants were taught self-monitoring of LPA, goal setting, dealing with symptom flares, problem solving strategies to overcome barriers to being more physically active, as well as instruction in finding new ways to integrate short bouts of LPA into their daily lives. Feedback focused on whether participants achieved the prescribed level of LPA, as well as the LPA's influence on symptoms. Participants wore the waist-mounted pedometers to record their steps each day (that is, as an assessment of adherence to LPA). Participants were shown how to use the pedometer, where to place it, and how to record their steps on a step diary form. At the end of each day they recorded their steps on a diary form and zeroed their pedometer so they could record their steps for the next day. They also kept a diary that categorized the types of LPA's they engaged in (for example, garden/outdoor activity, household activity, leisure activity). The step count data and diary entries were collected at each intervention session.
BODY.MATERIALS AND METHODS.FIBROMYALGIA EDUCATION (FME):
Participants assigned to the FME group met monthly for three months. FME was a minimal intervention with each session divided into three components: (1) education (45 to 60 minutes), (2) question and answer (20 to 30 minutes), and (3) social support (20 to 30 minutes). Conducted by an experienced FM support group facilitator, these 90- to 120-minute sessions presented information on the symptoms, diagnosis, and treatment of FM. The rationale for FME was to provide education and to control for the effects of being enrolled in a clinical trial and receiving increased attention and social support. Moreover, by providing a minimal intervention, as opposed to a standard care control, we anticipated enhancing retention. The final session of FME presented information on exercise and physical activity, but no specific recommendations or prescription concerning exercise was given. To avoid the possibility that wearing a pedometer would increase their physical activity, FME participants only wore one for the baseline and post-testing assessments.
BODY.MATERIALS AND METHODS.OUTCOMES MEASURES:
The following outcome measures were collected at baseline and after the 12-week intervention.
BODY.MATERIALS AND METHODS.PRIMARY OUTCOME.PERCEIVED PHYSICAL FUNCTION:
Perceived physical function was assessed using the Fibromyalgia Impact Questionnaire (FIQ) total score. The FIQ is a well-validated 10-item questionnaire that measures aspects of physical functioning in patients with FM [15]. The FIQ is scored so that higher scores are indicative of poorer functioning. Test-retest reliability ranged from .56 to .95 and construct validity relative to tender points was acceptable (rs = approximately .56) [15].
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.PAIN:
Pain was assessed using a 100 mm Visual Analogue Scale (VAS) where participants rated their current level of pain, ranging from 0 (no pain) to 100 (worse pain imaginable).
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.FATIGUE:
The Fatigue Severity Scale (FSS) [16] was used to assess the current level of fatigue. The FSS is a nine-item questionnaire, answered on a seven-point scale, ranging from strongly agree to strongly disagree. The FSS has good internal consistency (Cronbach's alpha = .81) and correlates with VAS fatigue measures (r = .68) [16].
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.DEPRESSION:
Depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) [17]. The CES-D contains 20-items rated on a four-point Likert scale ranging from 0 (rarely or none of the time) to 3 (most or all of the time), and measures symptoms during the past week. The CES-D is a widely used measure of depressive symptoms and has acceptable internal consistency (.84 to .90) and validity (r = .56 with clinical rating of depression severity) [17].
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.TENDERNESS:
A digital tender point examination, at the 18 sites specified in the American College of Rheumatology FM classification criteria [13], was completed at baseline and after the intervention. Tender point counts are moderately reliable in classifying the tenderness associated with FM (kappa = .75) and inter-rater agreement on the presence of tenderness through digital examination is .51 [13].
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.BODY MASS INDEX (BMI: KG/M:
Weight and height were recorded at each assessment and these variables were used to calculate BMI, an index of body weight adjusted for height.
BODY.MATERIALS AND METHODS.SECONDARY OUTCOMES.SIX-MINUTE WALK TEST:
The six-minute walk [18] is a measure of aerobic endurance. For this test, participants walked as far they could in six minutes on a preselected course, with the distance walked recorded. The reliability of the six-minute walk test is excellent (r = .91) and it correlates with the FIQ (r = -.49) and is sensitive to change due to exercise in distance walked (+78 m), and VO2 (+1.8 ml/kg/min) [18]. The six-minute walk test was measured at baseline and at post-testing. We expressed the results as meters per second, an index of gait speed.
BODY.MATERIALS AND METHODS.SAMPLE SIZE AND DATA ANALYSIS:
Thirty-five adults with FM per group were projected to provide a power of 80% to detect a clinically significant 20% difference between the groups on the FIQ score. Ninety-two participants were enrolled to allow for a 25% post-randomization drop out rate. Baseline data between the two groups were compared using t-tests or Chi Square tests. Changes in perceived physical function, depression, pain, tenderness, fatigue, BMI, and the six-minute walk test were compared between the LPA and FME groups using between-subjects t-tests. Because there was a significant difference between the LPA and FME groups on self-reported duration of FM (see Table 2), as a sensitivity analysis, we adjusted scores of the outcome measures for the duration of FM and replicated the analyses. We also used regression techniques to adjust the outcome measures on the basis of whether or not the participant reported any change in their ongoing FM treatments, either pharmacologic or non-pharmacologic (0 = no change, 1 = change) during the trial. Because the results did not differ as a function of these adjustments, we present the results for the unadjusted outcome variables. Although data from all subjects were analyzed regardless of whether those subjects complied with or remained in treatment, participants with missing data on a particular variable were excluded from that particular analysis. We also performed an analysis among participants who completed the 12-week trial (completers only). Cohen's d effects size estimates [19] were calculated for each difference on the outcome measures between LPA and FME. Analyses were performed using SPSS software, Version 16. Two-tailed P values of < 0.05 were used to denote statistical significance. Table 2 Baseline characteristics of the randomized participants* Characteristic Lifestyle Physical Activity (LPA) Fibromyalgia Education (FME) P value N (%) of participants 46 (55) 38 (45) Age, years 46.4 ± 11.6 49.0 ± 10.2 0.287 Female, N (%) 43 (94) 38 (100) 0.248 Self-reported race, N (%) 0.789 White 36 (78) 31 (82) Non-White 10 (22) 7 (18) Marital status, N (%) 0.519 Married or cohabitating 24 (52) 24 (63) Widowed, divorced, or separated 12 (27) 11 (29) Single 10 (22) 3 (8) Educational level, N (%) 0.454 Postgraduate 9 (20) 5 (13) College graduate 16 (34) 11 (32) Some college 11 (24) 13 (34) High school 10 (22) 8 (21) Employment status, N (%) 0.923 Employed 20 (43) 18 (47) Unemployed or Disabled 11 (24) 9 (24) Retired or Other 15 (33) 11 (29) Years since diagnosis a 5.9 ± 5.1 9.6 ± 6.8 0.007 Steps per day 3,788 ± 2,135 3,071 ± 1,810 0.139 Taking FM medications, N (%) a 31 (82) 40 (87) 0.498 Taking other medications, N (%) a 33 (87) 44 (96) 0.146 * Data for categorical variables are presented as N' and percentages; data for continuous variables are presented as means ± standard deviation. a Obtained from self-report. FME, fibromyalgia education; LPA, lifestyle physical activity
BODY.RESULTS:
Nine participants withdrew after baseline testing but prior to randomization (see Figure 1). We randomized 46 participants into the LPA intervention and 38 into the FME group in five separate cohorts of approximately 8 to 10 per cohort at six-month intervals. (Because the FME facilitator was unavailable, one smaller cohort (N = 4) was comprised of only LPA participants). Selected baseline characteristics of the 84 participants are shown in Table 2. With the exception of duration of FM, the two groups were comparable on age, race, education, employment status, BMI, and the use of medications for FM or for other medical conditions. Figure 1Participant flow. Seventy-three of the 84 participants (87%) completed the 12-week intervention and post-testing. Drop outs were unrelated to randomized treatment assignment (P = .988) and there were no significant differences on any baseline variables between those who dropped out and those who completed post-testing. There was also no difference in the mean percentage of meetings attended by those randomized to the FME (77%) and LPA (72%) groups (P = .542). As shown in Figure 2, the LPA group significantly increased the mean number of daily steps from 3,788 ± 2,135 at baseline to 5,837 ± 1,770 at the final intervention session (P = .001). This represents a 54% increase in the mean number of daily steps over the course of the 12-week intervention. Although walking was the most common form of LPA, other popular forms of LPA included garden/outdoor activity (for example, mowing the lawn, planting flowers, pulling weeds); household activity (for example, cleaning out a closet, vacuuming, doing laundry); and sports activity (for example, cycling, swimming, field hockey). Figure 2Average steps per day (with 95% confidence interval) for the study groups. At baseline, there were no significant differences between the LPA and FME groups on FIQ, pain, fatigue, depression, number of tender points, BMI, and six-minute walk distance (see Table 3). At post-testing, compared to the FME group, the LPA group reported significant reductions in the FIQ score (P = .032; Cohen's d = .53) and in pain (P = .006; Cohen's d = .67). The difference between the LPA and FME groups on the six-minute walk test approached significance (P = .067; Cohen's d = .53). There were no significant differences between the groups on BMI, fatigue, depression, or the number of tender points. The results (data not shown) were not materially altered when the analysis was restricted to only participants who completed the entire 12-week trial (that is, completers only analysis). Table 3 Differences between lifestyle physical activity (LPA) and fibromyalgia education (FME) groups on the primary and secondary study measures a Variable Mean ± SD Mean difference between groups at baseline and at 12-weeks (95% CI) P Value Cohen's d N LPA FME FM impact questionnaire Baseline 84 67.5 ± 12.0 69.7 ± 13.4 2.2 (-3.3 to 7.8) 0.424 .17 Post intervention 73 56.7 ± 20.6 67.0 ± 18.6 10.2 (.91 to 19.6) 0.032 .53 Pain Baseline 84 54.6 ± 25.6 58.9 ± 25.0 4.3 (-7.2 to 14.9) 0.489 .17 Post intervention 73 46.3 ± 24.2 62.4 ± 24.5 16.1 (4.6 to 27.5) 0.006 .67 Fatigue severity scale Baseline 84 51.9 ± 9.3 52.3 ± 9.1 .4 (-3.6 to 4.4) 0.843 .04 Post intervention 73 50.6 ± 9.9 51.4 ± 10.1 .8 (-3.9 to 5.5) 0.727 .07 CES-D* Baseline 84 23.4 ± 8.6 24.0 ± 10 .6 (-3.8 to 4.5) 0.798 .06 Post intervention 73 21.6 ± 9.8 21.2 ± 11.3 .4 (-5.3 to 4.6) 0.888 .04 Number of tender points Baseline 84 16.2 ± 2.3 16.1 ± 3.2 .1 (-1.2 to 1.0) 0.979 .03 Post intervention 72 16.0 ± 2.3 16.8 ± 2.0 .8 (-.35 to 1.9) 0.172 .37 Body mass index (BMI) Baseline 82 31.4 ± 8.4 29.8 ± 6.2 1.6 (-4.7 to 1.7) 0.360 .22 Post intervention 60 31.0 ± 9.0 29.9 ± 6.2 1.1 (-5.3 to 2.9) 0.575 .14 Six-minute walk test, yd/sec Baseline 77 1.08 ± 0.15 1.08 ± 0.19 .0004 (-0.78 to 0.79) 0.991 0 Post intervention 62 1.24 ± 0.28 1.11 ± 0.20 1.21 (-0.25 to 0.008) 0.067 .53 * Center for Epidemiologic Studies Depression Scale; a between-subjects t-tests were used to derive P values; b Cohen's d [ 19 ] effect size estimates ( d = .20 (small effect); d = .50 (medium effect); d = .80 (large effect)). FME, fibromyalgia education; LPA, lifestyle physical activity
BODY.DISCUSSION:
The 12-week program, designed to help minimally active adults with FM increase their physical activity by working toward accumulating at least 30 minutes of self-selected moderate-intensity physical activity most days of the week, produced a 54% increase in the average number of steps taken per day. Compared to the FME control group, LPA participants significantly reduced their perceived functional deficits (that is, FIQ score) and pain. Moreover, compared to FME, the LPA participants had a greater improvement on the six-minute walk (expressed as gait speed), although this difference failed to reach statistical significance. The magnitude of the post-intervention differences, expressed as percent change from LPA to FME groups, were 18% for the FIQ score and 35% for the pain VAS score. When expressed as Cohen's d effect sizes these are indicative of medium-sized effects. Moreover, the change on the FIQ score exceeds the minimally clinically important difference of 14% recently identified [20], suggesting that increasing physical activity via LPA produces changes on perceived physical function that are of a relevant magnitude. On the other hand, the effect of LPA on the six-minute walk test was not statistically significant (although it produced a Cohen's d of .53). It is important to note that there was a smaller sample size available for this analysis which reduced statistical power. In general our results are in accord with studies investigating the effects of exercise on people with FM [7,8,21,22]. Specifically, the majority of studies suggest that exercise can produce mild-to-moderate benefits on aerobic endurance, strength, functional status, and quality of life [7,23,24]. However, because the exercise interventions investigated vary so markedly in type (for example, water aerobics, traditional aerobics, T'ai Chi, strength training), frequency, intensity, and duration it is difficult to compare results across studies. One thing seems clear from the FM exercise literature, people with FM have difficulty adhering to exercise. Indeed, in FM clinical exercise trials drop-out rates often nearly exceed 30% [for example, [8,24]] suggesting that developing exercise interventions that can be sustained is perhaps as important a goal as finding the particular interventions that produce optimal benefits. The magnitude of the effects of LPA observed in this study on perceived physical function and pain were similar to those obtained in our smaller pilot study [12]. These effects were also generally consistent with other protocols that involve low-to-moderate intensity exercise, interventions that appear to produce the greatest level of compliance in people with FM [for example, [7,8,24]]. It is important to note that even though the LPA group increased their mean daily steps by 54%, it only moved them, as defined by the pedometer-determined physical activity classifications developed by Tudor-Locke and colleagues [25], from the sedentary (<5,000 steps/day) to the low active (5,000 to 7,499 steps/day) category. Indeed, the mean steps per day at post-testing among the LPA participants were comparable to the mean daily steps observed in patients with progressive neuromuscular disease, and are significantly lower than other special populations such as diabetics, patients undergoing breast cancer treatment, and those with joint replacements [26]. This suggests that, even with the initiation of LPA, people with FM progress only to a relatively low level of physical activity. It is important to note, however, that the trajectory of the mean step count continued to rise over the 12 weeks suggesting that, had the trial continued, their physical activity may have continued to increase. It may be that people with FM require more time to eventually reach physical activity recommendations compared to persons with other chronic conditions. This study has limitations and strengths. First, to minimize attrition and control for the effects of increased attention, participants randomized to the FME group did receive a minimal intervention. Thus, we cannot determine how LPA compares with a traditional no treatment control group. Second, with the exception of BMI, the tender point count and six-minute walk test, the outcomes described herein were derived from self-report and may be influenced by a variety of factors, including those associated with enrollment in a clinical trial. Third, using pedometers to assess LPA is relatively crude and does not quantify other sorts of physical activities that participants may have engaged in such as cycling or water exercise. Fourth, we did not measure muscle strength during the trial so we are unable to determine whether LPA influences strength. Finally, we excluded persons with FM who had other co-morbid conditions such as uncontrolled hypertension or arthritis which may limit the generalizability of our findings. Strengths of this study include the randomized design, a relatively small drop-out rate (13%), the LPA group's adherence to standardized intervention protocol, and the relatively high rates of attendance to the group sessions.
BODY.CONCLUSIONS:
The results of this study suggest that promoting increased physical activity by asking persons with FM to accumulate short bouts of activity throughout the day can markedly increase the average number of steps taken per day and produces clinically relevant reductions in perceived functional deficits and pain. However, the LPA intervention only moved the participants from the sedentary to low physical activity category. This suggests that it is essential to encourage FM patients to increase the duration of their physical activity in ways that do not compromise their ability to sustain the increased level of activity over the intermediate- and long-term.
BODY.ABBREVIATIONS:
BMI: Body Mass Index; CES-D: Center for Epidemiologic Studies Depression Scale; FIQ: Fibromyalgia Impact Questionnaire; FM: fibromyalgia; FME: Fibromyalgia Education Control Group; FSS: Fatigue Severity Scale; LPA: lifestyle physical activity; SD: standard deviation; VAS: Visual Analogue Scale.
BODY.COMPETING INTERESTS:
Kevin R. Fontaine and Lora Conn declare that they have no competing interests. Daniel J. Clauw has acted as a consultant for Pfizer, Lilly, Forest Laboratories, Cypress Biosciences, Pierre Fabre, UCB, and Wyeth, and has received grant support from Pfizer, Cypress Bioscience, and Forest.
BODY.AUTHORS' CONTRIBUTIONS:
KF conceived of the study, acquired the funding, participated in the design of the study, the delivery of the intervention, performed the statistical analysis, and drafted the manuscript. LC carried out the recruitment, enrollment, and data collection. DC participated in designing the study and assisted with the drafting of the manuscript. All authors read and approved the final manuscript. | 2,888,205 | {
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TITLE: Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial
ABSTRACT.SUMMARY.BACKGROUND:
Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care.
ABSTRACT.SUMMARY.METHODS:
We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per μL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0·69–1·45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at http://isrctn.org, number ISRCTN 17184129.
ABSTRACT.SUMMARY.FINDINGS:
859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8·19 (95% CI 6·84–9·82) for home and 8·67 (6·96–10·79) for facility care (rate ratio [RR] 1·04, 0·78–1·40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0·95 [0·71–1·28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0·91, 0·64–1·28).
ABSTRACT.SUMMARY.INTERPRETATION:
This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.
ABSTRACT.SUMMARY.FUNDING:
US Centers for Disease Control and Prevention and UK Medical Research Council.
BODY.INTRODUCTION:
Antiretroviral drug therapy has been scaled up rapidly in Africa, and is now given to more than 2 million people.1 A global commitment has been made to provide universal coverage,2 but another 5 million people, mostly living in rural and semiurban areas, are estimated to need such treatment. Achievement of high coverage in these populations will be a challenge. Two major barriers to increasing coverage exist—a severe shortage of clinically qualified staff, which has reached crisis point in most of Africa,3 and difficulty for patients in accessing clinics because of high costs and poor availability of transport and low-cash incomes.4,5 WHO proposes decentralised antiretroviral therapy delivery,6,7 and so far services for such therapy have been provided through nurse-led centres with simplified protocols in several settings, including in Malawi,8,9 Zambia,10 Mozambique,11 Botswana,12 and South Africa.13 Good patient outcomes have been reported8,10 from short-term assessments done in some sites, but interpretation of this evidence is difficult because of poor retention rates.14 Furthermore, nursing staff as well as doctors are in very short supply3,15 and care needs to be delegated to non-clinical workers, although evidence for use of non-clinical workers in HIV care is scarce. In Tororo, Uganda, a home-based programme16,17 with lay workers has achieved good outcomes, but it consisted of home visits made every week with good access to clinical staff when needed—a model that would be difficult to scale up. No direct comparisons of hospital-based HIV care versus any form of decentralised HIV care have been done in Africa. We assessed home-based HIV care, with lay workers delivering antiretroviral therapy and monitoring patients, versus facility-based HIV care.
BODY.METHODS.STUDY SETTING AND PATIENTS:
We undertook a trial based at the AIDS Support Organisation (TASO) clinic in Jinja district, southeast Uganda.18 TASO is a large non-governmental organisation with 11 centres in the country, offering counselling and social and clinical services to people with HIV. The Jinja district and surrounding area is poor, with inhabitants on low-cash incomes.18 TASO clinic serves a predominantly rural and semiurban population from a radius of about 100 km. Most TASO clients are subsistence farmers, and very few work in the formal sector earning wages. In accordance with guidelines from the Ugandan Ministry of Health, people with HIV were eligible to start antiretroviral therapy if they were assessed to be at WHO stage IV or late stage III disease, or if they had a CD4-cell count of fewer than 200 cells per μL. Eligible patients were prepared for therapy by TASO staff during three visits to clinic, which were usually spread over 4 weeks. Information and counselling were provided both in groups and in one-to-one sessions. Participants were given drugs for 28 days of treatment and issued with a pill box. A buffer supply for 2 days was provided. Patients were also strongly encouraged to identify a so-called medicine companion to provide support and reminders. Medicine companions were given information by TASO about the basic principles of antiretroviral therapy and adherence. All TASO patients older than 18 years who were starting on antiretroviral therapy for the first time were invited to join the trial, apart from those living on islands, which were about 100 km away and where provision of home-based care was not possible. All patients provided written informed consent. The trial protocol was approved by the Ugandan National Council of Science and Technology and the Institutional Review Boards of the Uganda Virus Research Institute, Centers for Disease Control and Prevention, and London School of Hygiene and Tropical Medicine. Patients were informed about their rights to refuse to join the trial or withdraw subsequently. Those who did were offered facility-based HIV care (including antiretroviral therapy) from TASO Jinja.
BODY.METHODS.STUDY DESIGN:
Recruitment began Feb 15, 2005, and ended Dec 19, 2006, and follow-up continued until Jan 31, 2009. Numbers of patients eligible for antiretroviral therapy were not known in advance—participants were identified after they were tested for CD4-cell counts and clinically assessed. The catchment area was divided into nine strata according to ratio of urban and rural participants and approximate distance from a central point to the TASO Jinja clinic. In every stratum, an even number of clusters (geographical areas) were defined for randomisation along subdistrict boundaries, or, in the case of a few large subdistricts, by known barriers within the subdistrict. Clusters in every stratum had a similar estimated number of people with HIV who were registered at TASO Jinja. Distribution of strata and clusters was as follows: (1) four clusters in urban areas or near the TASO Jinja facility; (2) eight in periurban intermediate distance; (3) eight in rural and far; (4) four in Kamuli district; (5) four in Mukono district near; (6) six in Mukono district far; (7) six in Mayuge district; (8) two in Iganga district near; and (9) two in Iganga district far. Strata and clusters were devised by two people with knowledge of the area (one TASO staff member and one researcher) and cross-checked independently by two other people on two separate occasions. For all patients, antiretroviral therapy was started at the TASO Jinja clinic, and thereafter patients received care according to the treatment to which their residential area had been assigned. After giving consent, patients were enrolled into the study by research staff, and their addresses were confirmed from TASO records. At every clinic visit, research staff interviewed participants in privacy in a separate building soon after their arrival and before they saw TASO staff.19
BODY.METHODS.RANDOMISATION:
Clusters in each strata were allocated to either home-based or facility-based care by drawing cards from a concealed box. The cards were sealed in advance and labelled with the stratum number by the trial coordinator and TASO senior medical officer who organised the allocation event and placed the cards into the box for each stratum. Cards were drawn by two patient representatives, a TASO medical officer, TASO counsellor, and TASO field officer, each taking turns. This process was done in the presence of senior TASO staff, researchers, and local public health representatives.
BODY.METHODS.MODELS OF CARE:
The trial was done in conditions similar to those of actual health services, with TASO staff responsible for service delivery.19 Numbers of counsellors, nurses, and laboratory and pharmacy staff in Jinja were similar to those at other TASO centres. The clinic had five medical officers but the number present usually varied between two and four, with some support from local part-time physicians during the trial. Most medical officers were newly qualified. Clinical staff were trained on antiretroviral therapy and supported by a senior medical officer. For the home-based group, trained field officers travelling on motorcycles visited patients at home every month to deliver drugs, monitor participants with a checklist that included signs and symptoms of drug toxicity or disease progression, and provide adherence support. Most field officers had degree qualifications or college diplomas and underwent 4 weeks of intensive training at the start of the study and yearly refresher courses thereafter about the principles of antiretroviral therapy and adherence support. They were supported at the TASO clinic by counsellors and medical officers. Field officers referred patients to a physician or counsellor at the TASO clinic when they judged referral to be necessary. They had mobile phones and could contact physicians when unsure about referral. At the end of every day, a medical officer reviewed the notes made by field officers and, when needed, asked officers to return to the patient's home to refer them. Patients who were not at home for their monthly appointment were visited again—usually the next day. If they were absent again, fieldworkers left a message for them to come to the clinic. All patients were invited to the clinic for routine reviews by a medical officer and a counsellor at 2 and 6 months after starting therapy and every 6 months thereafter. Drugs were not dispensed during clinic visits for those allocated to home-based case. Before antiretroviral therapy started, TASO offered free voluntary counselling and testing in the home to household members of participants. This offer was repeated during home visits for drug delivery for those who were absent previously. In the facility-based group, patients obtained drugs every month from the clinic and had routine reviews with a medical officer and counsellor that were scheduled at 2 and 3 months after start of treatment and every 3 months thereafter. Apart from scheduled reviews, patients were assessed during clinic visits by a nurse and referred to a doctor when necessary. When an appointment was missed, patients were followed up at home by a field officer (if patients had given permission for home visits), usually after 2–3 days, and reminded to attend clinic. Participants were also given vouchers for their household for free voluntary counselling and testing at TASO Jinja. Patients in both groups were asked to come to the clinic any time that they felt unwell. They were also given a telephone number to call for advice. In exceptional cases, and when TASO resources allowed, home care was provided by a team, including a physician, to patients who were bedridden. No financial or other incentives were provided to patients or staff and TASO clinical management procedures were identical for trial and non-trial participants.
BODY.METHODS.PROCEDURES:
Independent research staff assessed adherence.19 Patients in both groups were interviewed during routine clinical and counselling visits at 2 months and 6 months after starting therapy and then every 6 months. Questionnaires were translated into the local language, Luganda, and then back into English by an independent person, and cross-checked by another researcher who was not involved with the trial. Clinical data were transcribed from patient notes. A change to a second-line regimen was decided by a TASO case conference, consisting of physicians and counsellors, and was made when a patient had one of the following criteria: (1) new or recurrent WHO clinical stage IV or advanced stage III disease; (2) clinical deterioration (eg, weight loss) and two or more consecutive CD4-cell counts less than baseline, or a fall to 50% less than peak CD4-cell count attained after the start of antiretroviral therapy; or (3) CD4-cell counts persistently fewer than 100 cells per μL. Survival status was established through home follow-ups or hospital records, dependent on where deaths took place. We established the status of participants who withdrew from TASO records. CD4-cell counts were monitored by TASO staff every 6 months for all patients as part of their clinical care. CD4-positive cells were measured with TriTEST reagents (Becton-Dickenson, Franklin Lakes, NJ, USA), according to an inhouse dual-platform protocol and MultiSET and Attractors software (version 2.2) with a FACScan flow cytometer (Becton-Dickinson, Franklin Lakes, NJ, USA). Additional blood was taken to measure plasma viral load, but this testing was for research reasons and done in batches later. Plasma was separated within 2 h and stored immediately at −80°C. HIV-1 RNA was tested with the VERSANT RNA 3.0 (Bayer, Bayer HealthCare, NY, USA) assay (with a lower limit of detection of 50 copies per mL) for baseline samples, and the Amplicor MONITOR 1.5 (Roche, Roche Molecular Systems, NJ, USA) for other samples (400 per copies per mL). After we established close correlation between results of the two assays, the Amplicor assay was used to keep costs to a minimum. Our economic analysis took a societal perspective and included recurrent and capital costs incurred by the provider, transport and other related costs, and income lost by patients while accessing care. We reported all costs in 2008 US$; the mean exchange rate from 2005 to 2008 was 1732 Ugandan shillings to $1. Cost data and all data for care provided by TASO were obtained from TASO accounts. We used three steps to allocate costs. First, we established the proportion of all TASO clients who were receiving antiretroviral therapy. Second, we calculated the percentage of TASO clients on therapy who entered the trial. Both percentages changed over time, rising initially as numbers of patients who were put on therapy increased, and then falling when recruitment stopped. To capture this dynamic situation, we gathered and aggregated monthly cost data every 6 months, and converted data to US$ with the prevailing exchange rate, with adjustment for inflation. Third, we allocated costs to facility and home groups. When possible, we used actual service data—eg, information about numbers of doctor visits was used to allocate staff time. We assigned antiretroviral therapy costs proportionally by patient numbers in both groups for that period. Drug prices included purchase cost, insurance, and freight to Uganda and were adjusted to account for substantial price reductions that occurred early in the project. We established costs incurred by patients through a questionnaire. Health-services costs consisted of: staff costs (doctors, field officers, cousellors, and other staff), transport (motorcycle and vehicle costs of fuel and maintenance, and other transport costs); all drugs; laboratory and clinical expenses (radiograph, ultrasound, and laboratory and CD4 tests); sensitisation (AIDS education via radio, other media, and drama); training, teambuilding, and workshops; utilities (electricity, telephone, postage, and security), supervision and overheads (stationery, repairs, overheads, and supervision costs), and capital costs (buildings, furniture, vehicles, equipment, and inventory). Buildings depreciated over 50 years and other elements 5 years (eg, The AIDS Support Organisation practice). Patient costs consisted of: cost of transport (including transport of medicine companion), childcare, and lunches, if applicable, median weighted by proportion ($2·88 for women and $3·46 for men); and lost work time, estimated 1 day for clinic visits and 0·5 days for home visits, valued at Uganda mean per head gross domestic product from 2005–08 (World Bank data) for 300 working days per year. The primary endpoint was rate of virological failure, defined as time (starting from 6 months) to a plasma RNA viral load of more than 500 copies per mL. The secondary outcome measures were time to either detectable plasma viral load of more than 500 copies per mL at any visit from 12 months onwards in patients with viral loads of fewer than 500 copies per mL at 6 months, or an increase of 1000 copies per mL between two consecutive tests in those not achieving a viral load of fewer than 500 copies per mL at 6 months. Other secondary outcomes were all-cause mortality; virological failure as defined in the primary outcome or death; time to first admission; death, admission, or change to second-line antiretroviral therapy; outpatient attendance; adherence during the previous 28 days (measured with a standardised questionnaire); and costs incurred by the health service and patients.
BODY.METHODS.STATISTICAL ANALYSIS:
We designed the study as an equivalence trial. Virological failure time was taken as halfway between the last measure of RNA of 500 copies per mL or fewer and the first of more than 500 copies per mL. Testing was repeated in patients who had viral loads between 500 and 1000 copies per mL to exclude the possibility of small transient increases. We assumed that in one group the rate of virological failure during follow-up would be about 20%,20–22 and that the other group could be regarded as equivalent if the rate of virological failure did not exceed 20% by more than 9%—ie, 29% or less. Thus, the upper limit of our equivalence interval was 29/20 or 1·45, and by symmetry the lower limit was 20/29 or 0·69. A sample size of 20 clusters per group with a total of 1200 participants gave more than 95% power to show equivalence, on the assumption of a between-cluster coefficient of variation of 0·2. Analysis was by intention to treat, in which all participants were regarded as randomly assigned to the group corresponding to the cluster in which they lived. Analyses were done for the individual by fitting generalised linear mixed models with a log-link and poisson distribution, with every patient contributing an outcome of 1 if they had virological failure and 0 if they did not. The model had fixed terms for study regions, baseline CD4-cell counts (categorised as a four-level factor with counts of 0–49, 50–99, 100–149, and 150 or more cells per μL), and study groups, with the log of exposure time included as an offset variable, and a random term for study cluster. The model was fitted with the assumption that the random cluster effects followed a γ distribution. For the primary endpoint, exposure time was calculated from the 6-month visit to midway between the last date on which the patient did not have virological failure and the date of virological failure. For other endpoints, exposure time was calculated from enrolment. Those who withdrew or were lost to follow-up before 12 months were excluded from the primary endpoint analysis, and for other endpoints they were censored on the last date seen.
BODY.METHODS.ROLE OF THE FUNDING SOURCE:
Sponsor staff had a role in the study design, data collection, data analysis, data interpretation, and writing of the report. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication.
BODY.RESULTS:
Figure 1 shows the trial profile. The two groups were well balanced according to baseline characteristics apart from CD4-cell count, which was lower in the home-based than in the facility-based group (table 1). The median cluster size for home-based care was 36 people (range 6–84) and for facility-based care was 25 (2–65). Overall, 1403 patients (97%) were taking co-trimoxazole prophylaxis and 101 (7%) were being treated for tuberculosis. 119 patients withdrew during the course of the trial. Their status at the end of the trial was: three (3%, one from the facility and two from the home group) had died, 98 (82%, 48 facility and 50 home) were receiving antiretroviral therapy, one (<1%, facility) was alive and not receiving antiretroviral therapy, and 17 (15%, eight home and nine facility) were no longer in contact with TASO. The median follow-up of survivors on home-based care was 28 months (IQR 18–35) and on facility-based care was 27 months (13–34). Table 2 shows rates of virological failure, death, and hospital admission by group. Figure 2 shows HIV-RNA virological suppression and survival over time by study group. Rates of detection of plasma viral loads of more than 500 copies per mL after a 6-month visit were much the same in both groups. Also similar were the composite rates of either plasma RNA viral loads of more than 500 copies per mL after a 6-month visit in those who had undetectable viral loads at 6 months, or an increase in plasma RNA viral load of 1000 copies per mL between two consecutive tests in those who had detectable viral loads at 6 months. 184 (24%) patients having home and 145 (27%) facility care either had virological failure, were lost to follow-up, or withdrew from the trial (adjusted rate ratio [RR] 0·88, 95% CI 0·70–1·10). Mortality rates were much the same in the two groups during the study (figure 2). Combined mortality rates per 100 person-years were 16·47 (95% CI 13·69–19·82) during the first 5 months after treatment started, 6·69 (4·94–9·05) for 6–11 months, 2·71 (1·92–3·84) for 12–23 months, and 0·97 (0·54–1·76) for 24 months and after. By the end of the study, 566 (66%) participants in the home group and 377 (63%) in the facility group were alive, receiving follow-up, and had undetectable plasma viral loads. Admission diagnoses were similar in both groups (table 3). 20 (13%) patients who were admitted died (15 on home and five on facility care) and eight (5%) worsened and requested discharge (six on home and two on facility care)—seven died subsequently. Table 4 shows frequency of outpatient attendance at clinic, number of presentations in which a new diagnosis was made, and new diagnoses by number and type. Distribution of diagnoses was similar between groups and more than half were infectious and parasitic disease. CD4-cell counts increased rapidly in both groups (figure 3). 748 (87%) participants in home care and 521 (88%) in facility care were tested for CD4-cell count at least once after starting treatment, with median intervals between baseline and final tests of 32 months (IQR 25–39) for home and 29 months (23–35) for facility. 608 (81%) in home and 419 (80%) in facility had CD4-cell counts of greater than 200 cells per μL at the final visit. Counts at this visit were lower than baseline in 32 (4%) of those in home compared with 29 (6%) in facility care. At routine clinical and counselling reviews, home participants reported complete adherence to therapy in the past 28 days in 3698 of 3951 (94%) visits compared with 2527 of 2768 (91%) visits made by facility participants (figure 4). Patients were too sick to be interviewed in a further 78 (2%) home-group and 39 (1%) facility-group visits. Only two patients, both in home-based care, refused to answer adherence questions—saying they were in a hurry to return home. 138 (16%) of patients in home care had a drug substitution at a median 9 months (IQR 2–24) versus 123 (21%) in facility care at 8 months (3–22) after treatment started. Most substitutions were because of adverse reactions to antiretroviral therapy (table 5). Only one person in home-based and two in facility-based care had their first-line treatment changed to second-line. Table 6 shows mean yearly health services cost per patient calculated during 4 years, (including capital and recurrent expenses, and those of the starting phase and subsequent years). A large proportion of the costs were for drugs and staff salaries. The main cause of excess expenditure for the facility-based group was the increased number of contacts with health staff—especially with nurses and medical officers. These costs outweighed those of transport for field officers in the home-based group. Patient costs (transport of patient and companion, lunches, child care, and time lost from work) were much higher for the facility-based than for the home-based group (table 6). During the first year, when many visits were needed to start antiretroviral therapy, median yearly costs incurred by every patient were higher in facility than in home (table 6). Much of this expense was for transport. After the first year, patient costs for the home-based group were fairly low but remained high for the facility-based group, showing the economic burden of monthly clinic visits. Overall, the median cost of a clinic visit was $2·30—about 13% of reported monthly cash incomes for men and 20% for women.
BODY.DISCUSSION:
We have shown that a home-based HIV-care strategy with trained lay workers supporting drug delivery and monitoring patients was as effective as was a nurse-led and doctor-led clinic-based strategy for prevention of virological failure, mortality, and other adverse outcomes. For our primary endpoint of virological failure, the adjusted RR was contained between the pre-specified equivalence limits of 0·69 to 1·45. Results were similar for other endpoints. The home-based strategy did not result in higher costs for the health service. Moreover, home-based care was slightly cheaper than facility-based care by about $45 per patient per year, or 6% of the total cost. Costs incurred by patients to access care were much less for those in the home group than for those receiving facility-based care. We have identified a strategy to provide effective HIV care in the many settings in Africa in which clinical staff are scarce and patient access to clinics is difficult. Our findings were achieved in a standard resource-constrained health-service setting. Mortality rates in our facility-based group of about six deaths per 100 person-years and virological failure rates of nine per 100 person-years were better than or at least as good as were those reported from most other settings. Other researchers8,10,16,21,24–26 have reported mortality rates ranging from six to more than 15 deaths per 100 person-years and virological failure rates20–22,27,28 from 15% to more than 40% for 12–24 months. Thus, findings from our home-based care strategy were compared with a well functioning facility-based model and identified to be equivalent. Mortality rates in developed countries are about two deaths per 100 person-years27 and most of the increased mortality in Africa takes place during the first year of follow-up,29 as we identified. This mortality rate could be reduced through starting of antiretroviral therapy earlier than it is at present, but how people with HIV infection who need treatment can be identified early and encouraged to seek care is less clear, and needs to be investigated. Our study shows that community-based approaches would be important. We transferred care from the clinic to trained lay workers visiting homes of patients. The costs of the home visits were offset by the savings from reduced attendence at clinic—thus, 75% fewer clinic visits were made by patients in the home-based group, and 50% fewer consultations with a doctor took place when a new clinical disorder was recorded. We recorded no negative effect on survival, plasma viral load, or other outcomes. Patients had regular counselling and adherence support, especially in the home group in which support was personalised and often provided by the same individual. This support could have had a major positive effect on outcomes. Such an approach should be achievable throughout Africa since counsellors and other support staff are more easily available and rapidly trained than are clinical staff and incur much less expense for health services. A large randomised trial30 at two sites in Uganda and one in Zimbabwe recorded health-service costs of $846 (2008 exchange rate) for a model of laboratory and clinical monitoring at a health facility, which is similar to $793 in our home group and $838 in our facility group. Costs of access to care are a major burden for most African people, especially for those living in rural areas, because cash incomes are very low. In our study, one clinic visit was 15–20% of monthly earnings for most people. In Africa, high travel costs relative to income are major determinants of poor access to care, late presentation, poor adherence, and low retention of people in antiretroviral-therapy programmes.4,14,31 Our study shows that home-based care could substantially reduce costs for patients and this outcome might have a major beneficial effect on their long-term adherence and retention. In our study, TASO changed treatment to second-line therapy for three people only, which was substantially fewer than those who had falls in CD4-cell counts to less than their baseline or virological failure, showing the major differences in the diagnostic accuracy of clinical and laboratory assessments. When to change HIV treatment is a dilemma in many settings in Africa because of poor availability and high costs of second-line regimens and the absence of information about resistance to antiretroviral therapy—a situation that is unlikely to greatly change in the near future. We should, therefore, identify means to achieve the best possible adherence to extend the life of existing drugs. Our results suggest that community-based support of patients receiving antiretroviral therapy could lead to high adherence. Very few studies have been done in which models of care are randomly assigned because of strong preferences of some individuals for a specific method of care and the role of stigma, which might result from HIV status disclosure—eg, if a field worker from a known AIDS support organisation visits a patient in the community. We overcame these difficulties by developing a partnership with the service provider, the community, and with patients from the beginning when the research question was defined, and then held regular meetings with stakeholders to discuss difficulties and provide information. No monetary incentives were provided to either the service provider or patients. Only 41 (3%) of participants refused to join the trial or later withdrew and cited stigma as a reason. All received antiretrovirals from TASO or other providers. The importance and effects of stigma in the long term when patients have sustained improved health and, for example, resumed normal relationships, is unclear. However, we have shown that community-based HIV care is feasible and that stigma is probably not an impediment to increasing coverage in settings in which trust and good relations between service providers and the community are present. Our study could have been affected by selection bias, but numbers of refusals and withdrawals were low and almost identical in both groups. Most people who withdrew were alive at the end of the study—survival status was unknown for just 51 (4%) of participants. More were recruited in the home group than in the facility group but many more in the home group were screened, suggesting that this imbalance arose by chance. Median baseline CD4-cell count was also lower in the home group than in the facility group, but again this finding was probably attributable to chance (and was adjusted for in the analysis). These imbalances show the weakness of cluster-randomised trials32 in achievement of balance through randomisation, even in trials such as ours in which a large number of clusters were randomised. We have shown that home-based HIV care with antiretroviral therapy is an effective strategy, which relies less on clinical staff and hospital services than does facility-based care and provides large savings for patients. Such community-based strategies could enable improved and equitable access to HIV treatment—especially in areas in which clinical infrastructure is scarce and patient access to clinic-based care is poor. | 2,806,484 | {
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TITLE: A Randomized Controlled Trial Investigating the Effects of a Low–Glycemic Index Diet on Pregnancy Outcomes in Gestational Diabetes Mellitus
ABSTRACT.OBJECTIVE:
The prevalence of gestational diabetes mellitus (GDM) is rising. There is little evidence to demonstrate the effectiveness of one dietary therapy over another. We aimed to investigate the effect of a low–glycemic index (LGI) versus a conventional high-fiber diet on pregnancy outcomes, neonatal anthropometry, and maternal metabolic profile in GDM.
ABSTRACT.RESEARCH DESIGN AND METHODS:
Ninety-nine women (age 26–42 years; mean ± SD prepregnancy BMI 24 ± 5 kg/m2) diagnosed with GDM at 20–32 weeks' gestation were randomized to follow either an LGI (n = 50; target glycemic index [GI] ~50) or a high-fiber moderate-GI diet (HF) (n = 49; target GI ~60). Dietary intake was assessed by 3-day food records. Pregnancy outcomes were collected from medical records.
ABSTRACT.RESULTS:
The LGI group achieved a modestly lower GI than the HF group (mean ± SEM 47 ± 1 vs. 53 ± 1; P < 0.001). At birth, there was no significant difference in birth weight (LGI 3.3 ± 0.1 kg vs. HF 3.3 ± 0.1 kg; P = 0.619), birth weight centile (LGI 52.5 ± 4.3 vs. HF 52.2 ± 4.0; P = 0.969), prevalence of macrosomia (LGI 2.1% vs. HF 6.7%; P = 0.157), insulin treatment (LGI 53% vs. HF 65%; P = 0.251), or adverse pregnancy outcomes.
ABSTRACT.CONCLUSIONS:
In intensively monitored women with GDM, an LGI diet and a conventional HF diet produce similar pregnancy outcomes.
BODY:
Gestational diabetes mellitus (GDM) is commonly defined as any degree of glucose intolerance with onset or first recognition during pregnancy (1). In developed nations, between 4 and 8% of pregnant women are presently affected (2–4), and the prevalence will rise dramatically if the guidelines of the new International Association of Diabetes in Pregnancy Study Groups (IADPSG) are adopted (3). The main adverse outcome of GDM is excessive fetal growth resulting in higher risk of large-for-gestational-age (LGA) infants (birth weight >90th centile). Higher birth weight has been linked with childhood obesity (5), cardiovascular disease (6), and diabetes (5) later in life. In the medical management of GDM, the primary goal is to maintain maternal blood glucose concentrations, especially postprandial levels, within an acceptable range (7). Interventions that reduce postprandial glucose levels, including dietary strategies such as carbohydrate restriction, have been shown to be effective in reducing LGA and later obesity in type 1 diabetic offspring (8). Postprandial glycemia can be reduced without carbohydrate restriction by slowing down the rate of carbohydrate digestion and absorption. Compared with moderate–or high–glycemic index (GI) foods containing similar amount of carbohydrates, low-GI (LGI) foods have been demonstrated to reduce postprandial glucose in healthy individuals (9). The GI of various foods has been shown to be the same in pregnancy as in the nonpregnant state (10). An LGI meal pattern may therefore represent an alternative strategy for reducing postprandial glycemia in GDM without restricting carbohydrate (11). The effect of an LGI eating pattern on obstetric outcomes in GDM has been little studied. Moses et al. (12) found that a significantly higher proportion of women in the higher-GI group met the criteria to commence insulin compared with women in the LGI group. In addition, 47% of the women in the high-GI group who met the criteria for insulin commencement avoided insulin by switching to an LGI diet. However, they found no significant differences in key fetal and obstetric outcomes. To our knowledge, this study is the first randomized controlled trial to determine the efficacy of an LGI diet versus a conventional healthy diet on pregnancy outcomes in GDM. Our hypothesis was that an LGI diet would reduce birth weight (primary end point), birth weight centile, ponderal index, and the prevalence of LGA infants.
BODY.RESEARCH DESIGN AND METHODS:
This study was a two-arm parallel randomized controlled trial based at the Diabetes Antenatal Clinic of the Royal Prince Alfred Hospital, Camperdown, Australia. With the exception of the study dietitian (J.C.Y.L.), who provided the dietary education, all study personnel and participants were blinded to dietary assignment.
BODY.RESEARCH DESIGN AND METHODS.SUBJECT RECRUITMENT, RANDOMIZATION, AND STRATIFICATION:
Women aged 18–45 years diagnosed with GDM by a 75-g oral glucose tolerance test at 20–32 weeks' gestation, with an otherwise healthy singleton pregnancy, were eligible for the study. GDM diagnosis was based on the modified Australasian Diabetes in Pregnancy Society (ADIPS) criteria: fasting blood glucose level (BGL) ≥5.5 mmol/L, 1-h BGL ≥10.0 mmol/L, or 2-h BGL ≥8.0 mmol/L. Most women were tested at 26–32 weeks, but testing occurred earlier in those at high risk. Women who had special dietary requirements (including vegetarianism/veganism), preexisting diabetes, or pregnancy achieved by assisted reproduction and those who smoked or consumed alcohol during pregnancy were excluded. A total of 482 women were approached between September 2008 and November 2010, of whom 99 met the inclusion criteria and agreed to participate. The enrolled subjects were centrally randomized to study diet by computer-generated random numbers, stratified by BMI (BMI <30 vs. ≥30 kg/m2) and weeks of gestation (<28 or ≥28 weeks). The allocation sequence was unpredictable and concealed from the recruiter. Participants received routine GDM care regardless of dietary assignment, including instructions to monitor BGL before breakfast and 1 h after meals. The treating endocrinologist (T.P.M. or N.P.) reviewed the subjects every 2–4 weeks prior to 36 weeks and then every week until delivery. Insulin treatment was commenced if the mean fasting BGL or 1-h postprandial BGL in the preceding week exceeded 5.2 and 7.5 mmol/L, respectively.
BODY.RESEARCH DESIGN AND METHODS.DEMOGRAPHICS AND DIETARY ASSESSMENT:
At enrollment, demographic information, family history of diabetes, and ethnicity were recorded. Subjects were asked to recall their prepregnancy weight, were weighed, and were asked to complete a 3-day food record (including 2 weekdays and 1 weekend day) at baseline and again at 36–37 weeks' gestation. A two-dimensional food model booklet was provided to the subjects to assist in portion size estimation. Last recorded weight before delivery was obtained from the medical record.
BODY.RESEARCH DESIGN AND METHODS.DIETARY INTERVENTIONS:
Subjects were randomized to one of two healthy diets of similar protein (15–25%), fat (25–30%), and carbohydrate (40–45%) content—one with an LGI (target GI ≤50) and the other with a high-fiber content and moderate GI, similar to the Australian population average (HF) (target GI ∼60) (13–15). Both study diets provided all essential nutrients for pregnancy other than iron and iodine, which were supplemented as appropriate by the treating endocrinologist. The baseline 3-day food diary provided information on baseline dietary composition and served as the basis of individualized dietary counseling. Sample menus and their nutritional analyses are given in Supplementary Table A1. Subjects attended at least three face-to-face visits with the study dietitian, scheduled to coincide with regular antenatal visits. A 24-h recall of all food and drink intake was conducted during each session to assess compliance. In the case of noncompliance, suitable alternative foods were encouraged. Food sample baskets containing key foods for the assigned diet were provided to promote product recognition and dietary adherence. The content of the sample baskets is listed in Supplementary Table A2.
BODY.RESEARCH DESIGN AND METHODS.DATA COLLECTION:
Subjects provided blood samples at baseline and ∼36 weeks' gestation. Pregnancy outcomes, including birth weight, infant length, infant head circumference, and the need for emergency caesarean section, were obtained from the electronic medical records system. Gestational age was based on the last menstrual period and early pregnancy ultrasound. Birth weight centile was calculated using a macro program for Microsoft Excel (available from http://www.gestation.net) that adjusted for ethnic differences (16). The calculated birth weight centile was used to categorize the infant as small for gestational age (birth weight <10th centile), normal, or LGA (birth weight >90th centile). Ponderal index, an estimate of neonatal adiposity, was calculated as birth weight in kg × infant length (m)−3. Macrosomia was defined as birth weight >4 kg.
BODY.RESEARCH DESIGN AND METHODS.NUTRITIONAL ANALYSIS AND ASSESSMENT OF COMPLIANCE:
The study dietitian entered the food records into Australian nutrition analysis software based on AUSNUT2001 (FoodWorks Professional 2009; Xyris Software, Brisbane, Australia). The GI of individual food items was assigned according to a published method (17). Dietary glycemic load (GL) was calculated as follows: ∑ GI × available carbohydrate of each food in a day/100. Dietary GI was calculated as follows: (dietary GL/total daily available carbohydrate) × 100. Subjects were deemed compliant if their final dietary GI was ≤50 in the LGI group and >50 in the HF group.
BODY.RESEARCH DESIGN AND METHODS.POWER CALCULATION:
Based on previous data, the study was designed to provide 80% statistical power to detect an ∼260 g difference in birth weight, with 60 subjects in each group. Recruitment was halted at 99 subjects because the SD in birth weight among the study population was smaller than expected. In the primary analysis, the observed SD of 416 g in birth weight provided 80% power to detect a group difference of 246 g in birth weight or an ∼17% point difference in birth weight centile.
BODY.RESEARCH DESIGN AND METHODS.STATISTICAL ANALYSES:
A biostatistician blinded to the diet allocation performed the statistical analyses. The primary analysis included all women randomized who attended at least one dietary education session but excluded those with preterm delivery (<37 weeks; n = 4; two from each group) regardless of compliance. All statistical analyses were performed with SPSS (version 19; IBM Australia, St. Leonards, Australia). Results for continuous data are reported as mean ± SD or mean ± SEM, and categorical data (e.g., need for insulin) are reported as percentage. Pearson χ2 test was used to test for differences between groups for categorical data, and continuous data were tested using one-way ANOVA. A paired t test was used to assess within-group changes from baseline to final outcomes. The study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the Human Research Ethics Committee of the Sydney South West Area Health Service (Royal Prince Alfred Hospital Zone). Informed consent was obtained from all subjects in this study.
BODY.RESULTS:
The flow of subjects through the study is shown in Supplementary Fig. 1. Of the 99 subjects recruited, four delivered prematurely (<37 weeks) and three withdrew before the first dietary instruction session, leaving 92 subjects in the primary analysis. Subject characteristics are shown in Table 1. At baseline, subjects in the LGI group had significantly higher 2-h postload blood glucose levels (LGI 8.6 ± 1.2 mmol/L vs. HF 8.0 ± 1.3 mmol/L; P = 0.024) but were otherwise similar to those in the HF group. At baseline, both groups had a relatively LGI diet (LGI 49 ± 1 vs. HF 52 ± 2) (Table 2). At the end of the intervention (36–37 weeks' gestation), the diets were matched for macro- and micronutrients, but the LGI group had a significantly lower GI and GL than the HF group as per protocol (both P < 0.001). Compared with data at baseline, intake of fat, fiber, calcium, iron, zinc, and folate significantly increased in subjects in the LGI group. Subjects in the HF group had increased energy intake and GL but not GI. The results were similar in the secondary analysis of "compliers" only except that compliers in the LGI group (n = 30) had significantly decreased their GI, whereas those in the HF group (n = 34) remained unchanged from baseline (data not shown). Table 1 Subject characteristics LGI HF P * n 47 45 — Age (years) 34.0 ± 4.1 32.4 ± 4.5 0.062 Prepregnancy BMI (kg/m 2 ) 23.9 ± 4.4 24.1 ± 5.7 0.837 Ethnicity (%) Asian 59.6 55.6 0.697 Caucasian 31.9 40.0 0.419 Others 8.5 4.4 0.430 Week of gestation at diagnosis 26.1 ± 4.0 26.0 ± 4.3 0.951 Family history of type 2 diabetes (%) Maternal 23.4 20.0 0.692 Paternal 21.3 33.3 0.194 Week of gestation at start of intervention 29.0 ± 4.0 29.7 ± 3.5 0.410 75-g OGTT results (mmol/L) Fasting 4.6 ± 0.5 4.7 ± 0.7 0.279 1 h 9.4 ± 1.4 9.7 ± 1.6 0.501 2 h 8.6 ± 1.2 8.0 ± 1.3 0.024 Nulliparous (%) 61.7 64.4 0.785 Data are mean ± SD except for ethnicity, family history of type 2 diabetes, and nulliparous, which are expressed as percentages. OGTT, oral glucose tolerance test. * P values calculated by one-way ANOVA for continuous variables and Pearson χ 2 for categorical variables. P < 0.05 indicates statistical significance. Table 2 Baseline and end-of-intervention diet analysis Baseline P * End of intervention P * P † LGI HF LGI HF LGI HF n 44 40 42 42 Energy (kJ) 7,240 ± 240 6,630 ± 260 0.089 7,680 ± 260 8,090 ± 300 0.307 0.141 <0.001 Protein (g) 99.2 ± 4.4 93.1 ± 5.4 0.389 107.5 ± 4.2 107.2 ± 5.6 0.971 0.100 0.049 Total fat (g) 70.2 ± 3.7 61.4 ± 3.1 0.073 71.2 ± 3.5 75.3 ± 5.6 0.532 <0.001 0.029 Saturated fat (g) 23.5 ± 1.3 22.3 ± 1.4 0.553 24.2 ± 1.3 28.8 ± 3.1 0.181 0.515 0.090 Monounsaturated fat (g) 27.0 ± 1.7 22.4 ± 1.3 0.035 27.4 ± 1.6 26.8 ± 1.7 0.797 0.887 0.034 Polyunsaturated fat (g) 12.6 ± 0.9 10.1 ± 0.7 0.032 13.5 ± 0.8 12.5 ± 1.3 0.488 0.465 0.065 Total available carbohydrate (g) 165.1 ± 5.4 155.0 ± 7.9 0.289 177.8 ± 5.9 194.8 ± 6.2 0.051 0.066 <0.001 Sugars (g) 59.1 ± 3.3 56.0 ± 15.5 0.470 66.9 ± 4.1 70.5 ± 2.7 0.464 0.087 <0.001 Starch (g) 105.0 ± 3.5 99.6 ± 8.1 0.523 111.1 ± 4.1 124.6 ± 5.6 0.056 0.190 0.001 Dietary fiber (g) 23 ± 1 21 ± 1 0.245 27 ± 1 25 ± 1 0.222 0.001 0.012 Calcium (mg) 887 ± 54 915 ± 41 0.680 1,080 ± 62 1,030 ± 43 0.507 0.005 0.013 GI 49 ± 1 52 ± 2 0.171 47 ± 1 53 ± 1 <0.001 0.187 0.600 GL 81 ± 3 84 ± 6 0.598 84 ± 3 105 ± 4 <0.001 0.453 0.001 Data are mean ± SEM. * P values calculated by one-way ANOVA to test for difference between groups. † P values calculated by paired sample t test to test for difference compared with baseline. At the end of the intervention, biochemical parameters were similar between groups (Table 3). The results were similar in the compliers-only analysis (data not shown).In the primary analysis, there were no significant differences between groups in any of the pregnancy outcomes (Table 4). Fewer women in the LGI group gained an excessive amount of weight according to the American Institute of Medicine guidelines (LGI 25% vs. HF 42%; P = 0.095). Compliers in the LGI group appeared to gain less weight than those in the HF group (LGI 11.2 ± 0.9 kg vs. HF 13.7 ± 1.0 kg; P = 0.073). There was no significant difference in fetal abdominal circumference at 36–37 weeks' gestation (mean ± SEM LGI 327.6 ± 19.2 mm vs. HF 322.6 ± 14.6 mm; P = 0.186). Additional analyses with adjustments for ethnicity (Asian vs. Caucasian), BMI; oral glucose tolerance test results; baseline characteristics including daily intakes of energy, monounsaturated fatty acid, polyunsaturated fatty acid, and sodium; fasting BGL; fasting insulin; homeostasis model assessment of insulin resistance; and total cholesterol did not change the lack of significance of the between-group comparisons. Table 3 Biochemical parameters at baseline and end of intervention Baseline P * End of intervention P * LGI HF LGI HF n Mean ± SEM n Mean ± SEM n Mean ± SEM n Mean ± SEM BGL (mmol/L) 44 4.7 ± 0.1 42 4.6 ± 0.1 0.665 42 4.3 ± 0.1 32 4.4 ± 0.1 0.464 Insulin (pmol/L) 44 73.1 ± 9.4 42 70.5 ± 5.3 0.813 40 83.8 ± 16.1 30 73.0 ± 5.2 0.525 HOMA2-IR (%) 44 1.3 ± 0.2 42 1.3 ± 0.1 0.780 38 1.2 ± 0.1 39 1.3 ± 0.1 0.670 Fructosamine (μmol/L) 43 202.3 ± 2.5 41 199.9 ± 2.3 0.479 41 196.3 ± 2.3 40 193.7 ± 2.2 0.412 HbA 1c (%) 44 5.4 ± 0.1 42 5.4 ± 0.1 0.995 43 5.5 ± 0.1 41 5.5 ± 0.0 0.665 HOMA2-IR, homeostasis model assessment of insulin resistance. * P values calculated by one-way ANOVA to test for difference between groups. Table 4 Pregnancy outcomes by diet group LGI HF P * n Value n Value Gestational age (weeks) 47 39.1 ± 0.1 45 39.2 ± 0.1 0.552 Birth weight (kg) 47 3.3 ± 0.1 45 3.3 ± 0.1 0.619 Birth weight centile 47 52.5 ± 4.3 45 52.2 ± 4.0 0.969 LGA (%) 47 12.8 45 4.4 0.157 Small for gestational age (%) 47 10.6 45 8.9 0.778 Macrosomia (%) 47 2.1 45 6.7 0.286 Infant head circumference (cm) 43 34.4 ± 0.2 39 34.6 ± 0.3 0.478 Infant length (cm) 47 49.7 ± 0.3 45 49.7 ± 0.3 0.995 Ponderal index (kg/m 3 ) 47 27.2 ± 0.3 45 27.0 ± 0.4 0.614 Maternal weight gain (kg) 44 11.9 ± 0.7 43 13.1 ± 0.9 0.305 Below target (%) † 31.8 25.6 0.520 Within target (%) † 43.2 32.6 0.307 Above target (%) † 25.0 41.9 0.095 Insulin treatment (%) 47 53.2 45 65.1 0.251 Final daily insulin dose (units) 47 17.7 ± 4.1 43 20.0 ± 3.8 0.676 Emergency caesarean (%) 44 20.5 44 11.6 0.263 Data are mean ± SEM or percent. * P values calculated by one-way ANOVA for continuous variables and Pearson χ 2 for categorical variables. P < 0.05 indicates statistical significance. †Based on Institute of Medicine. Weight gain during pregnancy: reexamining the guidelines [article online], 2009. Available from http://www.iom.edu/~/media/files/report%20files/2009/weight-gain-during-pregnancy-reexamining-the-guidelines/report%20brief%20-%20weight%20gain%20during%20pregnancy.pdf .
BODY.CONCLUSIONS:
Contrary to our hypothesis, this randomized controlled trial of an LGI diet versus a conventional high-fiber diet found no differences in key pregnancy outcomes in GDM. Average infant birth weight, birth weight centile, and ponderal index were within healthy norms in both groups. One explanation for the findings is that both groups of women achieved a relatively LGI diet, with only a modest 5-point difference between groups. Irrespective of dietary assignment, all had received early nutrition counseling in a group setting. Thus, on enrollment, both groups were found to be consuming a diet with a lower GI than population norms. Compared with routine care in another Australian study (18), both dietary interventions resulted in a lower prevalence of LGA (9 vs. 22%), macrosomia (4 vs. 21%), and emergency caesarean section (16 vs. 20%). Hence, in the setting of intensive medical management of GDM, our findings suggest that both an LGI and HF diet produce optimal pregnancy outcomes. Our findings increase the evidence supporting the safety and efficacy of an LGI diet in GDM. Moses et al. (12) also found no significant differences in key fetal and obstetric outcomes between subjects who followed an LGI diet (GI = 48) versus a higher-GI diet (GI = 56). However, unlike in the current study, they found that a significantly higher proportion of women in the higher-GI group met the criteria to commence insulin (59 vs. 29% in the LGI group). In addition, almost one-half of the women in the higher-GI group who met the criteria for insulin commencement avoided insulin by switching to an LGI diet. Their insulin treatment protocol, however, was different from that of the current study, in which more stringent criteria were used as the basis for insulin treatment. A recent Canadian study (19), in which women with GDM or impaired glucose tolerance monitored their own blood glucose levels, found that those who were randomized to an LGI diet versus those assigned to the conventional diet had a greater proportion of their 2-h postprandial levels on or below the treatment target. Although there was a tendency for higher birth weight in the control group, the study was a pilot and underpowered to detect a statistically significant difference. Another explanation for our findings is the relatively normal weight of most of our subjects (68% had a BMI <25 kg/m2). It is possible that an LGI diet may be more effective among overweight and obese gravidas with higher degrees of insulin resistance and β-cell deficiency (20). Rhodes et al. (21) reported higher head circumference and a lower proportion of early delivery (<38 weeks' gestation) in overweight and obese nondiabetic pregnant women assigned to a low GL diet. However, there was no significant difference in birth weight, ponderal index, or pregnancy weight gain, which are more sensitive to maternal glycemic control (22). The lack of difference in our study may also relate to the timing and duration of the intervention. Dietary instruction began at the start of the third trimester (29 weeks' gestation) and lasted, on average, 6–7 weeks. It is likely that maternal hyperglycemia during the first and second trimester will also drive excessive fetal growth. In a post hoc analysis of women who started dietary intervention before 25 weeks of gestation (10 from the LGI group and 5 from the HF group), those in the LGI group showed a tendency to lower birth weight (LGI 3.2 ± 0.2 kg vs. HF 3.5 ± 0.1 kg; P = 0.224) and lower birth centile (LGI 45.3 ± 11.0 vs. HF 57.5 ± 12.2; P = 0.476), suggesting that an earlier intervention may be beneficial. However, apart from a small number of high-risk women who are screened early, in most countries GDM screening occurs at 26–28 weeks' gestation (23,24), which means that any intervention in GDM will be necessarily short. A more viable test of our hypothesis would therefore be an appropriately powered study in women at high risk of developing GDM (e.g., women with a BMI >30 kg/m2 or previous GDM), starting on or before the start of the second trimester, to determine the effect of an LGI diet on both pregnancy outcome and risk of developing GDM. The failure to achieve the target GI of ∼60 in the HF group could reflect high recognition of the GI concept among Australians diagnosed with diabetes, particularly among those with higher education (in the current study, two of three subjects had a university degree). In the group education session conducted soon after diagnosis, all the women, irrespective of future dietary assignment, were encouraged to limit total carbohydrate to ∼180 g per day and to consume a greater proportion as fruit and dairy products—changes which are likely to lower the GI of the overall diet. Self-monitoring of blood glucose levels was also encouraged and may have provided feedback that discouraged consumption of high glycemic foods. Finally, the use of data collected from medical record may be subject to inaccuracy, e.g., birth weights were measured and entered by different staff, therefore biasing the result toward the null hypothesis. In conclusion, we found that both an LGI diet and a conventional high-fiber diet produced comparable pregnancy outcomes in women with GDM. Both groups achieved a relatively low GI diet and had mean birth weight, birth weight centile, and pregnancy weight gain within population norms. An LGI diet appears to be a safe alternative to the traditional pregnancy diet for women with GDM and expands the range of dietary strategies that can be offered. Further studies in overweight and obese individuals and earlier interventions in women with risk factors for GDM are warranted.
BODY.SUPPLEMENTARY MATERIAL:
Supplementary Data
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TITLE: A randomized comparison between three types of irrigating fluids during transurethral resection in benign prostatic hyperplasia
ABSTRACT.BACKGROUND:
Central nervous system changes, circulatory and electrolyte imbalances are the main complications of endoscopic transurethral resection of the prostate (TURP) which is known as transurethral resection (TUR) syndrome, which occurs as result of excessive absorption of irrigating fluid. We compare glycine 1.5% versus glucose 5% and normal saline 0.9% as irrigating solutions during TURP in patients with moderate to severe bladder outlet obstruction due to benign prostatic hyperplasia (BPH).
ABSTRACT.METHODS:
Three hundred sixty patients with symptomatic BPH were randomized into a prospective, controlled trial comparing the three irrigation modalities. One-hundred twenty patients used glycine 1.5% solution as irrigating fluid (glycine group), 120 patients used glucose 5% solution (glucose group) and 120 patients used normal saline 0.9% solution (saline group). Patient's demographics, operation time, hospital stay, postoperative amino acid glycine assay, postoperative serum cardiac troponin I and perioperative complications were noted.
ABSTRACT.RESULTS:
No difference was found between the groups in the immediate postoperative levels of hemoglobin and hematocrite. A high glycine level was associated with the TUR syndrome. Seventeen patients had TUR syndrome; all were in glycine group and they had the highest postoperative amino acid glycine levels. Slight increase in serum sodium (142.6 ± 12.6 mmol/l) was detected in saline group. Transient Hyperglycemia (170 ± 35.9 mg/dl) and hypokalemia (3.67 ± 0.92 mmol/l) occurred in the immediate postoperative period in the glucose group.
ABSTRACT.CONCLUSION:
Endoscopic TURP performed using either glucose 5% or saline 0.9% irrigating solution during and after surgery is associated with lower incidence of TUR syndrome, lower catheterization period, shorter hospital stay and no cardiac toxicity in comparison with glycine 1.5% solution.
ABSTRACT.TRIAL REGISTRATION:
This clinical trail had been approved and registered in PACT Registry; with identification number for the registry is ATMR2010010001793131.
BODY.BACKGROUND:
Many endoscopic surgical procedures require the use of an irrigating fluid to dilate the operating field and to wash away debris and blood. A potential complication of such irrigation is a systemic absorption of the fluid to the extent that overt symptoms are produced [1]. The ideal irrigant for endoscopic resection would be a user-friendly, non-conductor medium that does not interfere with diathermia, has a high degree of translucency, has similar osmolarity to the serum and causes only minimal side effects when absorbed [2]. There are several different irrigating fluids available commercially and it may be difficult to know which one to use. The choice tends to be governed largely by tradition, although the price and properties of the fluid (e.g. stickiness and transparency) also play a role. The pharmacological effects of the fluid become important whenever it is absorbed by the patient. Glycine is an endogenous amino acid without an allergic reaction potential. It is transparent and reasonably inexpensive. However, the solution is unphysiological because it lacks electrolyte and excessive absorption is a recognized complication [3]. Nausea, vomiting, confusion and arterial hypotension occur significantly more often when between 1.000 and 2.000 ml of glycine solution are absorbed. Severe forms of TUR syndrome are more rare but they require treatment in the intensive care unite (ICU) at least over night. The incidence and severity of symptoms of TUR syndrome increase progressively as more glycine solution is absorbed during TURP and the severity of symptoms is markedly aggravated when more than 3,000 ml are absorbed [4]. Deaths have been reported in patients undergoing TURP. Laboratory studies in animals showed that glycine has direct and indirect cardiotoxic effects [5]. Unlike glycine, glucose is a physiological solution that is readily metabolized when absorbed in most patients [6]. The aim of this study is to compare perioperative morbidity, operation time, and length of hospital stay for glycine 1.5% versus glucose 5% and saline 0.9% as irrigating solutions during TURP in patients with moderate to severe bladder outlet obstruction due to benign prostatic hyperplasia (BPH).
BODY.METHODS:
After the study was approved by an Investigational Review Board of Faculty of Medicine, Tanta University, an informed consent was obtained from patients participating in the study. Randomization was performed by computer-generated random allocations sequence by simple randomization. A total of 360 patients undergoing TURP for BPH at Urology Department, Tanta University Hospitals were included in the study. Patients were divided into three groups according to the irrigating fluid used and randomly allocated to use either glycine 1.5% solution (glycine group, n = 120), glucose 5% (glucose group, n = 120) or normal saline 0.9% solution (saline group, n = 120) as irrigating fluid during and immediately after TURP (Figure 1). TURP was performed using 24 Ch continuous irrigating resectoscope (Storez, Tottling, Germany). Patients in saline group used bipolar loop (Storez, Tottling, Germany) as a working element for bipolar current, while the other two groups used 24Ch cutting loop and 24Ch roller loop as a working element for resectoscope for monopolar current (Storez, Tottling, Germany). Figure 1Schematic presentation of patient flow through out trail period. The operating room nurse assisting in the procedure randomized the patients and prepared the irrigating fluids appropriately, also enrolled the participants and assigned participants to their respective groups. All patients had been designed to receive spinal anesthesia in the form of 2.5 ml 0.5% hyperbaric bupivacaine mixed with fentanyl 20 μg intrathecally, commencement of surgery is allowed when adequate sensory block to T 10 at the umbilical level was achieved. Surgical intervention was performed by surgeons of the same qualification and clinical experience. Evaluation of the patients included complete medical history, ultrasound for abdomen and pelvis, routine laboratory investigations (complete blood count, blood urea nitrogen, blood sugar, serum sodium, potassium, prothrombin time, albumin) and prostatic specific antigen (PSA). Immediate preoperative as well as postoperative hemoglobin, hematocrite, serum sodium and potassium, blood urea, serum creatinine, random blood glucose, serum osmolarity, arterial blood gas, as well as serum troponin-I as a cardiac cell injury marker were measured. No patients had received colloid, plasma products, hypertonic saline, diuretic therapy or blood transfusion approximately 10 hours before surgery. Exclusions criteria included patients with bleeding disorders or existing coagulopathy, diabetes mellitus or other metabolic acidosis and apparent cardiac disease with ECG evidence of ischemia, history of myocardial infarctions and congestive cardiac failure, renal insufficiency as well as any contraindication to spinal anesthesia. All patients were pre-loaded with 500 ml ringer solution one hour before induction of spinal anesthesia. No patients received intravenous glucose or glucose saline before, during or immediately after surgical procedure. Central venous pressure catheter was inserted just before surgery to judge the status of the intravascular volume and trans-compartmental fluid shift. Hemodynamic monitoring including: heart rate (HR), electrocardiogram (ECG), mean arterial blood pressure (MABP) and central venous pressure (CVP) were recorded. Hypotension, defined as 20% fall in blood pressure from pre-induction levels or a systolic blood pressure lower than 100 mmHg, was treated immediately by intravenous injecting of 5-10 mg ephedrine. The amount of irrigation fluids used in each patient is calculated depending upon gravimetric methods and the height of the irrigating fluid reservoir is fixed at 60 cm height from patients' bed. TUR syndrome was defined as sodium of 125 mmol/l or less after TURP with 2 or more symptoms or signs of TUR syndrome such as nausea, vomiting, bradycardia, hypotension, chest pain, mental confusion, anxiety, parasthesia and visual disturbance [7]. Operative details including operation time, resected tissue weight, irrigating volume used, evidence of prostatic capsule perforation, catheterization time, duration of hospital stay as well as any perioperative complication were recorded. The medical and nursing stuff involved in patients care, monitoring in the post-operative period and assessment of the complications and the incidence and the severity of TUR syndrome were completely blinded to the patient's group assignment and the type irrigating fluid used.
BODY.METHODS.GLYCINE ASSAY USING THIN LAYER CHROMATOGRAPHY:
Thin layer chromatography is semi-quantitative method for amino acid glycine separation and assay. The principle of separation depends on differences in both the degree of adsorption by the adsorbent and solubility in the solvent used for separation, using a uniform thin layer of adsorbent on a supporting glass plate then plates are dried in an oven at 100-120°C [8].
BODY.METHODS.TROPONIN I ASSAY:
It is a qualitative membrane fixed immunoassay for the detection of calcium troponin I (cTnI) in whole blood, serum or plasma. The membrane is pre-coated with capture reagent in the test line regions. During the test, the serum or plasma sample react with the particle coated anti-c TnI antibodies. The mixture migrates upward on the membrane chromatographically by capillary action to react with capture reagent on the membrane and generate a colored line according to the manufacturer guide (ACON Laboratories, Inc. San Diego, USA). The presence of this colored line in the test line region indicates a positive result; while its absence indicates negative results [9].
BODY.METHODS.STATISTICS:
Continuous parametric data variables are reported as mean ± SD and were analyzed with analysis of variance, while categorical and non-parametric variables were analyzed using x2 tests. A p value < 0.05 was considered significant. Based on a previous study of fluid irrigation of TUR syndrome, considering a 0.05 2-sided significance level, a power of 80%, and allocation ratio of 1:1, and allowing for 10% attrition/non-compliance rate, a group size contains 100-120 patients in each group were estimated to be sufficient [2,6]. This clinical trail had been approved and registered in PACT Registry; with identification number for the registry is ATMR2010010001793131.
BODY.RESULTS:
The age of the patients ranged from 53 to 70 years old (60.7 ± 5.1) in the glycine group and 55-71 years old (60.9 ± 4.9) in the glucose group while it was 50-67 years old (62 ± 6.5) in the saline group. The operation time range was 45-70 min in glycine group (57.1 ± 8.2) and it was 40-75 min (58.3 ± 10.8) minutes in glucose group while it was 55-80 min (62.5 ± 11.2) in saline group. The mean amount of prostatic tissue resected was 89.16 gm ± 18.3(range70 to 125) gm in the glycine group and 91.9 gm ± 16 (range 75 to 120) gm in the glucose group while it was 82.5 gm ± 15.5 in saline group (range70-110). Only12 resections in glycine group and 8 in glucose group the amount of tissue resected exceed or equal to 120 gm. The indwelling catheter was removed after 2.4 ± 0.71 days (range 2 to 4) in the glycine group and after1.67 ± 0.45 days (range1 to 2) in the glucose group while after 1.54 ± 0.34 (range1 to2) in saline group. Hospital stay was 3.31 ± 0.63 days (range3 to 5) in glycine group and 2.29 ± 0.46 days (range 2 to 3) in glucose group, while it was 2.19 ± 0.38 days in saline group (range 2 to 3). (Table 1) Table 1 Patients characteristic of studied groups. (Means ± SD) Glycine group (n = 120) Glucose group (n = 120) Saline group (n = 120) Age (years) 60.7 ± 5.1 60.9 ± 4.9 62 ± 6.5 Operative time (min) 57.1 ± 8.2 58.3 ± 10.8 62.5 ± 11.2 Resection wt (gm) 89.16 ± 18.3 91.94 ± 16 82.5 ± 15.5 Catheterization time (days) 2.4 ± 0.71 1.67 ± 0.45 1.54 ± 0.34 Hospital stay (days) 3.31 ± 0.63 2.29 ± 0.46 2.19 ± 0.38 Analysis of variance tests were used. The hemodynamic changes regarding heart rate (HR), mean arterial blood pressure (MABP) and central venous pressure (CVP) were compared between groups. There was no significant difference in the preoperative mean value of HR (beat/min) between the studied groups. Ten minutes after induction of anesthesia, there was a significant decrease in the mean value of HR (57.5 ± 12.6 beat/min & 56.4 ± 13.5 beat/min & 54.6 ± 11.9 beat/min) in the glycine, glucose and saline groups respectively. Then, no significant change was found through out the intra-operative and immediate postoperative period in the studied groups. There was no significant difference in the preoperative average MABP (mmHg) between the studied groups. Ten minutes after induction of anesthesia, there was a significant decrease in the average MABP (71.6 ± 19.6 mmHg & 73.4 ± 18.5 mmHg & 72.5 ± 18.8 mmHg) in the glycine, glucose and saline groups respectively. Then, No significant change in the average MABP was found in the studied groups through out the study period. The mean value of CVP in the studied groups was similar in the preoperative period in the studied groups. Then, significant decrease in the mean value (3.26 ± 0.95 cm/H2O & 3.1 ± 0.85 cm/H2O & 3.3 ± 0.7 cm/H2O) occurred 10 min after induction of anesthesia in the glycine, glucose and saline groups respectively. After 20 and 30 min, no significant change was found in the studied groups, however, significant increase in the mean value of CVP was measured at 60 min to mean value of (8.5 ± 2.4 cm/H2O & 8.4 ± 2.12 cm/H2O & 9.2 ± 2.6 cm/H2O) and (9.5 ± 2.54 & 9.4 ± 2.15 cm/H2O & 10.2 ± 2.95 cm/H2O) in the postoperative period in the studied groups respectively. (Table 2) Table 2 Homodynamic changes in the studied groups. (Means) Pre-op Gly/Glu/Sal 10 min Gly/Glu/Sal 20 min Gly/Glu/Sal 30 min Gly/Glu/Sal 60 min Gly/Glu/Sal post-op Gly/Glu/Sal HR 62.4/64.2/63.6 57.5*/56.4*/54.6* 63.2/63/62.6 64.1/64/63.6 60.26/61.5/64.5 60.9/61.8/65.2 MABP 90.3/91.5/92.6 71.6*/73.4*/72.5 * 87.9/88.8/94 89.2/91.2/96.4 91.6/95.8/98.2 93.2/96.1/99.4 CVP 5.15/5.3/5.9 3.26*/3.1*/ 3.3* 5.6/5.09/5.2 6.66/6.4/5.9 8.5*/8.4*/9.2* 9.5*/9.4*/10.2* Gly/Glu/Sal : Glycine/Glucose/Saline groups, MABP : mean arterial blood pressure (mmHg), CVP : central venous pressure (cm/H 2 o), HR : heart rate (beat/m). *Statistically significance (p < 0.05%). Analysis of variance tests were used. There was no significant difference in the mean value between the studied groups regarding the preoperative hemoglobin, serum sodium, serum potassium and random blood sugar. Insignificant decrease in the postoperative serum sodium was observed in glycine and glucose groups, while insignificant increase was observed in saline group (142.6 ± 12.6 mmol/l). Insignificant reduction in serum potassium in glycine and saline group was observed, but more pronounced decrease in glucose group (3.67 ± 0.92 mmol/l) was measured postoperatively. There was a significant elevation in the postoperative mean value of blood sugar level in the glucose group (170.2 ± 35.9 mg/dl) which returned back to normal level 6 hours postoperatively. (Table 3) Table 3 Chemical and hematological values of studied groups in the immediate postoperative period. (Means ± SD) Glycine group (n = 120) Glucose group (n = 120) Saline group (n = 120) Hemoglobin (gm/dl) 11.1 ± 1 10.9 ± 9 11.4 ± 1.2 Sodium (mmol/l) 134.7 ± 13.4 135.5 ± 12.9 142.6 ± 12.6 Potassium (mmol/ l) 3.87 ± 1.17 3.67 ± 0.92 4.16 ± 1.32 Random blood sugar (mg/dl) 113.5 ± 25.5 170.2* ± 35.9 116.8 ± 28.4 * Statistically significance (p < 0.05%). Analysis of variance tests were used. Two Patients in glycine and another 2 patients in glucose group needed blood transfusion, who experienced a decrease in hemoglobin concentration to less than 9 g/dl. TUR syndrome developed in 17 patients in the glycine group but non in neither glucose nor saline groups. Elevated glycine levels was observed in 36 patients in glycine group of whom the highest 17 values suffered TUR syndrome. Six patients in the glycine group developed ischemic ECG changes. Three patients in glycine group developed elevated troponin I. These patients admitted to post anesthesia care unite for proper treatment. (Table 4) Table 4 Peri-operative complications in the studied groups. Glycine group (n = 120) Glucose group (n = 120) Saline group (n = 120) TUR syndrome 17* 0 0 ECG changes 6 0 0 Elevated glycine 36* 0 0 Elevated tropnin-I 3 0 0 Clot retention 0 0 1 Blood transfusion 2 2 0 Urinary retention 0 0 0 Statistically significance (p < 0.05%). X 2 test was used. TUR syndrome: trans-urethral resection syndrome.
BODY.DISCUSSION:
This randomized single blinded trail was performed in patients with prostatic hyperplasia admitted for endoscopic resection of the prostate using three different types of irrigating fluids during resection, demonstrated high incidence of TUR syndrome in patients used glycine 1.5% solution, while non in neither glucose nor saline groups developed TUR syndrome. Elevated glycine levels was observed in patients in glycine group of whom the highest values suffered TUR syndrome and was associated with ischemic ECG changes and elevated troponin I in these patients. The use of an irrigating fluid during many endoscopic surgical procedures is mandatory to dilate the operating field and to wash away debris and blood. The systemic absorption of such an irrigating fluid may be associated with serious complications. Large-scale fluid absorption is rare but leads to symptoms severe enough to require intensive care. Patho-physiological mechanisms consist of pharmacological effects of irrigant solutes, the volume effect of irrigant water, dilutional hyponatraemia and brain edema [1]. Glycine solution is the most commonly used irrigant in TURP. Many studies performed on human denoting that glycine absorption causes echocardiogram changes and it is associated with increased troponin I [6]. Another experimental studies showed that glycine has a cardio-toxic properties and fluid absorption during TURP has devitalizing effect on the heart [10]. High glycine levels are suspected of causing cerebral edema [11], visual disturbances and even transient blindness [12,13]. Hyper-ammonaemic encephalopathy may develop as ammonia is an intermediate product in glycine metabolism [14]. Another disorder of glycine metabolism characterized by episodes of ketosis and metabolic acidosis that may proceed to coma had been reported [15]. Potentially safer alternatives to glycine irrigation are normal saline 0.9% and glucose 5% to be used as irrigating fluid during TURP. Normal saline is the ideal irrigation fluid for TURP; however its electrical conducting properties prohibit its use with conventional monpolar TURP system in the past. The advance of using bipolar resectoscope that allows resection using normal saline allows us to use it safely with no risks of precipitating hyponatreamia which is the main pathology in TUR syndrome. However, it is rapid infusion of normal saline 0.09% that can cause hypercholeramic metabolic acidosis [7,11]. Glucose 5% is relatively more physiological than glycine because it can be given intravenously and with lower incidence of complication. A solution of glucose 5% is metabolized throughout the body, it requires 13 L to be given/absorbed intravenously to expand the intravascular compartment by 1 L [2]. Normal serum osmolality is ≈ 290 mOsm/L. The osmolality of normal saline 0.9% is about 300 mOsm/L, and that of glucose 5% is 285 mOsm/L, as opposed to the osmolality of glycine 1.5%, which is 190 mOsm/L. This higher osmolality provided by both normal saline 0.9% and glucose 5% solution may be beneficial in reducing the possible side effects of cerebral edema. Issa et al., [11] in a case study concluded that bipolar saline is a safe and eliminates the risk of TUR syndrome in high-risk patients with large prostates. Michielsen et al., [7] concluded in his study that a bipolar transurethral resection in saline system is as efficacious as monopolar transurethral prostate resection but it is safer than the latter because of the lesser changes in post-operative sodium, and the smaller risk of transurethral resection syndrome. Two studies done by Collins et al, [2,6] the first study concluded that an increase in serum glycine was associated with TUR syndrome; there were large variations in the amounts of glycine absorbed, reaching levels many times the upper limit of normal, and although there was immediate postoperative hyperglycemia in patients used glucose 5% as irrigation fluid during TURP, it was not associated with either ECG changes nor elevated serum troponin I. In the second study, glycine was reportedly toxic, producing ECG changes and increase in the serum troponin I. Unrecognized blood loss or glycine absorption may explain the increase in morbidity and mortality reported in patients who undergo TURP.
BODY.CONCLUSION:
Endoscopic transurethral of the prostate performed using either bipolar normal saline 0.9% resection, or monoplar glucose 5% resection as irrigating solution during and after surgery, when compared with monoplar glycine 1.5% resection, are associated with lower perioperative morbidity including TUR syndrome, lower catheterization period and shorter hospital stay. Except for the transient postoperative hyperglycemia, in glucose group, both systems are nearly equivalent.
BODY.ABBREVIATIONS:
TURP: Transurethral resection of the prostate; CVP: Central venous pressure; TUR Syndrome: Transurethral resection syndrome; HR: Heart rate; BPH: Benign prostatic hyperplasia; PSA: Prostatic specific antigen; C Tn I: Calcium troponin I; ECG: Electrocardiogram; MABP: Mean arterial blood pressure.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
AAY performed the anesthetic management, prepared the manuscript, and patients follow up. O M Elashry, M D Elsharaby and A K Elgamasy performed the surgical intervention and patients follow up. GAS prepared the lab results and assessed in manuscript preparation. All authors read and approved the final manuscript.
BODY.AUTHORS' DETAILS:
Ayman A Yousef. Lecturer of Anesthesiology, Department of Anesthesia, Tanta University Hospitals, El-Geish street, Tanta, 31527, Egypt. Ghada A Suliman. Lecturer of Clinical Pathology, Department of Clinical Pathology, Tanta University Hospitals, El-Geish street, Tanta, 31527, Egypt. Osama M Elashry. Assistant professor of Urology, Department of Urology, Tanta University Hospitals, El-Geish street, Tanta, 31527, Egypt. Mahmoud D Elsharaby. Professor of Urology, Department of Urology, Tanta University Hospitals, El-Geish street, Tanta, 31527, Egypt. Abd El-naser K Elgamasy. Professor of Urology, Department of Urology, Tanta University Hospitals, El-Geish street, Tanta, 31527, Egypt.
BODY.PRE-PUBLICATION HISTORY:
The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2253/10/7/prepub | 2,891,743 | {
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TITLE: Improvements in survival of the uncemented Nottingham Total Shoulder prosthesis: a prospective comparative study
ABSTRACT.BACKGROUND:
The uncemented Nottingham Total Shoulder Replacement prosthesis system (Nottingham TSR) was developed from the previous BioModular® shoulder prosthesis taking into consideration the causes of the initial implant's failure. We investigated the impact of changes in the design of Nottingham TSR prosthesis on its survivorship rate.
ABSTRACT.METHODS:
Survivorship analyses of three types of uncemented total shoulder arthroplasty prostheses (BioModular®, initial Nottingham TSR and current Nottingham TSR systems with 11, 8 and 4 year survivorship data respectively) were compared. All these prostheses were implanted for the treatment of disabling pain in the shoulder due to primary and secondary osteoarthritis or rheumatoid arthritis. Each type of the prosthesis studied was implanted in consecutive group of patients – 90 patients with BioModular® system, 103 with the initial Nottingham TSR and 34 patients with the current Nottingham TSR system. The comparison of the annual cumulative survivorship values in the compatible time range between the three groups was done according to the paired t test.
ABSTRACT.RESULTS:
The 8-year and 11-year survivorship rates for the initially used modified BioModular® uncemented prosthesis were relatively low (75.6% and 71.7% respectively) comparing to the reported survivorship of the conventional cemented implants. The 8-year survivorship for the uncemented Nottingham TSR prosthesis was significantly higher (81.8%), but still not in the desired range of above 90%, that is found in other cemented designs. Glenoid component loosening was the main factor of prosthesis failure in both prostheses and mainly occurred in the first 4 postoperative years. The 4-year survivorship of the currently re-designed Nottingham TSR prosthesis, with hydroxylapatite coating of the glenoid baseplate, was significantly higher, 93.1% as compared to 85.1% of the previous Nottingham TSR.
ABSTRACT.CONCLUSION:
The initial Nottingham shoulder prosthesis showed significantly higher survivorship than the BioModular® uncemented prosthesis, but lower than expected. Subsequently re-designed Nottingham TSR system presented a high short term survivorship rate that encourages its ongoing use
BODY.BACKGROUND:
Inflammatory or degenerative processes of glenohumeral joint lead to pain and restriction of movements of the shoulder. Prosthetic replacement of the glenohumeral joint has gained in popularity because of its efficacy in relieving pain. The pioneering successful prostheses for total shoulder arthroplasty have been based on an unconstrained design, i.e. a metal spherical head component fixed to a metal intramedullary stem articulating with a high-density polyethylene socket (Table 1). These components are stabilized in the adjacent bone using polymethylmethacrylate bone cement [1]. The important cause for failure of the cemented prostheses was related to the glenoid component, with a 0.01–6% rate of loosening [2-4]. Table 1 Long term survivorship data on cemented and the outcome of a large series of a cementless total shoulder replacement prostheses Reference Type of prosthesis No. of Patients Survivorship End point criteria Glenoid failure rate Overall failure rate Tarchia, Cofield & Settergren [5] Neer I & II cemented 113 [31 = OA, 36 = RA 12 = 2ary OA] 10years = 93% 15years = 87% Revision – severe pain, abd < 90°, ext rot < 20° 7/113 14/113 Brenner, Perlic, Clayton & Dennis [8] Neer II & Gristina cemented 51 [37 = OA 14 = RA] 11years = 75% Severe pain, radiographic evidence of component loosening 3/51 6/51 Cofield [6] Cofield cementless 180 [110 = OA 28 =RA 30 = 2ary OA 12 = revisions] Not calculated Revision 5/180 12/180 Pfahler et al [4] Aequalis cemented 705 [418 = OA 107 = RA 180 = 2ary OA] Not calculated Revision 9/705 43/705 OA = osteoarthritis, RA = rheumatoid arthritis The long term survivorship of the prosthesis developed by C. Neer for the cemented total shoulder arthroplasty (TSA) is almost the single one with well documented outcomes [5] with 87% fifteen year survivorship rate for Neer I & II cemented shoulder prostheses. This implant has become the gold standard, against which all the successive prosthetic designs are compared. Further developments of TSA implants have been aimed at enhancing longevity by addressing the following three most critical issues: (1) Improving the incorporation of the glenoid component using a more "biological" type of fixation in order to reduce the rate of mechanical loosening; (2) Designing a better glenoid component to achieve the lowest possible rate of wear; (3) Finding the best method for the fixation of the humeral component while allowing good preservation of the humeral bone stock, taking into consideration need for possible future revision surgery. These goals can potentially be achieved using an uncemented design, with press fit and/or tissue in-growth porous coating of the metal, at its bone interface. There is evidence that the porous coating at the proximal part of the stem is superior to the press fit design [6], possibly because of lesser stress shielding of the proximal humerus and subsequently less bone resorption, and preservation of the proximal humeral bone stock. Biological fixation of the glenoid component currently requires the use of a metal backing or metal base-plate that serves as the "bone in-growth" surface and results in a more even distribution of the compression forces on the bone. On this baseplate a high-density polyethylene insert is mounted, either molded onto the metal or fixed using some form of fastening mechanism at the time of surgery. This bearing should be at least 3 mm thick (at its thinnest part) to reduce polyethylene wear [2,7]. Currently there are very few long-term peer reviewed large series survivorship data on cemented TSAs [5,8] and no survivorship data on cementless designs (Table 1). Survivorship studies with commonly acceptable clinical outcome criteria are important, but currently there is no uniform agreement on these types of criteria. Most authors consider revision of the prosthesis an end point in its survivorship [9]. Furthermore published reports on single prosthetic designs so far have only provided short-term postoperative follow-up data or a small number of patients. All these factors result in wide confidence intervals in survivorship tables and lead to difficulty in drawing a meaningful interpretation of the results [9]. In spite of these problems we can reach some tentative conclusions from TSA outcome by different authors (Table 1). The best long-term outcome is that reported for the Neer II cemented prosthesis, with a 93% ten years survivorship. Short-term glenoid failure, requiring implant removal, reaches the rate of around 6% for cemented designs and 3% for cementless designs. Glenoid failure is the cause of between 20% – 50% of all failed TSAs, cemented or cementless. Survivorship of cemented TSA is highest in patients with rheumatoid arthritis. We are nor aware of survivorship data available for rheumatoid patients with cementless designs. It is logical to conclude that any cementless prosthetic design should possess at least the best survivorship characteristics of the cemented prostheses in order to be considered as an alternative. In order to achieve the goal of the desired survivorship rates of cementless TSA a chain of modification of the initial BioModular® prosthesis was employed with eventual evolvement of the current Nottingham TSR design. The main characteristics of this prosthesis are: (1) The use of an indexable offset modular head, to improve the anatomical configuration of the implant and the optimal soft tissue balancing [10,11]. (2) A porous proximal stem in order to eliminate the stress shielding effect. (3) Conformed radii of humeral and glenoid components in order to reduce point loading and point wear of the polyethylene glenoid liner [12]. (4) Hydroxyapatite lining of the glenoid baseplate-bone interface in order to provide a "biologic" milieu to improve an osseo-integration [13]. (5) An improved capture mechanism for holding the polyethylene bearing onto the base-plate in order to reduce the liner disengagement rate. Following these design changes we hypothesize that the TSA with cementless implantation will present improved survivorship rates. Therefore in order to estimate the improvement in a performance of the prostheses design we have compared survivorship data of the BioModular® prosthesis – with or without the "Wallace" prototype offset head (Fig 1) – with the survivorship of the initial design of the Nottingham TSR (Fig 2) and the latest design of the Nottingham TSR with the glenoid component base-plate covered by hydroxyapatite (Fig 3). We show that Nottingham TSR uncemented prosthesis has better short and midterm survivorship than the BioModular® uncemented design. Figure 1The BioModular® total shoulder arthroplasty prosthetic design is shown. (A) A titanium BioModular® stem. (B) An offset "Wallace" head. (C) The glenoid trays: on the right – the low-profile version, top row – view from the side, bottom row – view into the tray, showing the glenoid liner capture mechanisms. Figure 2The Nottingham TSR total shoulder arthroplasty prosthetic design is shown. (A) A chrome cobalt stem. (B) A glenoid tray showing the capture mechanism for the polyethylene liner. (C) A glenoid tray seen from the back, showing the areas for bone in-growth. (D) An off-set head with a morse taper assembling interface. Figure 3The Nottingham TSR total shoulder arthroplasty prosthetic design with glenoid base-plate coated with hydroxyapatite. (A) A lateral view of the base-plate with fixation screws and with mounted polyethylene liner. (B) A view on the bone interface side of the base-plate covered by hydroxyapatite.
BODY.METHODS:
Survivorship analyses of three types of uncemented TSA prostheses, implanted for the treatment of disabling pain in the shoulder due to primary and secondary osteoarthritis or rheumatoid arthritis, were compared. Each type of the prosthesis studied was implanted in consecutive group of patients, i.e. Group 1: the BioModular® TSA prosthesis, Group 2: The initial Nottingham TSR prosthesis and Group 3: The most recently redesigned Nottingham TSR prosthesis. The indication for surgery and criteria for inclusion in the study were pain in the shoulder with functional disability combined with radiographic evidence of an advanced destruction of the humeral and glenoid articular surfaces. Patients compatible with these criteria but who were medically unfit for surgery, due to advanced systemic disease, were not offered the procedure and were therefore excluded from the study. Group 1 was comprised of 90 patients who were operated between 1989–1994 (15 men and 75 women, mean age 61 years, range 19 – 92 years). These patients had the uncemented BioModular® Total Shoulder Prostheses implanted, either with the standard non-offset head or the prototype ("Wallace") offset humeral head. The mean follow up period in this group was 8.8 years. Group 2 patients were treated with the initial Nottingham TSR cementless prosthesis where the glenoid component had no hydroxyapatite backing. This group included 103 patients – 12 men and 91 women, average age of 58 years (range: 20–84 years). This design has been used between 1994 and 1997 and the patients had a mean follow up period of 6.4 years. Group 3 comprised of 34 patients, who had a hydroxyapatite coated glenoid component base plate implanted, as part of their most recent Nottingham TSR. In this group there were two men and 32 women, with a mean age of 64 years (range 31–89 years). These patients were operated in 1998–99 and had a mean follow up of 3.2 years. The characteristics of the different groups of patients are given in the Table 2. All these patients were included in the survivorship analyses. Table 2 Characteristics of the study groups Study Group Age (years) Male/Female Mean follow up (years) OA RA 2 nd ary OA Total Number Group 1 Mean: 61 Range: 19–92 15/75 8.8 48 (1 with RC tear) 31 (2 with RC tear) 11 90 Group 2 Mean: 58 Range: 20–84 12/91 6.4 47 36 (2 with RC tear) 20 103 Group 3 Mean: 64 Range: 31–89 2/32 3.2 19 12 (1 with RC tear) 3 34 OA = osteoarthritis, RA = rheumatoid arthritis, RC – rotator cuff muscle For the comparison of the three TSA prostheses' clinical outcome we used a survivorship analysis according to the method described by Murray et al [14] which is based on Rothman's formula for the confidence limits determination. The criterion for failure in this series was revision surgery requiring removal or exchange of either part of or a whole prosthesis. The indications for these re-operations were: (1) An increased level of pain during follow-up, that appeared to be related to the implant, with restriction of external rotation to under 20° and abduction to under 60° and/or newly developed radiolucency around the glenoid peg or complete peri-prosthetic radiolucency at the metal-bone interface, more then 2 mm in width, around either the humeral or glenoid components [7]. The radiographic evaluation was done by the surgical team and by the radiologist; (2) Deep wound infection; (3) Migration of any of the prosthetic components. For the purpose of postoperative follow up and identification of the possible failure of the implants the patients were monitored annually. This review evaluation included estimation of the level of pain using a Visual Analog Scale, a clinical examination of the range of movements of the shoulder and radiographic evaluation of the shoulder with an anterior – posterior view and an axillary view to allow assessment of the alignment and position of the components, the presence of any change in position over time and measurement of any radiolucency at the prosthesis-bone interface. Information on patients who died during the follow up period, which is included in the survivorship analysis, was obtained either from the Registrar for Births, Marriages and Deaths or from the hospitals' registration systems and through direct contact with General Practitioners or relatives. The comparison of the annual cumulative survivorship values (quantitative type of variables) in the compatible time range between the three groups was done according to the paired t test and the p < 0.05 was considered significant. The TSA operations were performed through a proximally extended deltopectoral approach with a longitudinal clavicle osteotomy and a lesser tuberosity osteotomy [15]. This approach was used to facilitate glenoid exposure and to ensure stable deltoid and subscapularis muscle reattachment, that allows early postoperative shoulder mobilization [16]. The authors prefer this surgical approach also because it protects the deltoid muscle during retraction. After humeral head resection, humeral stem alignment was established using the anatomical neck as a guide to prosthesis placement, preserving the rotator cuff. Humeral medullary canal and glenoid surface preparation were carried out using specially designed reamers. With the standard BioModular® stems either a standard or an offset prototype modular head was used. The head geometry, apart from the off-set feature, was identical in the two types of prostetic heads used with the BioModular® implant. In the Nottingham TSR system humeral stems in four sizes, offset modular heads in five sizes and glenoid bearings in three thicknesses were available for optimal component fitting and soft tissue balancing. In six patients (three in the Group 1, two in the Group 2 and one patient in the Group 3 – Table 2) tears in rotator cuff muscles were identified and firmly repaired. Five of six patients with rotator cuff muscles tears suffered from the rheumatoid arthritis. During the first three months postoperatively every patient underwent intensive physiotherapy following a standard programme aimed at improving strength and range of movements. Since the surgical procedure was carried out through a deltopectoral approach with a lesser tuberosity osteotomy and its strong reattachment, an immediate postoperative rehabilitation was possible with very few limitations. Usually a work on external rotation and elevation was commenced from the first postoperative day with isometrics, passive and active elevation and external rotation up to the level of movement achieved during the surgery. Patients used the broad arm sling intermittently only during the first 2–3 postoperative days. The exercise programme was increased as the patients gain confidence and pain relief aiming to achieve a maximal possible active and passive range of movements.
BODY.RESULTS:
The eight year survivorship of the initial Nottingham TSR design (Group 2) was higher (p < 0.001) than observed in Group 1 patients with implanted BioModular® prostheses (Fig 4,5). The eight-year cumulative survivorship in the Group 2 was 81.8% and remained constant from the sixth postoperative year (Fig 5). The eight – and ten- year cumulative survival rates of Group 1 (BioModular® prosthesis) were 75.6% and 71.7% (Fig 4). The main causes of failure of the BioModular® prosthesis were related to the glenoid component, i.e. aseptic glenoid component loosening in 13 patients and uncoupling of the polyethylene bearing liner in 4 patients, overall 71% of failed cases (Table 3). Seventy one percent of the failed cases occurred during the first four postoperative years (Table 3) showing four year cumulative survivorship rate of 80.9% (Fig 4). The main drop in survivorship of the initial Nottingham TSR occurred also during the initial four postoperative years and was mainly due to glenoid component failure (11 of the 17 failed cases, Table 4). About half of the failures in Group 2 during the eight years of the survivorship analysis were due to aseptic loosening of the glenoid base-plate in eight patients, six of these patients were treated for primary or secondary osteoarthritis (Table 5). Table 3 Time distribution of the occurrence of prostheses failure in the Group 1 (patients operated in 1989 – 94 with BioModular ® uncemented TSA) according to the mode of failure Year Post Op Glenoid Loosening Bearing failure Infection Dislocation 1 3 1 0 1 2 1 1 0 1 3 0 0 1 3 4 3 1 1 0 5 1 0 0 0 6 2 0 0 0 7 2 0 0 0 8 0 0 0 0 9 1 0 0 0 10 0 1 0 0 11 0 0 0 0 Total 13 4 2 5 Table 4 Time distribution of the occurrence of prostheses failure in the Group 2 (patients operated in 1994 – 97 with the initial Nottingham TSR prosthesis) according to the mode of failure Year Post Op Glenoid Loosening Bearing failure Infection Dislocation 1 0 1 0 0 2 0 3 0 1 3 2 1 0 2 4 4 0 0 1 5 0 0 0 0 6 1 0 0 0 7 1 0 0 0 8 0 0 0 0 Total 8 5 0 4 Figure 4This graph shows the survival results of BioModular® total shoulder arthroplasty (vertical bars represent 95% confidence intervals). Figure 5This graph shows the survival rate of the initial design for the Nottingham TSR (vertical bars represent 95% confidence intervals). Table 5 Failed uncemented Nottingham TSR prostheses in Group 2 (patients operated in 1994 – 97) according to their mode of failure Component Mode of Failure Loosening Infection Malposition: bearing failure/head dislocation, stem malposition Glenoid 8 (OA = 4, RA = 2, 2 nd ary OA = 2) 0 7 [OA = 4, 2 nd ary OA = 3] Humeral 0 0 2 [2 nd ary OA = 2] OA = osteoarthritis, RA = rheumatoid arthritis Survivorship in patients with rheumatoid arthritis (RA) in both groups 1 and 2 was higher (p < 0.001) than in patients with osteoarthritis. The patients with RA who had the BioModular® prosthesis implanted, presented a 96.8% and 93.1% cumulative five and eight year survivorships respectively (Fig 6) and the RA patients with the initial Nottingham TSR had presented a constant 94.4% cumulative survivorships from the fourth to eights year postoperatively (Fig 7). Figure 6This graph shows the survival rates of the BioModular® total shoulder arthroplasty in patients with RA (vertical bars represent 95% confidence intervals). Figure 7This graph shows the survival rate of the initial design of the Nottingham TSR in patients with RA (vertical bars represent 95% confidence intervals). The initial Nottingham TSR prostheses showed higher eight year survivorship than BioModular® prostheses in patients with OA (p < 0.01). Survivorship of the BioModular® prosthesis in patients with primary osteoarthritis was 70.9% and 64.3% at five and eight years respectively and for the initial Nottingham TSR these values were 84.5% and 80.4% (Fig 8,9). Figure 8This graph shows the survival rate of the initial design for the Nottingham TSR in patients with OA (vertical bars represent 95% confidence intervals). Figure 9This graph shows the survival results of the BioModular® total shoulder arthroplasty in patients with OA (vertical bars represent 95% confidence intervals). The observed four-year survivorship of the patients in Group 3 was also significantly higher than the survivorship rates of the BioModular® prosthesis observed after the first four years after implantation (p = 0.02), with a 93.1% cumulative four year survivorship of the re-designed Nottingham TSR (Fig 10) comparing to the 80.9% of cumulative four year survivorship of the BioModular® prosthesis (Fig 4). Among the Group 3 patients only two prostheses failed, both in patients with osteoarthritis (Table 6). One failure was due to glenoid bearing disassembly, two years after the operation, and the other due to glenohumeral dislocation three years after the operation (Table 7). Table 6 Failed uncemented Nottingham TSR prostheses in the Group 3 (patients operated in 1998 -99) according to the mode of failure Component Mode of Failure Loosening Infection Malposition: bearing failure/head dislocation Glenoid 0 0 2 (OA = 2) Humeral 0 0 0 OA = osteoarthritis Table 7 Time distribution of the occurrence of prostheses failures in the Group 3 (patients operated in 1998 – 99 with the current Nottingham TSR prosthesis) according to the mode of failure Year Post Op Glenoid Loosening Bearing failure Infection Dislocation 1 0 0 0 0 2 0 1 0 0 3 0 0 0 1 4 0 0 0 0 Total 0 1 0 1 Figure 10This graph shows the survival of the current Nottingham TSR with a hydroxyapatite coated glenoid baseplate (vertical bars represent 95% confidence intervals).
BODY.DISCUSSION:
The evolving cementless TSA prostheses should present longevity that is comparable with or better than conventionally used cemented implants. We evaluated the short and midterm survivorship of the Nottingham TSR cementless prosthesis, with comparison to the survivorship of the BioModular® TSA prosthesis from which the Nottingham TSR evolved, in order to estimate the ability of these implants to achieve the desirable survivorship rates. The transitions from one design to another occurred following recognition of causes of implant failure. The use of the offset head on the standard BioModular® stem design did not prevent a considerably high loosening rate. The subsequent change to a conforming design with an identical radii of curvature of the humeral head component and glenoid component and to a different glenoid component with a conical peg, allowing press-fit implantation, led to significant improvement in the middle term survivorship among the patients who had an implant of the initial Nottingham TSR design. We are aware of suggestions by other authors, that full conformity between the components may lead to an enhanced stress on the globoid rim due to loss of the humeral head translation possible in the normal shoulder joint, and as a consequence a higher risk for prosthetic loosening. [12,17]. Since this hypothesis has been raised following cadaveric studies and in vivo radiographic evaluation and has been never confirmed in clinical trials and since the exact degree of optimal mismatch of the glenoid and the humeral head radii is not known, the authors preferred the conforming design. This choice of conformity is based on the hypothesis that mismatch of the glenoid and humeral component curvature can lead to a considerable rate of polyethylene wear due to uneven force distribution between the components and point loading and point wear of the polyethylene [12]. The midterm survivorship in the Group 2 patients shows that the original Nottingham TSR had less favorable results when compared with the existing published survivorship studies on the Neer I & II cemented implants [5], with the outcome studies of the Cofield uncemented prostheses [6] and with the "Aequalis" cemented prosthesis [4], but is comparable with the study on the Neer II and Gristina prostheses [8]. The comparison with the latter study is more realistic because the groups of patients are more comparable to our patients, i.e.both series consist mainly of patients with primary osteoarthritis, smaller groups of patients with rheumatoid arthritis and some patients with secondary osteoarthritis, and they have similar indications for failure recognition. Although the midterm survivorship of the initial Nottingham TSR design showed a significant improvement over the survivorship rate of the BioModular® prosthesis, especially in the patients with osteoarthritis, this improvement did not reach the desired values of survivorship above 90% that has been reported for the cemented Neer I&II prostheses. We note that the overall lower than desired midterm survivorship rates in the Group 2 patients are due to less favorable performance of the Nottingham TSR prosthesis in patients with primary osteoarthritis, who had an eight year survivorship rate of only 80.4%. The interesting finding is the evidence of a significantly higher (and in the desirable range of above 90%) survivorship in patients with rheumatoid arthritis compared to the patients with osteoarthritis in both Group 1 and Group 2. The difference in the survivorship between patients with osteoarthritis and rheumatoid arthritis is consistent with observations in other reports on other prosthetic shoulder arthroplasty systems [8] and can be explained by the lower level of demand placed on a shoulder prostheses in a rheumatoid patient. In spite of the improved survivorship in the initial design of the Nottingham TSR it still showed an unsatisfactory short term loosening rate. It should be realized that the two most serious complications of any prosthetic surgery, e.g. deep wound infection and periprosthetic fracture, did not occur among any of the patients treated by the initial design of the Nottingham TSR. This can probably be attributed to the use of an appropriate surgical technique and instrumentation for the prosthesis implantation. The glenohumeral dislocation rate appeared to be similarly low in Group 1, five of 90 patients, and Group 2, four of 103 patients, (Tables 3,4). This finding shows that the tissue balancing technique for the Nottingham TSR prosthesis implantation, i.e. systematic intraoperative evaluation of an adequate free subacromial space, flush and stable alignment of the glenoid and humeral components with correct offset of the humeral head, adequate anterior – posterior laxity and ability to reattach the lesser tuberosity with the arm in external rotation without loosing of the desired glenohumeral reduction, was effective. The main mode of failure of the prostheses in Group 2 patients was aseptic loosening of the glenoid component predominantly occurring in the first four postoperative years and the second most important cause of failure cause bearing disassembly during the same postoperative period (Table 4). After having identified the two main causes of failure for the intermediate design of the Nottingham TSR prosthesis, steps were taken to change of the design of the metal base-plate of the glenoid component. To achieve an optimal bone osseointegration coating of the implant with hydroxyapatite was introduced. In order to eliminate glenoid bearing disassembly improvement of the capture mechanism for the glenoid bearing was implimented. When looking at the data for Group 3, the addition of hydroxyapatite to the porous coating of the glenoid base-plate has eliminated the original 3.9–5.6% rate of aseptic glenoid loosening from the second to the fourth postoperative years (Tables 3, 4, 7). Additionally by improving the capture mechanism of the glenoid bearing its disassembly has now became rare (Tables 3, 4, 7). Following these changes in design the four-year survivorship of the Nottingham TSR prostheses in the Group 3 patients showed a satisfactory 93.1 % rate, which is significantly higher than the four-year survivorship rates of the BioModular® system. Since in the Groups 1 and 2 the deterioration in the survivorships occurred predominantly in the first four postoperative years, the present high four-year survivorship rate of the newly designed prosthesis might indicate on a sustained long-term improvement of the prosthesis survivorship. Since Group 3 comprised of only 34 patients we have not subdivided and compared the subgroups according to the underlying pathology as we did in Groups 1 and 2. Furthermore, because the number of patients in Group 3 is not sufficient for the adequate power of the statistical comparison with the survivorship in Group 2 patients we can only suggest that the further improvement of the present Nottingham TSR system survivorship is likely to be seen. Future long-term survivorship studies will verify this point more precisely. However, with regard to its initial design (Group 2), there is a clear evidence that the cementless Nottingham TSR system led to a significant improvement in its midterm survivorship comparing to its predecessor, the BioModular® prosthesis.
BODY.CONCLUSION:
We have shown that the discussed cementless TSA prosthesis design (Nottingham TSR), following a chain of modifications according to recognition of previous causes of failure, have reached short term survivorship rates that are comparable to the conventional cemented designs. Therefore, in the light of potential long term "biological" advantages of uncemented implants, these results are encouraging for the ongoing use and development of this type of prosthesis.
BODY.ABBREVIATIONS:
TSA – total shoulder arthroplasty TSR – total shoulder replacemen
BODY.COMPETING INTERESTS:
The authors has received research funding from Biomet Merck Ltd.
BODY.AUTHORS' CONTRIBUTIONS:
NR – processed the data and wrote the paper. LN – collected and analyzed the data. AM – collected the data. IJM – collected the data. WAW – collected and analyzed the data.
BODY.PRE-PUBLICATION HISTORY:
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TITLE: Comparative Study of Low Doses of Rosuvastatin and Atorvastatin on Lipid and Glycemic Control in Patients with Metabolic Syndrome and Hypercholesterolemia
ABSTRACT.BACKGROUND/AIMS:
This multicenter, open-labeled, randomized trial was performed to compare the effects of rosuvastatin 10 mg and atorvastatin 10 mg on lipid and glycemic control in Korean patients with nondiabetic metabolic syndrome.
ABSTRACT.METHODS:
In total, 351 patients who met the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome with low-density lipoprotein cholesterol (LDL-C) levels ≥ 130 mg/dL were randomized to receive either rosuvastatin 10 mg (n = 173) or atorvastatin 10 mg (n = 178) for over 6 weeks.
ABSTRACT.RESULTS:
After 6 weeks of treatment, greater reductions in total cholesterol (- 35.94 ± 11.38 vs. - 30.07 ± 10.46%, p < 0.001), LDL-C (48.04 ± 14.45 vs. 39.52 ± 14.42%, p < 0.001), non-high-density lipoprotein cholesterol (- 42.93 ± 13.15 vs. - 35.52 ± 11.76%, p < 0.001), and apolipoprotein-B (- 38.7 ± 18.85 vs. - 32.57 ± 17.56%, p = 0.002) levels were observed in the rosuvastatin group as compared to the atorvastatin group. Overall, the percentage of patients attaining the NCEP ATP III goal was higher with rosuvastatin as compared to atorvastatin (87.64 vs. 69.88%, p < 0.001). Changes in glucose and insulin levels, and homeostasis model assessment of insulin resistance index were not significantly different between the two groups. The safety and tolerability of the two agents were similar.
ABSTRACT.CONCLUSIONS:
Rosuvastatin 10 mg was more effective than atorvastatin 10 mg in achieving NCEP ATP III LDL-C goals in patients with nondiabetic metabolic syndrome, especially in those with lower NCEP ATP III target level goals.
BODY.INTRODUCTION:
Metabolic syndrome consists of a group of cardiovascular risk factors, namely dyslipidemia, high blood pressure (BP), abdominal obesity, and insulin intolerance, whose concurrent appearance increases the risk of atherosclerotic cardiovascular disease [1]. Using the modified National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) criteria, the prevalence of atherosclerotic cardiovascular disease is estimated to be as high as 24.8% in Korea and is continuing to rapidly increase to epidemic proportions [2]. Elevated cholesterol levels have also been shown to be a strong risk factor for the development of coronary heart disease (CHD). This clustering of risk factors may interact synergistically to affect atherosclerosis and cardiovascular events [3]. Current guidelines for lipid management stress the importance of low-density lipoprotein cholesterol (LDL-C) levels as the primary goal of therapy [4]; however, a high proportion of patients, especially those having high lipid levels, do not achieve their target LDL-C levels despite lipid-lowering therapy [5,6]. Statins effectively lower blood cholesterol levels and reduce the risk of cardiovascular events in many patient types, and are therefore recommended as first-line agents for lowering LDL-C levels [4,7]. Statins also improve other aspects of the lipid profile, such as increasing high-density lipoprotein cholesterol (HDL-C) and lowering triglyceride levels to some extent. Rosuvastatin is a highly effective HMG-CoA reductase inhibitor, which was registered in 2002 in Korea. Rosuvastatin use has been previously shown in numerous studies to be associated with greater LDL-C level reductions as compared to atorvastatin, simvastatin, or pravastatin use [8-10]. The primary objective of the current trial was to compare the effects of rosuvastatin 10 mg with that of atorvastatin 10 mg, which are the lowest-dose tablets available, on the percentage of patients who reach the NCEP ATP III LDL-C goal and safety in subjects with nondiabetic metabolic syndrome after 6 weeks of treatment. The secondary objective was to compare the effects of rosuvastatin with that of atorvastatin on glucose control and insulin resistance.
BODY.METHODS.STUDY DESIGN:
This 6-week, multicenter, randomized, open-label, parallel-group, single-dose trial (NCT00335699) was designed to compare the efficacy of a single dose of rosuvastatin and atorvastatin in patients having nondiabetic metabolic syndrome with dyslipidemia (Fig. 1). The study was conducted from August 2005 to January 2006 at 20 medical centers in Korea. The study included a 6-week dietary run-in period before randomization, followed by a 6-week treatment phase. Subjects entering the run-in period were asked to follow the NCEP Step I diet and required to discontinue any previous lipid lowering therapy. Following the dietary lead-in period, patients with fasting LDL-C levels ≥ 130 mg/dL to < 220 mg/dL were selected and randomly assigned to two parallel treatment groups. At baseline, eligible subjects were randomized 1 : 1 to receive either rosuvastatin (Astra-Zeneca Korea, Seoul, Korea) 10 mg or atorvastatin (Pfizer Pharmaceuticals Korea, Seoul, Korea) 10 mg once daily at bedtime for 6 weeks. The study drug was discontinued and subjects were removed from the study if they withdrew informed consent, became pregnant, or developed creatine kinase levels greater than 10 times the upper normal limit. The ethics committees and institutional review boards at each participating hospital approved the study protocol. All patients provided informed consent to participate in this study.
BODY.METHODS.SUBJECTS:
Patients were ≥ 18 years of age and had nondiabetic metabolic syndrome. Metabolic syndrome was defined according to the modified NCEP ATP III criteria [11], which requires at least three of the following: abdominal obesity (waist circumference): men > 90 cm (36 inches), women > 80 cm (32 inches); triglyceride levels ≥ 150 mg/dL (1.70 mmol/L); HDL-C levels: men < 40 mg/dL (1.04 mmol/L) and women < 50 mg/dL (1.3 mmol/L); BP ≥ 130 / ≥ 85 mmHg or subject receiving antihypertensive treatment; and fasting blood glucose 110 mg/dL (6.11 mmol/L) to 125 mg/dL (6.94 mmol/L). Patients were excluded if they were pregnant or had malignancy. Additional exclusion criteria included diabetes, and active arterial disease such as unstable angina, myocardial infarction, cerebrovascular accident, coronary artery bypass surgery, or angioplasty within 2 months prior to enrollment. After completing the 6-week dietary run-in period, fasting LDL-C concentrations were required to be ≥ 130 mg/dL (3.36 mmol/L) to < 220 mg/dL (5.69 mmol/L) and fasting triglyceride levels were required to be < 400 mg/dL (4.52 mmol/L).
BODY.METHODS.ASSESSMENTS:
Sample analysis for efficacy endpoints was performed in the Green Cross Reference Laboratory, Yongin, Korea, which was certified by the American College of Pathology (LAP No. 6708401) and the National Committee for Clinical Laboratory Standards. Blood samples from patients who had fasted for 12 hours were collected at all investigational sites and delivered by courier to the central laboratory within 24 hours of blood draw. To assess the primary efficacy endpoint, lipid parameters such as total cholesterol, LDL-C, HDL-C, and triglyceride levels were measured during the dietary lead-in period, at randomization, and 6 weeks after treatment. Additionally, levels of apolipoprotein A-1 and B, high-sensitivity C-reactive protein (hsCRP), insulin, glucose, and hemoglobin A1c (HbA1c) were measured at randomization and at 6 weeks after treatment. LDL-C levels were calculated using the Friedewald equation (LDL-C = total cholesterol - (HDL-C + triglyceride/5). The insulin resistance index was estimated using the homeostasis model assessment (HOMA) for insulin resistance based on the following formula: fasting serum insulin (μU/mL) × fasting plasma glucose (mmol/L)/22.5. According to the NCEP ATP III guidelines, the goal LDL-C level for each patient and the proportion of patients achieving the goal in each group was assessed. Persons with CHD or CHD risk equivalent (Framingham 10-year CHD risk > 20%) had a LDL-C level goal of < 100 mg/dL. Those with multiple risk factors had a LDL cholesterol level goal of < 130 mg/dL and those with 0 - 1 risk factor (s) had a goal LDL cholesterol of < 160 mg/dL. Individual demographic data, physical findings, vital signs, and adverse events were evaluated and recorded in the given case record form. To evaluate adverse events, various laboratory assessments including blood counts, and hemoglobin, aspartate aminotransferase, alanine aminotransferase, creatine kinase, electrolyte, and creatinine levels were performed at each time point.
BODY.METHODS.STATISTICAL ANALYSIS:
One-hundred and forty-three evaluable subjects per treatment group were required to achieve 95% power for detecting a clinically significant difference of 6% at the 5% two-sided level in percentage change from baseline in LDL-C levels at 6 weeks with an assumed standard deviation of 14% [12]. Assuming a dropout rate of 20% during the randomized treatment period, approximately 180 subjects were recruited to each active treatment group. To obtain the required number of randomized subjects (360 in total), approximately 900 subjects were assumed to be needed for screening based on a screening failure rate of 60%. The primary analysis population was the last observation carried forward on the intention-to-treat population. This included all subjects with a baseline and at least one post-baseline lipid level measurement. All numeric variables were expressed as the mean ± SEM (standard error of the mean). Efficacy endpoints were analyzed using the unpaired t-test for continuous variables and Pearson's chi-square test for frequencies with 95% confidence intervals. Multivariate logistic regression analysis was used to evaluate the predictors for reaching target NCEP ATP III LDL-C levels after treatment. Variables used for analysis included the statin used, presence of coronary artery disease and hypertension, body mass index, gender, age, waist circumference, and lipid parameters. On the basis of the actual treatment received, safety data were evaluated for all patients who received at least one dose of study medication.
BODY.RESULTS.SUBJECT CHARACTERISTICS:
In total, 645 subjects were screened for participation in this study. Of them, 370 patients entered the dietary lead-in phase and 351 patients met the inclusion criteria and were randomly assigned to treatment with either rosuvastatin 10 mg or atorvastatin 10 mg (Fig. 1). One patient was lost to follow-up and had no safety assessment. Table 1 shows demographic data and baseline characteristics of all 350 subjects who took at least one dose of the study drug at baseline. In terms of demographic data and baseline characteristics, no statistically significant differences existed between the two treatment groups. Patients had a mean age of 60 years in the rosuvastatin group and 58 years in the atorvastatin group. Mean body weights were 66 kg in the rosuvastatin group and 66 kg in the atorvastatin group. Mean systolic and diastolic BP and waist circumstance were comparable between the two groups (Table 1). A total of five patients dropped out before efficacy assessment. Data from 346 patients were analyzed for efficacy in the intention-to-treat population defined as those who took at least one dose of study drug and had lipid levels checked at baseline and follow-up. Safety assessments were performed in 350 patients who were randomized and available for follow-up.
BODY.RESULTS.CHANGES IN METABOLIC PARAMETERS:
Lipid levels, glucose levels, insulin resistance indices, and hsCRP levels at baseline and 6 weeks are shown in Table 2. In each group, atherogenic lipid parameters including total cholesterol, LDL-C, triglyceride, non-HDL-C, and apolipoprotein B had significantly decreased after 6 weeks of treatment (p < 0.001 vs. baseline). Only the atorvastatin treatment produced a modest decrease in HDL-C. Rosuvastatin treatment significantly increased HbA1c and the HOMA index; however, no significant change occurred in the atorvastatin group. Data from two groups were analyzed for an efficacy comparison in the intention-to-treat population. Baseline values of all parameters were similar between the two groups. At 6 weeks after treatment, rosuvastatin 10 mg produced a significantly greater reduction in total cholesterol, LDL-C, non-HDL-C, and apolipoprotein B levels. Otherwise, no significant differences were detected in HDL-C and apolipoprotein A-1 levels between the two groups. In addition, no significant differences were observed with respect to glucose, HbA1c, and hsCRP levels, and HOMA index between the rosuvastatin and atorvastatin groups at 6 weeks (Table 2). At 6 weeks, LDL-C absolute values decreased by 48.04 ± 14.45 mg/dL in the rosuvastatin group and by 39.52 ± 14.42 mg/dL in the atorvastatin group; the former reduction associated with rosuvastatin use was significantly larger than that with atorvastatin (p < 0.0001). Percent changes from baseline in lipid profiles after treatment for 6 weeks, including LDL-C, are shown in Fig. 2. Reductions in total cholesterol (- 35.94 ± 11.38 vs. - 30.07 ± 10.46%, p < 0.0001), non-HDL-C (- 42.93 ± 13.15 vs. - 35.52 ± 11.76%, p < 0.0001), and apolipoprotein B (- 38.7 ± 18.85 vs. - 32.57 ± 17.56%, p = 0.0019) levels were larger in the rosuvastatin group as compared to the atorvastatin group (Fig. 2).
BODY.RESULTS.LDL-C TARGET ACHIEVEMENT:
According to the reported CHD or/and CHD risk equivalents and/or number of risk factors and/or Framingham 10-year risk, the NCEP ATP III LDL-C target goal was determined in each patient and the success rate in reaching their target goal was analyzed after 6 weeks in each group. The percentage of patients who reached their ATP III LDL-C level goals was higher in the rosuvastatin group (87.6 vs. 69.9%, p < 0.001). Among them, patients having LDL-C target cholesterol level goals of < 100 mg and < 130 mg reached their LDL-C target level goals more frequently in the rosuvastatin group as compared to the atorvastatin group. In contrast, in patients with a LDL-C target level goal < 160 mg, more than 96% reached their target goal without a significant difference between the rosuvastatin- and atorvastatin-treated groups (Fig. 3). The overall achievement rate for NCEP non-HDL-C level target goals after 6 weeks of treatment was 76.08% in the rosuvastatin group and 58.92% in the atorvastatin group (p = 0.067).
BODY.RESULTS.PERCENT CHANGES IN GLUCOSE LEVELS AND INSULIN RESISTANCE:
Percent changes in glucose levels and insulin resistance at 6 weeks are summarized in Table 3. Changes in glucose and insulin levels were not significantly different between the two groups; however, HbA1c levels were slightly higher in the rosuvastatin group with marginal significance. To evaluate insulin resistance in the two groups, the HOMA index was calculated. At 6 weeks, the HOMA index increased in both groups and the difference between groups was not significant.
BODY.RESULTS.SAFETY:
Both rosuvastatin 10 mg and atorvastatin 10 mg were well tolerated, with similar incidences of adverse events. During the treatment period, 13 subjects in the rosuvastatin group and 9 subjects in the atorvastatin group reported adverse events (Table 4). The most frequent adverse events in the rosuvastatin group were edema and dizziness, both with incidences of 1.16%. Only five adverse events were reported in the atorvastatin group as related to the study drug; myalgia was reported in one case (0.56%). All adverse events were mild, developed within 2 weeks after starting treatment, had no action taken, and resolved spontaneously. No drug-related adverse effects were observed in the rosuvastatin group. Also, no patient had an increase in alanine aminotransferase level > 3 times the upper limit of normal or rhabdomyolysis.
BODY.RESULTS.PREDICTORS FOR LDL-C LEVEL GOAL ACHIEVEMENT AT 6 WEEKS:
Overall, the percentage of patients who reached NCEP ATP III LDL-C target level goals was higher in the rosuvastatin group as compared to the atorvastatin group. Univariate analysis showed that patients with target LDL-C levels at 6 weeks tended to be rosuvastatin-treated and have coronary artery disease. Multivariate logistic regression analyses that included age, gender, statin, coronary artery disease, hypertension, body mass index, waist circumference, baseline total cholesterol levels, and triglyceride levels showed that rosuvastatin treatment, the presence of coronary artery disease, female gender, lower total cholesterol level, and lower LDL-C levels at baseline were independent predictors for achievement of target LDL-C levels at 6 weeks (Table 5).
BODY.DISCUSSION:
This study evaluated the comparative efficacy of the lowest doses available for two effective statins, rosuvastatin and atorvastatin, in Korean patients with nondiabetic metabolic syndrome. Rosuvastatin 10 mg was more effective than atorvastatin 10 mg in reducing LDL-C levels in subjects with nondiabetic metabolic syndrome after 6 weeks of treatment. Consistent with the greater reductions in LDL-C levels, more patients in the rosuvastatin group achieved LDL-C level goals as compared to the atorvastatin group. Otherwise, no significant difference was observed in glucose levels and insulin resistance. Metabolic syndrome, especially in the presence of high LDL-C levels, is already known to increase the risk of cardiovascular mortality and morbidity [13]. Statins are effective in decreasing LDL-C levels in patients with dyslipidemia. Survey studies have demonstrated that in real-world settings, only 67% of patients with treated dyslipidemia reach their LDL-C target level goals [14]. In this study, rosuvastatin treatment was associated with reaching recommended LDL-C level goals in a higher percentage of patients overall as compared to atorvastatin (87.6 vs. 69.9%). In particular, rosuvastatin was more effective in patients requiring more intensive LDL-C level lowering to less than 100 or 130 mg/dL. In high-risk patients with stronger targets of LDL-C levels < 100 mg/dL, rosuvastatin brought 83% of patients in this trial to the ATP III LDL-C level goal, which was higher than achieved in other studies conducted in South-Asian (76%) and Hispanic-American (61%) patients [15,16]. Both statins, however, were effective in patients with high target LDL-C level goals < 160 mg/dL. These data highlight the importance of using highly effective statins in high-risk patients to enable them to achieve their lower NCEP ATP III LDL-C level goals. With respect to other elements of the lipid profile, improvements in total cholesterol, apolipoprotein B, and non-HDL-C levels were also significantly greater with rosuvastatin as compared to atorvastatin, whereas changes in HDL-C, triglyceride, and apolipoprotein A1 levels were similar in both treatment groups. Unlike other studies in which rosuvastatin effectively raised HDL-C levels [9,15], HDL-C levels in this study were not effectively improved in either group [9]. Metabolic syndrome is associated with an increased risk of both insulin resistance and diabetes [17]. Additionally, changes in the insulin resistance index were investigated by evaluating the HOMA index, which is a positive predictor of metabolic syndrome [18]. Studies in an animal model of insulin resistance suggest that rosuvastatin treatment increases whole-body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction [19]. In contrast, in our study conducted in nondiabetic subjects, a tendency was detected for an increased HOMA index in both treatment arms. Major changes in this parameter were attributable to high increases in insulin concentrations. The degrees of percent change in fasting glucose, insulin concentrations, and HOMA index were not significantly different between the rosuvastatin and atorvastatin treatment groups. Thus, further studies are needed to elucidate the effects of statins on glucose metabolism, insulin secretion, and insulin sensitivity under diabetic or nondiabetic conditions. A multivariate analysis was performed to determine independent predictors of LDL-C goal achievement at 6 weeks. Overall, sex, the presence of coronary artery disease, LDL-C levels, and rosuvastatin treatment were predictive of target LDL-C achievement. Among these factors, rosuvastatin was the strongest predictor, with an odds ratio of 3.26. Moreover, the presence of coronary artery disease was an independent predictor of achieving target LDL-C levels. These patients were assumed to have been more likely to take interest in diet control or exercise than patients without coronary artery disease. Although the findings of this study are provocative, this study has important limitations. Recently, intensive regimens with 80 mg of atorvastatin or 20 mg of rosuvastatin have become available in Korea and produce greater reductions in atherosclerotic lipoprotein levels, which is particularly useful in patients with established coronary artery disease or acute coronary syndrome. Further studies comparing statins across dose ranges in patients not reaching their target goal with low-dose statins are required. Additionally, although changes metabolic parameters were not the primary endpoint of this study, a trend toward differences in blood glucose levels was observed between the two statins. Further studies are needed to elucidate the metabolic effects of statins. In conclusion, this study demonstrated that rosuvastatin 10 mg is significantly more effective than atorvastatin 10 mg in reducing LDL-C levels in patients with nondiabetic metabolic syndrome, especially among those with lower NCEP ATP III target level goals. Both statins were well tolerated. | 2,829,413 | {
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TITLE: Abdominal Wound Problems After Hysterectomy With
Electrocautery vs. Scalpel Subcutaneous Incision
ABSTRACT:
The purpose of this study was to evaluate the relationship between postoperative abdominal incision
problems and opening subcutaneous tissues with electrocautery or scalpel. Women scheduled for
elective abdominal hysterectomy who gave informed consent were randomly assigned to subcutaneous
abdominal wall tissue incision by electrocautery or scalpel. Postoperative abdominal wound
problem diagnoses included seroma, hematoma, infection, or dehiscence without identifiable etiology.
Fifteen of 380 women (3.9%) developed a wound problem; six had scalpel and nine had
electrosurgical subcutaneous incisions (P = 0.4). Thicker subcutaneous tissues (P = 0.04) and concurrent
pelvic infection (P < 0.001) were significant risk factors for postoperative wound problems.
Only two women (0.5%) developed an infection. We conclude that the method of subcutaneous
tissue incision was unrelated to the development of postoperative abdominal incision problems in
380 women undergoing elective abdominal hysterectomy.
| 2,364,680 | {
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} |
TITLE: Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial
ABSTRACT:
Intraperitoneal treatment with interferon-γ (IFN-γ) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic–IIIc ovarian cancer. In the control arm women received 100 mg m−2cisplatin and 600 mg m−2cyclophosphamide, the experimental arm included the above regimen with IFN-γ 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P = 0.031, relative risk of progression 0.48, confidence interval 0.28–0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-γ versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-γ. Thus, with acceptable toxicity, the inclusion of IFN-γ in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival. © 2000 Cancer Research Campaign | 2,363,351 | {
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TITLE: Double-Blind Placebo-Controlled Treatment Trial of
ABSTRACT:
Objective: The purpose of this study was to determine if treatment of pregnant women with Chlamydia trachomatis infection would lower the incidence of preterm delivery and/or low birth weight.
Methods: Pregnant women between the 23rd and 29th weeks of gestation were randomized in double-blind fashion to receive either erythromycin 333 mg three times daily or an identical placebo. The trial continued until the end of the 35th week of gestation.
Results: When the results were examined without regard to study site, erythromycin had little impact on reducing low birth weight (8% vs. 11%, P = 0.4) or preterm delivery (13% vs. 15%, P = 0.7). At the sites with high persistence of C. trachomatis in the placebo-treated women, low birth weight infants occurred in 9 (8%) of 114 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.04) and delivery <37 weeks occurred in 15 (13%) of 115 erythromycin-treated and 18 (17%) of 105 placebo-treated women (P = 0.4).
Conclusions: The results of this trial suggest that the risk of low birth weight can be decreased by giving erythromycin to some women with C. trachomatis. Due to the high clearance rate of C. trachomatis in the placebo group, these data do not provide unequivocal evidence that erythromycin use in all C. trachomatis-infected women prevents low birth weight.
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TITLE: Antibiotic Prophylaxis Using Third Generation Cephalosporins Can Reduce the Risk of Early Rebleeding in the First Acute Gastroesophageal Variceal Hemorrhage: A Prospective Randomized Study
ABSTRACT:
Bacterial infection may be a critical trigger for variceal bleeding. Antibiotic prophylaxis can prevent rebleeding in patients with acute gastroesophageal variceal bleeding (GEVB). The aim of the study was to compare prophylactic third generation cephalosporins with on-demand antibiotics for the prevention of gastroesophageal variceal rebleeding. In a prospective trial, patients with the first acute GEVB were randomly assigned to receive prophylactic antibiotics (intravenous cefotaxime 2 g q 8 hr for 7 days, prophylactic antibiotics group) or to receive the same antibiotics only when infection became evident (on-demand group). Sixty-two patients in the prophylactic group and 58 patients in the on-demand group were included for analysis. Antibiotic prophylaxis decreased infection (3.2% vs. 15.5%, p=0.026). The actuarial rebleeding rate in the prophylactic group was significantly lower than that in the ondemand group (33.9% vs. 62.1%, p=0.004). The difference of rebleeding rate was mostly due to early rebleeding within 6 weeks (4.8% vs. 20.7%, p=0.012). On multivariate analysis, antibiotic prophylaxis (relative hazard: 0.248, 95% confidence interval (CI): 0.067-0.919, p=0.037) and bacterial infection (relative hazard: 3.901, 95% CI: 1.053-14.448, p=0.042) were two independent determinants of early rebleeding. In conclusion, antibiotic prophylaxis using third generation cephalosporins can prevent bacterial infection and early rebleeding in patients with the first acute GEVB.
BODY.INTRODUCTION:
Gastroesophageal variceal bleeding (GEVB) is the most serious complication of portal hypertension and represents the leading cause of death in patients with liver cirrhosis. The patients who survive the initial episode of GEVB have a risk of recurrent bleeding approaching 80% at 2 yr (1). Failure to control bleeding and early rebleeding are the most important prognostic factors influencing the 6-week outcome of these patients (2). Rebleeding is associated with an increased risk of exsanguinations, development of liver failure, encephalopathy, and sepsis which contribute to mortality (3). Over the past two decades, many new treatment modalities have been introduced to improve the management of variceal bleeding, including endoscopic injection sclerotherapy (EIS) and variceal ligation (EVL), and new vasoactive agents such as terlipressin and somatostatin (4). Among them, EIS has been replaced almost universally by EVL, because EVL eradicates varices and provides a lower variceal rebleeding rate with fewer secondary effects than EIS does (5). However, the rebleeding rate following endoscopic treatment is still high; at around 25-50% (6). It is therefore important to define how to further reduce the rebleeding rate. Bacterial infections are frequently associated with upper gastrointestinal bleeding in cirrhotic patients (7). Bacterial infections are more common in cirrhotic patients with acute GEVB than those admitted to hospital with other forms of decompensation, such as encephalopathy (8). Infection may favour variceal bleeding by increasing sinusoidal pressure and altering hemostasis (9). In fact, endotoxemia secondary to bacterial infection may be the critical trigger for variceal bleeding as it produces a wide series of effects that may predispose the cirrhotic patient to bleeding (10). A recent randomized controlled clinical trial has documented the value of quinolone use in preventing rebleeding (6). Prophylactic quinolone can thus further reduce the rebleeding rate in cirrhotic patients with GEVB. However, the use of prophylactic antibiotics can lead to antibiotic resistance with potentially disastrous consequences. It is necessary to prove the benefit of other antibiotics including third generation cephalosporins in preventing rebleeding in cirrhotic patients with GEVB. Therefore, the aim of this study was to compare prophylactic third generation cephalosporins with on-demand antibiotics for the prevention of gastroesophageal variceal rebleeding.
BODY.MATERIALS AND METHODS.PATIENTS:
From June 2000 to December 2004, all patients with cirrhosis admitted with upper gastrointestinal bleeding via our hospital emergency room underwent endoscopy within 12 hr of admission. Male or female patients aged over 18 yr were eligible for inclusion in the study after fulfilling the following criteria: 1) diagnosis of cirrhosis on the basis of previous liver biopsy or clinical, biochemical, and radiologic findings of hepatic failure and portal hypertension; 2) bleeding from esophageal varices or gastric varices; and 3) no signs of infection at admission. The severity of cirrhosis was classified according to Child-Pugh's score (11). GEVB was diagnosed when the emergency endoscopy showed any of the following signs: 1) active bleeding from esophageal varices or gastric varices; 2) stigmata of recent hemorrhage over varices (adherent blood clots); or 3) when there was no other cause of upper gastrointestinal bleeding but fresh blood was found in the stomach. Possible complications of endoscopic treatment were discussed with the patients and their relatives, and written informed consent was obtained before entry into the trial. Patients were excluded from the study if they met the following criteria. First, the patient had a past history of GEVB, or surgical or endoscopic treatment of gastroesophageal varices. Second, the patient received antibiotics within the last 2 weeks. Third, the patient had a terminal illness of any major organ system, or non hepatic malignancy. Forth, the patient had any other causes of upper gastrointestinal bleeding. The diagnosis of hepatocellular carcinoma (HCC) was based on liver biopsy or two coincidental imaging studies as well as one imaging study associated with alpha fetoprotein (AFP) more than 400 ng/mL (12). The Ethics Committee of Chonnam National University Hospital approved the treatment protocol.
BODY.MATERIALS AND METHODS.RANDOMIZATION:
Randomization was performed at the time of the therapeutic endoscopy by an investigator after patients met clinical and laboratory entry criteria, lacked exclusions, and gave written informed consent for entry into this study. The allocation of patients to treatment was done by drawing sequentially numbered envelopes, each containing a previously determined, randomly selected assignment based on a table of random numbers. Patients in the prophylactic group received antibiotics treatment after randomization with intravenous cefotaxime 2 gram q 8 hr for 7 days. Patients in the on-demand group received antibiotics only when infection was suspected or established. Antibiotics were changed according to the antibiotic sensitivity profile of cultured microorganisms.
BODY.MATERIALS AND METHODS.INFECTION ASSESSMENT:
A physical examination, complete blood cell count, chest radiography, urine analysis and culture, blood culture, and ascitic fluid neutrophil count with culture (in patients with ascites) were routinely carried out before randomization. Patients were excluded when the initial bacteriologic examination turned out positive finding. If a new infection was suspected, the same procedures were carried out to assess infection. New infections were suspected when there was fever (>38°C), hypothermia (<36°C), unexplained hemodynamic instability, tachypnea, new onset of chest symptoms, dysuria, deterioration of renal function, bowel habit changes, abdominal pain, abdominal distention, as well as alteration of mental state (6). Respiratory infections were diagnosed by clinical symptoms and signs and positive chest radiography findings. Urinary tract infections were diagnosed by the positive urine culture of ≥105 colonies/mL and associated clinical pictures. The diagnosis of bacteremia was based on positive blood culture and clinical signs or symptoms of infection without other recognized causes. The diagnosis of spontaneous bacterial peritonitis was based on ≥250 neutrophils/μL in ascitic fluid (13). Patients without any identified infection source but with fever >38°C and leukocytosis >11,000/μL with neutrophilia were considered as having possible infections and received on demand antibiotics. In analyzing the incidence of infection and determining the effect of antibiotic prophylaxis, only infectious episodes occurring during the first hospitalization were considered. Therefore, the infection rate was compared by number of events in this period.
BODY.MATERIALS AND METHODS.ENDOSCOPIC TREATMENT PROCEDURES:
Before endoscopic treatment, octreotide was used. If active bleeding was found during endoscopy, endoscopic treatment was performed immediately. EVL was performed for esophageal varices, and EIS was performed for gastric varices. Two experienced therapeutic endoscopists performed the diagnostic and therapeutic endoscopic procedures. They had 4 yr' experience of standard endoscopy. They did not participate in the postprocedure care of the patients, which was conducted by other physicians. Endoscopy was performed with a standard upper endoscope (Olympus GIF-XQ240, Olympus Optical Co., Ltd., Tokyo, Japan). After endoscopic treatment, octreotide was used for 5 days. EVL was performed by using a varioligator kit with a single-shot device (Top Corp., Tokyo, Japan) and a flexible overtube or multiband ligators (Wilson-Cook Medical, Winston-Salem, NC, U.S.A.). Size of esophageal varices was graded according to Conn's classification (14). Grade I-visible only during one phase of respiration/performance of Valsalva maneuver. Grade II-visible during both phases of respiration. Grade III-3-6 mm. Grade IV-varices of >6 mm. EVL was performed biweekly for the first 6 weeks until the varices were obliterated or reduced to Grade I size and could not be banded any further. Follow-up endoscopy was performed every 3 months and, if unremarkable, was moved to every 6 months. EIS was performed by using intravariceal injection with the 1:1 mixture of 0.5 mL N-butyl-2-cyanoacrylate (Histoacryl blue, Braun-Melsungen, Germany) and 0.5 mL Lipiodol (Guerbet Laboratory, Aulnay-Sous-Bris, France) in each shot. Rebleeding was defined as one or more of the ongoing bleeding signs including fresh hematemesis, hematochezia, fresh blood aspirated via a nasogastric tube, instability of vital signs, or a reduction of hemoglobin by more than 2 g/dL within 24 hr after initial hemostasis. When rebleeding was suspected, immediate endoscopy was performed. If active bleeding or a fresh blood clot was found at the varices, and if fresh blood was found in the stomach without any other causes of upper gastrointestinal bleeding, rebleeding was confirmed. Bleeding esophageal varices were ligated and bleeding gastric varices were injected with the previously mentioned tissue glue again. Rebleeding within 6 weeks of enrollment after initial control of active bleeding was defined as early rebleeding. Treatment failure was defined as a failure to control active bleeding after two attempts of endoscopic treatment, rebleeding more than twice, or bleeding-related death. Rebleeding index for each patient was calculated by dividing the months of follow-up by the number of rebleeding episodes plus one (6).
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Rebleeding rate as a primary outcome was compared between two groups, and secondary outcomes such as rebleeding index, treatment failure, bleeding related death, infection rate, transfusion requirements, and admission duration, were also compared between two groups. Quantitative data were summarized as mean±standard deviation. The Student t test was utilized to compare the mean values of continuous variables, and the chi-square test with Yate's correction or Fisher exact test was utilized for the comparison of discrete variables. Kaplan-Meier analysis with the log-rank test was used to compare differences of actuarial probability of rebleeding and survival between two groups. Univariate analysis and stepwise multivariate analysis were performed to assess the potential risk factors of early rebleeding using the Cox proportion hazards regression. A p value of less than 0.05 was accepted as statistically significant. The analysis was performed with statistical software package (SPSS 13.0 version for Windows, SPSS, Chicago, IL, U.S.A.). This study hypothesized a reduction of rebleeding rate from 45% to 20% by using prophylactic antibiotics (6). According to the sample size calculation, the study would require 54 patients in each group. The type I error and type II error were set to 0.05 and 0.2, respectively.
BODY.RESULTS:
During the study period, 152 patients with the first acute GEVB were recruited and randomized. Eight patients in the prophylactic group and 7 patients in the on-demand group were excluded from analysis due to occult infections. Six patients in the prophylactic group and 11 patients in the on-demand group were excluded due to their refusal to continue in the study. Therefore, 62 patients in the prophylactic group and 58 patients in the on-demand group were included for analysis. Data regarding the clinical characteristics of the patients at entry are outlined in Table 1. There were no significant differences between two groups with respect to age, gender, etiology, association of HCC, Child-Pugh's score, severity of bleeding, endoscopic characteristics, and period of follow-up (Table 1).
BODY.RESULTS.INFECTION OUTCOMES AND BACTERIOLOGY:
Summary of the infection sources and bacteriology is outlined in Table 2. The incidence of bacterial infection was significantly lower in patient receiving antibiotic prophylaxis (2/62, 3.2% vs. 9/58, 15.5%, p=0.026). Bacteremia and spontaneous bacterial peritonitis were the most common sources of infection. Enteric bacteria were more frequently identified in patients without antibiotic prophylaxis (0/62, 0% vs. 5/58, 8.6%, p=0.018). There were no significant side effects in antibiotic prophylactic group.
BODY.RESULTS.HEMOSTATIC OUTCOMES:
Summary of hemostatic outcome data is outlined in Table 3. The rebleeding rate in the prophylactic group was significantly lower than that in the on-demand group (21/62, 33.9% vs. 36/58, 62.1%, p=0.004). The difference of rebleeding was mostly due to early rebleeding within 6 weeks (3/62, 4.8% vs. 12/58, 20.7%, p=0.012). The cumulative total rebleeding rate and early rebleeding rate were also higher in the on-demand group (Fig. 1, 2). However, there was no significant difference in cumulative late rebleeding rate between the two groups (Fig. 3). The rebleeding sources were not different between the two groups (Table 2). The early rebleeding rate in the infected patients was significantly higher than that in the noninfected patients (4/11, 36.4% vs. 11/109, 10.1%, p=0.031). However, there was no difference in total rebleeding rate between the infected and the noninfected (6/11, 54.5% vs. 52/109, 47.7%, p=0.760). The transfusion requirement was significantly larger in on-demand group than that in prophylactic group (p=0.002). There were no differences in rebleeding index, treatment failure, and duration of hospital stay between the two groups. Univariate analysis showed the early rebleeding risk significantly linked to antibiotic prophylaxis and bacterial infection (Table 4). On multivariate analysis, antibiotic prophylaxis (relative hazard: 0.248, 95% confidence interval (CI): 0.067-0.919, p=0.037) and bacterial infection (relative hazard: 3.901, 95% CI: 1.053-14.448, p=0.042) were two independent determinants of early rebleeding (Table 5). Univariate analysis showed the late rebleeding risk significantly linked to alcoholics and presence of HCC (Table 6). On multivariate analysis, alcoholics (relative hazard: 1.968, 95% CI: 1.133-3.502, p=0.016) and association with hepatocellular carcinoma (relative hazard: 1.904, 95% CI: 1.035-3.502, p=0.039) were two independent factors predictive of late rebleeding.
BODY.RESULTS.MORTALITY AND SURVIVAL:
Twenty patients and 24 patients died in the prophylactic and on-demand group, respectively. Total mortality and 30-day mortality were not different between the two groups (Table 7). The overall rate of survival was similar between the two groups (Fig. 4). Univariate analysis showed that the survival was significantly related to the presence of HCC, Child-Pugh's score, and bacterial infection (Table 8). On multivariate analysis, presence of HCC (relative hazard: 4.134, 95% CI: 2.261-7.560, p<0.001) and Child-Pugh's score (relative hazard: 1.372, 95% CI: 1.173-1.603, p<0.001) were two independent risk factors determining survival.
BODY.DISCUSSION:
In cirrhotic patients, there is a predisposition to intestinal bacterial overgrowth, intestinal dysmotility, and increased intestinal permeability, all leading to an increase in bacterial translocation. Bacterial translocation is the probable source of bacterial byproducts such as endotoxin which can cause an increase in portal pressure, impairment of liver function, and worsening of hemostasis (10). Endotoxemia secondary to bacterial infection may indeed be the critical trigger for variceal bleeding (15). Norfloxacin, ciprofloxacin, and ofloxacin have all been used with these indications (6, 16-21). According to our knowledge, previous studies have never used single third generation cephalosporin for antibiotic prophylaxis for gastrointestinal bleeding. For this reason, third generation cephalosporin can also be used to prevent bacterial infection and rebleeding in cirrhotic patients with an antibacterial resistance after a long term quinolone prophylaxis. In our study, third generation cephalosporin was used in order to prevent bacterial infection and rebleeding not only because it is safe and efficacious for enteric Gram-negative bacteria, which are the most common causative organisms in cirrhotic patients with acute gastrointestinal bleeding (16-20), but it also has a benefit of covering Gram positive bacteria. The benefit of third generation cephalosporins for preventing early rebleeding in cirrhotic patients with GEVB by decreasing bacterial infection is proved in our study. The prophylactic effect may not sustain over six weeks. However, the period of the greatest risk of early rebleeding is within the first 48 hr after admission (22). The use of early short term antibiotics is very effective in preventing early rebleeding in cirrhotic patients. In the present study, univariate analysis showed the early rebleeding risk significantly linked to antibiotic prophylaxis and bacterial infection. And, antibiotic prophylaxis (relative hazard: 0.248, 95% CI: 0.067-0.919, p=0.037) and bacterial infection (relative hazard: 3.901, 95% CI: 1.053-14.448, p=0.042) were two independent determinants of early rebleeding by the multivariate analysis. The results suggest that bacterial infection produces a wide series of effects that may predispose the cirrhotic patient to bleeding (10). Therefore, the effective antibiotic prophylaxis should be considered as an essential treatment to prevent early rebleeding. In our study, total rebleeding rates were higher than those of previous prospective randomized study (47% vs. 32%) (6). There are several possible explanations for these differences in the rebleeding rates. First, this may be because of a difference in the clinical characteristics of the study population, including habitual alcohol drinking. In our study, alcoholism was the most common etiology of liver cirrhosis compared with other study. Second, the difference in the rebleeding rates may stem from the type of antibiotics (quinolone vs. cephalosporin). In a recent survey, 26% of spontaneous bacterial peritonitis episodes were caused by quinolone resistant Gram negative bacilli over a two year period, related to long term treatment with quinolone (23). Fortunately, quinolone resistant E coli are still sensitive to third generation cephalosporins (9). In addition, there is a substantially increased likelihood of infections from Gram positive bacteria in patients who received quinolone prophylaxis (24). Finally, there was a difference in total follow-up periods between the studies. The total follow-up periods in our study (mean, 22 months) were longer than those in the other study (mean, 9 months) (6). Patients who survived after an initial episode have a risk of rebleeding rate approaching 80% in 2 yr (1). The risk of late rebleeding (more than 6 weeks after the initial episode) is related to such factors as continued alcohol consumption, variceal size, renal failure, degree of liver failure, and presence of HCC (2). Alcohol consumption continues to influence prognosis even after cirrhosis has developed. Patients with clinically compensated cirrhosis who become abstinent have a 90% chance of surviving for 5 yr. In contrast, if these patients continue to drink, their chance of survival falls to about 70% (25). In our study, continued alcohol drinking and the presence of HCC were the most important determinants of the late rebleeding. All alcoholic patients with variceal rebleeding continued their habitual alcohol consumption. Accordingly, there was a trend of more episodes of rebleeding in cirrhotic patients after longer follow-up period without correction of this risk factor. In order to lower the risk of late rebleeding, abstinence of alcohol and effective treatment of HCC should be encouraged. Although the effect of short-term prophylactic antibiotics in patients with GEVB is proved by the reduction of bacterial infection and early rebleeding rate, these beneficial effects are not reflected in terms of mortality and survival in this study. The lack of influence of antibiotic prophylaxis on mortality is likely because of infection is not an independent predictive factor for survival (6). The small impact of rebleeding on survival is possibly due to the fact that most rebleeding episodes can be further controlled by repeated endoscopic treatments (6). Furthermore, on multivariate analysis, presence of HCC (relative hazard: 4.134, 95% CI: 2.261-7.560, p<0.001) and Child-Pugh's score (relative hazard: 1.372, 95% CI: 1.173-1.603, p<0.001) were the only two independent risk factors determining survival in the present study. Actually, most patients died of hepatic failure or multiorgan failure associated with decreased residual liver function and HCC. However, a recent study reported that in-hospital mortality of patients with cirrhosis and acute variceal bleeding has greatly decreased over the past two decades, in concurrence with an early and combined use of pharmacological and endoscopic therapies and short-term antibiotic prophylaxis (26). The use of prophylactic antibiotics decreased the rate of bacterial infections in randomized controlled trials, and a meta-analysis showed that it was associated with improved survival (27). It warrants larger studies to confirm this benefit of antibiotic prophylaxis on mortality. In conclusion, antibiotic prophylaxis with third generation cephalosporins can prevent bacterial infection and early rebleeding in patients with the first acute GEVB. 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TITLE: Fibrin Glue Reduces the Duration of Lymphatic Drainage after Lumpectomy and Level II or III Axillary Lymph Node Dissection for Breast Cancer: A Prospective Randomized Trial
ABSTRACT:
This randomized prospective study investigated the effect of fibrin glue use on drainage duration and overall drain output after lumpectomy and axillary dissection in breast cancer patients. A total of 100 patients undergoing breast lumpectomy and axillary dissection were randomized to a fibrin glue group (N=50; glue sprayed onto the axillary dissection site) or a control group (N=50). Outcome measures were drainage duration, overall drain output, and incidence of seroma. Overall, the fibrin glue and control groups were similar in terms of drainage duration, overall drain output, and incidence of seroma. However, subgroup analysis showed that fibrin glue use resulted in a shorter drainage duration (3.5 vs. 4.7 days; p=0.0006) and overall drain output (196 vs. 278 mL; p=0.0255) in patients undergoing level II or III axillary dissection. Fibrin glue use reduced drainage duration and overall drain output in breast cancer patients undergoing a lumpectomy and level II or III axillary dissection.
BODY.INTRODUCTION:
Prolonged lymphatic drainage following axillary dissection in breast cancer remains a significant clinical problem Shortening the drainage duration is associated with shorter in-patient times and hence lower health care costs. Methods applied to reduce lymphatic drainage include compression dressings (1), closed suction drains (2), postoperative shoulder immobilization (3) and fibrin glue application to the axillary dissection site (4-6). The use of fibrin glue may reduce lymphatic drainage by reducing the number of transections of small vessels and lymphatics during axillary lymph node removal (7). However, conflicting clinical trial results exist regarding fibrin glue use in breast cancer surgery. Previous trials involved a wide variety of breast cancer surgery types or degrees of axillary dissection (8). The present randomized study investigated the effect of fibrin glue use on the duration of drainage and overall drain output after breast lumpectomy and axillary dissection for breast cancer.
BODY.MATERIALS AND METHODS.PARTICIPANTS:
A prospective, randomized study was performed between September 2006 and July 2007 at the Department of Surgery, Seoul National University Hospital. The inclusion criteria (9) were 1) newly diagnosed breast cancer, 2) female gender, 3) elective breast lumpectomy and axillary dissection, 4) informed consent, and 5) being outside of any exclusion criteria. The exclusion criteria (9) were: 1) male gender, 2) a body mass index (kg/m2) <18.5 or >30, 3) current steroid use, 4) systemic anticoagulation or significant coagulation disorder, 5) diabetes, 6) heart disease, 7) history of chest radiation, 8) receiving preoperative chemotherapy, 9) planned immediate breast reconstruction, 10) pregnant or lactating, 11) limited to sentinel node biopsy, or 12) no consent. The study was approved by the Institutional Review Board of the Seoul National University Hospital.
BODY.MATERIALS AND METHODS.TREATMENT PROTOCOL:
Surgery was performed by two surgeons using principally identical methods. All patients underwent a lumpectomy and level I or greater axillary lymph node dissection, and an effort was made to ligate major vessels. For the patients in the fibrin glue group, fibrin glue (Greenplast kit®, Green Cross, Seoul, Korea) was mixed intraoperatively and diluted twice according to standard instructions, and 2 mL was sprayed onto the axillary dissection site using an aerosol spray applicator (Green Jet V2®, Green Cross, Seoul, Korea), after which manual compression was applied for 2 min according to manufacturer's manual. A Jackson-Pratt closed suction 100 mL/3.2 mm drain was placed into the axillary dissection site for all patients. Compression dressings with surgical bras and pads were applied to all patients for the first 5 days after surgery. Arm movement was restricted to below 90 degrees for 5 days (3). Participants were discharged on postoperative day 5±1 regardless of drain removal, and were routinely followed-up on postoperative days 12±1 and 30±2.
BODY.MATERIALS AND METHODS.OUTCOMES:
The primary outcome measure was the duration of drainage. Drainage was assessed daily from the day of surgery, and drains were removed when the drainage volume fell to <30 mL over a 24-hr period. Secondary outcome measures were overall drain output and the incidence of symptomatic seroma formation. A symptomatic seroma was defined as a palpable fluid collection under the wound with symptoms, and was treated using aspiration or open drain insertion. In addition, all wound-related complications were recorded. The wound was examined daily until discharge and during each clinic visit. Wound infections were defined as erythema and/or purulent discharge from the incision site, and were treated using an oral antibiotic for at least 3 days.
BODY.MATERIALS AND METHODS.SAMPLE SIZE:
The primary endpoint was the duration of drainage. In a pilot study with 21 patients, the mean drainage duration was 3.0 days for the case group and 3.2 days for the control group, and the standard deviation of the mean difference between the case and control groups was 0.255. The current study had a power of 90 percent to show whether the drainage duration differed between the fibrin glue and non-fibrin glue groups. This approach assumed that the drainage duration for the two groups was equal, and that a difference of 10 percent or less was clinically irrelevant. This approach required each group to have a sample size of 49 considering a 30% dropout, and α (two-sided) was set at 0.05. The enrollment procedure engaged 50 patients per group.
BODY.MATERIALS AND METHODS.RANDOMIZATION:
Patients were randomized using a web-based program hosted at the Medical Research Collaborating Center at Seoul National University Hospital. Participant randomization was done after bleeding control and confirmation of a negative margin status, immediately before wound closure. Fig. 1 shows the Consolidated Standards of Reporting Trials (CONSORT) flow chart outlining the progress of participants through the study (10). One hundred participants were randomized, 50 to the fibrin glue group and 50 to the control group (non-fibrin glue). Three fibrin glue patients and two control patients were excluded after randomization due to postoperative bleeding.
BODY.MATERIALS AND METHODS.BLINDING:
The surgical team was 'blinded' to treatment assignment until the completion of the surgical dissection and bleeding control just prior to randomization. The personnel involved in recording drainage volumes and complications were also blinded to the treatment assignment.
BODY.MATERIALS AND METHODS.STATISTICAL METHODS:
Data were stored using the Excel (Microsoft Corporation, Redmond, WA, U.S.A.) spread sheet program, and statistical analyses were performed using SPSS software version 12.0 (SPSS, Chicago, IL, U.S.A.) and SAS (SAS Inc., Cray, NC, U.S.A.). Outcome criteria were analyzed on an intension-to-treat basis and all tests were two-tailed. Qualitative data were compared using the Pearson's chi-square-test for more than 30 samples and Fisher's exact test for less than 30 samples. Quantitative data were expressed as means (standard deviations), and were compared using Student t-tests for all group samples and using Mann-Whitney U tests for subgroup samples. Using the general linear model (GLM) procedure, two-way analysis of variance (ANOVA) was used to identify subgroups showing the greatest benefit from use of fibrin glue. A p value <0.05 was considered to indicate a significant difference.
BODY.RESULTS:
Of the 100 patients enrolled (50 fibrin glue, 50 control), 95 completed the study to the endpoint. All five of those that did not complete the study developed postoperative bleeding on the day of surgery, and four of them were conservatively treated (compression dressing with elastic bandage and open drain insertion) and the other underwent re-exploration for bleeding control and hematoma evacuation. It was not possible to measure the drainage duration or overall drain output in those five patients because the Jackson-Pratt closed suction drain was removed and an open drain inserted. There were no significant differences between the fibrin glue and control groups with respect to age, body mass index (BMI), tumor size, the number of lymph nodes removed, and the number of tumor-involved lymph nodes (Table 1). Level I axillary dissection and node-negative status were found to be associated with a shorter drainage duration (p=0.0001 and p=0.004, respectively) and lower overall drain output (p=0.0001 and p=0.003, respectively), while other factors such as age <60 yr and BMI <25 kg/m2 were not (Table 2).
BODY.RESULTS.DURATION OF DRAINAGE, OVERALL DRAIN OUTPUT AND COMPLICATIONS:
The mean drainage duration was 3.3 days for the fibrin glue group and 3.8 days for the control group (p=0.067). The overall drain output was 174 mL for the fibrin glue group and 197 mL for the control group (p=0.309). The differences between groups for these two factors were not found to be statistically significant (Table 2). In addition, the fibrin glue and control groups were found to be similar in terms of the incidence of seroma, postoperative bleeding and wound infection (Table 4).
BODY.RESULTS.SUBGROUP ANALYSIS:
Participants were classified according to two categorical factors and the data underwent an analysis of variance. One factor was the use of fibrin glue and the other factor was the axillary dissection level or node status. The variance between groups classified according to the use of fibrin glue and axillary dissection level was significant in terms of drainage duration (p=0.0005) and overall drain output (p=0.0098) (Table 3). The drainage duration was shorter (3.5 vs. 4.7 days; p=0.0006) and the overall drain output was lower (196 vs. 278 mL; p=0.0255) in the fibrin glue group compared with the control group among those undergoing level II or III axillary dissection. These differences were not apparent in those undergoing level I axillary dissection. While the data appeared to suggest there may have been a greater benefit from the use of fibrin glue in patients with a positive node status compared with a negative node status, the differences were not statistically significant (p=0.0818 for drainage duration and p=0.1123 for overall drain output).
BODY.DISCUSSION:
While prolonged axillary lymphatic drainage is not a serious complication after axillary dissection in breast cancer, it remains the main cause of prolonged hospital stays resulting in increased health care costs. Therefore, several approaches have been used to reduce axillary lymphatic drainage, such as the use of fibrin glue and immobilization of the affected arm (11). Although Lindsey et al. (12) reported that fibrin glue reduced lymphatic drainage in rats, conflicting results have been reported in clinical trials. Five studies (4-6, 9, 13) have examined the association between fibrin glue use and drainage duration or overall drain output. Three of those studies (4-6) showed that fibrin glue reduced both axillary lymphatic drainage and drainage duration, while two (9, 13) reported that fibrin glue had no effect on either axillary lymphatic drainage and drainage duration. Moreover, a meta-analysis of several published trials (8) reported that while the data appeared to suggest decreased overall drain output and a shorter drainage duration in patients receiving fibrin sealant, the findings were not statistically significant. Those studies enrolled almost exclusively mastectomy cases or various cases rarely involving lumpectomy, therefore making it difficult to accurately evaluate axillary lymphatic drainage due to the influence of fluid from the mastectomy site or the heterogeneity of surgery. The present study enrolled patients undergoing only breast lumpectomy and axillary dissection to minimize the influence of fluid from mastectomy or lumpectomy. The analysis of all patients showed that fibrin glue use did not reduce the drainage duration or the overall drain output. However, subgroup analysis showed that the use of fibrin glue reduced both drainage duration and overall drain output in patients undergoing level II or III axillary dissection. Fibrin glue had no such effect in patients undergoing level I axillary dissection. The current study found that in both fibrin glue and control groups, drainage duration and overall drain output increased as the level of axillary dissection or nodal stage increased, and that the benefit from the use of fibrin glue was greater in those undergoing higher level dissections. Moreover, the data suggest that a study using a larger population may find that there is greater benefit from fibrin glue use in node-positive patients compared to node-negative patients. The present results suggest that fibrin glue use will be beneficial under conditions of high drainage, such as axillary dissection extended to two or three levels, higher nodal stage (14), following preoperative chemotherapy, old age (2) and obesity (11). In contrast to previous studies (2, 11), the present study did not find an association between lymphatic drainage and age or obesity. This may have been because in this study the body mass index of participants was restricted ≤30 kg/m2 and the number of participants aged ≥60 yr was only 10. The current study found that the use of fibrin glue did not prevent seroma formation, which is consistent with other reports (4, 6, 8, 9, 13). One explanation is that perhaps fibrin glue had only a short and transient effect on drainage (4). Despite subgroup analysis showing a shorter drainage duration in the fibrin glue group compared to the control group, the groups did not differ in terms of seroma formation or the number of outpatient clinic visits due to wound issues. Thus, it appears that the use of fibrin glue can reduce the length of hospital stay and has no detrimental effect on the complication rate. In conclusion, the present results indicate that fibrin glue use can decrease the drainage duration and overall drain output after breast lumpectomy and axillary dissection in patients undergoing level II or III axillary dissection. Thus, fibrin glue use might be recommended in patients at a risk of high lymphatic drainage in order to reduce the length of hospital stays. | 2,650,992 | {
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TITLE: A Theory-Based Video Messaging Mobile Phone Intervention for Smoking Cessation: Randomized Controlled Trial
ABSTRACT.BACKGROUND:
Advances in technology allowed the development of a novel smoking cessation program delivered by video messages sent to mobile phones. This social cognitive theory-based intervention (called "STUB IT") used observational learning via short video diary messages from role models going through the quitting process to teach behavioral change techniques.
ABSTRACT.OBJECTIVE:
The objective of our study was to assess the effectiveness of a multimedia mobile phone intervention for smoking cessation.
ABSTRACT.METHODS:
A randomized controlled trial was conducted with 6-month follow-up. Participants had to be 16 years of age or over, be current daily smokers, be ready to quit, and have a video message-capable phone. Recruitment targeted younger adults predominantly through radio and online advertising. Registration and data collection were completed online, prompted by text messages. The intervention group received an automated package of video and text messages over 6 months that was tailored to self-selected quit date, role model, and timing of messages. Extra messages were available on demand to beat cravings and address lapses. The control group also set a quit date and received a general health video message sent to their phone every 2 weeks.
ABSTRACT.RESULTS:
The target sample size was not achieved due to difficulty recruiting young adult quitters. Of the 226 randomized participants, 47% (107/226) were female and 24% (54/226) were Maori (indigenous population of New Zealand). Their mean age was 27 years (SD 8.7), and there was a high level of nicotine addiction. Continuous abstinence at 6 months was 26.4% (29/110) in the intervention group and 27.6% (32/116) in the control group (P = .8). Feedback from participants indicated that the support provided by the video role models was important and appreciated.
ABSTRACT.CONCLUSIONS:
This study was not able to demonstrate a statistically significant effect of the complex video messaging mobile phone intervention compared with simple general health video messages via mobile phone. However, there was sufficient positive feedback about the ease of use of this novel intervention, and the support obtained by observing the role model video messages, to warrant further investigation.
ABSTRACT.TRIAL REGISTRATION:
Australian New Zealand Clinical Trials Registry Number: ACTRN12606000476538; http://www.anzctr.org.au/trial_view.aspx?ID=81688 (Archived by WebCite at http://www.webcitation.org/5umMU4sZi)
BODY.INTRODUCTION :
While smoking prevalence has been declining in many countries [1,2] high prevalence rates are a cause for concern in developing countries [3-5], in disadvantaged or vulnerable populations [6-8], and in young people [8-10]. New Zealand Maori (the indigenous population of New Zealand) have particularly high smoking prevalence rates (40.4% of males and 49.7% of females aged 15-64 years [10]) and new interventions must be appropriate for this population group in New Zealand. Smoking quit rates are low even where intensive behavioral and pharmacological support is available [11], although most smokers who try to quit do so without extra assistance [12]. Providing more options for smoking cessation support is one strategy to try to encourage more quit attempts. Mobile phones have good potential as one option because they tend to be always with people, and messages can be sent directly to quitters wherever they are and at the most appropriate times (eg, for cravings or for usual cues to smoke). There is some evidence of more equitable access to mobile phones than to other communications services in developed countries [13,14] and rapid uptake in developing countries [15,16]. There is also emerging evidence that those with high health needs may use mobile phones more than those without [13,17,18]. Our successful text messaging smoking cessation program [19] was recently implemented as a national government-funded program in New Zealand [20]. In order to use new advances in mobile phone technology to continue to improve uptake and effectiveness, we proposed and developed an updated intervention ("STUB IT"). A randomized controlled trial was undertaken between November 2007 and August 2009 to determine whether a video-based smoking cessation intervention delivered via mobile phone was effective at increasing smoking cessation rates compared with a control group over a 6-month period. In this paper we describe this trial, and reflect on challenges faced in recruitment that undermined its capacity to adequately test the effectiveness of the intervention.
BODY.METHODS:
Recruitment was targeted at young adults (16-25 years) and particularly toward young Maori. The study was advertised extensively via radio, internet, mobile phone (to those who had signed up for such a service), paper-based and online magazines, Maori-specific media of all types, local and national newspapers, and media releases to national media outlets. Advertisements were placed in tertiary education institutions (via campus posters, student magazines, student websites, student health services, and student radio), primary health care services, smoking cessation services, large employer health promotion programs, and posters or leaflets at cafes, bars, and sports grounds. Participants were eligible if they were at least 16 years of age, smoked daily, and wanted to quit. Participants were required to have a mobile phone that was capable of receiving video messages. The video messages were sent as a text message with a universal resource locator (URL) address in the text. Participants highlighted the URL to trigger automatic downloading and playing of the video on the phone (Figure 1; see also Multimedia Appendix 1 and 2 for sample videos). Participants could return to the text message to replay the video if desired. This process does not require extremely high-end technology phones, but was available on most recent mobile phones. The video messages were made as small as possible (<300 kB) to allow the lowest-specification common phone to be able to access them. Due to a partnership with Vodafone New Zealand Ltd (one of only two mobile phone networks in New Zealand at the time), this whole process was free to participants. Figure 1Screenshot of the intervention Potential participants completed an online eligibility check and, if eligible, were advised to read the study information online (or it could be emailed or posted) and reply to a consent text message with the words "I consent." Consenting participants were directed to complete baseline data collection on an online form. On submission of this information, computer randomization allocated participants to an intervention or control group, using stratified minimization for age (25 years and under, over 25 years), ethnicity (Maori, non-Maori), and level of nicotine dependence (time to first cigarette 30 minutes or less, more than 30 minutes). Both groups nominated a quit day (QD) on which they aimed to stop smoking that was between 1 and 3 weeks from randomization. Participants also nominated two time periods (in a 24-hour clock) during which they wished to receive the mobile phone messages. Those in the intervention group were also directed to an online brief description and photograph of the six role models (three of whom were Maori) and asked to select one person from whom they would receive messages (although they were able to change this later if desired). The steps in the development of the intervention have been described in detail elsewhere [21]. In brief, we drew on social cognitive theory [22] to inform the use of role models via short video messages providing observational learning. We hypothesized that this role modeling by "ordinary" young people would enhance self-efficacy to quit smoking and thereby increase the chances of a quit attempt being successful [23-25]. The video messages were filmed as video diaries during a quit attempt, with the role models discussing issues they had found difficult and the techniques and coping strategies they used to remain smoke-free. These vignettes were based on the role model's own story (all six role models were ex-smokers), plus theory and evidence-based behavior change techniques usually taught in cessation counseling (such as setting goals, being reminded of reasons for quitting, identifying triggers and cues to smoking, planning to manage or avoid triggers and cues, receiving positive reinforcement, and using social support). The intervention was arranged into a chronological schedule of mobile phone messages that included the role model videos, text messages (short message service; SMS), and other video messages (animations about reasons to stop smoking; and "truth" campaign mass media advertisements supplied by the American Centers for Disease Control and Prevention). Table 1 shows the number and type of messages in each phase, along with the duration of each phase. Table 1 Chronological sequence of mobile phone messages Phase Number of messages Timing and duration of phase Format of messages in each phase Countdown to QD a 1/day For 1 week prior to QD Role model videos and texts QD 3/day 1 day (QD) Role model videos and texts Intensive phase 3/day For 4 weeks post-QD Role model videos and texts Maintenance phase 1 every 2 days For 2 weeks after intensive phase SMS b messages, other mixed videos Maintenance continued 1 every 4 days For about 20 weeks until 6 months after randomization SMS messages, other mixed videos
a Quit day.
b Short message service, or text messages. Additional features included a website for intervention group participants that allowed them to review video messages they had been sent (and rate them if desired), change their selected time periods, and change (or add to) their selected role model. Intervention group participants could also ask for extra support messages on demand by texting keywords to the study shortcode (four-digit number). Texting "crave" and the context (either "stress," "bored," or "drinking" – three common triggers for smoking in young adults) would result in the immediate automated sending of an appropriate video or text message on how to beat cravings within that context. Texting "relapse" would result in three messages over the next 90 minutes to motivate to keep going with the quit attempt and suggest ways of getting extra support. The control group participants received one video message every 2 weeks with general health messages and reminders about the study for 6 months. The primary outcome for the study was continuous abstinence as defined by the Russell standard [26], which allows up to five cigarettes over 6 months after QD. Other outcomes were 7-day point prevalence abstinence; confidence in ability to quit/stay quit (as a percentage on a scale from 0%, not confident, to 100%, fully confident); number of quit attempts and use of nicotine replacement therapies during the study period; participant satisfaction with aspects of the program (intervention group only); and any motor vehicle accidents that occurred while driving and using a mobile phone during the study period (as possible adverse events). Smoking status was verified on a random sample of 10% of eligible participants prior to randomization. Verification of quitting status was attempted in all participants reporting continuous abstinence at 6 months using salivary cotinine reading on a mailed-out and returned NicAlert (Nymox Pharmaceutical Corporation, Hasbrouck Heights, NJ, USA) test-strip pack. Salivary cotinine has a half-life of 15-40 hours and is able to distinguish smokers from nonsmokers using a cutoff of 10 ng/mL of cotinine (sensitivity 93%, specificity 95%, and a positive predictive value of 95%) [27]. Two staff members independently read the NicAlert test strips. The nature of the intervention ensured the study could only be single blinded – that is, participants were aware of which group they were allocated to. However, most data were collected via web-based forms completed by participants, and researchers involved in data collection, particularly outcome assessment, were blind to allocation. Initial calculations indicated that a target sample size of 1300 participants would detect a relative risk of 1.75 for a control group 6-month quit rate of 8.5% (intervention group quit rate of 15%), with 90% power at P = .05. This included a loss to follow-up of 20%. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc, Cary, NC, USA), all statistical tests were two-tailed, and a 5% significance level was maintained throughout the analyses. The main analyses were based on the intention-to-treat principle as recommended for cessation studies [26], where participants lost to follow-up were considered not to have quit at follow-up. Simple chi-square analyses compared the proportion quit at different stages of follow-up between the intervention groups.
BODY.RESULTS :
Participants were recruited into the study between November 2007 and February 2009, and this proved much more difficult than expected. We attempted multiple sequential "waves" of recruitment efforts via new and multiple sources. However, each wave did little to change the overall recruitment rate. The study catchment area was also increased sequentially from the Auckland region (population approximately 1.4 million), to the Northern Region of the North Island (population approximately 2.3 million), to the whole of New Zealand (population 4.1 million). Initial incentives of monthly prize draws of new third-generation (3G) phones were deemed insufficient to attract new participants, and reimbursements to all participants for their time and participation were later added. Due to these problems, and the costs involved in recruitment, we decided to close the study to recruitment with 226 randomized participants. Figure 2 shows the numbers of registrants, randomized participants, and those completing follow-up. Due to the nature of online data collection at follow-up points, it was possible for participants to enter some follow-up data but not complete the entire form. The follow-up numbers presented in the figure are based on those providing the primary outcome data (at 6 months) and the main smoking outcomes data (at 4 and 12 weeks). Figure 2Consort flowchart for the randomized controlled study of STUB IT
Table 2 shows the baseline characteristics of randomized participants. Due to the targeted recruitment strategies, the mean age of participants was 27 years; although there was no upper age limit and the oldest person in the study was 63 years old. The majority of participants were of New Zealand European ethnicity, with nearly 24% (54/226) of participants self-selecting Maori ethnicity. Baseline smoking characteristics were similar in the two groups, with some indication that this was a highly addicted cohort due to Hooked on Nicotine Checklist mean scores of 8 (SD 1.9) out of 10 [28]. Table 2 Baseline characteristics of randomized participants, n (%) a
Intervention (n = 110) Control (n = 116) Mean (SD) age, years 27.5 (9.5) 26.6 (7.8) Female 58 (52.7) 49 (42.2) Ethnicity New Zealand European 55 (50.0) 63 (54.3) Maori 24 (21.8) 30 (25.9) Pacific 12 (10.9) 5 (4.3) Asian 10 (9.1) 13 (11.2) Other 6 (5.5) 5 (4.3) Missing 3 (2.7) 0 (0) Total income in previous 12 months Less than NZ$30,000 53 (48.2) 51 (44.0) NZ$30,001-60,000 35 (31.8) 40 (34.5) Over NZ$60,000 7 (6.4) 12 (10.3) Don’t wish to answer 15 (13.6) 13 (11.2) How soon after waking do you smoke? Within 5 minutes 26 (23.6) 27 (23.3) 6-30 minutes 45 (40.9) 52 (44.8) 31-60 minutes 21 (19.1) 24 (20.7) After 60 minutes 18 (16.4) 13 (11.2) Have you ever tried to quit smoking but couldn’t? Yes 102 (92.7) 104 (89.7) Do you smoke now because it is really hard to quit? Yes 75 (68.2) 82 (70.7) Have you ever felt addicted to tobacco? Yes 98 (89.1) 107 (92.2) Mean (SD) Hooked on Nicotine Checklist (HONC) score 7.99 (2.11) 8.03 (1.68) Mean (SD) confidence in being able to quit this time % 62.4 (22.0) 66.5 (21.8)
a Unless otherwise stated.
Table 3 reports continuous abstinence rates (the primary outcome). Intention-to-treat continuous abstinence at 6 months was 26.4% (29/110) in the intervention group and 27.6% (32/116 in the control group (P = .8). Of the 61 participants reporting continuous abstinence at 6 months, 10 were either noncontactable or stated they had relapsed since the end of the study period (when they had claimed to have quit) and therefore could not undergo verification of quitting status. The remaining 51 were sent NicAlert test-strip packs and were contacted repeatedly to return the strips. Fourteen quitters in the intervention group (48% of 29) returned the strip and seven (24%) were confirmed as nonsmokers. Fifteen quitters in the control group (47% of 32) returned the strip and 11 (31%) were confirmed as nonsmokers. Table 3 Continuous abstinence from quit day to 6 months, n (%) Have you smoked tobacco at all since quit day? Intervention Control P -value a Responders-only analysis .7 Not a single puff or between 1 and 5 cigarettes 29 (38.7) 32 (35.6) More than 5 cigarettes 46 (61.3) 58 (64.4) Missing data 35 26 Intention - to - treat analysis . 8 Not a single puff or between 1 and 5 cigarettes 29 (26.4) 32 (27.6) More than 5 cigarettes or missing data 81 (73.6) 84 (72.4)
a
P -value for chi-square test comparing groups. No significant difference was found between the groups in the intention-to-treat point prevalence abstinence (no smoking at all in the past 7 days), which was recorded at three time points and is shown in Table 4. Table 4 Point prevalence abstinence at 4 weeks, 12 weeks, and 6 months, n (%) Have you smoked at all in the past 7 days? Intervention Control P -value a 4 weeks .8 Not a single puff 12 (10.9) 14 (12.1) Yes or missing data 98 (89.1) 102 (87.9) 12 weeks .3 Not a single puff 30 (27.3) 25 (21.6) Yes or missing data 80 (72.7) 91 (78.4) 6 months .99 Not a single puff 25 (22.7) 26 (22.4) Yes or missing data 85 (77.3) 88 (77.6)
a
P -value for chi-square test comparing groups. At 6 months those who reported quitting were asked to rate their confidence in being able to stay quit, and those who had relapsed were asked to rate their confidence in being able to quit again. There were no significant differences between the intervention and control group mean scores at any of these points (data not shown). At 6 months all participants were asked how many quit attempts they had made during the study period. In the intervention group 7/73 respondents (9.6%) and in the control group 4/81 (4.9%) (P = .3) stated they did not attempt to quit at all, but the majority of respondents in both groups made multiple quit attempts. In the intervention group 17 of 69 respondents (25%) and in the control group 26 of 68 respondents (38%) (P = .2) had used pharmacological quitting support (nicotine patches, nicotine gum, or nortryptiline) at any stage in the 6-month study period. Participants in the intervention group were asked for their feedback on the program. In general the majority of responders stated they liked the video messages from quitters, and appeared to appreciate the frequency and timing of messages (Table 5, 6). Table 5 Intervention group satisfaction with the program, n=67 (%) a
Which aspects did you… like? dislike? no comment did not use That I would relate to quitters 46 (69) 3 (4) 13 (19) 5 (7) What quitter has to say 44 (66) 6 (9) 10 (15) 7 (10) Video messages from quitters 43 (64) 6 (9) 9 (13) 9 (13) The timing of messages 41 (61) 15 (22) 10 (15) 1 (1) Receiving lots of messages 39 (58) 20 (30) 6 (9) 2 (3) The website 34 (51) 3 (4) 16 (24) 14 (21) Crave messages 32 (48) 8 (12) 8 (12) 19 (28) Antitobacco industry messages 25 (37) 13 (19) 10 (15) 19 (28) Animations 23 (34) 3 (4) 8 (12) 33 (49)
a Missing data have been excluded. Table 6 Aspects of the program that aided cessation in the intervention group Which aspects helped you to stop smoking even if you relapsed later? Yes Watching someone like me go through the quitting process 59 (88) Being supported to feel like I could do it 55 (86) Feeling like I belonged/like others were going through same thing 52 (81) Things the people in the video clips said 50 (76) Getting messages at the right times 47 (75) The free stuff 44 (69) It was fun 39 (61) Made me get support from my friends or family 39 (60) The website/other people videos 35 (57) Realizing I had been manipulated by tobacco industry 31 (48) Messages/games/whatever distracting me from cravings 30 (47) Crave messages 29 (45) Free text answers to what they liked most about the program could be divided into three groups: those who reported something about feeling supported (29/54, eg, from the role model, because they felt part of a group, because others were going through it too); those whose comments related to the program (11/54, eg, timing of messages, constant messages, nonintrusiveness, use of technology); and those who said all of it (5/59). When asked what they disliked most about the program, 20/49 said they disliked nothing, six complained of some sort of technical issue, and seven did not feel the content was right or did not relate to the models. Five said there were too many messages, one said the messages reminded them to smoke, and one had the (false) perception they were being charged for messages. The most common suggestions to improve the program were around having more personal (human) contact, individually or via support groups or internet social networking. A report from the intervention program confirmed that 29/110 participants (26.4%) had used the text "crave" function and 18/110 (16.4%) the text "relapse" function. Equal numbers of participants in each group (n = 4) reported having a motor vehicle accident during the study period where the participant was the driver. In the control group one such accident occurred while the participant was using their mobile phone, one within 5 minutes of receiving a message, and two while the participant was smoking, whereas none of the accidents in the intervention group were reported as being temporally related to mobile phone use or smoking.
BODY.DISCUSSION :
This study is the first to have developed and trialed a smoking cessation intervention delivered via video messaging on mobile phones. We found no significant differences in quit rates between the intervention and control groups (with trends in different directions depending on time point and type of analysis). However, the trial was substantially underpowered due to our failure to recruit sufficient participants to reach the desired sample size and the higher than expected self-reported control group quit rate. In fact, quit rates in both groups were high compared to New Zealand's quitline quit rates of 17% (6-month continuous abstinence) and 10% in the 18- to 24-year age group, but similar to those reported in our previous study of a text messaging cessation intervention [19]. Therefore, it is possible that with adequate power, an effect may have been found. The strengths of the study include a study design in accordance with CONSORT guidelines and the strict definitions and analysis of smoking abstinence outcomes. We also used theory on which to base the intervention: this has been shown to be important in technology-based health behavior change [29] and ensures the intentions and drivers in the development of the intervention are clear and replicable. Indeed, participants commented positively on the use of role models as a means of support in their quitting attempts. The obvious limitation of the study is the suboptimal recruitment. There are several potential reasons for this, which present challenges to be addressed in future trials. First, our recruitment efforts were targeted at adolescents (16 years and over) and young adults. We found that, despite indicating their interest in quitting, most young people were not actually ready to commit to a cessation intervention. This has been demonstrated elsewhere in focus groups and surveys of young people [30-32]. The recent updated Cochrane review of smoking cessation interventions for young people [33] commented that many of the included studies were underpowered, with only 5032 participants from 24 studies. Only two of these studies recruited directly from the community as we did. Lipkus and colleagues randomized 402 participants despite approaching nearly 40,000 young people in shopping malls [34], while Patten et al required 42 months to randomize 139 participants [35]. Recruitment to youth smoking cessation services has also been shown to be problematic [36], as has recruitment of youth to other types of research [37]. Second, the costs of messaging and advanced technology may have proved a barrier for some. At the time of recruitment, New Zealand mobile phone data charges (or anything other than SMS and voice calling) were expensive. We spoke to two participants who were wary of being charged (despite being advised the program was free) and there may have been more who did not register for this reason. Also many people were unaware whether their mobile phone could receive video messages. These factors may have dissuaded people even registering their interest and therefore we have no information on their relative importance in our recruitment. However, if poor recruitment was related to a wariness of new multimedia messaging, we feel that this will have been short-lived: in our current trial of a multimedia mobile phone program to prevent adolescent depression we have recruited 1200 participants over 30 school weeks. Thirdly, plans to incentivize participation were hampered by several factors. Monetary incentives are considered to be effective in encouraging participation of adolescents in research [38], so we planned to offer free data or top-ups to participants' mobile phone accounts. After commencing the study this was deemed not technically possible, so instead we instituted monthly prize draws of new 3G mobile phones. However, the ethics committee did not approve promotional material that advertised the prize draws. Nevertheless, when recruitment was found to be falling behind target, we obtained ethics approval to provide participants with vouchers (for a mobile phone, the supermarket, or gasoline) as reimbursements for their time, and recruitment rose in response but was not sufficient to make a large difference. Finally, and somewhat ironically, the text messaging cessation program trialed in our own earlier study [19] may have provided competition with our trial: the tx2quit program went live in New Zealand in June 2008 with national promotion by Quitline, and recruited approximately 4000 participants in the following 12 months [20]. Mobile phones are increasingly being used globally in health services as a means of more frequent and convenient contacts with health providers [39,40], remote monitoring of progress [41,42], and to reduce wastage of scarce health resources [40,43]. There are several aspects of mobile phones that also make them a valuable component of healthy behavior change support, such as being with people in times of need, providing two-way communications for help on demand, allowing proactive reminders of motivations to change behavior, providing social support from people's own networks, and providing a long-term means of support [44]. A Cochrane systematic review of the use of mobile phones in smoking cessation support programs [45] demonstrated short-term effectiveness of mobile phone-only programs and long-term effectiveness of a mobile phone and internet program. This study adds to this body of knowledge by demonstrating the feasibility and participant appreciation of video messages via mobile phones to provide observational learning and support for healthy behavior change. It is also of note that participants were happy to complete research procedures such as consent and data collection by mobile phone. Indeed we achieved higher response rates to text message questions (217/226 or 96% response rate to a question about confidence at QD and 170/226 or 75% response rate to a smoking status question at 12 weeks post-QD) than to our online data collection forms (despite text message reminders to complete them). In conclusion, this trial struggled to recruit participants, in particular young adults who wanted to quit smoking. This may explain the failure to show an effect of the intervention, or it may be that the complex theory-based intervention is no more effective than simple less-frequent video messages from researchers. However, there was sufficient positive feedback about the support obtained by observing the role models in the program to warrant further investigation in this area. Further research should explore the effect of this role model-based mobile phone smoking cessation intervention for older adults – a group that are perhaps more serious about stopping smoking and are becoming higher users of newer mobile phone technology. | 3,221,331 | {
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TITLE: The role of somatostatin in 67 consecutive pancreatectomies: a randomized clinical trial
ABSTRACT.BACKGROUND::
Somatostatin has been found to be effective in the prevention of postoperative complications in pancreatic surgery. It can inhibit the pancreatic secretions that, quite often, are responsible for complications during the postoperative period.
ABSTRACT.METHODS::
We randomized 67 patients in 2 groups. In the study group (n = 35), somatostatin was administered 30 minutes prior to surgery as well as intraoperatively and postoperatively. No medication was given to the control group (n = 32). Biopsies were taken and processed for electron microscopy and ultrastructural morphometric analysis.
ABSTRACT.RESULTS::
Administration of somatostatin reduced the exocrine granule number, and the patients suffered from fewer postoperative complications.
ABSTRACT.CONCLUSIONS::
Somatostatin reduces granule number and size of pancreatic cells, which can partially explain the prophylactic effect of the drug on early complications of pancreatic surgery, and which is confirmed by the clinical findings.
BODY.INTRODUCTION:
Release and activation of pancreatic enzymes during an operation and the postoperative period are responsible for complicating pancreatic surgery.1,2 Somatostatin can inhibit pancreatic exocrine secretion.3–8 Somatostatin involves a broad range of biological actions, which include the inhibition of pancreatic exocrine secretion. The actions of somatostatin are mediated by a family of 7 transmembrane-based G-protein-coupled receptors that comprise 5 distinct subtypes (SSTR1-5). The receptors have common signaling pathways such as inhibition of adenyl cyclase, activation of phosphotyrosine phosphatase, and modulation of mitogen-activated protein kinase. The mechanisms whereby somatostatin receptors transduce messages into intracellular responses under different conditions and in different cells are complex. Inhibition of pancreatic exocrine secretion should improve the postoperative course and consequently reduce complications after pancreatic resection.9 The aim of this study was to assess the effect of somatostatin administration on the ultra-structure of exocrine pancreatic cells by comparing electron microscopy with clinical results.
BODY.METHODS.PATIENTS:
Consecutive patients suffering mainly from pancreatic tumor (n = 60/67) and chronic pancreatitis (n = 9/67) that were suitable for pancreatic resection were enrolled in the study (Table 1). The patients who met the preliminary criteria were randomly assigned to receive a continuous intravenous infusion of somatostatin-14 (Somastin Sb, Faran, Athens, Greece). The dose was 3000 μg within 12 hours at an infusion rate of 3.5 μg/kg/h, perioperatively (30 minutes before surgery, intraoperatively, and 7 days after surgery). The study group consisted of 35 patients and the control group 32. Patients were maintained on their usual diet and fasted for 12 hours before surgery. No patient was on total parenteral nutrition. Each patient received intravenous antibiotic prophylaxis 30 minutes preoperatively and a second dose 3 hours after the start of the operation. All patients were treated in the intensive care unit for the first 24 hours. Intravenous crystalloid solutions were administrated (2.5–3.0 L/d) according to clinical requirements and these were supplemented by plasma or blood components in order to maintain a positive central venous pressure and a blood hemoglobin ≥8–9 g/dL. The patients were given nothing orally during the first 3 postoperative days. Each patient was traced up to the 90th postoperative day. The patients were treated according to the ethical guidelines of the World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, as revised in Tokyo 2004. All participants gave informed consent to participation before enrolment.
BODY.METHODS.STUDY DESIGN:
The study was an open-label, parallel-group, simple randomized clinical trial and the patients were selected according to the CONSORT (Consolidated Standards of Reporting Trials) criteria. The operations were performed and all data were collected at the hospital-based surgical department at the General Hospital "Agios Dimitrios", Thessaloniki, Greece. The statistical analysis was performed using SPSS software (v. 15.0.1.1; SPSS Inc., Chicago, IL, USA). The histopathological assessment and the morphometric analysis were performed at the department of Histology and Embryology, School of Medicine, Aristotelian University of Thessaloniki. The review was standardized. It was performed by the same pathologist, who was blinded to the study group of the patients.
BODY.METHODS.OPERATIVE PROCEDURES:
After induction of general anesthesia, 13 patients underwent Kausch–Whipple operation, 46 Traverso–Longmire, 5 patients distal pancreatectomy and spleenectomy, and 1 distal pancreatectomy with preservation of the spleen (Table 2). All patients were operated on by the same surgical team using the same technique and type of materials. A 2-layer technique of end-to-side pancreatojejunal anastomosis was performed with 5/0 Monosyn® (B. Brawn Aesculap Melsungen AG) and 4/0 PDSII® (Ethicon), an end-to-side 1-layer choledochojejunal anastomosis was performed with 4/0 PDSII, and a 1-layer gastrojejunal anastomosis was performed with 4/0 Monosyn. The total operative time was an average of 6 hours for the Kausch–Whipple or Traverso–Longmire operation and 4 hours for the distal pancreatectomy. All patients, with the exception of those who underwent distal pancreatectomy, were transferred to the intensive care unit.
BODY.METHODS.HISTOPATHOLOGY:
After the division of the pancreas, a small piece from the healthy tissue (pancreatic remnant) was taken for electron microscope histopathological assessment. The mean time between injection of somatostatin, tissue resection, and fixation was 3 hours. The samples were cut into smaller pieces (1 mm3) and fixed in 3% glutaraldehyde in phosphate buffer pH 7.4 for 2 hours and postfixed in 2% osmium tetroxide for 1 hour. After staining with 1% aqueous solution of uranyl acetate for 14 hours, the tissue pieces were dehydrated in an increasing series of alcohol solutions and then embedded in EPON 812. After the observation of the morphology on the semi-thin sections stained with toluidine blue, thin sections were stained with lead citrate and then observed in a Jeol TEM 2000FXII at 80 kV (Table 3).
BODY.RESULTS.CLINICAL FINDINGS:
Within 90 days of surgery, surgical mortality was 4.4% and morbidity was 35.8% (24/67 patients, 6 of whom were from the somatostatin group and 18 from the control group). The most frequent complication (Table 4) was fistula (25%) followed by abscess (20.8%), delayed gastric emptying, upper respiratory infection, urinary tract infection, fever, and multi-organ failure. The frequency of postoperative complications was lower in the somatostatin group than in the control group (Table 5). The levels of bilirubin and amylase were calculated both in serum and surgical drainage during the first, third, and fifth postoperative day in order to establish the presence of fistula or anastomosis leakage. Initially, hypoglycemia followed by hyperglycemia due to inhibition of insulin secretion, nausea, vomiting, and a burning sensation were the most common side effects of somatostatin. Mild side effects that did not rule out the interruption of the drug were observed in 3 patients who received somatostatin. Skin rash developed in 2 patients, and nausea with vomiting in one of these.
BODY.RESULTS.HISTOLOGICAL FINDINGS:
In control patients the acini were normal with many membrane-bound granules of variable size, dilated rough endoplasmic reticulum, and many Golgi complexes (Figures 1 and 2). Also, we observed dense connective tissue between the acini, some destroyed cells, and some cells with pycnotic nucleus. The fine structure of the acinar cells after the administration of somatostatin was different. Many of the acinar cells had few granules or none at all. The electron density of membrane-bound granules varied. The cell organelles (rough endoplasmic reticulum, c. Golgi) were few (Figures 3 and 4). There were also acinar cells with a physiological appearance and many granules, as in the case of the control group. A reduction in size was observed in almost all acinar cells in more than 80% of cases. Selected tissue areas from the above specimens were randomized for morphometric analysis. Data were acquired by the same operator using dedicated software. In each area the number of granules and the total granular area were obtained (Table 6).
BODY.RESULTS.STATISTICAL ANALYSIS:
Using several statistical methods we came to the following conclusions. Initially, 6 of 35 (17%) in the treated group who received somatostatin developed complications, whereas 18 of 32 (56%) in the control group developed complications. Then we hypothesized whether these two percentages were equal by using the simple test of equality, but this should be rejected because P = 0.000. In order to be more accurate we used Fisher's exact test, and came to the same conclusion (P = 0.001), ie, the percentages of the treated group and the control group are not equal. Finally, with the help of logistic regression we concluded that the patients who did not receive somatostatin (control group) had a 6.2 times higher probability of developing complications than the treatment group.
BODY.DISCUSSION:
Many clinical studies have been performed since the first observation that somatostatin, and especially its synthetic analog octreotide, can modify pancreatic exocrine secretion. Most double-blind, placebo-controlled, randomized studies have shown that administration of somatostatin in the perioperative and preoperative period reduces postoperative complications of pancreatic resection, which are currently ascribed to excess release of pancreatic enzymes.10 However, a meta-analysis of randomized controlled trials has failed to show any benefit from the administration of somatostatin, especially if the administration was done only after surgery.11 Finally, a systemic review of the Cochrane database has revealed that somatostatin can reduce the complications associated with pancreatic surgery.12 The mechanism by which somatostatin and its analog octreotide affect the exocrine secretion of the pancreas has not been adequately investigated. The administration of somatostatin reduces pancreatic enzyme secretion in response to exogenous cholecystokinin and secretin. Gullo and other researchers have shown that somatostatin can reduce amino acid uptake by the pancreas with a consequent reduction of enzymic synthesis and release, while others have demonstrated that somatostatin acts indirectly on acinar cells and inhibits secretin potentiation of secretory response by inhibiting secretin-induced c-AMP production as well as the calcium sensitivity of exocytosis.13–15 Moreover, somatostatin inhibits amylase secretion from isolated rat pancreatic acini. Other studies have suggested that somatostatin inhibits pancreatic secretion when it is injected into a central vagal site via cholecystokinin octapeptide or 2-deoxy-D-glucose-stimulated pancreatic protein secretion in a dose-dependent manner, and that this inhibition is via somatostatin receptor-2.16,17 Somatostatin acts on the neurons in the central vagal site, resulting in modulation of the vagal tone, thereby inhibiting pancreatic enzyme secretion. The parasympathetic innervation of the pancreas plays a major role in the control of pancreatic exocrine secretion. In our study, the number of patients who received somatostatin (treated group) was relatively small (n = 35). However, ultrastructurally we observed a reduction in the synthesis of pancreatic enzymes after the administration of somatostatin. The images revealed a smaller number of granules and changes in the synthetic machinery, as confirmed by morphometric analysis as well as by statistical analysis of the clinical results. In conclusion, the perioperative administration of somatostatin may provide some benefit in preventing pancreatic-related complications by diminishing the synthesis of pancreatic enzymes, and is probably associated with the inhibition of exocrine secretion by the gland. | 3,108,665 | {
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TITLE: Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib
ABSTRACT.BACKGROUND::
In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis.
ABSTRACT.METHODS::
In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes.
ABSTRACT.RESULTS::
Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α.
ABSTRACT.CONCLUSION::
Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.
BODY:
Targeted treatment with antiangiogenic therapy has become standard of care for the treatment of most patients with metastatic clear cell renal cell carcinoma (mRCC) based upon improvements in progression-free survival (PFS) in several randomised phase III clinical trials (Escudier et al, 2007a, 2007b; Motzer et al, 2007; Sternberg et al, 2010). With more than one choice of therapy available for patients with mRCC, clinical decision making is more complex, and data on other outcomes in addition to efficacy, such as quality of life and safety, have become increasingly important. Most often, treatments are compared by a head-to-head analysis of each trial endpoint separately. For purposes of a primary analysis, this approach is reasonable. However, this approach may not be ideal if there are important tradeoffs between endpoints such as an increased time with side effects of treatment but longer time to progression in one arm compared with the other. One method that allows integration of both the quality and quantity of survival time is the Time Without Symptoms of disease progression or Toxicity of treatment or TWiST analysis, and its extension the quality-adjusted TWiST or Q-TWiST (Gelber and Goldhirsch, 1986; Goldhirsch et al, 1989). The primary hypothesis of these methods is that patients with no disease symptoms or treatment toxicity have better health-related quality of life than those who have disease symptoms and toxicity. Q-TWiST was first used to evaluate adjuvant therapy for breast cancer (Gelber et al, 1991), and has since been widely applied to other settings and cancers (Gelber et al, 1996; Rosendahl et al, 1999; Sherrill et al, 2008; Marcus et al, 2010; Zbrozek et al, 2010). In this paper, we report the results of a Q-TWiST analysis from a phase III randomised clinical trial comparing the oral antiangiogenic compound sunitinib (SUTENT; Pfizer, Inc; New York, NY, USA), with interferon-α (IFN-α) as first-line treatment for patients with mRCC (Motzer et al, 2007; Motzer et al, 2009). In this trial, sunitinib showed superior PFS compared with IFN-α (median PFS 11 vs 5 months, P<0.001); in addition, median overall survival with sunitinib was more than 2 years (26.4 months). In general, more adverse events of all grades were reported in the sunitinib arm than in the IFN-α arm, although the proportion of patients experiencing grade 3 or 4 toxicities was relatively low for both treatment groups. The Q-TWiST analysis was used to simultaneously compare the two treatments in terms of PFS, overall survival, and grade 3 or 4 toxicities.
BODY.MATERIALS AND METHODS.PATIENTS AND STUDY DESIGN:
The design and main results of the randomised phase III clinical trial have been reported previously (Motzer et al, 2007; Motzer et al, 2009). In this trial, 750 patients with mRCC were randomised in a 1 : 1 ratio to receive either sunitinib or IFN-α. Key patient eligibility criteria included no previous systemic therapy for RCC, measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, as well as adequate hepatic, renal, and cardiac function. All patients provided signed informed consent. The primary endpoint was PFS. Sunitinib was administered orally at an initial dose of 50 mg per day for 4 weeks, followed by 2 weeks off treatment (Schedule 4/2). IFN-α was administered as a subcutaneous injection on three nonconsecutive days per week, starting at 3 million units (MU) for the first week, 6 MU for the second week, and 9 MU thereafter.
BODY.MATERIALS AND METHODS.STATISTICAL METHODS AND ANALYSIS:
The Q-TWiST analysis considered three health states, TOX, TWiST, and REL, and the duration of each state was calculated for every patient. The TOX state comprised the total number of days after randomisation and before progression spent with toxicity, regardless of when the toxicity started or whether there were gaps between toxicities. All grade 3 or 4 toxicities attributable to the study drugs were included in the analysis, apart from those starting after progression. The model included only the more severe toxicities because they were the events considered most likely to have more effect on a patient's quality of life. The type, date of onset, and date of resolution of each toxicity were recorded prospectively as a part of the standard procedure in conducting a randomised phase III trial. Time spent with toxicities unresolved by progression was capped at the date of progression. There were 44 sunitinib and 34 IFN-α patients with unresolved toxicities at the time of progression. It is possible for a patient to have more than one type of toxicity during a period of time. Care was taken so that these overlapping toxicity intervals were not double counted. That is, if a patient had a toxicity that lasted from day 1 to day 5 and another toxicity that lasted from day 1 to day 10, the number of days spent with toxicity was 10 days. The TWiST state was defined as PFS time minus time with toxicities. Progression-free survival time was defined from randomisation to the last date of follow-up or progression. Patients without progression were censored at their last date of follow-up (median follow-up was similar in each treatment arm, being 853 days for sunitinib and 863 days for IFN-α). The duration of the relapse or REL state was defined as overall survival time minus PFS time, or the period of time from progression to death. Patients alive at the end of the study were censored for the overall survival endpoint. The mean time spent in each of the three health states was calculated for each treatment arm separately, and a 95% confidence interval for the difference by treatment was calculated using the nonparametric bootstrap method. Progression-free and overall survival curves were generated using Kaplan–Meier methods, which account for differential follow-up. These curves, along with a curve for time on toxicity, were overlaid on a single graph generated separately for each treatment. We used a threshold utility analysis to assess quality-adjusted or Q-TWiST outcomes, in which the TOX and REL health states are each weighted by utility scores or weights. These weights are represented by μTOX and μREL in the equation below: The utility weights reflect the relative value for the TOX and REL states and range from zero to one, with values closer to one discounting fewer days than those closer to zero for each state. A value of one represents a time period that is denoted by patients as a time of perfect health. Conversely, a value of zero represents a time period that is akin to death. Q-TWiST scores were calculated for a combination of utility weights increasing from zero to one by increments of 0.25.
BODY.RESULTS:
There were more reported occurrences of most general adverse events of all grades in the sunitinib arm than in the IFN-α arm (Motzer et al, 2007). Figures 1A and B show survival times partitioned into the three health states over the follow-up period separately for sunitinib and IFN-α. In each graph, the overall survival curve (blue) is partitioned by the Kaplan–Meier curves for PFS (red) and time with treatment toxicity (green). The area between the Kaplan–Meier curves gives the average time spent in each of the three health states. The mean number of days spent with grade 3 or 4 toxicity (i.e., TOX) was 27 days higher among patients in the sunitinib arm than in patients from the IFN-α arm (95% CI: 18, 37; Table 1). However, the mean time spent without symptoms of disease progression or toxicity of treatment (i.e., TWiST) was 151 days higher in the sunitinib than in the IFN-α arm (95% CI: 118, 180; Table 1), and the mean time spent in relapse (i.e., REL) was 96 days lower among patients randomised to sunitinib (95% CI: −126, −56; Table 1). Results from a threshold utility analysis where the TOX and REL health states were weighted from 0 to 1 are provided in Table 2. The difference in Q-TWiST ranged from a maximum of 177 ((95% CI: 146, 212; Table 2) weight for TOX=1 and weight for REL=0) to a minimum of 56 ((95% CI: 16, 102; Table 2) weight for TOX=0 and weight for REL=1). The first scenario reflects the case when a patient's quality of life before progression is unaffected by toxicity, but quality of life after progression is severely affected. The second scenario is a reverse of this, when a patient's quality of life before progression is severely affected, but quality of life after progression is unaffected.
BODY.DISCUSSION AND CONCLUSIONS:
Results from this phase III trial of sunitinib vs IFN-α showed that sunitinib was superior to IFN-α, based on a longer duration of median PFS; overall survival was also longer with sunitinib than with IFN-α, although the difference did not reach statistical significance (Motzer et al, 2009). The results of exploratory analyses were consistent with the hypothesis that the overall survival endpoint was confounded by crossover treatment and use of alternate anticancer drugs after discontinuation. A total of 25 patients from the IFN-α group crossed over to receive sunitinib on study and one-third (117/359=33%) of the patients from the IFN-α group received post-study treatment with sunitinib. The rate of adverse events was low in both treatment groups, but occurred in more patients treated with sunitinib than with IFN-α. This is likely to be attributable to the much longer average duration of therapy with sunitinib than with IFN-α. Quality-of-life scores as measured by the FACT-G and FKSI questionnaires were higher among patients randomised to sunitinib than among those randomised to IFN-α, with minimal regional variation (Cella et al, 2008; Cella et al, 2010). In this Q-TWiST analysis, we integrated efficacy and safety endpoints, and found that patients on the sunitinib arm spent on average 27 more days with grade 3 or 4 treatment-related toxicity than patients on the IFN-α arm. For both treatment arms, the number of days during which a patient experienced toxicity was low compared with the time during which the average patient remained progression-free. This effect was more pronounced for the sunitinib arm; time spent without progression or toxicity was 151 days greater in the sunitinib than in the IFN-α arm. The Q-TWiST analysis provides a way by which we can compare PFS, overall survival, and time spent without toxicity in the two treatment arms in one metric. Patients can value time spent in relapse and time spent undergoing active therapy differently. For the Q-TWiST analysis, we assigned a range of utility weights to reflect 25 such scenarios. A utility weight of one discounts zero days from a health state, while a utility weight of zero discounts all days from a health state. In our analysis, all utility combinations resulted in positive Q-TWiST treatment differences (sunitinib Q-TWiST–IFN-α Q-TWiST). The difference in scores ranged from 177 to 56 days. Interpreted another way, sunitinib had higher quality-adjusted survival times than IFN-α across the entire range of utility combinations. Revicki et al (2006) recommended that differences in Q-TWiST equal to at least 10% of overall survival should be considered clinically meaningful. Based on the median overall survival of 26.4 months or ∼803 days in the sunitinib arm, a 10% or greater difference corresponds to 80 days or greater. In Table 2, Q-TWiST differences in all scenarios apart from five can be deemed as clinically important. Four of the five smallest differences occurred when time from progression to death or end of study was not discounted (REL weight=1), but time before progression was discounted (TOX weight <1). In this Q-TWiST analysis, we used overall utility weights to reflect the average value patients place on time spent in relapse and time spent experiencing toxicity. However, it is possible that there is heterogeneity in how a specific patient would value time spent with toxicity and time spent from progression to death or end of study. Another limitation of our analysis is that patients progressing on IFN-α were given the choice to crossover to the sunitinib arm. This resulted in 25 patients switching to sunitinib during the study and could affect estimation of the REL health state for the IFN-α arm. Q-TWiST methodology can provide useful advice on treatment choice when PFS differences are significant but overall survival differences are not, as is the case with the sunitinib vs IFN-α trial analysed herein. Applying Q-TWiST methodology to examine progression, overall survival, and toxicity as a single metric showed that sunitinib has a greater quality-adjusted survival time than IFN-α. For sunitinib patients, the greater amount of time spent with a toxicity is offset by far longer PFS. These results support the conclusion that sunitinib offers improved clinical and quality-of-life outcomes compared with IFN-α for mRCC patients. | 3,349,250 | {
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TITLE: Effects of 3-Dimensional Lumbar Stabilization Training for Balance in Chronic Hemiplegic Stroke Patients: A Randomized Controlled Trial
ABSTRACT.OBJECTIVE:
To investigate the effects of the newly developed Spine Balance 3D system on the balance and gait abilities of hemiplegic stroke patients.
ABSTRACT.METHODS:
Twenty-eight hemiplegic patients with chronic stroke were randomly assigned to an experimental (n=14) or control group (n=14). The experimental and control groups performed balance training by using the newly developed Spine Balance 3D system and the well-known Biodex Balance System 30 minutes per day, three times a week for 7 weeks. The Berg Balance Scale (BBS), 10-m walking test (10mWT), Timed Up and Go Test (TUG), Functional Reach Test (FRT), the Korean version of the Fall Efficacy Scale-International (KFES-I), trunk muscle strength and stability were evaluated before and after 7 weeks of intervention.
ABSTRACT.RESULTS:
The 10mWT improved significantly (p=0.001) in the experimental group (using the Spine Balance 3D system) but not in the control group, and core muscle strength, which we checked using Spine Balance 3D system evaluation program, improved more in the experimental group as well. The results of the BBS, FRT, TUG, KFES-I, and Biodex Balance System evaluation program improved in both groups after 7 weeks of balance training.
ABSTRACT.CONCLUSION:
We suggest that the newly-developed Spine Balance 3D system can be a more useful therapeutic tool for gait and dynamic balance rehabilitation in hemiplegic patients than a conventional 2D-based balance training system. A large-scale randomized controlled study is needed to prove the effect of this system.
BODY.INTRODUCTION:
A decrease in balance control can be caused by various factors, including central nervous system diseases (such as stroke and traumatic brain injury), musculoskeletal disorders (such as back pain or arthritis), and vestibular diseases. Loss of balance control decreases the ability and speed of patients' gait, especially in those with hemiplegia caused by brain damage. Fear of falling in these patients reduces their activity level and makes daily activities of living difficult for these patients. Therefore, improvements in balance control and mechanical movements are important treatment goals [1]. A combination of several factors, including vestibular, visual, somatosensory, and trunk strength, enables the maintenance of postural balance. Therefore, comprehensive, objective treatment methods are needed. Previous studies have reported on the relationship between gait ability, speed, and independence of performing daily activities from multiple angles. Physicians use various treatment methods and exercises, including trampoline training [2], visual feedback training [3], and sling exercise therapy for trunk muscles [456]. Along with the active development of rehabilitation equipment, physicians use many types of equipment that are already made in Korea in treatments to improve balance, including the iBalance (CyberMedic, Iksan, Korea) and Space Balance 3D (CyberMedic) systems. However, few studies exist on the actual effectiveness of this equipment, and established criteria to evaluate functional improvements are scarce. This study aimed to investigate whether the Spine Balance three-dimensional (3D) system, which was developed to strengthen the deep muscles of the vertebra via stabilization exercise of the lumbar spine, improves postural balance in patients with hemiplegia performing 3D rotational exercises. We expected that this exercise would increase trunk muscle strength and stabilize movement of the vertebra. In addition, this study aimed to study the improvement in gait and ability to carry out daily activities while proving the positive effects of using the Spine Balance 3D system's program and several balance control tests. The results were compared to those obtained with a Biodex Balance System [7], which is widely used for balance training, to prove its effectiveness.
BODY.MATERIALS AND METHODS.SUBJECTS:
This study required patients to meet the following inclusion criteria: (1) patients at 6 months or more after stroke, (2) unilateral stroke (infarction, hemorrhage), (3) ability to understand and perform three-step verbal instructions, and (4) ability to stand independently. Patients with severe abnormalities in their biorhythms who require inpatient treatment and those who were deemed unqualified for the study were excluded. Thirty patients who met the requirements were chosen as subjects. The subjects were randomly divided into two groups of 15 to create experimental and control groups to be respectively treated using Spine Balance 3D (CyberMedic) and Biodex Balance System (Biodex Medical Systems, Shirley, NY, USA). The random distribution of the subjects into the experimental and control groups is based on a random allocation table in the order of registration of the subjects, and the process of patient recruitment took a total of 4 months. We conducted this prospective study at the Chonbuk National University Hospital, and we notified the subjects regarding the content of the study and obtained their written consent before the experiment was conducted. The hospital's board of audit and inspection approved our study.
BODY.MATERIALS AND METHODS.METHOD:
The Berg Balance Scale (BBS), 10-m walking test (10mWT), Timed Up and Go (TUG) and Functional Reach Tests (FRT), and trunk strength evaluated using Spine Balance 3D system's evaluation program were used as clinical indicators to evaluate the level of function before the exercise. The Korean version of the Fall Efficacy Scale-International (KFES-I) was recorded using the information from the survey. The patients performed 30-minute exercises, three times a week for 7 weeks (Fig. 1). The Spine Balance 3D system allows balance training to be performed in 3D space detached from the ground surface by using a lift system that locks the hip and ankles to stabilize the body and prevent twisting. Exercises in eight directions (front, back, left, right, and diagonal) are possible in 3D space, and the system can be tilted up to 60° in each direction. The 3-axis sensor on the trunk accurately measures the movement of the patient's trunk and identifies and displays the center of gravity on the monitor (Fig. 2A). The experimental group underwent training in eight directions using the Spine Balance 3D system, starting from a 15° tilt and increasing up to 30° depending on the patient's condition. The control group underwent training by using the training mode in the Biodex Balance System. We configured the platform to the static state, and the patients underwent posture maintenance training and center of gravity transferring postural training in eight directions after initially aligning the center of gravity with the middle line of the monitor. We did not restrict any of the groups' activities to balance training, and we advised the subjects to perform their same daily activities as before (Fig. 2B).
BODY.MATERIALS AND METHODS.METHOD.ASSESSMENT METHOD:
BBS (range, 0–56 scores) and TUG indicated the dynamic balance, Biodex Balance System's evaluation program indicated stability, Spine Balance 3D system's evaluation program indicated trunk muscle strength, and 10mWT indicated gait ability. The FRT indicated static balance, and the KFES-I measured the risk of falling. The patients performed TUG, a test that measures the time it takes a patient to rise from a chair, walk 3 m, turn around, walk back to the chair and sit down, and a stopwatch was used to measure timing. We measured the time it takes a patient to walk a distance of 10 m marked by tapelines when performing the 10mWT, and sufficient space was provided before and after the 10 m region to allow acceleration and deceleration. The forward FRT was performed by measuring the difference between the locations of the 3rd metacarpophalangeal joint of the unaffected side from a normal standing position and from a maximally forward-leaning position, and a 100 cm-long ruler was set horizontally at the acromion level to measure the difference. The patients placed both clavicles perpendicular to the long ruler lines on the wall to avoid error caused by the decrease in ipsilateral muscle strength. We separately measured the values for the affected and unaffected side in the lateral FRT. The lateral FRT measures the differences in the location of the metacarpophalangeal joints after abduction of the arm on the desired side from a natural upright position and from a laterally tilted trunk position. If the strength of the affected arm was not sufficiently strong, we measured the acromion locations instead. The Biodex Balance System and Spine Balance 3D system objectively evaluated the balance control. We used Biodex Balance System's evaluation program to conduct postural stability test with eyes open and closed, along with the limits of the stability test. We conducted the postural stability test by having the subjects maintain a relaxed standing position with eyes open and closed for 10 seconds each. We obtained three measurements from each condition to calculate the overall stability index, which reflected the stability as it approximates 0. We conducted the limits of the stability test on an easy level. We obtained three measurements to calculate the overall direction control score, which reflected a higher ability to control direction as the score decreased. Spine Balance 3D system's blind and open modes were used to evaluate the balance control. The difference between the blind mode and the open mode is defined as the ability to display the actual balance status on the screen by using the sensors attached to the back of the patient. The monitor displayed the actual balance status in the open mode whereas the screen turned black in the blind mode to restrict compensation. We increased the tilt in each of the eight directions to 15° and 30° by 2°/s and stopped for 5 seconds at the maximum tilt (15° and 30°). The subjects maintained a certain trunk position, depending on the tilt, and the results were reported as the Balance Position Ratio (BRP), expressed as the percentage of deviation from reference for the direction and tilt measured using the trunk sensor system. A score close to 100% reflects a good trunk muscle strength.
BODY.MATERIALS AND METHODS.METHOD.STATISTICAL ANALYSIS:
We performed the statistical analyses using SPSS ver. 18.0 (SPSS Inc., Chicago, IL, USA), and analyzed the demographics of the two groups and pre-treatment evaluations by using an independent t-test. We compared the pre-treatment evaluations with post-treatment evaluations in both groups to determine whether statistical changes were present. We analyzed the measured values before and after the treatment in each group by using Wilcoxon signed-rank tests, and considered only p-values less than 0.05 to be statistically significant.
BODY.RESULTS.GENERAL CHARACTERISTICS OF SUBJECTS:
The experimental and control groups comprised 15 subjects each. However, one patient from the experimental group failed due to the aggravation of gout in the ankle joint, and a follow-up loss in the control group occurred due to a MERS coronavirus outbreak. Fourteen subjects in each group completed the clinical experiment. Table 1 shows the distribution of sex, age, average education, duration of stroke, and hemiplegic side in both groups. The demographics in the two groups did not show significant differences. The unaffected lateral FRT showed significantly higher results in the Biodex Balance System training group; whereas the rest of the tests showed no significant differences between the two groups (Table 2).
BODY.RESULTS.TREATMENT EFFECTS:
Table 3 shows that the experimental group showed significant improvements in all tests—BBS (p=0.001), TUG (p=0.001), forward FRT (p=0.001), affected lateral FRT (p=0.001), and unaffected lateral FRT (p=0.002)—when the values before and after training were compared in each group. The control group also showed significant improvements in the same tests. However, the results for the 10mWT showed only significant improvements in the experimental group (11.38±3.0 to 10.12±2.47 seconds; p=0.01); whereas the control group did not show significant improvements. The improvement levels of the trunk strength (BPR score) for the experimental group using Spine Balance 3D system's evaluation program showed significant improvements at the 15° open mode; whereas the control group did not show any significant improvement. However, both groups showed significant improvements during the experiment under the following three conditions: 15° blind, 30° open, and 30° blind (Table 3). In addition, among the three conditions used in Biodex Balance System's evaluation program, the experimental group showed significant improvements in a postural stability test with eyes open and closed under two conditions while the control group showed significant improvements in a postural stability test under a condition with closed eyes and a limit of stability test. As such, the two groups showed similar levels of improvement in terms of stability (Table 3).
BODY.DISCUSSION:
The goal of this study was to investigate the effectiveness of the Spine Balance 3D system in improving gait and balance in patients with hemiplegia. This study confirms that balance training using the Spine Balance 3D system effectively improves dynamic balance, static balance, and gait by improving trunk muscle strength. Treatment using the Spine Balance 3D system showed significant improvements in gait, as measure in the 10mWT, compared to that achieved using the Biodex Balance System, and the Spine Balance 3D system's evaluation program showed that improvements in trunk control ability were relatively superior than those observed for the control group. The postural stability test, conducted using Biodex Balance System's evaluation program, revealed that the two groups showed similar levels of improvement in stability. The trunk stability maintains the overall balance and regulates the technical movement of the lower limbs. Hodges and Richardson [8] report that stabilization of the spine caused by the contraction of abdominal and multifidus muscles plays a role in inducing technical movement in the lower limbs. In addition, Kim et al. [9] report that trunk-activating exercises are important because weakening of the trunk is relevant to functional performance in patients with chronic stroke. Abdominal muscle strength exercises improve gait and balance in stroke patients [10], and improvements in trunk regulation increase dynamic balance, gait speed, and symmetrical movement of the trunk during gait in stroke patients [11]. Subsequently, various core stability exercises have been introduced to strengthen the trunk [12131415], and many types of modern equipment are currently in development, aiming to improve trunk strength through gait training. However, studies evaluating the effects of such equipment are rare. A study conducted 1-minute sit-up tests in a single-leg squat position on athletes after training with the Biodex Balance System and reported a relatively significant improvement in balance compared to the control group. This study proves that treatment using the Biodex Balance System improves stability by fortifying core strength [16]. Treatment using the Biodex Balance System significantly reduces the fear of falling (FES-I score >26) among the elderly, and their knee extensor and flexor isometric strength improves as a secondary gain [17]. Therefore, core muscle and lower extremity strength are expected to increase when training using the Biodex Balance System, and improvements in balance have been confirmed. Our study showed significant improvements not only in trunk muscle strength, but also in BBS, TUG, FRT, and KFES-I. This result coincides with the results from a study by Saeys et al. [18], which reports that trunk reposition error, trunk impairment scale, and TUG results improved in the weight-shifting training group compared to those in the control group. The only difference with the study by Saeys et al. [18] is that our weight-shifting training was conducted using the Biodex Balance System. We expect that the newly-developed Spine Balance 3D systems stabilize and fortify trunk muscles by inducing symmetrical contraction and relaxation of abdominal and multifidus muscles in 3D space when the body is tilted, and studies are currently in progress to determine its effectiveness. A recent study confirmed changes in the trunk muscle strength and body composition among elderly subjects after training using the Spine Balance 3D system. The experimental group showed a significant improvement in trunk muscle strength after analyzing the alignment of the system direction and tilt with the trunk sensors by using trunk maintenance ability as a reference for trunk muscle strength [19]. Our study showed a significant improvement in trunk muscle strength in both groups after the experiment when measured using the same method. However, the control group showed significant improvements in trunk muscle strength only under three conditions while the experimental group showed improvements in trunk muscle strength under all four tested conditions, and the experimental group showed a relatively higher improvement in the trunk muscle strength. The tests conducted using Biodex Balance System's evaluation program revealed that both the experimental and the control groups showed significant improvements in two of three conditions with similar magnitude. The experimental group showed significant improvements in a postural stability test with eyes open and closed under two conditions while the control group showed significant improvements in postural stability test under a condition with closed eyes condition and in the limit of stability test. Although each system's learning effect on outcomes cannot be neglected, the treatment effect of the experimental group who used the Spine Balance 3D system for training was confirmed to be superior to that of the control group through a comparative analysis. Compared to the Biodex Balance System, where balance training is conducted horizontally while standing perpendicular to the surface, the Spine Balance 3D system might be more effective because the trunk muscle is activated to maintain the body balance against increasing gravitational force caused by the increase in tilt angle in 3D space. We conclude that both the Biodex Balance System and the Spine Balance 3D system increase core muscle strength. However, the 3D stimulation in the Spine Balance 3D system is more effective to activate the trunk muscles. The dynamic balance improves as shown in the BBS, TUG, FRT, and KFES-I, and the 10mWT, which refers to gait ability, and shows a relatively higher improvement compared to the Biodex Balance System. We expect that the Spine Balance 3D system's superior treatment improves static balance, dynamic balance, and gait in stroke patients. This study has several limitations. First, both the experimental and control groups comprise a small number of subjects of only 14 each. Second, although there were no restrictions for registration, each subject was able to walk independently for 10 m or more, and their BBS scores were over 40, which means that the subjects had relatively mild conditions. Third the long-term effects of the treatment could not be confirmed. In addition, we could not exclude the learning effect for each evaluation system. Finally, the level of the trunk muscle activity could not be directly proven. Therefore, future studies need to include more subjects, and treatment methods should also be confirmed in subjects with more severe conditions. In addition, a method that can directly quantify trunk muscle strength, such as electromyography (EMG) activity, should also be attempted, and the studies should be designed to explore whether the treatment effects are still present months after the experiment. In conclusion, the Spine Balance 3D system, a newly-developed trunk-stabilizing exercise equipment, and the Biodex Balance system were applied to patients with hemiplegia. Although significant improvements in dynamic and static balance were confirmed in both the experimental and control groups, the 10mWT showed a significant improvement only in the experimental group treated with the Spine Balance 3D system, which means that the gait ability also showed a significant improvement and that the activation of the trunk muscles was more effective when using the program of the Spine Balance 3D system. The results indicate that the Spine Balance 3D System induces the activation of trunk muscles and comprises an effective treatment to improve the balance and gait in patients with hemiplegia. | 5,256,321 | {
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TITLE: Implementing a structured education program for children with diabetes: lessons learnt from an integrated process evaluation
ABSTRACT.BACKGROUND:
There is recognition of an urgent need for clinic-based interventions for young people with type 1 diabetes mellitus that improve glycemic control and quality of life. The Child and Adolescent Structured Competencies Approach to Diabetes Education (CASCADE) is a structured educational group program, using psychological techniques, delivered primarily by diabetes nurses. Composed of four modules, it is designed for children with poor diabetic control and their parents. A mixed methods process evaluation, embedded within a cluster randomized control trial, aimed to assess the feasibility, acceptability, fidelity, and perceived impact of CASCADE.
ABSTRACT.METHODS:
28 pediatric diabetes clinics across England participated and 362 children aged 8–16 years, with type 1 diabetes and a mean glycosylated hemoglobin (HbA1c) of 8.5 or above, took part. The process evaluation used a wide range of research methods.
ABSTRACT.RESULTS:
Of the 180 families in the intervention group, only 55 (30%) received the full program with 53% attending at least one module. Only 68% of possible groups were run. Staff found organizing the groups burdensome in terms of arranging suitable dates/times and satisfactory group composition. Some staff also reported difficulties in mastering the psychological techniques. Uptake, by families, was influenced by the number of groups run and by school, work and other commitments. Attendees described improved: family relationships; knowledge and understanding; confidence; motivation to manage the disease. The results of the trial showed that the intervention did not significantly improve HbA1c at 12 or 24 months.
ABSTRACT.CONCLUSIONS:
Clinic-based structured group education delivered by staff using psychological techniques had perceived benefits for parents and young people. Staff and families considered it a valuable intervention, yet uptake was poor and the burden on staff was high. Recommendations are made to inform issues related to organization, design, and delivery in order to potentially enhance the impact of CASCADE and future programs.
ABSTRACT.CURRENT CONTROLLED TRIALS:
ISRCTN52537669.
BODY:
Key messagesThe Child and Adolescent Structured Competencies Approach to Diabetes Education (CASCADE) structured education program is perceived by young people and parents who attend as having benefits but practical challenges associated with attendance result in low uptake.Staff are positive about the potential of the program but organizational aspects are unacceptably burdensome.CASCADE is potentially deliverable to families as part of routine care and could be a useful intervention. However, improvements in clinical and administrative support, staff training, program content, and service structures are required to ensure fidelity to the program and feasibility and acceptability to key stakeholders.
BODY.INTRODUCTION:
Type 1 diabetes mellitus (T1DM) in children and young people is increasing worldwide. Fewer than one in six children and young people achieve glycosylated fraction of hemoglobin (HbA1c) values in the range identified as providing best future outcomes.1 It has been recognized that there is an urgent need for clinic-based pragmatic, feasible, and effective interventions that improve both glycemic control and quality of life, with a particular emphasis on structured education programs.2 In recent years, a number of large multicenter studies have trialed a standard education intervention.3–5 Findings published, to date, report no significant positive impact on glycemic control as measured by HbA1c and only limited impact on a wide range of secondary measures.4
5 Nevertheless, the recent Best Practice Tariff for Paediatric Diabetes for diabetes services in the UK6 requires the provision of structured educational programs for young people and their families and, as a consequence, there is an urgent need for high-quality evidence to inform the implementation of this recommendation. The CASCADE (Child and Adolescent Structured Competencies Approach to Diabetes Education) pragmatic cluster randomized controlled trial (RCT) with integral process and economic evaluation is the most recent study. It was undertaken by a team that included clinicians from a London-based pediatric diabetes clinic, a representative from a diabetes patient organization and researcher teams from three universities in London. The CASCADE intervention is a structured education program designed for children and young people with T1DM aged between 8 and 16 years and their parents or carers.7 The intervention underwent phase 1 pilot work and a non-randomized trial, in which the delivery was carried out by a psychologist.8 The CASCADE intervention was then modified to be delivered by two members of a diabetes multidisciplinary team (MDT) who receive 2 days of training to enable them to become 'site educators'. CASCADE is a manual-based program. It is delivered in four modules over 4 months, each lasting approximately 2 hours, to groups of three to four families with children and young people grouped according to age (8–11 or 12–16 years). Two psychological approaches, motivational interviewing and solution-focused brief therapy, shown to have potential with children with diabetes are central to the CASCADE intervention.9
10 These aim to engage participants to identify and develop their own positive approaches and consequent behavior change relevant to the management of their condition. The intervention thus offers both structured education, to ensure young people (and their parents) know what they need to know, and a delivery model designed to motivate self-management through empowerment techniques (see table 1). Table 1 Outline of the CASCADE program (as set out in the manual) The teaching plan Session activities, objectives, time guides, and resources including key information essential for the educator, learning objective for the family, and brief descriptions of each activity Each module starts with a review of, and since, the previous session, creating an opportunity for families to highlight any changes that have taken place and to congratulate young people on successes Module 1 Focuses on the relationship between food, insulin, and BG ( eg, considering the pros and cons of matching insulin to food to attain better glycemic control ) Module 2 Reviews BG testing and factors influencing BG fluctuation ( eg, identifying factors that cause BG to rise and fall and explore hypoglycemia definitions, reviewing symptoms according to severity) Module 3 Looks at the pros and cons of adjusting insulin (eg, a brainstorming session considers when, how, and who to contact for help managing hyperglycemia) Module 4 Addresses aspects of living with diabetes, including managing BG levels and exercise ( eg, young people and families complete a ‘blueprint for success’. This marks the end of the sessions and acknowledges the steps into the future the young person has already made) Homework tasks are given to families to consolidate learning after each module BG, blood glucose; CASCADE, Child and Adolescent Structured Competencies Approach to Diabetes Education. The intention is that delivering CASCADE to groups will provide staff with an alternative mode of working with young people in the clinic setting to improve outcomes, rather than requiring additional work.
BODY.CASCADE TRIAL SUMMARY:
The trial involved young people with T1DM and family members in 28 English pediatric diabetes clinics (randomly assigned at clinic level to intervention or control) in London, South East England, and the Midlands. Clinics eligible to participate were staffed by at least one pediatrician and pediatric nurse with an interest in diabetes. Other inclusion criteria included not running a group education program at time of recruitment and not participating in a similar pediatric diabetes trial within the past 12 months. It was approved by the University College London (UCL)/UCLH Research Ethics Committee (REC) reference number 07/HO714/112. Site-specific approval was granted at each site. Three hundred and sixty-two young people were recruited to the study. Inclusion criteria included: diagnosis with a duration ≥12 months; mean 12-month HbA1c of 8.5 or above; aged 8–16 years. Clinical staff identified eligible young people from their patient list. Researchers sent letters and information sheets to these young people and their parents or carers inviting them to participate in the research and to speak to a researcher at their next clinical appointment. Recruitment was primarily carried out by members of the process evaluation team who attended clinics at which eligible young people had an appointment. Signed consent forms were collected from parents and children wishing to participate. The primary outcome measure was venous HbA1c at 12 and 24 months. Secondary outcomes included: knowledge, skills and responsibilities associated with diabetes management; emotional and behavioral adjustment; quality of life. Two staff members from each intervention site clinical team participated in the 2 days CASCADE training program. These site educators then took responsibility for organizing the modules at their clinics and delivering the intervention. The extensive and integral process evaluation was designed to enable an understanding of the implementation of CASCADE and examination of the interaction of causal mechanisms and contextual factors that may be determinants of the intervention's success or failure, as assessed by the trial.11 Given that the trial found no evidence of benefits on venous HbA1c at 12 and 24 months and little evidence of benefits on secondary outcomes, the focus of this paper is to use the findings of the process evaluation to suggest how future structured education may be more effectively implemented.12
BODY.PROCESS EVALUATION METHODS:
The process evaluation aimed to assess the feasibility, acceptability, fidelity and perceived impact of the CASCADE intervention. It ran for the 4-year life of the trial and included the multiple methods shown in table 2. Researchers from the process evaluation teams at the Institute of Education (IOE) and the School of Pharmacy (SOP) conducted the fieldwork. Table 2 Process evaluation methods and response rates Phase of the study Methods Purpose of methods Response rates Two-day training of site educators Unstructured observation of training of site educators by a member of the research team Fidelity of training 6 training days observed Participant questionnaires (completed 2 weeks after training) Description of participants Participant experience/acceptability of training 27 participant questionnaires from 18 nurses, 8 dietitians, and 1 doctor (63% of participants) Semistructured interviews with the two trainers Background to intervention development; views on training days Both trainers Delivery of CASCADE modules with patients/carers Observation of modules carried out by a member of research team including rating of fidelity to psychological techniques and content of manual Fidelity of delivery Experience/acceptability of delivery of program to site educators Experience/acceptability of participation in the program by young people/parents 47 CASCADE modules observed across 13 intervention sites (12 each of modules 1, 2, and 4; 11 of module 3) Self-complete feedback proformas for site educators Who delivered each module; who attended each module Self-assessment of delivery fidelity and general feedback on each module Site educators returned 125 feedback proformas (94% of 131 completed modules) Following delivery of all CASCADE groups Young person and parent 12 and 24 month questionnaires in intervention arm Perceptions of impact Acceptability of the intervention Process questions were completed on questionnaires by 135 young people (82%) and 121 parents (66%) at 12 months; 121 young people (66%) and 114 (63%) parents at 24 months Semistructured interviews (audio-recorded) with site staff (nurses and dietitians), young people, and parents/carers in both trial arms Description of standard care—including any structured education currently delivered Intervention arm only—experiences of the intervention (training and delivery) 30 site staff (16 intervention sites; 14 control) 53 young people (32 intervention/21 control) and 52 parents were interviewed. Of the young people, 31 were female; 17 were 10–11 years old; and 36 were 12–18 years old CASCADE, Child and Adolescent Structured Competencies Approach to Diabetes Education.
BODY.PROCESS EVALUATION DATA ANALYSIS:
Qualitative data analysis was carried out by the process evaluation teams at IOE and SOP (all the authors except LB, RT, and DC). Qualitative analysis of the interview data, supported by the use of NVivo software, identified key topics and issues that emerged through familiarization with transcripts.13 Pertinent excerpts were coded and memos written to summarize and synthesize emerging themes. Researchers refined their analysis ensuring that themes were crosschecked with other data, first within and then between transcripts. Analysis of each training workshop observation was carried out by a researcher, who was not the observer, reading through the notes made by the observer and identifying key themes and fidelity issues emerging from the data. Quantitative data were analyzed by MW using Excel and the SPSS V.19 software for statistical tests. In terms of the CASCADE modules delivered in the sites, composite fidelity delivery scores were created for content and for technique from individual researcher observer and site educator self-rated scores. A further composite variable was then calculated which summed the content and technique scores for each site across all four modules, allowing comparison across sites and modules.
BODY.PROCESS EVALUATION RESULTS:
The results are structured under the following themes: recruitment and training of site educators; organizing the groups; delivery of the modules; uptake and acceptability of the modules; and perceptions of impact. Response rates are reported in table 2.
BODY.PROCESS EVALUATION RESULTS.RECRUITMENT AND TRAINING OF SITE EDUCATORS:
The National Institute for Health and Care Excellence (NICE) requirement,2 that structured education programs are delivered as part of routine care was widely recognized by clinic staff and, as a consequence, it proved relatively straightforward to recruit two members of the MDT from each of the 14 intervention sites to become site educators. The majority of site educators were experienced pediatric diabetes specialist nurses (PDSNs); in approximately half of the sites one of the educators was a dietitian. The diabetes specialist nurse and psychologist who developed the intervention delivered the 2 day CASCADE training for site educators in four workshop sessions. In general, it was feasible for sites to send the required minimum of two staff to the core workshops. A few sites sent additional interested members of the MDT though only four consultants attended some or all of the training. The training was delivered in a central London location, except for one site where following a request, training was delivered locally. Site staff reported this change in location to be helpful. The majority of staff who completed the questionnaire following the workshops indicated they had been 'extremely' or 'very' keen to participate. Most staff thought the training was very good, motivating, and comprehensive. The most common concern raised in staff interviews about becoming site educators and running the CASCADE program, both before and after the training, was additional workload. Other concerns included practical constraints such as finding available rooms in which to run the groups and ability to rapidly change their practice to employ the psychological approaches underpinning CASCADE. One site educator commented.It [the training] was a lot in the few days. Teaching people theories and expecting them to suddenly change their behaviour I think is very difficult. The two trainers, and some attendees, expressed concern about levels of diabetes knowledge among the site educators.Some of it [the training] was ending up teaching them the content as opposed to teaching them the style of delivery. (UCLH trainer)At the time [of the training] I'd got very little diabetes knowledge so, for me, I was actually learning from it and I know that's not really what it was about but a lot of it was that...I found it quite intimidating because of my lack of knowledge. (Site educator)
BODY.PROCESS EVALUATION RESULTS.ORGANIZING THE GROUPS:
A total of 30 complete CASCADE groups, comprising all four modules, were run across 12 of the 14 intervention sites. A post hoc calculation, based on the number of study recruits in a site and the optimum group size of 3–4 young people, suggested 44 groups should have been run across the 14 intervention sites. Thus, 68% of possible groups ran, with only three clinics completing the maximum number of groups possible for their site. A key reason for this limited delivery was difficulties with organizing the groups. The organization was undertaken by the site educators in all the sites. This involved: deciding which participants should be grouped together using similar ages as a key criterion; setting dates and times; inviting families to attend; and booking a room. Interviews revealed that site educators found these processes frustrating and very time-consuming. One site educator commented:I didn't notice that it saved me any time because I was constantly chasing them [families] up to be there. One site delivered no modules because the lead site educator left her PDSN post soon after the training. Another site delivered only the first module because of a number of challenges which included: the small number of potential eligible patients on the clinic list; poor uptake of the first module by young people/parents; practical organizational constraints. All the sites ran the groups in addition to routine clinics where standard care continued to be received by patients on an individual basis. Staff interview data revealed that the pressure on hospital clinic facilities was too great to make running the groups feasible during clinics. Establishing a date and time for the group sessions that was acceptable to the families was extremely challenging. To maximize attendance, some site educators tried a range of timings including during school hours, after school, weekends, and school holidays. Communication with families, about groups, was via a combination of letter, telephone, and (occasionally) text messages. No sites used email or online meeting booking sites. Despite all the negotiation and careful planning by site educators, late cancellation or non-attendance by participants was reported as common.Some didn't even bother to get back to us and some did and said they were still gonna come but still didn't come. It is frustrating and I think that's what was time consuming, which I hadn't really accounted for...(Site educator) As a result of these difficulties, compromises were made to the intended group size and composition. Groups often had small numbers (sometimes one family only) and/or a wide age range among the young people attending. Although the intention was to run four modules with the same participants, the composition of many groups changed.
BODY.PROCESS EVALUATION RESULTS.DELIVERY OF THE MODULES:
The site educators believed they were appropriate individuals to deliver the intervention because they knew patients well, although familiarity with patients was not a requirement. Participating families appeared to support this view. All sites had continuity of at least one trained site educator, but complications in sustaining the availability of a second educator in a few sites resulted in some lack of continuity of trainer pairs. Site educators reported that the time required to organize sessions meant that they often had little or no time for planning and practising delivery of the modules. Observation data and some staff interviews suggested that this lack of practice time was particularly challenging when staff had limited experience in group work. Researcher observation of the modules and site educator feedback forms indicated that site educators generally delivered activities as described in the manual. However, less time than was recommended was spent on some of the key exercises due to staff finding them difficult to deliver and/or not well received by groups. One such example was the 'review since the previous session' exercise at the beginning of each module. Also, while researcher observation and staff feedback showed fidelity of CASCADE psychological techniques was good across sessions in half the sites, it was not optimal in the remainder. Difficulties in delivering the intervention particularly occurred when sessions had groups of participants with a wide age range or group numbers were very small.The first group that we ran had two girls and a boy and the boy was at the younger end of the teenage years and the girls were at the older, it was unfortunate because we didn't have that many patients as part of the study so it was very difficult then to get the groups sorted out so we kind of had to put them together. [...] He was just a bit of a silly boy in that...I don't mean horribly, he was lovely, but just kind of played the fool a little bit whereas the girls were older and a similar age and a lot more grown up about it all. (Site educator) Staff reported that the organization and delivery of the intervention was affected by the research context in a number of ways. First, having to restrict the education groups to a subset of recruited patients, instead of offering them to the entire clinic list, was perceived as making the organization of the groups more challenging. This meant that natural groupings of patients (by age or geographical area) often proved too difficult to achieve. Second, delays encountered in the recruitment of families to the trial in many sites (see12 for detail on this), meant site educators often had to wait several months after their training before they could start to organize groups and deliver the intervention. Third, some site educators reported that additional trial-related tasks, such as organizing research blood samples added to their workload and took time away from organization of, and preparation for, groups.
BODY.PROCESS EVALUATION RESULTS.UPTAKE AND ACCEPTABILITY OF THE MODULES:
Of the 180 young people recruited to the intervention arm, only 55 (30%) received the full education program of four modules with just over half of the original recruits (53%) attending at least one module. Eighty-four young people (47%) failed to attend any modules. Those who attended had significantly lower mean baseline HbA1c scores than those who were offered the sessions but did not attend (9.52 vs 10.33, p<0.01). Significantly more children (8–12 years) attended at least one module compared with teenagers (13–16 years; 64% vs 44%, p<0.01). Clinics were permitted to offer sessions at a time of their choice. If out of school hours sessions were not offered, the main reason given for young people not attending modules was that they did not want to miss school. For parents, taking time off work during the day was a barrier to attendance. Other reasons for non-attendance cited by children and parents included holidays and other extracurricular activities. On most occasions a parent/carer attended with the young person. Parents and young people reported that joint attendance was a very positive aspect of the experience (see table 3). Staff also, in most instances, found it helpful to include parents. Table 3 Acceptability of CASCADE to parents and young people attending at least one CASCADE module (12-month questionnaire) Themes Young people Parents/carers ‘Quite a lot’ or ‘A great deal’ n/N (%) ‘Quite a lot’ or ‘A great deal’ n/N (%) Group dynamic Liked parents/young people being together in modules 81/90 (90) 81/84 (96) Felt learnt something from other people in the group 64/93 (69) 60/85 (71) Teaching style and length Liked the way the trainers taught 74/93 (81) 81/86 (94) Felt the sessions were too long 22/94 (23) 7/85 (8) Content Felt that some of the things covered were too complicated 7/92 (8) 8/85 (9) Felt that some of the things covered they knew before 48/91 (53) 42/86 (49)
BODY.PROCESS EVALUATION RESULTS.PERCEPTIONS OF IMPACT:
The majority of parents and young people who attended CASCADE groups described some positive impacts, including improved family relationships, wider knowledge and understanding of diabetes, greater confidence, and increased motivation to manage the disease (see table 4 and young person's comment below).
I've been more happier...yeah, like around the house I've been more happier. Not so many strops...'cause my readings are better and we've been given a lot more information about the ketones and how to treat it....I found it really good. [Young person] Table 4 Parents’ and young people's perceptions of influence of CASCADE (12-month questionnaire) Questionnaire items Answered ‘Quite a lot’/‘A great deal’ Question: After attending some or all of the CASCADE diabetes education sessions, how much did your child/you…? Parent N=90 Young person N=97 Knowledge Understand better how insulin works 66 (74%) 70 (73%) Understand better which foods contain CHO 73 (81%) 68 (70%) See why counting the CHO in the food your child/you eat(s) can be helpful 80 (90%) 73 (75%) Intention to change Want to stop your child's/your glucose levels from going too low or high 85 (94%) 85 (87.5%) Want to test your child's/your BG levels more often 56 (43%) 40 (42%) Control Feel more in charge of your child's/your diabetes 61 (69%) 65 (68%) Feel able to change your child's/your insulin dose when they are exercising 68 (77%) 66 (69%) Feel you are able to control your child's/your BG levels better 70 (78%) 64 (67%) Access to care Feel more able to ring/contact your diabetes nurse/GP/hospital if your child/ you need(s) help 72 (82%) 52 (54%) Family dynamic Feel you had a better understanding of how diabetes affects your family 67 (75%) 69 (72%) BG, blood glucose; CASCADE, Child and Adolescent Structured Competencies Approach to Diabetes Education; CHO, carbohydrate; GP, general practitioner. A number of young people and parents mentioned that timing of the CASCADE sessions would be more appropriate and useful sooner after diagnosis; site educators also commented that this may lead to better uptake of the sessions and have greater impact.I felt they were of little use to me as I already knew everything however this kind of session would be useful to someone who had just been diagnosed. (Young person)They're a bit sort of more 'do as they're told' for the first 12 months, they're more likely to attend and perhaps take it on board, it gets them in the right frame of mind early. (Site educator) Twenty-four months after the intervention, when asked in the questionnaire what effect the program had had, nearly half of the young people selected the response "The sessions made me want to try harder and I have carried on trying". However, these impacts were not reflected in the primary or secondary outcome measures, even for the subgroup of those who attended.
BODY.DISCUSSION:
The CASCADE intervention aimed to train PDSNs and other members of diabetes teams to deliver a manualised, structured education program, based on behavior change methods, to groups of families. Training of these site educators took place over 2 days. Few members of the MDT, other than PDSNs, attended the training. Trainee educators expressed enthusiasm for the program but highlighted concerns including that: CASCADE would increase their workload; there would be practical constraints to setting up and running groups; and that incorporating the CASCADE psychological model into their practice would be challenging. Following delivery of CASCADE in the sites, PDSNs and other clinical staff were positive about the program. Having PDSNs and dietitians, who knew the patients, as site educators worked well for both the educators and families. There were, however, feasibility issues with regard to running the program in its current form in the 'real world' of the National Health Service. These were evidenced by low uptake by families and staff feeling unacceptably burdened by organizational aspects of the intervention. Organizing groups was, as anticipated by staff, challenging and time-consuming and many groups did not comprise the recommended number or age range of young people. This affected group dynamics and made it difficult to run the sessions as set out in the manual. It was also difficult to keep a group together for the planned four modules. Delivery of the modules was further compromised by: the gap in time between training and delivering sessions; time spent on organizing group sessions at the expense of practising delivery of the modules; and finding some exercises consistently hard to deliver. Despite the fact that families and staff reported that they liked the program and felt that it offered benefits, the trial found no evidence of impact on venous HbA1c at 12 and 24 months and little evidence of benefits on secondary outcomes, even with the subgroup who attended the training. We think the reasons behind this are twofold. First the organizational difficulties that made the intended group composition problematic and second the difficulties with delivery, especially the lack of fidelity to the psychological techniques. To address these issues, and to support the development of other structured education programs, we make a range of recommendations.
BODY.DISCUSSION.RECOMMENDATIONS:
To reduce the burden on the site educators more members of the MDT, including consultants, could attend the program training to foster greater buy-in and a team approach to facilitate sharing of the workload. To make this feasible, including containing cost, training of teams could be conducted at local sites rather than centrally in London. Furthermore, dedicated administrative support to organize venues, appointments, groups, and effective reminder systems would increase the likelihood of improved overall uptake, and would help with grouping the young people by age, as intended. Additional support for site educators in practising and sustaining quality of delivery would have been beneficial. Possible approaches could include: those associated with the successful DAFNE program,14 such as longer training, a greater focus in the training on improving group work skills, and an observation of CASCADE experts delivering the program; site level mentoring from CASCADE experts including feedback on site educators delivering trial runs; face-to-face mentoring from local colleagues, such as psychologists. In addition, before undertaking structured education programs, there may be a need to improve the knowledge base of some of the current pediatric diabetes service workforce, as levels of knowledge were very variable. Raising knowledge levels may be addressed by the development of a curriculum for professionals specifically in diabetes, ranging from a core curriculum (basic knowledge that all team members would be expected to know) to an extended curriculum (covering high level application of knowledge specific to individual team members). This finding may have relevance to other medical specialisms where structured education programs are being considered. The uptake of the education sessions was low. For families the key issue was the challenge of fitting attendance into busy day-to-day routines. The education modules were offered in sessions independent of routine clinic appointments. Our data suggest that to improve accessibility it could have been advantageous to make the modules an integral part of routine clinic appointments, thereby overcoming the need for families to make additional hospital visits, with the implications this has for time away from school and work. This would require those in organizational administrative roles to assist with sustainable organizational adjustments required for extending clinic services. This finding and the suggestion that there should be greater 'buy-in' from the wider clinic team echo those in the broader literature on group-based programs.15 Furthermore in the study, participants had to have been diagnosed with diabetes for more than a year to meet the inclusion criteria for participation. Our data suggest that if the program was offered to families sooner after the initial diabetes diagnosis, this might lead to improved motivation to attend the groups. Additionally offering this structured group education more universally might be more successful, including making the organization of groups by age more feasible, than targeting those with the poorest control of their blood glucose levels. It may be more realistic to assume that those with the very poorest control might also require the greater flexibility and intensity that individualized interventions with a psychologist would offer. A summary of the key recommendations is presented in box 1.
Box 1Summary of key recommendations to improve training in, and delivery of, structured education sessionsMore involvement of the wider clinical team facilitated by local training;Greater mentoring of site educators by trainers;Practice sessions with feedback from trainers for site educators before going 'live' and time between training and delivery of first session kept to a minimum;More diabetes-specific training for the pediatric diabetes service workforce to guarantee a basic level of diabetes knowledge prior to training in the program;Dedicated administrative support to assist with organizing the sessions;Education sessions to be held within clinic time;Offer the sessions to all young people on clinic lists and soon after diagnosis.
BODY.DISCUSSION.STRENGTHS AND LIMITATIONS OF THE STUDY:
It is a strength of the study that the process evaluation was unusually extensive and fully integrated into the main trial. Data were collected from all key stakeholders through a range of different methods throughout the different phases of the implementation of the intervention. Triangulation of findings enabled an evaluation of the implementation, barriers, and facilitators in relation to all aspects of implementation, operation, and perceived impact to be examined. It was also a strength that as a pragmatic RCT this intervention was evaluated in 'real-life' and representative settings. One limitation of the study was the impact of the research context on implementation, but steps were taken in the information and reassurance provided, methods, and timing of data collection to minimize effects as much as possible. Additionally, a major hindrance to the intervention was the lower than expected number of CASCADE groups run and the poor uptake of these groups by families. This might suggest a weakness in the intervention's pilot, which was not carried out within the same clinical contexts as the main trial. As such, opportunities to address challenges in organization and delivery were missed prior to, or through carefully managed processes within, the full trial.16 Experience from pragmatic studies of complex interventions such as CASCADE has yielded valuable new learning on the importance of particular investment in the developmental and piloting stages of complex interventions.17
BODY.CONCLUSION:
The extensive multimethod process evaluation showed that the CASCADE structured education program was deliverable; however, improvements in clinical and administrative support, staff training, program content, and service structures to improve accessibility for families were required. The suggested improvements identified in this study all have resource implications, and thus any future research requires cost-benefit considerations. These findings give valuable information on what is required not only in CASCADE but also other similar programs to achieve their aims. | 4,419,460 | {
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TITLE: Premedication with midazolam prior to cesarean delivery in preeclamptic parturients: A randomized controlled trial
ABSTRACT.BACKGROUND::
Anxiety is a concern in obstetrics, especially in preeclamptic mothers. Sedation is not commonly used in parturients for fear of adverse neonatal effect. We investigated maternal and neonatal outcome of midazolam as an adjuvant to spinal anesthesia for elective cesarean delivery.
ABSTRACT.METHODS::
A prospective randomized controlled trial, in which eighty preeclamptic parturients received either an intravenous dose of 0.035 mg/kg of midazolam or an equal volume of normal saline, 30 min before spinal anesthesia. Maternal anxiety was assessed using Amsterdam Preoperative Anxiety and Information Scale (APAIS); postoperative maternal satisfaction was assessed using Maternal Satisfaction Scale for Cesarean Section (MSSCS). Newborns were assessed using Apgar score, Neonatal Neurologic and Adaptive Capacity Score (NACS), and umbilical artery blood gases.
ABSTRACT.RESULTS::
Mothers premedicated with midazolam showed a lower level of preoperative anxiety and a higher degree of postoperative satisfaction than the control group. There were no between-group differences regarding the neonatal outcome.
ABSTRACT.CONCLUSION::
Preeclamptic parturients premedicated with midazolam (0.035 mg/kg) before spinal anesthesia have lower anxiety and higher postoperative satisfaction levels, with no adverse effects on the newborns.
BODY.INTRODUCTION:
Neuraxial anesthesia is progressively used for elective cesarean delivery as it is associated with the best maternal and neonatal outcomes. In preeclampsia, spinal anesthesia provides hemodynamic stability and best risk-benefit outcome; it avoids the detrimental effects of general anesthesia on maternal blood pressure and the risk of difficult intubation.[1] By the mid-1990s, clinical trials demonstrated the safety of neuraxial anesthesia as an accepted alternative to general anesthesia for preeclamptic patients.[234] Recently, a focused review confirmed this fact.[5] One study has reported that 60–80% of patients suffers from preoperative anxiety.[6] Some studies showed a clear correlation between anxiety and preeclampsia.[78] Anxiety is a particular concern in obstetrics, as it may lead to autonomic vasoconstriction in the uterine arteries, which may induce fetal distress.[910] Parturients may endure a great level of anxiety and discomfort during the placement of the spinal needle; a condition could be worsened by preeclampsia. Sedation for neuraxial blockade in pregnant patients remained controversial, based on its potential adverse effects on the fetus, such as decreased motor tone and respiratory compromise. In the 1960s, several case reports showed decreased motor tone in newborns related to maternal diazepam.[1112] In contrast, midazolam is three to four times more potent than diazepam and is used mainly for maternal sedation. Although it crosses the placental barrier, in small doses, it does not cause any adverse effects in the neonate.[13] However, when used in high doses of 0.3 mg/kg for the induction of general anesthesia, the umbilical vein to maternal vein ratio was high (0.96), and the elimination half-life in the neonate was 6.3 h.[14] In the 1980s, a few reports discussed the intravenous (iv) administration of midazolam during pregnancy without providing much information about its use close to delivery.[1516] More recent studies investigated the sedative effect of midazolam with or without narcotics on normal parturients.[171819] However, the impact of midazolam as a sedative on preeclamptics has not been sufficiently studied prospectively. In this concern, we decided to study the maternal and neonatal outcomes of a sedative dose of midazolam in these cases.
BODY.INTRODUCTION.AIMS:
This work aimed to determine the effect of premedication with midazolam on preoperative anxiety, perioperative hemodynamics, and postoperative satisfaction of preeclamptic parturients scheduled for elective cesarean delivery under spinal anesthesia. It was also designed to observe the adverse effects of midazolam on the neonatal outcome.
BODY.METHODS:
After approval of our Institutional Ethical Committee and obtaining informed written consents from all parturients included in this study, this prospective randomized controlled study was conducted on eighty full-term, of American Society of Anesthesiologists (ASA) Class I or II, 18–40-year-old parturients presenting with mild preeclampsia as defined by the American College of Obstetricians and Gynecologists.[20] They were scheduled for elective cesarean delivery under spinal anesthesia after excluding the contraindications of technique. This study was performed in our university hospital from October 1, 2014, to September 30, 2015. Emergency cases, patients with evidence of intrauterine growth restriction or fetal compromise, patients with severe preeclampsia, thrombocytopenia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet levels), parturients receiving magnesium therapy, or with a body mass index >30 were excluded from the study. History of cardiac, pulmonary, hepatic, renal, neuropsychiatric or other diseases or substance abuse also were excluded from the study. All patients had fetal heart monitoring preoperatively to exclude fetal heart rate (HR) abnormalities. Preoperatively, a complete blood count, prothrombin time, liver and kidney function tests were done and recorded for each participant. All patients were assessed clinically and investigated for the exclusion of any of the above-mentioned contraindications. All patients were randomly allocated into two groups, midazolam group (Group M) and normal saline control group (Group S), using a computer-generated randomization list and a sealed envelope technique (n = 40/group). The study solution (midazolam or normal saline) was prepared in a 2 mL volume, by an anesthesiologist not involved in the care of the woman or collecting the data for the study. Another anesthesiologist who was blinded to the study provided perioperative care and collected perioperative data. All patients were booked on a morning list, instructed for the same preoperative fasting protocol and were educated as to how to complete the questionnaires required for the study. On arrival of the patients to the preoperative waiting room, routine monitoring (Electrocardiography, pulse oximeter probe, and a noninvasive blood pressure cuff) were applied, and wide-bore venous access was established for the infusion of lactated Ringer's solution. Thirty minutes before the induction of spinal anesthesia, group (M) was given iv premedication with midazolam (0.035 mg/kg) in 2 mL solution, whereas group (S) was given an equal quantity of normal saline. The Amsterdam Preoperative Anxiety and Information Scale (APAIS) was used in this study for the objective analysis of anxiety in all patients [Figure 1]. It consists of six questions receiving a score between one (none) and five (most), with a total score of 30, investigating patients' concerns and anxieties. It is short, reliable, and easy to administer. Figure 1Amsterdam Preoperative Anxiety and Information Scale APAIS was applied twice by the same anesthesia assistant in a preoperative visit to all patients in their rooms 1⁄2 h before their transfer to the operating theater (A1), and 5 min after the administration of the study drug (A2). Twenty minutes before the induction of spinal anesthesia, all patients received a rapid iv infusion of 500 mL of lactated Ringer's solution as a preload, followed by a replacement rate of 15 mL/kg/h. For spinal anesthesia, 2.5 mL of intrathecal hyperbaric bupivacaine (0.5%) was injected using a 25-gauge spinal needle with patients in the lateral decubitus position at the L 3/4 interspace, under strict aseptic precautions. Parturients were then immediately placed in the tilted supine position. The level of sensory block was determined with cold and pinprick tests. Oxygen by nasal cannula (2 L/min) was applied to all patients. Urinary catheterization was performed, and surgery started when a sufficient level of sensory block (T4) was achieved. The maternal HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) noninvasive arterial pressure were recorded on arrival to the preoperative waiting room (T0), 5 min after injecting the tested drug (T1), during the insertion of spinal needle (TS), 2 min (T2), and 5 min (T5) after the induction of spinal anesthesia. Hypotension was defined as a drop of SBP <100 mmHg or a drop >20% from (T1), which was considered as the baseline value. SBP <90 mmHg was treated with ivboluses of ephedrine in increments of 10 mg. Tachycardia was defined as HR >100 and bradycardia when HR <60. When HR was lower than 50 beats/min, atropine 0.5 mg ivwas administered. Once the baby was delivered, the umbilical cord was double-clamped, and a blood sample from an umbilical artery (UA) was collected for blood gas analysis. Basic neonatal examination was performed, and Apgar scores were recorded at min 1 and 5, and the Neonatal Neurological and Adaptive Capacity Scoring (NACS) was measured and recorded at 15 min.[21] Postoperatively, patients were kept in the recovery room for 1 h and then sent to the ward. The Maternal Satisfaction Scale for cesarean section (MSSCS)[22] is a 22-item questionnaire specifically designed to evaluate maternal satisfaction with neuraxial anesthesia for elective cesarean delivery. Each item has a 7-point scale with minimum total score of 22 and maximum of 154, a higher score representing higher satisfaction. It was applied to all patients on the 1st postoperative day between 8:00 am and 1:00 pm. The development of seizures in cases of mild preeclampsia is extremely rare; however, if it took place, our protocol was to treat it with magnesium sulfate (loading dose of 4–6 g followed by continuous infusion of 1-2 g/h),[120] and the case was dropped out from the study. For sample size calculation, preoperative anxiety was taken as a primary parameter of interest. The power analysis is based on independent sample t-test and a 25% decrease of the APAIS score; the α value was 0.05 and the power (1-β) of the study was 0.80. Depending on the previous studies,[1823] it was calculated that a minimum of 36 patients would be required per group. However, we enrolled eighty patients (40/group) to allow for drop-outs. Data were analyzed using the SPSS statistics program (Version 16, SPSS Inc., Chicago, IL, USA). According to the type of data, they were represented as mean and standard deviation or frequencies and percentages. Comparisons of the two studied groups were performed using independent sample t-test or Mann–Whitney U-test as appropriate while repeated measures within the same group were compared using paired t-test. In all tests, results were considered statistically significant if P < 0.05.
BODY.RESULTS:
Eighty cases were initially investigated, but five cases were excluded during the study; two cases in group (M) and one case in group (S) due to an inadequate spinal block, and one case in each group because of failure to collect umbilical arterial blood. In both groups, there were no significant differences regarding age, body weight, height, and spinal injection to delivery time as shown in Table 1. Table 1 Patients characteristics in both groups After administration of the tested drug (midazolam or normal saline), there was a significant reduction in APAIS readings (A2) in group (M); with a significant difference in (A2) between the two groups while there was no between-group difference before administration (A1) as shown in Table 2. Maternal Satisfaction Scale for cesarean section showed a significant level of maternal satisfaction in group (M) compared to group (S). There was no difference between the groups regarding the newborn Apgar or NACS scores as shown in Table 2. No significant differences were found between the two groups regarding the pH, PaCO2, PaO2, and base deficit in the umbilical arterial samples as listed in Table 3. Table 2 Amsterdam Preoperative Anxiety and Information Scale, Maternal Satisfaction Scale for cesarean section, Apgar score and neonatal neurologic and adaptive capacity score in both groups Table 3 Blood gas analysis of umbilical artery blood samples in both groups Regarding maternal hemodynamics, baseline HR, SBP, and DBP were comparable between the two groups before the administration of the tested drug. However, 5 min after injecting the tested drug, there was a significant decrease in all parameters in group (M) compared to group (S). During insertion of the spinal needle, there was a rise in HR and SBP in group (S) compared to group (M) while DBP was at a lower level in group (M). After the induction of spinal anesthesia and placing the patient into the tilted supine position, there was an increase in HR with some decrease in blood pressure parameters in both groups as shown in Tables 4–6. Table 4 Maternal heart rate in both groups Table 5 Systolic blood pressure in both groups Table 6 Diastolic blood pressure in both groups Hypotension occurred in three patients in the group (M) and one patient in the group (S), requiring a single bolus of ephedrine for each. No bradycardia was observed in any patient. Hemodynamic parameters then remained stable and comparable in both groups.
BODY.DISCUSSION:
This study has shown a significant improvement of preoperative anxiety and postoperative satisfaction in parturients premedicated with midazolam compared to those in the control group, with no significant neonatal adverse effects. The study also documented improved maternal hemodynamics in the treated group before the administration of spinal anesthesia. However, there was no significant difference between groups regarding maternal hemodynamics throughout the rest of the procedure. The progressive increase in the number of cesarean sections[24] draws the attention to the psychological aspects of parturients, including their level of anxiety and perception of obstetric care they received.[25] Some studies tried to solve the problem of preoperative anxiety via nonpharmacological measures, such as the use of a preoperative information video in obstetric[26] and nonobstetric[27] patients, but their results were disappointing. However, other studies applied a preoperative information system and proved its effectiveness on the level of anxiety and postoperative satisfaction in nonobstetric patients.[282930] Midazolam is a commonly used sedative as it is fast-acting and of short duration, making it superior to other benzodiazepines. It is a lipophilic drug that can cross the placenta by passive diffusion. In large induction doses, midazolam and its metabolites cross the placenta in both animal[31] and human[14] studies. However, early in 1984, Kanto et al.[32] proved its excellent sedative effect following cesarean delivery performed under epidural anesthesia. They gave a relatively large iv dose (0.075 mg/kg) following baby removal, resulted in a rapid and marked sedative effect lasted for 2–3 h while patients were completely cooperative in the recovery room. Frölich et al.[19] gave a single iv dose of 0.02 mg/kg midazolam plus 1 μg/kg fentanyl to parturients undergoing cesarean delivery shortly before spinal needle insertion. Similar to our study, Apgar scores showed no difference between the treated group and the control group. They evaluated maternal anxiety with two methods; maternal plasma catecholamine levels at the time of delivery and three postoperative questions. They found a higher level of patient satisfaction in the treated group; otherwise, there were no between-group differences. In contrast, Senel and Mergan[18] gave a single iv dose of 0.025 mg/kg midazolam to parturients 30 min before cesarean delivery. They evaluated maternal anxiety using APAIS score and newborns with Apgar and NACS scores. They reported significantly lower anxiety scores in the treated groups, without any adverse neonatal outcome. However, they recommended further clinical trials with higher sample size to assess the larger doses of midazolam. Similar findings were found by Fung et al. in 1992, where 90% of mothers fell asleep with midazolam premedication before the start of surgery, with no adverse neonatal outcome; comparing the Apgar scores and umbilical venous pH values to the control group.[17] We chose the midazolam dose (0.035 mg/kg) based on these previous studies,[1819] and according to our own experience with Egyptian parturients, aiming for the best degree of maternal satisfaction without causing maternal hypoventilation or neonatal depression. We chose a single bolus based on body weight; however, in clinical practice, some may prefer to titrate iv drugs to effect. Thus, our results cannot be compared to other studies with repeated doses or iv infusion. The timing of premedication is also crucial. We chose it 30 min before the induction of spinal anesthesia, to allow enough time for suppression of anxiety; an important consideration in preeclampsia, whose cardiovascular responses are exaggerated. This is in contrast to Frölich et al., who gave their premedication immediately before the spinal anesthesia procedure. We employed several parameters of neonatal outcome. The Apgar scoring system is routinely used, due to its clear physiological correlation with neonatal well-being.[33] It is easily applied and gives a quick idea about newborn's clinical condition and efficiency of resuscitation efforts. We also used the NACS scoring system, a neurobehavioral scale that allows for the evaluation of potential effects of neonatal drug exposure. It is designed to distinguish drug-induced neonatal depression from that secondary to asphyxia. It stresses on motor tone as a main indicator of drug-induced depression.[21] However, Brockhurst et al. indicate its poor reliability regarding obstetric anesthesia research.[21] We also recorded UA blood gas values and noted no significant difference between groups. Again, the reliability of this test to detect neonatal depression has been questioned.[3435] That is why we employed a combination of several parameters to assess neonatal outcome. As part of this study, we evaluated the postoperative maternal satisfaction of anesthesia and birth. It is an important outcome that is commonly reported;[253637] since in healthy parturients, a pleasant experience is expected. Furthermore, anxiety may decrease the level of overall satisfaction with perioperative care.[38] In 1998, Robinson et al. highlighted some important factors that may affect satisfaction in the obstetric patient.[36] The development of a reliable and valid satisfaction scale for cesarean delivery has allowed to assess the effectiveness of sedatives on maternal satisfaction.[22] MSCCS has proven more sensitive than the standard VAS as it samples from the various physiological and psychological factors that make up satisfaction.[39] The reliability of a scale is directly related to the number of its items so that VAS would be expected to be of low reliability.[22] Our data revealed a remarkable level of maternal satisfaction in the group premedicated with midazolam compared to the control group. To the best of our knowledge, none of the studies concerned with sedatives during cesarean delivery under spinal anesthesia focused on this scale. Instead, Frölich et al. applied a simple questionnaire of three questions while Senel and Mergan and Fung et al. did not focus on this important outcome. The main limitation of this study was the inability to measure the placental transfer of midazolam and its plasma level in the fetal circulation, due to financial difficulties. However, this had been widely investigated by several authors.[143140] Another limitation is this study only enrolled mild preeclamptic patients. Thus, the extension of these findings to those with more severe features of preeclampsia (and potentially more adverse uteroplacental blood flow) remains to be investigated.
BODY.CONCLUSION:
A dose of 0.035 mg/kg of iv midazolam, administered 30 min before spinal anesthesia, is associated with improved preoperative anxiety, postoperative satisfaction, and maternal hemodynamics in preeclamptic parturients scheduled for elective cesarean delivery, with no adverse effects on the newborn.
BODY.CONCLUSION.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.
BODY.CONCLUSION.CONFLICTS OF INTEREST:
There are no conflicts of interest. | 5,062,194 | {
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TITLE: Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy – a randomized trial
ABSTRACT.BACKGROUND:
To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases.
ABSTRACT.METHODS:
In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT.
ABSTRACT.RESULTS:
Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938–0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950–0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001–1.049, p = 0.044) were related with an avoidance of SRE.
ABSTRACT.CONCLUSIONS:
In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE.
ABSTRACT.TRIAL REGISTRATION:
Clinical trial identifier NCT 01409720. August 2, 2011.
BODY.BACKGROUND:
Spinal bone metastases represent the most frequent site of skeletal metastasis [1], and radiotherapy (RT) is the most common treatment option of bone metastases in an advanced tumour disease [2]. As a result of the alteration in bone remodeling activity in patients with bone metastases, various markers of bone formation or resorption have been investigated as a measurement of activity of skeletal metastases. Balance between bone resorption and bone formation is required for maintenance of bone metabolism, and can be reflected by bone turnover markers (BTM). The usefulness of BTM as a tool for the diagnosis of bone metastases in many types of cancers has been investigated previously [3]. Previous studies have demonstrated that some BTM can indicate the existence of bone metastases [4], and have analyzed their relationship with clinical outcomes [5–9]. The two most clinically relevant markers of bone turnover in patients with skeletal metastases are bone-specific alkaline phosphatase (BAP) and N-terminal telopeptide of collagen type I (NTX). Total amino-terminal propeptide of type I collagen (PINP) and BAP are markers of bone formation; BAP has a linear relationship with osteoblast and osteoblastic precursor activity. NTX is a breakdown product of type I collagen produced by various proteolytic enzymes during bone resorption and dissolution of the organic bone matrix. Additionally, pyridinium cross-links pyridinoline (PYD) and desoxy-pyridinoline (DPD) are well-characterized markers for bone resorption. C-terminal cross-linking telopeptide of type I collagen (CTX-I) can be considered a complementary tool for prediction of clinical outcome as a marker of resorption. At the present time, although biochemical markers of bone turnover have shown some utility in clinical trials by predicting clinical outcomes such as death or development of SREs, they are not routinely used in clinical practice. Questions remain as to how clinicians should best use these markers to select and time appropriate treatments among patients with bone metastases. The use of these markers may, in the future, better allow physicians to selectively treat patients with bone metastases. In our recent work, we could show the feasibility of resistance training in patients with spinal bone metastases under RT [10]. Importantly, we demonstrated that the bone density in metastases of the resistance training arm was significantly higher than in the control arm after 3 months. Therefore, we hypothesized that resistance training concomitant to RT could influence bone metabolism, and would be reflected by BTM. The aim of this randomized trial was to compare the effect of resistance training concomitant to RT versus RT only on BTM, such as BAP, PINP, CTX-I, PYD, DPD, and NTX in patients with spinal bone metastases. Secondly, we evaluated an association of these markers as predicted factors for local response, prevention of SRE, and number of metastases.
BODY.METHODS.SETTINGS AND PATIENTS:
This is a randomized, controlled, two-armed intervention trial. A block randomization approach with block size 6 was used to ensure that the two intervention groups were balanced. After the baseline measurements, the patients with stable bone metastases were assigned to the respective treatment groups on a 1:1 basis according to the randomization list. Arm A (intervention group, resistance training) and arm B (control group, passive physical therapy) each consisted of 30 patients. The blood and urine parameters were measured before start of RT (t0) (day of the first fraction), and after three months (t2) on an empty stomach. The primary endpoint was to compare BTM after 3 months in patients treated with resistance training concomitant to RT versus RT only in spinal bone metastases. Secondary endpoint was to evaluate predictive bone markers for local response, prevention of SRE, and number of metastases. Local response of metastasis was assessed on the basis of computed tomography. Positive local response was defined as complete or partial re-calcification on the basis of computed tomography observation at 3 months after RT. The definition of SRE was the first of any of the following events: pathological fractures, severe pain (increase of more than 2 points according to numeric rating scale), hypercalcaemia, and spinal cord compression. Number of metastases was classified in 1 or >1 (solitary vs. multiple). The data of the patient records were collected by the authors. Patient characteristics are shown in Table 1.Table 1Patient characteristics at baselineIntervention group (n = 30)Control group (n = 30)
n
%
n
%Age (years)Mean (SD)61.3 +/− 10.164.1 +/− 10.9GenderMale1446.71963.3Female1653.31136.7Karnofsky-index (median, range)80 (70–100)80 (70–100)Primary siteLung cancer129.2826.6Breast cancer516.7620.1Prostate cancer516.7930.1Melanoma13.313.3Renal cancer13.326.7Other620.1413.4Localization metastasesThoracic1756.71446.7Lumbar930.01343.3Thoracic and lumbar26.726.7Sacrum26.713.3Number metastasesMean (range)1.4 (2–4)1.7 (1–5)Solitary2273.31860.0Multiple826.71240.0Type of metastasesosteoblast930.01033.3osteolytic2170.02066.7Size of metastasisMean (SD)318.6 +/− 230.0380.7 +/− 193.6Distant metastases at baselineVisceral1240.0516.7brain310.0310.0lung723.3413.3tissue826.7620.0Hormonotherapy1033.31653.3Immunotherapy723.3516.7Chemotherapy2583.32066.7Previous SRE930.01343.3Abbreviation: SD standard deviation Inclusion criteria were an age of 18 to 80 years, a Karnofsky performance score [11] ≥ 70, written consent to participate, and already initiated bisphosphonate therapy. Patients were excluded if they presented with concomitant pathologies that could interfere in the evaluation of bone turnover markers, such as bone metabolic disorders, Paget`s disease of bone, hyperparathyroidism, thyroid abnormalities, abnormal intestinal absorption, or hepatic or renal dysfunction. In all cases, anticancer treatment could be changed as clinically indicated throughout the course of the study. The patients were subjected to a staging of their vertebral column within the context of the computed tomography (CT) designed to plan the radiation schedule prior to enrolment into the trial. In this examination metastases were classified as "stable" or "unstable". This was diagnosed independently by a specialist for radiology as well as by a specialist for orthopedic surgery. The specifications for an unstable vertebral body were tumor occupancy more than 60 % of the vertebral body, and pedicle destruction [12]. Only a metastasis classified by both specialists as "stable" was suggested eligible for inclusion. Patients with significant neurological or psychiatric disorders were excluded. The study was approved by the Heidelberg Ethics Committee (Nr. S-316/2011).
BODY.METHODS.RADIOTHERAPY:
RT was performed in the Radiooncology Department of the Heidelberg University Clinic. After virtual simulation was performed to plan the radiation schedule, RT was carried out over a dorsal photon field of the 6MV energy range. Primary target volume (PTV) covered the specific vertebral body affected as well as the ones immediately above and below. In Arm A, 24 patients (80 %) were treated with 10 × 3 Gy, three patients (10 %) with 14 × 2.5 Gy, and three patients (10 %) with 20 × 2 Gy. In Arm B the dose fractions for 28 patients (93.4 %) were 10 × 3 Gy, for one patient (3.3 %) 14 × 2.5 Gy, and for one patient (3.3 %) 20 × 2 Gy. The median individual dose in all patients was 3 Gy (range 2–3 Gy), the median total dose 30 Gy (range 20–35 Gy). The individual and total doses were decided separately for each individual patient, depending on the histology, the patient's general state of health, and on the current staging and the corresponding prognosis.
BODY.METHODS.STUDY INTERVENTIONS:
The interventions commenced on the same day as RT and were performed on each day of RT treatment (Monday through Friday) over a 2-week period, independent of the number of fractions. During the 2-week RT period, the patients in the resistance training arm (Arm A) performed the exercises under the guidance of a physiotherapist. The patients were then instructed to practice the training in their homes three times a week and continued the resistance training themselves until the last investigation after three months, and conducted the documentation in form of a training diary. The resistance training lasted approx. 30 min, the passive physical therapy (Arm B) approx. 15 min. Since the site of the bone metastases differed from patient to patient, three different exercises were enacted to ensure an even isometric resistance training of the paravertebral muscles. Patients in the control arm (Arm B) received passive physical therapy in form of breathing exercises also for a period of 2 weeks. This was conducted so that these patients were not discouraged in comparison to the intervention arm, and for avoidance of a high drop-out rate. A detailed report of the intervention and its application has already been published [13].
BODY.METHODS.STATISTICAL ANALYSIS:
Bone marker values were presented in terms of mean and standard deviation (SD). The possible difference between arms at 3 months was calculated using ANCOVA with arm as factor and baseline value as covariate. Therefore as all surviving patients completed all surveys we assumed that 23 patients in Arm A and 24 patients in Arm B were eligible for the analysis. Multivariate binary logistic regression models were fitted to quantify the degree of association between potential predictors of markers at baseline according to local response (yes/no), prevention of SRE (yes/no), and number of metastases (1/more than one). Group had been included as a covariate in the analysis. Arm A with 23 survived patients was the reference. Level of significance was set to 0.05 for all tests. All statistical analyses were done using SAS software Version 9.4 (SAS Institute, Cary, NC, USA).
BODY.METHODS.ANALYTIC METHODS:
Samples were centrifuged at 3.500 rpm for 10 min after drawing, serum obtained and stored at −80°. First morning void of urine was collected, mixed and an aliquot of 10 ml stored at – 80 °C. Samples shipped on dry ice to the laboratory (Labor Limbach, Heidelberg, Germany) and again stored at −80 °C until analysis. Total aminoterminal propeptide of type I collagen (PINP; bone formation; interassay coefficient of variation [CV]: 2.7 %), C-terminal cross-linking telopeptide of type I collagen (CTX-I; bone resorption; CV: 3.1 %) and intact parathyroid hormone (iPTH; CV: 1.4 %) were measured by means of an automated electrochemiluminescence immunoassay (ECLIA; Modular Analytics E170, Roche Diagnostics, Penzberg, Germany). Bone-specific alkaline phosphatase (BAP; bone formation; CV: 5,2 %) was measured by means of a spectrophotometric immunoassay (IDS-ISYS Ostase BAP; Immunodiagnostic Systems Ltd [IDS Ltd], Boldon, Tyne & Wear, UK) on the fully automated immunoassay system (IDS-ISYS (Immunodiagnostic Systems Ltd [IDS Ltd], Boldon, Tyne & Wear, UK). Pyridinoline (PYD) and deoxypyridinoline (DPD; bone resorption; CV: 12.5 %) were assayed by high performance liquid chromatography (HPLC) [14, 15]. Analysis required first a sample extraction, hydrolysis and automated column-chromatographic pre-purification. To avoid any effect of different dilutions of urine, Pyr and Dpyr data are expressed against gram of creatinine. Cross-linked N-telopeptides of type I collagen (NTx; bone resorption; CV: 12.8 %) was determined with an commercially available ELISA (Osteomark Ntx; Wampole Laboratories, Princeton NJ, USA). All laboratory analyses were done in two batches after completion of the sample collection. To further reduce imprecision of measurement, all samples were analyzed utilizing one reagent lot. Tests and instruments were run strictly in accordance with the guidelines given by the manufacturer and were subject to continuous maintenance and service according to the laboratories standard operating procedures for good laboratory practice. Samples were thawed at the day of analysis at ambient temperature, mixed on a head-over-head mixer and centrifuged before measurement.
BODY.RESULTS:
From September 2011 to March 2013, consecutive 80 patients with a histologically confirmed cancer of any primary and spinal bone metastases of the thoracic or lumbar segments, or of the sacral region were considered in the Radiooncology Department of the Heidelberg University Clinic. Fifteen patients were excluded due to unstable metastases, and five patients declined to participate in the study. Sixty patients fulfilled the inclusion and were enrolled into the trial (Fig. 1). Arms were balanced at baseline without group differences, particularly number of metastases and tumor size (Table 1). Seven patients (23.3 %) died in arm A within the first 12 weeks following RT, six patients in arm B (20.0 %) died within 3 months. The mean follow-up was 3.3 months for both groups. All surviving patients completed all surveys. Mortality did not differ between groups.Fig. 1Flow of participants through the trial Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in arm A. DPD showed a tendency with a lower mean change value, but not significant. No changes were seen between the arms in BAP, NTX, and PINP. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers (Table 2).Table 2Results of bone turnover markersArm AArm BDifference between armsbaseline, n=233 months, n=23baseline, n=243 months, n=24LS meansParameterReference valuemeanSDmeanSDmeanSDmeanSDDifference (95 % CI)
p-value*PYD160–280 μg/g Cr375.63206.20299.89173.88402.00199.01405.50187.32−90.92 (−175.19; −6.65)0.035DPD26–65 μg/g Cr67.3039.6451.2035.8186.1078.8572.8837.11−18.20 (−38.84; 2.45)0.082CTX-I<0.5484 ng/ml0.290.270.200.230.390.370.420.45−0.10 (−0.20; −0.003))0.043BAP6–15 μg/l56.8992.3131.4663.3144.1747.3236.5237.58−12.10 (−31.51; 7.31)0.215NTX5.4–24.2 nmol/l19.097.2117.427.9821.429.3620.389.81−0.87 (−3.84; 2.10)0.556PINP15–59 μg/l67.5440.6949.5041.4387.9651.9866.7739.18−6.94 (−26.81; 12.93)0.485*Results of ANCOVAThis table shows the results of bone turnover markers of both groups at baseline and 3 months after RT. Differences are presented within and between groupsAbbreviation: LS means least square means In arm A, the local response was significantly higher [73.9 % (n = 17) vs. 25 % (n = 6)] (p = 0.003). At first, PINP could be identified as a predictor of local response (p = 0.043). BAP (p = 0.034) and PINP (p = 0.044) could be identified as a predictor for avoidance of SRE. No marker could be detected for solitary metastasis (Table 3).Table 3Results of multivariate binary logistic regression analysis of bone markersLocal response (no local response)OR95 % CI (OR)
p-value Arm (A – reference)0.0330.004 – 0.3110.003 PYD1.0000.992 – 1.0080.986 DPD1.0230.974 – 1.0740.371 CTX-I10.5500.003 – >1000.569 BAP1.0110.996 – 1.0250.142 NTX0.8700.688 – 1.1010.245 PINP0.9680.938 – 0.9990.043Prevention of SRE (SRE = 0)OR95 % CI (OR)
p-value Arm (A – reference)3.3020.877 – 12.4310.077 PYD0.9980.994 – 1.0020.373 DPD1.0060.982 – 1.0310.633 CTX-I0.3230.001 – 81.3360.689 BAP0.9740.950 – 0.9980.034 NTX0.9880.861 – 1.1340.865 PINP1.0251.001 – 1.0490.044Solitary metastasis (n = 1)OR95 % CI (OR)
p-value Arm (A – reference)1.6920.477 – 6.0070.416 PYD1.0010.997 – 1.0050.512 DPD1.0040.980 – 1.0290.761 CTX-I0.3590.001 – >1000.723 BAP0.9970.985 – 1.0090.592 NTX1.0830.939 – 1.2490.275 PINP0.9980.981 – 1.0160.829Abbreviation: SRE skeletal-related events
BODY.DISCUSSION:
Bone metastases are a very frequent secondary diagnosis associated with an advanced tumor disease, with the vertebral column being the most frequent localization [2, 10]. The usefulness of BTM as tool for the diagnosis of bone metastases in many types of cancers has been investigated previously [3]. Many studies have analyzed their relationship with clinical outcomes [7, 16] as well as their clinical importance [17, 18]. However, there is still no concensus among these studies as to which BTM is the ideal marker. In the current work, all BTM in arm A decreased after 3 months, especially the mean change values of PYD and CTX-I were significantly lower at 3 months after RT due to resistance training. BTM in arm B showed also decreased values after 3 months except of PYD and CTX-I, but not so distinctive as in arm A. Importantly, local response as re-calcification in metastasis was improved in arm A due to resistance training. In our recent work, we could show that bone density was significantly increased in metastasis 3 months after start of resistance training concomitant to RT [19]. This factor may influence the BTM and was demonstrated in our results. Therefore, PINP could be detected as a strong marker for bone formation after combined treatment with resistance training concomitant to RT. Determination of CTX-I is recommended for monitoring the efficacy of antiresorptive therapy. Patients with renal cell carcinoma who died or progressed had higher baseline B-CTX levels and those who experienced SRE during follow-up showed high BAP levels [20]. However, in our results we could not found any useful data in normal/abnormal values of BTM. A multicenter study found that increased values of BAP and NTX were associated with increased risk of SRE, and disease progression in patients with breast cancer, prostate cancer, and other solid tumors, treated with bisphosphonates [21]. These markers of bone turnover have been used clinically to predict the risk of SREs and disease outcomes. According our results, we could identify BAP and PINP for avoidance of SRE. In addition, biochemical markers of bone turnover may prove useful in the monitoring of patients on bisphosphonate treatment for bone metastases. One review [22] of 121 patients with skeletal metastases from variety of solid tumors revealed that mean values of NTX were consistently elevated in patients experiencing SREs compared with those who did not. An additional study [23] showed in 441 patients that patients with high NTX or BAP levels had a greater incidence of SREs compared with patients with low levels of NTX or BAP. Patients with increased NTX or BAP at baseline had an increased risk for SRE, shorter time to first event, disease progression and death. As NTX levels have been shown to correlate with response to bisphosphonate treatment. In our data, we could not show any correlation of NTX to local response, SRE, and number of metastases, but we were able to confirm the relation to BAP with prevention of SRE. Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. All of our participants were treated with bisphosphonates. Our data presented no differences between arms of NTX. However, a PINP could be identified as a predictor for local response and avoidance of SRE. In this novel study, our results showed that resistance training concomitant to RT can even enhance an effect on BTM. Since all patients were in advanced stages of their cancer, 40 % of the patients in either group were lost to follow-up due to progressive disease and subsequently death. Further limitations of the study were the relatively small sample size, the variety of primary tumors and patient conditions, and the exclusion of patients presenting with cervical spine metastases. Among the strengths of our novel and original study were the randomized design and the very first presentation of bone turnover markers in combined treatment of resistance training concomitant to RT in patients with spinal bone metastases.
BODY.CONCLUSION:
In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. More studies in larger groups of patients are necessary for further confirmatory research.
BODY.ETHICS APPROVAL:
The study was approved by the Heidelberg Ethics Committee (Nr. S-316/2011).
BODY.CONSENT FOR PUBLICATION:
Not applicable.
BODY.AVAILABILITY OF DATA AND MATERIALS:
The dataset supporting the conclusions of this article is included within the article | 4,794,897 | {
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TITLE: Oral mucositis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: a double-blind randomised clinical trial
ABSTRACT:
BODY:
Radiotherapy in head and neck cancer patients can induce oral mucositis, which is an acute inflammation of the oral mucosa. Until now no effective intervention has been developed to prevent oral mucositis in radiotherapy (Sutherland and Browman, 2001). This prevention is even more relevant now because altered fractionation schedules for the treatment of head and neck malignancies induce more severe mucositis (Kaanders et al, 1999). All patients receiving radiotherapy in the head and neck region develop oral mucositis to some extent, depending on radiation schedule, radiation field, radiation volume and cumulative dose (Miralbell et al, 1999). Clinically, mucositis appears in a conventional radiation scheme after a cumulative radiation dose of 10–20 Gy as a white discoloration of the mucosa because of hyperkeratinisation. The next stage is a deepening erythema followed by the development of pseudomembranes and ulcerations. Severe mucositis, appearing as pseudomembranes, will develop at the end of the third week of radiation, after about 30 Gy (Baker, 1982; Spijkervet et al, 1989b). Prevention of severe mucositis is important because mucositis affects the patient's feeding status, physical and mental well-being and it can influence the course of radiotherapy (Sutherland and Browman, 2001). Further oral pain because of mucositis has a serious impact on the quality of life of patients (Miralbell et al, 1999). Several mechanisms are supposed to play a role in the development of mucositis: changes at the cellular level of the basal cell layer, inflammatory process in the epithelium and influence of bacteria on mucosal surface. Changed oral flora, colonising the oral mucosa, may aggravate the mucosa reaction because of radiation (Van Saene and Martin, 1990). The carriage and colonisation of aerobic Gram-negative bacilli are thought to play a role in the pathogenesis of irradiation mucositis (Bernhoft and Skaug, 1985). A hypothesis has been proposed on the development of mucositis in four consecutive phases, in which the ulcerative/bacterial phase is thought to play a role in the development of fibrous pseudomembranes of the oral mucosa (Sonis, 1998). A pilot study in 15 patients reported the protective effect of an antibiotic lozenge for selective elimination of the oral flora (Spijkervet et al, 1990). Less severe mucositis and a less mean mucositis score compared to a historical control group was observed. None of the PTA-(polymyxin E 2 mg, tobramycin 1.8 mg and amphotericin B 10 mg) treated patients needed nasogastric tube feeding. In a cohort study including 36 patients, it was found that PTA lozenges may reduce irradiation mucositis (Kaanders et al, 1995). In contrast, randomised studies reported conflicting effects on mucositis by selective oral flora elimination (Symonds et al, 1996; Okuno et al, 1997; Wijers et al, 2001). The aim of this study was to evaluate in a randomised, double-blind, placebo-controlled trial the effects of selective oral flora elimination on the development of irradiation-induced oral mucositis, feeding, weight loss and colonisation of aerobic Gram-negative bacilli and yeast.
BODY.PATIENTS AND METHODS.PROTOCOL:
Patients with a malignant tumour in the head and neck regions to be treated with primary curative or postoperative radiotherapy were eligible for this study. Inclusion criteria for the study were: external bilateral irradiation via parallel-opposed portals by a linear accelerator (4–6 MeV), fractionation of 2 Gy daily, five times a week, with a prescribed dose of at least 50 Gy and at least 50% of the oral mucosa in the field of radiation. The dose specification was in line with ICRU 50 recommendations (Anonymous, 1993). Criteria for exclusion were: (1) an oral mucosa defect other than related to tumour surgery; (2) need for an obturator or resection prosthesis and; (3) treatment with antibiotics for an oral infection the last 2 weeks before the start of irradiation. As a standard procedure all patients were evaluated before radiation treatment for potential risk factors for oral complications by means of a thorough oral and dental evaluation, including a radiographic examination. All potential risk factors were eliminated appropriately before the start of radiotherapy. The supportive oral care regimen consisted of a daily protocol of cleansing the oral cavity by means of spraying with saline by the dental hygienist, and mouth rinsing by the patients with a salt–baking soda solution at least eight times a day to remove sticky saliva and debris. Dentate patients applied a neutral fluoride gel every second day with custom-made trays and edentulous patients were not allowed to wear their dentures during the course of radiotherapy (Jansma et al, 1992). The Medical Ethical Committee approved the study and all eligible patients gave written informed consent.
BODY.PATIENTS AND METHODS.ASSIGNMENT:
The eligible patients were randomised to receive active lozenges of 1 g containing polymyxin E 2 mg, tobramycin 1.8 mg and amphotericin B 10 mg (PTA) or placebo lozenges. The ingredients of the placebo lozenge were identical with the PTA lozenge except the active drugs. The colour, taste and form of the PTA and placebo lozenges were identical as well. Randomisation was performed by the hospital pharmacist according to a computer-generated, randomised allocation schedule. Patients, clinicians, dental hygienists and microbiologists were blind for who was taking antibiotics. The patients used a PTA or placebo lozenge four times daily starting the first day of irradiation during the total radiation period.
BODY.PATIENTS AND METHODS.ASSESSMENTS:
The study period included only the first 5 weeks of radiation because of the wide range of field changes above 50 Gy of radiation. During the study period mucositis, feeding and body weight scores were performed at the start of radiotherapy and twice weekly (Monday–Thursday). The assessments were performed by an assigned dental hygienist. For each patient a mean weekly score was calculated on the basis of these two scores. These mean scores were used for further statistical analyses. Twice weekly (Monday–Thursday) and two times before the start of radiation oral washings were obtained to examine the oral flora for Gram-negative bacilli, Candida species, viridans streptococci, Enterococci, Staphylococcus aureus and coagulase-negative Staphylococci.
BODY.PATIENTS AND METHODS.ASSESSMENTS.MUCOSITIS:
The mean mucositis was scored by using qualitative and quantitative parameters (Spijkervet et al, 1989b). Four different local signs of mucositis (k) might be distinguished: 1=white discoloration; 2=erythema; 3=formation of pseudomembranes; 4=ulceration. Mucositis of the oral cavity was determined for maximally eight distinguishable irradiated areas of the mouth: buccal mucosa (left and right), soft and hard palates, dorsum and border of the tongue (left and right), and the floor of the mouth. The degree of mucositis of each area was scored according to the local signs of mucositis. The length (E) of the local sign of mucositis was measured: 1=⩽1 cm; 2=1–2 cm; 3=2–4 cm; 4=⩾4 cm. The degree of mucositis was defined as the product of the values k and E. The mucositis score was defined as the mean of the scores assigned to the irradiated areas. The mucositis was also scored according to the WHO score (grade 0=normal, no mucositis; grade 1=soreness and erythema; grade 2=erythema, ulcers, can eat solids; grade 3=ulcers, requires liquid diet only; grade 4=alimentation not possible) (Anonymous, 1979).
BODY.PATIENTS AND METHODS.ASSESSMENTS.FEEDING:
The quality of feeding was scored (0=normal, no changes; 1=symptoms without medication; 2=symptoms with medication; 3=liquid diet only; 4=nasogastric tube feeding) and body weight was determined. Afterwards the changes in weight were scored.
BODY.PATIENTS AND METHODS.ASSESSMENTS.MICROBIOLOGICAL METHODS:
To acquire an oral washing, patients gargled and rinsed their mouth with 10 ml sterile saline for 30 s, and spit it into a sterile vial. One millilitre of the sample was diluted in 9 ml of Brain Heart infusion (BHI) (Oxoid, Basingstoke, England) and this suspension was serially diluted in BHI. The suspensions were than plated out onto 5% sheep blood agar, McConkey-3 agar (Oxoid) and Yeast morphology agar (Merck, Darmstadt, Germany). The agar plates and BHI broth cultures tubes were incubated overnight aerobically at 37°C. If an agar plate did not show growth and the corresponding BHI broth culture of the dilution series did show turbidity, then this suspension was plated again onto the agars mentioned above. With this enrichment step even low numbers of Candida species and Gram-negative bacilli could be detected (Spijkervet et al, 1989a). By reading and counting the plates after incubation the viable numbers of microorganisms per millilitre was estimated. The identification was performed by standard microbiological techniques.
BODY.PATIENTS AND METHODS.ASSESSMENTS.DEFINITIONS:
Carriage of a particular microorganism was defined as the condition in which a patient showed a minimum of two consecutive oral washings positive for that organism. Colonisation index of the oral cavity was defined as the sum of logarithms of the concentrations of a particular microorganism isolated from 1 ml of oral-washing specimens divided by the number of oral washings.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS:
Sample size calculation of this study was based on the study by Spijkervet (Spijkervet et al, 1990). A two-sided α of 5% and a power of 80% were used. Additionally, a 50% reduction of mucositis in the PTA group was determined as clinically relevant with a normal incidence of mucositis of 80%. Based on these assumptions, 27 patients in each group would be sufficient. Intention-to-treat analysis was performed. The difference of dropouts between both groups was analysed using Fisher's exact test. The results were analysed, with respect to mean mucositis, the loss of weight, and colonisation numbers for five different microorganisms (t-test for independent samples) and the WHO mucositis score and feeding (Mann–Whitney U test). Two-sided tests, performed at the 5% level of significance, were used.
BODY.RESULTS:
Patient characteristics are shown in Table 1
Table 1Patient characteristicsPatients characteristicsPlaceboPTAP-valueaAge mean±sd (years)54 (10.8)56 (12.5)0.36Gender: male/female (n)22/1024/90.79 Tumor site Oral cavity (n)17230.41 Oropharynx (n)108 Hypopharynx (n)11 Unknown primary(n)41 Histology Squamous (n)31321.0 Other (n)11 T-stage T1 (n)450.25 T2 (n)65 T3 (n)88 T4 (n)914 bTx (n)51 N-stage N0 (n)10140.12 N1 (n)610 N2a (n)21 N2b (n)93 N2c (n)13 N3 (n)42 Surgery Yes (n)21270.17 No (n)116 Dentures Yes (n)20250.29 No (n)128 All differences between the groups were analysed using χ2 test exceptain which t-test was used.bSix patients with an unknown primary tumour.. From January 1994 to February 1997, 65 patients were included, 33 patients received PTA lozenges and 32 the placebo lozenges. Out of the 65 included patients, 58 patients were evaluable for the total evaluation period of 5 weeks. Seven patients (11%) dropped out earlier from the study, five of the PTA group (15%) and two of the placebo group (6%). The difference of dropouts between both groups was not significant. One patient (PTA) developed a skin reaction, unlikely caused by the PTA lozenges, and one patient (placebo) could not suck the lozenges because of the tumour surgery of his tongue. The other five dropped out for reasons not related to one of the lozenges. Of the seven dropouts, one patient stopped after 1 week, two patients after 2 weeks, one patient after 3 weeks and three patients after 4 weeks radiation.
BODY.RESULTS.MUCOSITIS:
The mean mucositis was the same in the PTA group and the placebo group during the study period (P>0.2) (Figure 1Figure 1The mean mucositis score (±s.d.) for the PTA group (▵) and the placebo group (□).). During the 5-week observation period 89% of the patients in the PTA group developed pseudomembranes and in the placebo group 94%. The mucositis according to the WHO score did not differ throughout the study period between both groups (P>0.5). In the PTA group, 80% of the patients developed grades 3 and 4 mucositis according to the WHO score, and in the placebo group 90%. The appearance of pseudomembranes was for both groups at a similar radiation status; after 30 Gy of radiation.
BODY.RESULTS.FEEDING:
Six patients (19%) in the placebo group (n=32) and two patients (6%) in the PTA group (n=33) needed nasogastric tube feeding during the evaluation period (P=0.08).
BODY.RESULTS.BODY WEIGHT:
The mean weight loss after 5 weeks of radiation was less in the PTA group by 1.3 kg (s.d. 3.0) than in the placebo group 2.8 kg (s.d. 2.9) (P=0.05).
BODY.RESULTS.MICROORGANISMS:
For viridans streptococci, Enterococci, Staphylococcus aureus and coagulase-negative Staphylococci, a similar pattern of carriage and colonisation was found in both groups. The colonisation and carriage of Candida species at baseline was equal in both groups (P>0.8). During the first two radiation weeks the colonisation for Candida species showed an increase in the placebo group and a decrease in the PTA group. After 2 weeks, an increase in both groups was found but the difference between the two groups remained significant during the total study period (P<0.05) (Figure 2Figure 2Percentage of patients colonised for Candida species for the PTA group (lines) and the placebo group (solid).). During the first 4 weeks a significant difference was found for the carriage of Candida species (P<0.03). The colonisation and carriage of aerobic Gram-negative bacilli at baseline was equal in both groups (P=0.9). During the radiation period the colonisation in the PTA group was less than in the placebo group, but the difference was only significant in the second week of radiation (P=0.05) (Figure 3Figure 3Percentage of patients colonised for aerobic Gram-negative bacilli for the PTA group (lines) and the placebo group (solid).). During the first 2 weeks the carriage of aerobic Gram-negative bacilli was reduced in the PTA group (P<0.04). In weeks 3–5 the difference was no longer significant. All results are summarised in Table 2
Table 2Results of the PTA–placebo group for mean mucositis, weight loss, carriage and colonisation index of Candida species and aerobic Gram-negative bacilli 012345 WeekXs.d.Xs.d.Xs.d.Xs.d.Xs.d.Xs.d.Mean mucositis PTA000.50.72.21.74.62.74.52.75.02.3 Placebo000.30.42.62.04.82.34.92.55.22.8 Weight loss PTA00−0.31.00.41.30.62.11.02.71.33.0 Placebo000.30.9a0.61.21.31.72.22.32.82.9a Candida col. Index PTA1.01.30.40.80.50.90.60.90.81.51.01.5 Placebo1.11.31.21.6a1.61.7a1.71.7a2.01.7a1.91.8a Candida carriage PTA (%)48 23.5 17.6 31.8 30.8 36 Placebo (%)52 76.5b 82.4b 68.2b 69.2b 64 Aerobic Gram-negative bac. col. Index PTA0.71.20.40.80.40.90.61.20.51.00.40.9 Placebo0.71.40.81.10.91.1a0.81.00.81.40.81.5 Aerobic Gram-negative bac. Carriage PTA (%)52.4 23.1 25 42.9 54.5 40 Placebo (%)47.6 76.9b 75b 57.1 45.5 60 aRepresents a significant difference between the PTA and placebo group using an independent sample t-test.bRepresents a significant difference between the PTA and placebo group using χ2 test..
BODY.DISCUSSION:
In this study, no effect of selective oral flora elimination on mucositis was observed. The development of mucositis follows the same pattern as reported in an earlier cohort study (Spijkervet et al, 1989c). According to the WHO score, 80% of the patients in the PTA group and 90% in the placebo group developed mucositis grades 3 and 4. This severity of mucositis is in accordance with the outcomes of Okuno et al (1997). In other studies, different outcomes are reported. A significant reduction of mucositis in the PTA group was found by two groups (Spijkervet et al, 1990; Kaanders et al, 1995). Both studies are nonrandomised clinical trials and the PTA group is compared with a historical control group. A reduction in mucositis distribution and affected area, dysphagia and weight loss in the PTA group is reported by Symonds et al. (1996). From a total of 221 patients in that study, 98 (44%) patients had a larynx carcinoma (PTA=57, placebo=41). Of these patients, the radiation field included only a minor part of the oral mucosa, in which mucositis could develop. In the study of Okuno et al only a subjective patient-reported amelioration of mucositis was reported but no reduction was found in clinically observed mucositis (Okuno et al, 1997). The PTA group (n=54) in that study consisted of an unblinded (n=29) and a blinded (n=26) group. Only in the unblinded PTA group the mean mucositis, reported by the patients was lower than the placebo group. Recently, it was shown in a randomised study including 77 patients that selective oral flora elimination does not reduce radiation mucositis (Wijers et al, 2001). A problem in that study is the short evaluation time of only the first 3 weeks of radiotherapy. Whereas normally development of severe mucositis starts after 3 weeks of radiation (Kaanders et al, 1999). A complicating factor in comparing outcomes from different studies is the assessment method of mucositis. All studies used different scoring methods. Therefore, two scoring methods were used in the current study. The WHO score is a widely accepted method, but this score is a combination of local mucositis signs and general complaints (Anonymous, 1979). The other scoring method in the current study is based only on mucosal signs of mucositis (Spijkervet et al, 1989b). It therefore provides a more precise estimation of the mucositis development at the mucosal level. It further makes a comparison possible with outcomes of earlier publications (Spijkervet et al, 1989b; Parulekar et al, 1998). For future studies, we recommend the use of the OMAS-score from the mucositis study group because this scoring method is a reliable, well-validated and widely accepted method (Sonis et al, 1999). This scoring method was published later than the start of the current study and was therefore not used as a scoring method in this study. In the current study, patients who received PTA lozenges had less weight loss than patients receiving placebo lozenges, assuming a better feeding status of the PTA-group patients (mean difference 1.5 kg). Owing to the minimal effect of PTA on the mucositis level, we found the feeding outcome of minor clinical relevance. In our study, carriage and colonisation of aerobic Gram-negative bacilli and Candida species decreased in the PTA group but was not totally eradicated. These findings are in line with the findings of other studies (Spijkervet et al, 1990; Kaanders et al, 1995; Symonds et al, 1996; Wijers et al, 2001). Based on these findings and the development and severity of mucositis it can be concluded that the presence of Candida species and aerobic Gram-negative bacilli has no influence on the development of radiation-induced mucositis. The increase of the carriage and colonisation of Candida species and aerobic Gram-negative bacilli after 3 weeks of radiation may be explained by the development of xerostomia, which makes dissolving of the lozenges more difficult. Wijers et al tried to overcome this problem by using a paste instead of a lozenge. However, the paste appeared to be an unsuccessful form of application because already after randomisation 32% of the patients refused further participation and 77% of the patients dropped out after four study weeks because of bad taste and unpleasant sensation of the paste texture in the mouth (Wijers et al, 2001). In conclusion, PTA lozenges have a positive effect on the quality of feeding and the amount of weight loss but cannot prevent severe mucositis. The presence of Candida species and aerobic Gram-negative bacilli has no effect on the development and severity of radiation-induced mucositis. Based on our findings of this randomised clinical trial, we do not recommend this type of supportive care for the reduction or prevention of radiation mucositis. | 2,376,383 | {
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TITLE: Are CT Scans a Satisfactory Substitute for the Follow-Up of RSA Migration Studies of Uncemented Cups? A Comparison of RSA Double Examinations and CT Datasets of 46 Total Hip Arthroplasties
ABSTRACT:
As part of the 14-year follow-up of a prospectively randomized radiostereometry (RSA) study on uncemented cup fixation, two pairs of stereo radiographs and a CT scan of 46 hips were compared. Tantalum beads, inserted during the primary operation, were detected in the CT volume and the stereo radiographs and used to produce datasets of 3D coordinates. The limit of agreement between the combined CT and RSA datasets was calculated in the same way as the precision of the double RSA examination. The precision of RSA corresponding to the 99% confidence interval was 1.36°, 1.36°, and 0.60° for X-, Y-, and Z-rotation and 0.40, 0.17, and 0.37 mm for X-, Y-, and Z-translation. The limit of agreement between CT and RSA was 1.51°, 2.17°, and 1.05° for rotation and 0.59, 0.56, and 0.74 mm for translation. The differences between CT and RSA are close to the described normal 99% confidence interval for precision in RSA: 0.3° to 2° for rotation and 0.15 to 0.6 mm for translation. We conclude that measurements using CT and RSA are comparable and that CT can be used for migration studies for longitudinal evaluations of patients with RSA markers.
BODY.1. INTRODUCTION:
Reliable measurement of implant migration enables early detection of an inferiorly performing prosthesis as well as identifying patients in whom aseptic loosening may occur sooner than expected [1, 2]. Radiostereometry (RSA), introduced in 1974 [3], is considered the gold standard for evaluation of implant migration in vivo [4, 5]. In many patients (roughly 10,000 in Sweden alone [6]) tantalum beads were implanted into the bone and attached to or inserted into the prosthesis for assessment of joint replacements with RSA. However, RSA requires calibration cages, radiology facilities with two X-ray machines for simultaneous acquisition of two X-ray images, specialized software, and trained personnel [7]. The number of hospitals capable of this analysis is limited; thus alternative techniques, for following these patients over time, such as three-dimensional (3D) computed tomography (CT), should be considered. Today, CT-scanners are found in almost every hospital and these scanners make it possible to visualize the small tantalum beads (RSA markers) in CT volumes with a clinically acceptable accuracy of 1 mm or less [8–10]. Additionally, the effective radiation dose of CT scans is constantly being lowered and the quality of the scans with regard to metal artifacts is improving [11]. If 3D CT is comparable in precision to RSA, then CT could replace RSA, thus greatly expanding the cohort of patients who could be followed. Over the last decade, our group has refined and validated a 3D volumetric data processing tool [12–15], which exploits cohomologous points (landmarks) to enable volume fusion. This tool has been used with 3D CT volumes for studying the position, wear, and migration of orthopedic implants over time. This report explores the possibility of utilizing CT scans of patients with tantalum beads in the acetabulum and orthopedic hip implants, by directly comparing CT derived data to RSA data acquired on the same day. Specifically, we evaluate how similar a dataset of 3D bead positions derived from routine CT scans of patients is to a RSA dataset based upon these same RSA markers. If sufficiently similar, then CT could be used to follow patients from RSA migration studies, for example, to evaluate new prostheses [10].
BODY.2. MATERIALS AND METHODS.2.1. PATIENTS:
The data for this study resulted from a 14-year follow-up of total hip arthroplasty [21] whose purpose was to investigate the influence of different cup augmentation on cup stability and liner wear. Sixty-three patients (68 hips: 31 men, median age (range) 56 (36–66) years, median weight (range) 75 (51–102) kg) with primary and secondary hip osteoarthritis (OA) underwent total hip arthroplasty between 1995 and 1997 at the Department of Orthopedics, Umeå University Hospital. Fifty-two hips had primary and 16 had secondary OA with 37 hips in Charnley class A (unilateral OA) and 31 hips in class B (bilateral OA) [22]. A hemispherical porous-coated titanium alloy cup with ethylene oxide sterilized polyethylene liner (Reflection, Smith & Nephew, Memphis, TN) was used in all patients. During surgery, five to nine 0.8 mm tantalum beads were inserted into both the periphery of the polyethylene liner and the acetabular bone as RSA markers. At the 5-year follow-up [23] a high amount of wear of the polyethylene liner, which increases the risk of osteolysis development over time [24], was evident. Therefore, a CT scan was added for the 14-year follow-up to investigate the amount of osteolysis around the cup. This enabled comparing the 3D RSA marker positions (landmarks) derived from CT with those provided by RSA. The institutional review board approved the study (the Central Ethical Review Board of Umeå University Dnr 2010-100-31) and all patients gave their written consent. At the 14-year follow-up 48 hips in 45 patients remained and were included in this study. Reasons for not attending the follow-up were death (8 patients, 9 hips), revision (5 patients, 6 hips), or refusal to attend (5 patients, 5 hips). The median (range) follow-up time was 14 (13–15) years. Clinical outcome and results of the migration measurements were published in a separate paper [21]. Each patient had a CT scan and 2–4 stereo radiograph pair examinations (resulting in 4–8 individual X-rays) on the same day.
BODY.2. MATERIALS AND METHODS.2.2. CT SCANS:
CT scans (LightSpeed VCT General Electric Medical Systems, Milwaukee, WI) were acquired from spina iliaca anterior superior to a point at least two centimeters distal to the tip of the femoral component with scan parameters: data collection diameter: 500 mm, reconstruction diameter: 400 mm, source to detector distance: 949.08 mm, source to patient distance: 541 mm, peak kilovoltage (kVp): 120 kV, and exposure time: 800 ms. A bone reconstruction algorithm was used resulting in 225 to 366 slices at 0.625 mm increments with a matrix size of 512 × 512 and a pixel resolution of 0.78 × 0.78 mm in the axial (xy)-plane. The median (range) effective radiation dose was 6.9 (3.2–21.1) millisievert (mSv) [25]. To facilitate analysis of both CT and RSA derived data, the CT volume for each patient was duplicated and given a new name.
BODY.2. MATERIALS AND METHODS.2.3. RADIOSTEREOMETRY (RSA):
A ceiling stand (Aristos VX, Siemens, Munich, Germany) was combined with a mobile digital X-ray unit (Mobilett, Siemens, Munich, Germany), both having a resolution of 10 pixels per mm to obtain two simultaneous exposures of the hip joint. Patients were placed supine on the examination table with the planes of the two X-ray tubes angled by approximately 40° to each other combined with a uniplanar calibration cage No. 43 (RSA Biomedical, Umeå, Sweden). Two image pairs (a double examination: 4 X-ray images) were obtained with slightly different patient positions. In some cases an additional one or two extra image pairs were needed until two image pairs with optimal visualization of the tantalum markers on both foci were achieved. The median (range) effective radiation dose per complete examination, calculated using PCXMC version 1.0 [26], was 1.9 (1.9–3.8) mSv for a fully digitized acquisition at 120 kV and 150 mAs.
BODY.2. MATERIALS AND METHODS.2.4. RSA PROCEDURE:
The radiographs were analyzed using the UmRSA software 6.0 (RSA Biomedical AB, Umeå, Sweden) by a skilled operator with many years' experience. All tantalum beads (markers) that could be identified on both focuses 1 and 2 images were given a unique marker number. The 3D coordinates (in the standardized RSA cage coordinate system) for the markers were calculated, where the medial-lateral position is described on the x-axis, distal-proximal on the y-axis, and posterior-anterior on the z-axis [27]. The following data were saved for later analysis: focuses 1 and 2 stereo radiograph images (each showing the markers in the periacetabular skeleton and in the polyethylene liner with corresponding marker numbers) and a dataset consisting of marker number and 3D coordinates for this marker. The precision of the current RSA setup was calculated by double examinations of all 48 hips. Markers in both the acetabulum and the rim of the liner were accepted when the mean error of rigid body fitting was ≤0.25 mm with condition number (reflecting how well spread the markers are in 3D) < 90, or ≤0.35 mm with condition number <80, or ≤0.2 mm with condition number ≤130. Markers that did not meet these criteria were automatically excluded assuming instability of the marker or incorrect marking, resulting in 46 RSA double examinations (46 hips, 43 patients) for analysis.
BODY.2. MATERIALS AND METHODS.2.5. DATA PROCESSING:
The RSA coordinate system is determined by the reference cage, where normally for the first set of postoperative radiographs at least one set is acquired with the patient carefully oriented relative to the external reference cage [18]. In contrast, the orientation of the patient during the CT scan is unimportant because the volume can be freely rotated in 3D [15]. By designating landmarks in the CT volume (i.e., defining a landmark's 3D coordinates) and transforming the coordinates of the RSA markers from the RSA coordinate system into the CT coordinate system, we were able to treat the RSA dataset and the CT dataset as a double examination; hence we compared the limit of agreement (precision) of this calculation with that from a RSA double examination. For calculating the limit of agreement always the first of the two RSA image pairs was used. The analysis of the CT data to produce the 3D CT datasets and the comparison of these datasets with the RSA datasets were both performed using a previously described and validated 3D volume fusion (spatial registration) tool [12, 28, 29]. This semiautomated tool provides landmark-based fusion of two volumes, registering a "target" volume to a "reference" volume by exploiting cohomologous landmarks in each volume, via a variety of 3D transform modules, ranging from simple rigid body to 3D warping and including user-defined transformations. A technical description can be found in earlier publications [12, 14, 30]. Moreover, use of the CT volumes gives us the opportunity to work directly in three dimensions, while tracking each step graphically.
BODY.2. MATERIALS AND METHODS.2.6. CT-BASED PROCEDURE:
First the tantalum beads were visualized in the CT volume by setting the isosurface level such that voxels attenuating less than metal were not visible. Then, in order to assign landmark numbers consistent with the RSA marker numbers, in a separate display the RSA focuses 1 and 2 stereo radiograph images showing the tantalum beads with their marker numbers were displayed. The CT volumes were manually rotated in 3D so they were visually comparable with the stereo radiographs. Using the computer's pointing device, the tantalum beads in the bone were designated and assigned the same marker numbers as in RSA (Figure 1). When a bead was designated, the fusion tool automatically found a best fit center and recorded this as a 3D landmark (see in particular Figure 2 in [10] which shows that even in the presence of partial volume effects the landmark is visually embedded centrally in the volume of the bead). This created a set of "CT-based bone landmarks" in the CT data coordinate system. To utilize the RSA dataset, the fusion tool mapped the RSA cage coordinate system into the CT data coordinate system. This transformation process was previously described and validated to have a median (range) translation error of 0.22 (0.07–0.52) mm, a rotation error of 0.003 (0.001–0.006)°, and a goodness of fit of 0.0010 (0.0001–0.022) per bead [9]. We then imported and transformed the RSA bone marker dataset into a set of "RSA-based bone landmarks" in the CT coordinate system. This produced two CT data volumes: one containing bone landmarks generated from 3D CT analysis and the other containing bone landmarks generated from RSA (transformed into the CT coordinate system). The CT volume containing the "RSA-based bone landmarks" was used as the "reference" volume, while the CT volume containing the "CT-based bone landmarks" was used as the "target" volume. The fusion tool then registered the target volume with the reference volume using corresponding landmarks. The result was a rigid body transformation that registers the two CT volumes based upon the entire set of "CT-based bone landmarks" and "RSA-based bone landmarks" using singular value decomposition (SVD) [31]. The distances between each of the original landmarks of the reference volume and the new (transformed) landmarks of the target volume were automatically generated. Because the "RSA-based bone landmarks" used were derived from the original RSA dataset before the automated process where the RSA software deletes misplaced points or performs any "trial and error" interchanging of marker numbers, the set contains both correct points and incorrect points (i.e., those where the coordinates of a marker were derived from two different markers or from a marker and background noise, such as the femoral head or the acetabular shell). Corresponding landmark pairs that were not well matched (i.e., those whose distance is different from the corresponding landmark by ≥2.0 mm) were manually interchanged or excluded by the operator until a reasonable (i.e., the maximum 3D distance error of any landmark pair was ≤2.0 mm) registration between the two volumes based on "bone landmark" sets was established. The landmark selection procedure was then repeated for the "prosthesis" landmarks instead of the "bone" landmarks. This resulted in a corresponding set of "RSA-based prosthetic landmarks" in the "reference" volume and "CT-based prosthetic landmarks" in the "target" volume. A rigid body transformation that registered the entire set of "CT-based prosthetic landmarks" to the entire set of "RSA prosthetic landmarks" was then performed, followed by the verification of the landmark selection procedure. In summary, 6 steps are necessary to calculate the error of the cup position in relation to the acetabulum bone between CT and RSA: (1) assigning bone and prosthetic markers in CT consistent with the marker numbers in RSA, (2) importing landmark coordinates from RSA into a copy of the CT volume, (3) registering the target volume (CT) to the reference volume (RSA) based on the bone landmark sets using a rigid body transformation, (4) transforming the target prosthetic landmark set into the registered coordinate system, (5) rotating and translating both volumes and associated prosthetic landmarks to a standard orientation, and finally (6) computing the rigid body transformation that would move the resulting target prosthetic landmark sets into spatial alignment with the reference set [30]. Steps (1) and (2) were done manually, while steps (3) to (6) were performed automatically. The rotation point for the last rigid body transformation is by default the centroid (the geometric weight-point) of the prosthetic reference landmark set. Using the SVD registration method, the program computes this transformation as a 3 × 3 rotation matrix and a 1 × 3 translation matrix in the CT coordinate system. The main outputs from this process are (1) visual 2D and 3D images of the two volumes after registration of the bone landmark set and (2) numerical data indicating the movement of the prosthesis in six degrees of freedom (rotations about and translations along the x-, y-, and z-axes, where the translations are given for each individual prosthetic landmark with respect to the centroid of the prosthetic landmarks). The error of the measurement is the last registration movement between the rigid body from RSA dataset and CT dataset. The rotation errors are generated by decomposing the rotation matrix into Euler angles, which, although not unique, are computed as a clockwise rotation first around the x-, then the y-, and finally the z-axes as defined by the standardized RSA in the CT coordinate system. Numerical information, based on the distance between the original landmarks of the stationary body and the new (transformed) locations of the moved body for each landmark, for both the bone and the prosthetic landmarks is automatically generated. These differences are computed for each orthogonal direction, for the axial (xy)-plane and for the volume. If the registrations were perfect, these differences would be zero. For a more detailed description of this method, see the previous study [30].
BODY.2. MATERIALS AND METHODS.2.7. EVALUATION OF ERRORS:
The error in the bone and prosthetic landmark sets was expressed as the differences between the RSA and the CT-based coordinates of the markers. In the 3D view of the CT volume, it is easy to determine if the marking of the tantalum beads from RSA is correct. Hence, in contrast to the analysis of the RSA double examinations, we did not set a maximum value for the mean error but rather simply excluded those markers that, on visual inspection, could be seen to be incorrectly marked or not marked at all in the RSA setup. The relative movement of the prosthetic landmark group after the final transformation was expressed in 6 degrees of freedom (Euler angles and translation distances). All of the prostheses were considered to be stable in the bone [21]; therefore, the movement of the prosthesis landmarks between RSA and CT should ideally be zero. The limit of agreement was calculated as mean and median of the differences for both rotation and translation plus and minus two standard deviations [32]. This was acceptable as the data was determined to nearly follow a normal (Gaussian) distribution using histograms, box, density, and quantile-quantile plots [33]. The mean differences ± 1.96 ∗ standard deviation is the 95% confidence interval [34]. Additionally, we calculate the maximum total point motion (MTPM), that is, the length of the 3D vector of the marker that moved the most. Since calculation of the limit of agreement has been performed in several different ways in other studies, we also calculated the results as mean ± 2.01 (t statistic for 46 degrees of freedom) ∗ standard deviation giving the 95% quantile for 46 double examinations [35]. A third way of presenting this data has been frequently used in earlier RSA studies [5, 23, 36, 37] with the 95% confidence limit expressed as the mean of the absolute differences plus 1.96 ∗ standard deviation of the differences (and plus 2.575 ∗ standard deviation for the 99% confidence limit). The density plots shown, which express the frequency distribution between the first and third quantiles of the date, were calculated using Gaussian filter. The statistical program R version 3.1 was used [33].
BODY.3. RESULTS:
All markers designated on the radiographs could be visualized in the CT volumes. Further, a consistent finding was that additional markers were clearly identified in the CT volumes, which had not been designated on the stereo radiographs. Only markers that could be clearly identified on both focuses 1 and 2 of the stereo radiographs were used in the analysis. Of the excluded markers, one prosthetic marker that had been correctly designated on radiographs was excluded due to bad marking on CT. This marker was located less than one mm from the cup shell, and information from the cup interacted in the automated process, resulting in off-centering of the landmark. The remaining excluded markers were excluded due to being incorrectly marked on the radiographs. All 48 hips could be registered with respect to the tantalum beads in the acetabulum with a median (range) of eight (4–9) landmarks. After registration, a majority of the landmarks showed an overlapping pattern, with the center of all RSA derived landmarks placed inside the volume of the tantalum bead representation in the 3D CT volumes (Figure 1). In two patients, there were only two valid landmarks from the stereographs in the cup, leaving 46 hips for registering the cups and computing relative movement. The remaining cup landmark sets had a median (range) of five (3–9) landmarks. Figures 2(a)–2(c) show the process for identifying markers that had been inappropriately designated as being the same. The errors of individual markers after rigid body registration for both bone and prosthetic landmarks are given in Table 1 both for the RSA double examinations and between CT and RSA. For the RSA double examinations all markers with a mean error above 0.35 mm were excluded in the UmRSA software. Density plots for the landmark errors are given in Figure 3. The data were close to normal. Note that there are some outliers. A subanalysis of landmarks with large errors showed that several of these were "double balls," that is, two tantalum beads simultaneously in close proximity. The RSA images separated these quite effectively, but our automated routine tended to push the two CT designated landmarks together due to interference. This combination gives a pair of landmarks with somewhat higher error after rigid body registration, but the combined effect on the evaluation of relative movement is theoretically negligible, since these errors tend to eliminate each other. Analysis of relative movement, presenting the precision of our setup, is given in Tables 2(a)–2(c). Figure 4 shows the density plots for errors in the rotations and translations.
BODY.4. DISCUSSION:
From the user's standpoint, marking the volumes was easier and faster when using CT than RSA. In addition, in contrast to radiographs, where markers are often shadowed by the prosthesis, we could consistently find all markers in the CT volumes. For this study, we performed the analysis of component movement directly in the program developed for the CT volumes. Theoretically, it would also be possible to reverse the registration process between CT and RSA derived dataset, then importing the CT coordinate dataset into the existing RSA analysis software and performing the subsequent analysis using that software. A key feature of the UmRSA software is its calculation of mean error of rigid body fitting (ME). This reflects the relative motion of individual markers in each segment and the error of digitization between two different examinations and thus is a measure of the stability of the rigid body. In clinical RSA trials, ME values of 0.10–0.25 mm are typical [5] when using commercially available software (e.g., UmRSA 6.0, RSA Biomedical, Umeå, Sweden). Increasing ME decreased the precision of RSA in a laboratory study [38]. At the start of a normal RSA analysis, the user defines an upper limit for acceptable individual landmark error; then points outside of this limit are automatically excluded during subsequent calculations. In this study, we transformed the CT volumes into the RSA derived landmarks and then manually excluded points that were obviously misplaced during the marking of the radiographs (Figure 2). Therefore, the mean errors found in this study differ from the standard ME values, because all points that are accepted as being cohomologous are included. In addition, the automated routine in the program that finds the centroid of the tantalum beads in the CT dataset is not optimized for beads in close vicinity to another metal object, as was the case for double markers and markers less than a millimeter from the cup shell. For bone markers or markers placed in the liner this is rarely a problem. When markers are attached directly to the metal of the prosthesis it might be an issue. This can be addressed by changing parameters in the program or by manual designation of the marker's centroid [9]. However, in this study the aim was to evaluate how similar a RSA dataset and a dataset derived from routine CT scans of patients would be, when essentially everything but designating the marker sequence was calculated by the program. Slightly higher MEs were expected and also that these errors would be generated from both input modalities. The MEs of rigid body registration between the RSA and CT volumes in this study are of the same order of magnitude as ME for clinical RSA trials, indicating that, from a standpoint of quality of input data, it would be feasible to continue monitoring patients with tantalum beads. It might be possible to start new migration studies using CT if one lacks a facility for RSA radiographs [16, 29]. As stated in the introduction, the effective radiation dose of CT scans is constantly being lowered and the quality of the scans with regard to metal artifacts is improving [11]. The precision of RSA in a clinical setting, based on double examinations, has been shown to vary between 0.15 and 0.60 mm for translations and between 0.3 and 2° for rotations at a 99% confidence limit [5]. The agreement between the current CT and RSA datasets presented in this study as determined by multiple previously published methods is shown in Tables 2(a)–2(c). From the standpoint of precision, treating the comparison between RSA and CT as a double examination, we find that this is comparable with RSA double examinations (Table 2(a)). Many factors influence the ability to perform RSA analyses in a negative way. However, with CT several of these factors can be avoided, such as the loss of markers because of shadowing by the implant, the varying position of the patient in relation to the cage, and the mismatching of markers in the different focal planes. In the CT volume it was possible to identify more markers than were found in the pairs of RSA examination. Unfortunately, for this study we could not exploit this advantage because all markers not found via RSA were excluded. However, using all the available markers might give a more stable rigid body in the segments (bone or prosthesis) when following patients over time with CT. To achieve the results reported here, using a standard bone reconstruction algorithm for the CT scan was sufficient. This opens the possibility of measuring migration in a precise way when CT examinations are performed because of other reasons on patients with implanted tantalum beads, especially if it is impossible to perform RSA because the patient has moved to a place where RSA acquisition is unavailable. This CT derived data could also potentially be used to augment the data available for long term studies of patients by providing datasets at different times between the scheduled n-year follow-up periods, thus providing data for patients who perhaps do not complete the full study. From a standpoint of radiation exposure, the CT examinations used in this study did expose the patient to higher radiation levels than the RSA examinations. However, these CT volumes were primarily obtained to analyze osteolysis around the cup and were not optimized in any way for simply locating the tantalum beads. Several studies on the extremities and of the glenohumeral joint show that large acceptable effective radiation dose reductions can be obtained when imaging tantalum beads using CT without losing image quality [17, 19, 20]. A decade ago, Gurung et al. used a 16-row CT to study effective dose reduction in pelvic scans and showed that they could acquire scans at an effective radiation dose of 2.2 mSv which allowed valuation of the acetabulum and the iliosacral joints according to specific detailed criteria [39]. There is, to our knowledge, no study on dose reduction in patients when imaging tantalum beads in the hip. Theoretically, reasonable imaging of the tantalum beads in patients should be attainable at significant dose reductions, as has been shown in the shoulder and extremities. In a phantom study, where the precision and accuracy of the CT method is evaluated using double RSA examinations and double CT examinations, we have performed scans that, if applied to a patient, would give an effective dose of 0.4 mSv. In another study, this dose is further reduced in a porcine model [11]. Results from these two studies indicate that, under laboratory conditions, the effective radiation dose can be significantly reduced without significant loss of precision and CT's precision is comparable to RSA. In previous publications, we showed that RSA data could be retrospectively registered to and visualized in CT volumes [9, 40] and can be used to follow patients with implanted tantalum beads [10]. In this study we demonstrate that when RSA data of clinical patients is registered to CT data, the agreement is sufficient that longitudinal or double CT exams could be used for evaluation of prosthetic movement.
BODY.5. CONCLUSIONS:
CT scans can be used for migration measurements in longitudinal evaluations of patients with RSA markers without losing clinically significant precision. The use of CT scans enables following RSA studies started earlier using a normal CT scan, thus avoiding the need for special RSA radiology facilities. | 5,294,349 | {
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TITLE: Statin efficacy in the treatment of hepatitis C genotype I
ABSTRACT.BACKGROUND::
Lipid metabolism is one of the hepatitis C virus (HCV) life cycle steps. Statins can reduce cholesterol level and finally can decrease HCV replication. Thus, we assessed the effect of Statins in combination with standard antiviral treatment on hyperlipidemic genotype I HCV infected patients.
ABSTRACT.MATERIALS AND METHODS::
This study was a prospective clinical trial. 40 patients were selected from those referred to educational and Therapeutic Centers of Isfahan University of Medical Sciences from 2009 to 2010 with confirmed HCV viremia. All patients received Peg-interferon-a2a and ribavirin. 20 hyperlipidemic Patients received 20 mg atorvastatin nightly for 3 months and placebo was prescribed for 20 normolipidemic HCV infected patients as a control group. Liver enzymes and complete blood count were checked monthly and thyroid stimulating hormone was checked every 3 months. We also performed quantitative HCV-ribonucleic acid (RNA) test in 12th week of therapy, at the end of treatment and 6 months after therapy for all samples.
ABSTRACT.RESULTS::
We didn't find any significant differences in the mean of HCV-RNA numbers between statin and placebo groups in 12th week of treatment, in the end of treatment and 6 months after treatment (P > 0.05).
ABSTRACT.CONCLUSION::
Atorvastatin has no effect on the mean of HCV viral load when we added it to standard treatment for hepatitis C infection. Further studies are necessary to examine the possible antiviral properties of statins and their potential role as adjuncts to standard HCV therapy.
BODY.INTRODUCTION:
Hepatitis C virus (HCV) is an important human pathogen, not only because of its high prevalence and worldwide burden, but also because of the potentially serious complications of persistent HCV infection. These complications include cirrhosis, hepatocellular carcinoma, and end-stage liver disease necessitating liver transplantation. The incidence rates for all of these complications are expected to rise in the near future.[12] It is estimated that 130-170 million people have chronic HCV (about 3% of the world population).[34] More than 3,00,000 people die every year from hepatitis C related liver diseases.[5] There is no vaccination for HCV, so the treatment is very important. The standard medication of HCV (pegylated interferon (IFN) alpha plus ribavirin [RBV]) in HCV genotype I infected patients have shown 40-50% sustained virological response (SVR),[3] so we need more effective treatment method. Lipid metabolism is one of the HCV life cycle steps. HCV forms a replication complex in lipid raft membrane that is full of cholesterol and sphingolipids.[67] 3-hydroxy-3 methyl-glutaryl Coenzyme A inhibitors (statins) can reduce cholesterol level and finally can decrease HCV replication. Hence, statin therapy can be introduced as a complementary treatment. In vitro examinations have found that some statins, especially fluvastatin and atorvastatin can inhibit HCV replication,[8] although statins should be used with caution in advanced end-stage liver disease because of decompensation risk.[9] Recently, beneficial effect of statin use among patients with HCV-related liver disease has been suggested. In vitro studies show that high concentrations of statins disrupt HCV replication through depletion of isoprenoid geranylgeranyl pyrophosphate.[1011] Statins may thus have antiviral effects through mechanisms not related to lipid metabolism.[1213] The low-density lipoprotein (LDL) receptor and the high-density lipoprotein scavenger receptor B1 putatively facilitate HCV entry into hepatocytes. Complex host proteins are found to be closely associated with HCV nonstructural proteins. The process which links these host and HCV proteins is termed prenylation. Statin agents which block the formation of the lipid precursors for prenylation, could theoretically interfere with viral replication.[141516] Some human studies have done for assessing the effect of statins in hepatitis c treatment, but their results are different. O'Leary et al. have shown no reduction in HCV-ribonucleic acid (RNA) titers with 20 mg atorvastatin.[17] However, another study indicates non-dose-dependent discretion in HCV-RNA in %50 of patients,[18] the purpose of this study was to determine the effect of statin therapy on standard antiviral treatment response in hyperlipidemic genotype I HCV patients.
BODY.MATERIALS AND METHODS.SELECTION OF PATIENT GROUPS:
Our study was a prospective clinical trial which was done on genotype I HCV patients who had been referred to educational and therapeutic centers of Isfahan University of Medical Sciences between years 2009 and 2010. All patients were tested to confirm HCV viremia by Cobas Amplicor HCV Monitor test, version 2 (Roche Diagnostics, Mannheim, Germany). We selected our patients using simple random sampling. Subjects in the statin group were hyperlipidemic patients according to WHO definition for hyperlipidemia which is LDL cholesterol level more than 160 mg/dl, 130 mg/dl for patient with one risk factor and 100 mg/dl for patients with diabetes mellitus, 2 or more than risk factors. Patients in the placebo group were selected from HCV patients without hyperlipidemia. This study protocol was approved by Institutional Review Board and Ethics Committee of Isfahan University of Medical Sciences (research project number: 309079). Patients were included in the study if they were naïve for HCV treatment, more than 18 years old and patients who did not have any clinical sign for decompensate Cirrhosis. All cases who were affected by other genotypes of HCV and chronic liver disease such as hepatitis B virus, HIV, Wilson disease, hemochromathosis, autoimmune liver disease, primary biliary cirrhosis, secondary biliary cirrhosis, obstructive liver disease, viral infections that affect liver function, and who had the history of alcohol drinking and drugs related steatosis and hepatotoxicity were excluded from our study. Patients were excluded from the study if the level of their liver enzymes (alanine transaminase and aspartate aminotransferase) had risen >3 times during statin treatment. Patients were examined clinically before antiviral treatment. Fasting blood sugar, plasma lipids, liver enzymes tests and liver and abdomen sonography (Hitachi, Tokyo Japan) were done 2 times (with 1 month apart) before treatment for all of them. We also checked their blood pressure, waist size, and body mass index (BMI) according to related guideline.[19] All patients weekly received 180 μg Peg-IFN-a2a and 1000, 1200 and 1400 mg RBV for weights <75 kg, 75-100 kg, and more than 100 kg, respectively (Pegasys Co.). Statin group received 20 mg atorvastatin (Farabi Co., Tehran, Iran) nightly for 3 months and placebo was prescribed for the placebo group the same as atorvastatin in the statin group. Liver enzymes and complete blood count were checked monthly and thyroid stimulating hormone checked every 3 months. We also did quantitative HCV-RNA test to reveal patients with undetectable test in 12th week of therapy (early virological response [EVR]), after therapy (end of treatment virological response) and 6 months after therapy SVR for all samples. We analyzed our data using SPSS version 16 (Inc., Chicago, IL, USA) and considered P < 0.05 as valuable, Chi-square was applied for comparison of categorical parameters and Student's t-test for comparing the continuous parameters.
BODY.RESULT:
Our study included 40 HCV positive patients (20 hyperlipidemic and 20 normolipidemic patients). Our results showed that there are significant differences in the mean of BMI, triglyceride, LDL, and cholesterol between statin and placebo groups [Table 1]. Table 1 demographic and lipid character in statin and placebo group The evaluation of viral load before statin therapy did not show a significant difference between statin and placebo, also, we didn't find any significant differences in the mean of HCV-RNA numbers in statin and placebo groups in 12th week of Statins therapy (P > 0.05), at the end of treatment (P > 0.05) and 6 months after treatment (P > 0.05) [Table 2]. Our findings also implied that EVR in statin and placebo were 75 and 70% and SVR was 95% in both groups. ALT level was higher in statin group before treatment [Table 3]. Although both AST and ALT level rose after treatment, we did not find any difference between AST and ALT level after treatment. Table 2 Comparison between viral load before treatment and after start of treatment between statin and placebo groups Table 3 comparison between transaminases in statin and placebo group before and after treatment
BODY.DISCUSSION:
In the current study, we didn't find any significant differences in the mean of viral load of hepatitis c in statin and placebo groups in 12th week of statin therapy, at the end of treatment and 6 months after treatment. Our findings also implied that early response to treatment (EVR) in statin and placebo were 70 and 75% and Sustain response to treatment (SVR) in statin and placebo was 95% in both groups. A pilot study of 31 HCV-infected veterans who were given fluvastatin 20-320 mg/day for 2-12 weeks with weekly monitoring of HCV-RNA and liver tests reported modest reductions of viral load.[20] Furthermore, a pharmacoepidemiologic study found that the use of lovastatin was associated with a 40-50% lower incidence of moderate as well as severe liver injury among patients with preexisting liver disease.[21] Even though, prior individual studies examined important aspects of the association between statin and lowering the severity if liver disease in HCV-infected patients, these studies either did not adjust for histological severity of liver disease, had generally short follow-up, or did not use placebo subjects. Clearly, more information is needed about the possible beneficial effect of statins in HCV-infected.[22] The result of other in vivo studies has been same as our findings in this study. A study which has done by O'Leary et al. (2007) on 10 samples show that atorvastatin does not inhibit HCV-RNA replication in vivo.[17] Forde et al. in a cross-sectional study (2009) confirmed that statins don't have any apparent effect on HCV-RNA replication in vivo.[23] Unlike in vivo studies the result of in vitro research has shown that statins can decrease HCV-RNA replication.[3] Ikeda et al. evaluated the effect of statins on HCV-RNA replication in OR6 cells.[24] Fluvastatin exhibited the strongest anti-HCV activity while atorvastatin and simvastatin showed moderate inhibitory effects. The combination of IFN and the statins exhibited strong inhibitory effects on HCV-RNA replication.[2526] There are some reasons for differences between in vitro and in vivo studies. As we told before various factors affect on antiviral treatment response in the human body such as obesity, insulin resistance and liver steatosis[1516] so we need to do more studies to examine the effect of statins on HCV in relation to confounder factors. On the other hand, statins concentration in cell cultures is higher than their concentration in plasma. Studies have shown that serum levels of such agents after prolonged therapy are significantly lower than the statin concentrations those were used in replicon systems.[27] In our study, response rate of patients were higher than western studies, there are some similar reports that show high response rate of combination therapy in Iranian patients, it may be due to lower viral load in comparison to western patients.[2829] In summary in our study statins did not have any significant effect on HCV virus number and virologic response. Our limitation in this study was few sample size, and further studies are necessary to examine the possible antiviral properties of statins and their potential role as adjuncts to standard HCV therapy.
BODY.AUTHORS’ CONTRIBUTION:
All authors have contributed in designing and conducting the study. Ash, AB, SS, SSh, and Nkh collected the data and MM, MKh, MT, Ash, and BA did the analysis. All authors have assisted in preparation of the first draft of the manuscript or revising it critically for important intellectual content. All authors have read and approved the content of the manuscript and are accountable for all aspects of the work. | 4,078,386 | {
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TITLE: Short-term effects of physiotherapy combining repetitive facilitation
exercises and orthotic treatment in chronic post-stroke patients
ABSTRACT:
[Purpose] This study investigated the short-term effects of a combination therapy
consisting of repetitive facilitative exercises and orthotic treatment. [Subjects and
Methods] The subjects were chronic post-stroke patients (n=27; 24 males and 3 females;
59.3 ± 12.4 years old; duration after onset: 35.7 ± 28.9 months) with limited mobility and
motor function. Each subject received combination therapy consisting of repetitive
facilitative exercises for the hemiplegic lower limb and gait training with an ankle-foot
orthosis for 4 weeks. The Fugl-Meyer assessment of the lower extremity, the Stroke
Impairment Assessment Set as a measure of motor performance, the Timed Up & Go test,
and the 10-m walk test as a measure of functional ambulation were evaluated before and
after the combination therapy intervention. [Results] The findings of the Fugl-Meyer
assessment, Stroke Impairment Assessment Set, Timed Up & Go test, and 10-m walk test
significantly improved after the intervention. Moreover, the results of the 10-m walk test
at a fast speed reached the minimal detectible change threshold (0.13 m/s). [Conclusion]
Short-term physiotherapy combining repetitive facilitative exercises and orthotic
treatment may be more effective than the conventional neurofacilitation therapy, to
improve the lower-limb motor performance and functional ambulation of chronic post-stroke
patients.
BODY.INTRODUCTION:
The mobility of many stroke survivors is limited, and most identify walking as a top
priority for rehabilitation1). One way to
manage ambulatory difficulties is with an ankle-foot orthosis (AFO) or a foot-drop splint,
which aims to stabilize the foot and ankle while weight-bearing and lift the toes while
stepping1). In stroke rehabilitation,
various approaches, including robotic assistance, strength training, and
task-related/virtual reality techniques, have been shown to improve motor function2). The benefits of a high intensity stroke
rehabilitation program are well established, and although no clear guidelines exist
regarding the best levels of intensity in practice, the need for its incorporation into a
therapy program is widely acknowledged2). Repetitive facilitative exercises (RFE), which combine a high repetition rate and
neurofacilitation, are a recently developed approach to rehabilitation of stroke-related
limb impairment2,3,4,5). In the RFE program, therapists use muscle spindle stretching and
skin-generated reflexes to assist the patient's efforts to move an affected joint5). Previous studies have shown that an RFE
program improved lower-limb motor performance (Brunnstrom Recovery Stage, foot tapping, and
lower-limb strength) and the 10-m walk test in patients with brain damage3). An AFO is an assistive device to help stroke patients with hemiplegia walk and stand. A
properly prescribed AFO can improve gait performance and control abnormal kinematics arising
from coordination deficits6). Gait training
with an AFO has been also reported to improve gait speed and balance in post-stroke
patients7, 8). Therefore, we hypothesized that short-term physiotherapy combining RFE and orthotic
treatment would improve both lower-extremity motor performance and functional ambulation.
The present study aimed to confirm the efficacy of a combination therapy consisting of RFE
for the hemiplegic lower limb and gait training with AFO.
BODY.SUBJECTS AND METHODS:
The subjects consisted of 27 inpatients (24 males and 3 females) diagnosed with cerebral
hemorrhage (15 patients) or cerebral infarction (12 patients). The patients' average age was
59.3 ± 12.4 years (33–73 years), the duration after onset was 35.7 ± 28.9 months (5–115
months), and Brunnstrom Stage medians and quartiles of the hemiplegic lower limb were Stage
4.0 and 4–4.5 (stage 3–6), respectively. Eleven patients had right hemiplegia, and 16
patients had left hemiplegia. Among the 27 study participants, one used a rigid AFO with a
medial stainless steel upright9), two used
a posterior spring leaf10), and 24 used a
hinged AFO10). The inclusion criteria were as follows: age, 30–80 years; hemiplegia of the lower limb
(Brunnstrom stage 3–6); ability to walk without assistance using a T-cane and/or AFO;
diagnosis of hemiplegia due to stroke; morbidity period, 5 months or more; ability to
understand the purpose of the study and follow instructions, and agreement to participate in
this study. The exclusion criteria were as follows: onset of stroke, <4 weeks previously;
abnormal gait prior to the onset of stroke (such as joint disability or peripheral
neuropathy); any medical condition that limited the study design (such as severe
cardiopulmonary disease or severe sensory disturbance); severe aphasia and dementia that
made it impossible to follow verbal instructions; and lesions on both sides of the cerebral
hemisphere. The procedures complied with the 1975 Declaration of Helsinki, as revised in 2013. The
study was conducted after obtaining approval from the ethics committee of the Tarumizu Chuo
Hospital, and all participants provided written informed consent. The subjects were enrolled in a before-after study. Intervention was combination therapy
consisting of RFE for the hemiplegic lower limb and gait training with AFO. According to a
previous study, all subjects underwent an RFE program consisting of 7 specific exercise
patterns3), which were used to elicit
movement of the hip, knee, and ankle in a manner designed to minimize synergistic movements.
This technique involved the use of rapid passive stretching of the muscles in conjunction
with tapping and rubbing the skin to assist in generating contractions of the targeted
muscles5). Exercises were performed as
two sets of 50 repetitions with a 1–2 minute rest period in between sets5). In addition, all patients underwent gait
training with a self-made AFO. This intervention was performed 40 minutes/day, 6 days/week for 4 weeks. Outcomes were
measured before intervention and after 4 weeks of intervention. The outcome measures used to
assess motor performance were the Fugl-Meyer Assessment of the lower extremity (FMA-LE)11) and the Stroke Impairment Assessment Set
(SIAS)12). Functional ambulation was
assessed with a Timed Up & Go Test (TUG)13) and a 10-m walk test (10MWT). To determine whether physiotherapy that combined RFE and orthotic treatment improved the
lower-limb motor performance and functional ambulation, the Wilcoxon Signed-Rank Test was
performed, because the Shapiro-Wilk's test showed that the data were not normally
distributed. The analysis was performed with the statistical analysis program SPSS
Statistics for Windows version 22.0 (IBM Corporation, Armonk, NY, USA) with a significance
level of α=0.05.
BODY.RESULTS:
Table 1Table 1.Lower-limb motor performance and functional ambulation at the baseline and after
the combining trainingOutcome measurementsBaselineAfter the trainingDifference mean ± SDFMA-LE22.96 ± 4.0725.85 ± 4.032.89 ± 2.99**SIAS46.59 ± 8.3453.63 ± 7.637.04 ± 4.60**TUG (sec)17.35 ± 5.5714.02 ± 4.46−3.33 ± 3.52**10MWTCGS (m/sec)0.68 ± 0.220.81 ± 0.240.12 ± 0.09**FGS (m/sec)0.80 ± 0.280.96 ± 0.310.16 ± 0.16****Significant difference p<0.01. SD: standard deviation; FMA-LE: the Fugl-Meyer
Assessment of the lower extremity; SIAS: Stroke Impairment Assessment Set; TUG: Timed
"Up & Go" test; 10MWT: 10-m walk test; CGS: comfortable gait speed; FGS: fast gait
speed shows the changes in FMA-LE, SIAS, TUG, and 10MWT (comfortable gait speed and
fast gait speed). In terms of lower-limb motor performance, FMA-LE increased significantly
from 22.96 ± 4.07 to 25.85 ± 4.03 (p<0.01), and SIAS increased significantly from 46.59 ±
8.34 to 53.63 ± 7.63 (p<0.01). In terms of functional ambulation, TUG decreased
significantly from 17.35 ± 5.57 seconds to 14.02 ± 4.46 seconds (p<0.01), comfortable
gait speed increased significantly from 0.68 ± 0.22 (m/sec) to 0.81 ± 0.24 (m/sec)
(p<0.01), and fast gait speed increased significantly from 0.80 ± 0.28 (m/sec) to 0.96 ±
0.31 (m/sec) (p<0.01).
BODY.DISCUSSION:
In this study, short-term combination therapy consisting of RFE and orthotic treatment was
conducted to improve the lower-limb motor performance and functional ambulation of chronic
post-stroke patients. There were statistically significant improvements in FMA-LE, SIAS,
TUG, and 10MWT after the intervention. Furthermore, the results of the 10MWT at a fast gait
speed reached the minimal detectible change threshold (0.13 m/s)14). Recently, some systemic reviews of AFO have reported that gait training with AFO can
improve walking ability and balance in people with stroke1, 15). However, few studies
have focused on the correlation between AFO and motor performance changes of the lower limb
in post-stroke patients16,17,18). Changes seen in
this study were more marked in the lower-limb motor performance, with a substantial
clinically meaningful change in fast walking speed (0.13 m/s) being achieved by all
participants who completed the study protocol. The results of this study show that
short-term combination therapy consisting of RFE and gait training with AFO may enhance
lower-limb motor function, thereby improving walking ability in patients with chronic
stroke, which is beneficial for comprehensive stroke treatment. Several studies suggested that RFE might promote functional recovery of hemiplegia and
activities of daily living to a greater extent than conventional neurofacilitation therapy,
using a randomized controlled design2,3,4,5, 19, 20). Especially, RFE with other interventions
(i.e., neuromuscular electrical stimulation, direct application of vibratory stimulation
repetitive transcranial magnetic stimulation, and pharmacological treatments) may be more
effective than RFE only for the recovery of limb motor performance. In the present study,
patients who received RFE with gait training with AFO showed significant functional and
ambulatory improvements. This study had some limitations because it involved a small number of subjects, and its
intervention period of four weeks was short. In addition, this was not a randomized
controlled trial, and the efficacy of RFE with orthotic treatment could not be compared;
therefore, it is difficult to generalize its results. Further, this study could not exclude
observer bias and subject bias because the same staff implemented assessment and
training. In conclusion, the differences in FMA-LE, SIAS, TUG, and 10MWT demonstrated that
application of a short-term combination therapy consisting of RFE and orthotic treatment has
beneficial therapeutic effects on improving functional ambulation and motor performance of
the lower limb in chronic post-stroke patients.
BODY.DISCUSSION.CONFLICT OF INTEREST:
The authors have no conflicts of interest to declare. | 5,332,972 | {
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TITLE: Expanding access to parasite-based malaria diagnosis through retail drug shops in Tanzania: evidence from a randomized trial and implications for treatment
ABSTRACT.BACKGROUND:
Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices.
ABSTRACT.METHODS:
Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing.
ABSTRACT.RESULTS AND DISCUSSION:
A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8–69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT.
ABSTRACT.CONCLUSIONS:
Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy.
Trial registration ISRCTN ISRCTN14115509
BODY.BACKGROUND:
Malaria prevalence among children under 5 years old in Tanzania declined from 18% in 2007 to 9% in 2011, whereas 2-week fever prevalence remained approximately 20% over the same time period, from 19 to 20% [1, 2]. This reduction in the proportion of fevers caused by malaria is likely due at least in part to Tanzania's recent scale-up of prevention and treatment measures [3–5]. Presumptive treatment of fevers with artemisinin-based combination therapy (ACT) thus will increasingly result in incorrect malaria diagnoses, prescription and wastage of inappropriate medications, and subsequent delays in obtaining effective treatment for the true cause of illness [6–9]. The Tanzania National Malaria Control Programme (NMCP) case management guidelines require suspected malaria cases to receive parasite-based diagnosis by microscopy or rapid diagnostic test (RDT) prior to treatment with anti-malarial drugs [10, 11]. In practice, however, up to 54% of those seeking treatment for suspected malaria in Tanzania first visit the private retail sector, where malaria diagnostics are currently prohibited from being sold and administered [12]. As a result, parasite-based testing is not received by many suspected malaria patients. The Tanzanian private retail sector includes both unregistered outlets and a network of more than 6000 registered shops or Accredited Drug Dispensing Outlets (ADDOs) (duka la dawa muhimu or DLDM in Kiswahili) regulated by the Pharmacy Council. Unlike unregistered outlets, ADDOs are permitted to stock and sell both over-the-counter medicines and certain classes of prescription medications, including ACT [13–15]. To obtain a Pharmacy Council permit each year, ADDOs owners must meet certain conditions related to the premises, training and certification of a dispenser who may or may not be the owner, and the products stocked. Like all other private retail outlets, RDTs may not be sold or performed at ADDOs, however. Malaria RDTs have been safely administered by non-medical personnel in several previous settings [16–18]. The introduction of RDTs into ADDOs has the potential to improve fever case management by increasing availability, access, and use of parasite-based diagnosis. It is unclear, however, whether customers will be willing to pay the extra cost for diagnosis, whether ADDO owners would encourage RDT use, whether RDTs might require subsidization to encourage uptake in the private sector, and whether treatment choices would adhere to test results. To investigate these questions, this pilot evaluated the operational feasibility of selling RDTs through ADDOs and measured changes in suspected malaria patient case management that occurred as a result of making RDTs available at two different prices.
BODY.METHODS.STUDY AREA AND POPULATION:
This pilot was conceived and designed in partnership with the NMCP and Pharmacy Council, with a primary objective of informing national policymaking on legalizing the stocking and performance of RDTs through ADDOs. The study was conducted in three districts in Morogoro Region: Kilombero, Kilosa, and Mvomero. These three districts were selected due to their high density of ADDOs, moderate Plasmodium falciparum prevalence compared with national data (13% in Morogoro Region [2]), and convenient proximity to Dar es Salaam. The three districts are mostly rural, with a total estimated population of 1.7 million people in 2012 [19]. Peak malaria incidence corresponds to the two rainy seasons, one between March and May and the other between September and December. Kilombero and Kilosa were assigned via random number generator as the two intervention areas where ADDO dispensers were trained to stock, sell, and administer RDTs, and Mvomero served as the control area (Fig. 1).Fig. 1Map of the study area
BODY.METHODS.INTERVENTION DESIGN:
All licensed ADDO dispensers currently working in an ADDO in the two intervention areas were invited to participate in the study through the District Malaria Focal Person, who is responsible for overseeing local malaria-related activities under the leadership of the District Medical Officer. In April–May 2013, six two-day trainings were held in each intervention district, each led by a national-level trainer and the district malaria focal person. Trainings covered signs and symptoms of uncomplicated and severe malaria, stocking, use, and disposal of RDTs, and appropriate case management based on RDT results. Dispensers were instructed to prescribe Tanzania's first-line treatment, artemether + lumefantrine (commonly referred to as ALu in Tanzania), to test-positive customers based on an ALu dosing reference chart provided to the dispensers. Dispensers were trained to refer customers with signs and symptoms of severe illness, suspected malaria patients who tested negative for malaria, and suspected malaria patients whose illness did not improve within 48 h to the nearest public health facility along with the results of their malaria test. Upon passing both practical and written evaluations, certified RDT dispensers were provided with an ID badge granting permission to perform RDTs in their ADDO, a sharps box, an RDT performance and case management job aid, and a weather-proof storefront sign advertising that malaria testing was available. Permission was also granted for the ADDO dispenser to prescribe an ALu to all patients who tested positive for malaria. To mimic real market conditions, existing supply chains were utilized: ADDOs in the two districts were instructed to purchase ParaHIT® Ag Pf RDTs from seven wholesalers. The wholesalers, in turn, were instructed to purchase RDTs from an importer in Dar es Salaam, who purchased the RDTs directly from the manufacturer for a fixed price pre-negotiated by the research team. Importers, wholesalers and ADDOs all agreed to fixed mark ups. ADDOs in Kilosa were asked to sell RDTs for a recommended retail price (RRP) of 1100 Tanzanian Shillings (USD $0.67 in May 2013) each, based on willingness-to-pay responses from pre-intervention exit interviews, analysis of markups in analogous commodities, and price negotiation. In Kilombero, ADDOs were asked to sell RDTs for 50% less or 500 Tanzanian Shillings (USD $0.32 in May 2013) [20]. To enable the ADDOs in Kilombero to charge the lower price, the research team asked the importer to sell RDTs to wholesalers in Kilombero at a 50% discount. On a monthly basis, the importer received financial compensation from the research team equal to the total discount provided to wholesalers located in Kilombero. The research team monitored stock levels at the importer level to prevent stock outs. Gloves were included in the RDT boxes. A unique blue-and-white "mRDT" checkmark logo was placed on ParaHIT® boxes, ID badges, job aids, and storefront signs in order to build brand recognition. Trained study staff provided supportive supervision during quarterly monitoring visits. At each visit, the certified dispenser at each participating ADDO was observed performing an RDT on a patient and evaluated according to a 17-point checklist adapted from the WHO "Checklist for direct observation of health workers performing Rapid Diagnostic Tests (RDT) for malaria" [21]. The supervisors also reported on stocking safety, shop hygiene, and waste disposal practices [22].
BODY.METHODS.STUDY DESIGN:
The impact of the intervention was assessed by comparing the change in availability and use of RDTs at ADDOs in the intervention districts with those in the control district, Mvomero, where ADDOs were not given access to the RDTs, training, or supervision.
BODY.METHODS.STUDY DESIGN.OUTLET SURVEYS:
RDT and ACT availability were measured through two cross-sectional ADDO surveys, one conducted prior to the dispenser training in March 2013 and the second a year after the 2013 training, in May 2014. All ADDOs were eligible for selection for the pre-intervention survey, while only ADDOs with certified dispensers were eligible to participate in the post-intervention survey of the intervention districts. Ninety-one ADDOs per district were selected using random number generation based on sample-size calculations to ensure 80% power. The sample size is assumed to be sufficient to detect a five percentage-point difference in ADDO RDT availability. A Kiswahili or English-version structured questionnaire was used during the face-to-face interviews with ADDO dispensers depending on the language preference of the respondent. The primary outcome was RDT availability, defined as the proportion of ADDOs with RDTs in stock on the day of the survey and a trained, certified dispenser present to administer the test. A secondary outcome was ACT availability, defined as the proportion of ADDOs that reported having ACT medicines in stock for the 30 days prior to the survey.
BODY.METHODS.STUDY DESIGN.CUSTOMER EXIT INTERVIEWS:
Face-to-face exit interviews were conducted prior to the dispenser training (March 2013) and a year after the intervention began (May 2014) using a structured questionnaire in Kiswahili. Customers eligible for the exit interview were at least 18 years old and either seeking treatment in the ADDO for fever or suspected malaria or attempting to purchase an anti-malarial for themselves or someone else (the "patient"). A sample size of 400 eligible customers per district was estimated based on two-tailed sample size calculations designed to detect a 5%-point difference in RDT availability or 80% power. Pre-intervention, 1–3 customers were interviewed at each sampled ADDO. The sample size was halved for the pre-intervention survey based on very low predicted availability of RDTs and a primary goal of comparing similarity between districts. Post-intervention, enumerators attempted to survey all eligible customers during one full day at the ADDO in order to self-weight traffic variation between shops. If the customer and the patient were not the same person, demographic data were collected on both the customer and the patient, and illness data were collected about the patient. Customers were asked whether patients (either themselves or others) had received diagnostic testing at the ADDO, had been previously tested elsewhere, how much they had paid for RDTs at the ADDO, and whether they had purchased anti-malarial treatment.
BODY.METHODS.STUDY DESIGN.STATISTICAL ANALYSIS:
Chi square tests were used to compare differences before and after intervention and between intervention and control districts in (a) the proportion of patients seeking treatment at ADDOs who received a parasite-based diagnostic test, (b) the median price paid for an RDT in an ADDO, (c) the proportion of patients who received a parasite-based diagnosis, (d) adherence to test results in terms of receiving ACT when testing positive and not receiving one when testing negative, and (e) the proportion of test-negative patients who received an antibiotic. Logistic regression models were then used to identify factors associated with receiving an RDT in an ADDO or receiving a parasite-based diagnosis anywhere, with shop included as a random effect to account for repeated sampling of visits to the same ADDOs. Tested covariates included study district and survey, demographic variables (customer and patient gender, age, completed education, and wealth quintile) as well as RDT knowledge and practice indicators regarding previous experience and attitudes about testing. Wealth quintiles were derived from a wealth index based on a set of household asset questions estimated using principal components analysis using similar methodology to Demographic and Health Surveys [23]. Covariates with p < 0.2 in bivariable models were included in multivariable models. Logistic regression models were also used to compare odds of treatment outcomes controlling for study district, survey, parasite-based diagnosis, and test result.
BODY.RESULTS:
Ninety-five percent of ADDO dispensers passed the 2-day training. In total, 310 dispensers from 262 ADDOs, 164 (147 ADDOs) from Kilombero in the lower-priced or "subsidized" district and 146 (115 ADDOs) from Kilosa the higher priced or "unsubsidized" district, were certified and allowed to sell and perform RDTs. The number of outlet surveys and exit interviews completed are presented in Table 1.Table 1Total shop and exit interviews conducted and included in analysisDistrictPre-intervention (March 2013)Post-intervention (May 2014)ADDOs surveyedADDOs with ACT in Stocka
Total Exit InterviewsInterviews where patient present and ACT in Stockb
ADDOs surveyedADDOs with ACT in Stocka
Total Exit InterviewsInterviews where patient present and ACT in Stockb
Subsidized (Kilombero)875991547652266217Unsubsidized (Kilosa)856682468763330247Control (Mvomero)886986599157359244Total260194259159254172955708
a'ACT in stock' defined as no stock-outs in the past 30 days
bOnly customer interviews from shops with ACT medicines in stock and the patient present were included in analysis (i.e., the patient had the opportunity to be tested and purchase an ACT medicine)
BODY.RESULTS.DIAGNOSTIC AND TREATMENT AVAILABILITY IN ADDOS:
Pre-intervention outlet surveys found that RDTs were not available in any surveyed ADDOs. Post-intervention, 73% of ADDOs in intervention districts had RDTs in stock and an RDT-certified dispenser present. The proportion of ADDOs with a certified dispenser and RDTs available was higher in the "unsubsidized" district Kilosa (85%, 95% CI 78–92%) than the "subsidized" district Kilombero (64%, 95% CI 55–72%, p < 0.001). Across the study districts, the proportion of ADDOs with ACTs available was 75% pre-intervention and 68% post-intervention. ACT availability did not differ significantly between districts or pre- or post-intervention (p > 0.05 for all).
BODY.RESULTS.CUSTOMER AND PATIENT CHARACTERISTICS:
A total of 1214 customers seeking treatment for suspected malaria, either for themselves or someone else, were interviewed: 259 pre-intervention and 955 post-intervention (Table 1). Demographic characteristics of customers were generally similar between districts during each survey (Table 2). The proportion of exit interviews in which the patient was present at the ADDO was significantly higher in intervention districts post-intervention. ADDOs were the first place treatment was sought for 75% of patient visits across surveys and districts (Table 3).Table 2Characteristics of anti-malarial customersPre-interventionPost-interventionSubsidized (n = 91)Unsubsidized (n = 82)Control (n = 86)
χ
2 p valueSubsidized (n = 266)Unsubsidized (n = 330)Control (n = 359)
χ
2 p valueCustomer age (median, range)30 (18–67)34 (18–68)33 (18–83)30 (6–79)32 (12–92)30 (14–82)Male (%, 95% CI)44.0 (33.7–54.3)47.6 (36.6–58.5)52.3 (41.7–63.0)0.53647.4 (41.3–53.4)49.4 (44.0–54.8)51.5 (46.3–56.7)0.585Completed > Primary school (%, 95% CI)15.4 (7.9–22.9)24.4 (15.0–33.8)20.9 (12.2–29.6)0.32721.1 (16.1–26.0)13.9 (10.2–17.7)21.2 (16.9–25.4)0.025Wealth quintile (%, 95% CI) Lowest14.3 (7.0–21.5)30.5 (20.4–40.6)17.4 (9.3–25.5)0.33717.7 (13.1–22.3)18.2 (14.1–22.4)24.8 (20.3–29.3)0.248 Lower20.9 (12.4–29.3)18.3 (9.8–26.8)20.9 (12.2–29.6)21.8 (16.8–26.8)21.9 (17.4–26.4)18.1 (14.1–22.1) Middle23.1 (14.3–31.8)13.4 (6.0–20.9)22.1 (13.2–31.0)22.9 (17.9–28.0)18.2 (14.1–22.4)20.6 (16.4–24.8) Higher20.9 (12.4–29.3) 20.7 (11.9–29.6)20.9 (12.2–29.6) 20.3 (15.5–25.1)21.3 (16.8–25.7)17.5 (13.6–21.5) Highest20.9 (12.4–29.3)17.1 (8.8–25.3)18.6 (10.3–26.9)17.3 (12.7–21.9)20.4 (16.0–24.7)18.9 (14.9–23.0)Patient is customer or is with customer (present at ADDO) (%, 95% CI)59.3 (49.1–69.5)59.1 (45.2–67.0)68.6 (58.7–78.5)0.22181.6 (76.9–86.3)74.8 (70.2–79.5)68.0 (63.1–72.8)0.001
Table 3Characteristics of patients present at the ADDOPre-interventionPost-interventionSubsidized (n = 54)Unsubsidized (n = 46)Control (n = 59)
χ
2 p valueSubsidized (n = 217)Unsubsidized (n = 247)Control (n = 244)
χ
2 p valuePatient age (median, range)24.5 (1–66)22 (<1–62)27 (<1–83)23 (<1–79)22 (1–92)24 (1–74)Male (%, 95% CI)48.1 (34.6–61.7)47.8 (33.1–62.5)50.8 (37.8–63.8)0.94147.9 (41.2–54.6)53.0 (46.8–59.3)50.8 (44.5–57.1)0.546Days Ill (median, range)3 (<1, 14)3 (<1, 30)3 (<1, 14)2 (<1, 60)3 (<1, 30)2 (<1, 60)ADDO first place treatment sought (%, 95% CI)70.4 (58.0–82.8)65.2 (51.2–79.2)80.0 (69.2–90.1)0.24077.4 (71.8–83.0)74.8 (69.4–80.2)75.4 (70.0–80.8)0.792Malaria test prior to ADDO Visit (%, 95% CI)16.7 (6.6–26.8)21.7 (9.6–33.9)3.4 (0.0–8.1)0.01511.1 (6.8–15.4)13.4 (9.0–17.8)14.9 (10.2–19.7)0.502
BODY.RESULTS.DIAGNOSTIC UPTAKE:
Pre-intervention, no patients present in the ADDOs reported receiving a parasite-based test in an ADDO in any district. Post-intervention, 65% of patients present at ADDOs in the intervention districts (95% CI 60.8–69.6%) and 3% in the control district received an RDT (Fig. 2a). There was no difference in the fraction of eligible patients who were tested between the subsidized (66%, 95% CI 59–72%) and unsubsidized districts (67%, 95% CI 58–71%), (χ
2 < 0.1, p = 0.8).Fig. 2
a Proportion of patients present at the ADDO who received a parasite-based diagnosis before and after intervention (p < 0.001 for changes in intervention districts; p = 0.159 for the control district). b Proportion of patients present in the ADDO reporting receiving parasite-based diagnostics at any location (p < 0.05 for pre- to post-intervention changes within each district)
Overall diagnostic uptake (in ADDOs or elsewhere prior to the ADDO visit) improved significantly in the intervention and control groups during the study (Fig. 2b). The proportion of patients present at the ADDO who received a diagnostic test increased from 19% pre-intervention to 74% post-intervention in the intervention districts and from 3 to 18% in the control district (p < 0.01 for both groups). The relative changes in testing were not significantly different between the intervention and control districts (OR = 2.5, p = 0.271). Median prices for RDTs post-intervention reported by customers were 1100 Tanzanian Shillings in Kilosa, the unsubsidized district, and 500 Tanzanian Shillings in Kilombero, the subsidized district. There was no variance in median price from the recommended retail price in either district. No difference in RDT uptake was observed between the unsubsidized and subsidized districts (OR = 1.1, p = 0.868). Patient knowledge and practices were associated with RDT purchasing (Table 4). The odds of purchasing an RDT were significantly higher for patients who had previous experience taking an RDT or were already aware that RDTs were available before coming to the ADDO, while patients who had sought treatment elsewhere before visiting the ADDO were significantly less likely to purchase an RDT.Table 4Factors associated with purchasing an RDT in the ADDO when the patient was presentOutcome: receiving an RDT in an ADDO if present to be tested (n = 464)BivariableMultivariableOR95% CIp valueOR95% CIp valueIntervention No subsidyReference Subsidy1.1(0.6–1.9)0.868Customer gender (if not patient) FemaleReference Male1.2(0.5–2.7)0.654Patient gender FemaleReference Male1.0(0.7–1.4)0.920Customer age (if not patient)1.0(1.0–1.0)0.198Patient age <5 yearsReference 5− <14 years1.5(0.7–3.5)0.332 14+ years0.7(0.3–1.3)0.254Customer education PrimaryReference Secondary and above1.0(0.6–1.6)0.909Wealth index LowestReference Lower1.0(0.5–2.0)0.925 Middle0.9(0.4–1.8)0.723 Higher1.2(0.6–2.5)0.559 Highest1.0(0.5–2.2)0.943Has heard of RDTs3.1(2.0–4.8)<0.0011.7(0.9–3.1)0.088Has taken an RDT before3.1(2.1–4.7)<0.0011.9(1.2–3.0)0.005Sought treatment prior to ADDO visit0.3(0.2–0.5)<0.0010.3(0.2–0.5)<0.001Knew before coming that testing was available in ADDOs3.0(2.0–4.7)<0.0011.9(1.1–3.3)0.032Believes febrile patients should be blood tested before treating NeverReference Sometimes1.1(0.1–8.9)0.925 Always2.0(0.3–13.9)0.474
BODY.RESULTS.TREATMENT DECISIONS:
The overall proportion of patients who received an ACT increased from 40 to 43% in the control district and decreased from 40 to 32% in the intervention districts, although these changes were not significantly different after controlling for other factors (OR = 0.6, p = 0.294). Forty-one percent of patients who received an RDT tested positive for malaria across the intervention districts (95% CI 35.7–46.8%). Among patients with a positive test, 90% (95% CI 81.9–94.9%) received an anti-malarial, and 75% (95% CI 65.5–83.5%) received ACT. Among customers testing negative, 7% (95% CI 3.6–12.3%) received an anti-malarial (Fig. 3a). There was no significant difference in the proportion of those who did not receive an RDT who purchased an anti-malarial (35% in intervention districts, 41% in control) (Fig. 3b).Fig. 3
a Medications purchased by patients tested in ADDOs (intervention districts combined). b Medications purchased by untested ADDO patients. Percentages are not mutually exclusive; patients may have received more than one treatment type
The proportion of patients who received an antibiotic did not change significantly comparing intervention and control groups from pre- to post-intervention (OR = 0.9, p = 0.837). Post-intervention, the proportion of patients purchasing antibiotics also did not vary significantly comparing those who tested positive with those who tested negative (10% vs 9%, p = 0.73) (Fig. 3a).
BODY.DISCUSSION:
The results from this study suggest that ADDOs offer an important opportunity for improving malaria case management in Tanzania towards the national goal of 80% parasite-based diagnosis of suspected malaria patients. Two-thirds of suspected malaria patients who sought treatment at ADDOs with RDT-certified dispensers purchased RDTs. Improved testing rates through ADDOs in this pilot project resulted in improved targeting of ACTs to patients with malaria, with 90% of malaria-positive and 93% of malaria-negative ADDO-tested patients making appropriate treatment decisions according to their test results. These results add to a growing body of evidence that malaria case management can be performed well outside of the formal public health sector. A pilot in Ghana that measured vendor-reported adherence to test results after the introduction of RDTs to 28 Licensed Chemical Sellers (private retail sector shops) found 89% of positives and 3% of negatives received ACT [24]. Vendors of 59 licensed drug shops in Uganda also reported high uptake (98%) and favorable adherence to test results (ALu was prescribed to 98% of positives and 1% of negatives) in a small-scale pilot study [25]. The higher uptake observed in these studies compared with this one may be attributable to self-reporting by drug shop vendors compared with customer interviews, a lower $0.20 price point (Uganda) compared to $0.31–0.67 in Tanzania, and/or variance in length of training and frequency of supervision. Not all studies have found such positive outcomes, however: a different study in Uganda with 92 shops selling RDTs that measured adherence through household surveys found only 32% of positives purchased an ACT medicine (7% of negatives) at a median $0.40 per test [16]. This pilot was successful in improving case management practices for several reasons. First, ADDOs are a highly utilized source for anti-malarials in Tanzania: ADDOs were the first place treatment was sought for 75% of interviewed patients, emphasizing the need for access to parasite-based diagnosis at this point of care. Second, nearly all ADDOs in the study area participated in the trainings and RDT program. ADDOs were kept engaged in the study through quarterly supervision and monitoring visits, which also allowed for frequent quality assessments on safety protocol. Third, proximity of the region to Dar es Salaam and relatively good road infrastructure allowed for existing supply chains to be utilized, creating a more realistic market scenario. Finally, negotiations with RDT suppliers and agreements with wholesalers and ADDOs on mark ups, ensured affordable recommended retail prices and enabled comparison of price points. These results provided data to help guide several open questions surrounding an introduction of RDTs to the private retail market. A similar proportion of patients were willing to pay the higher 'unsubsidized' price of a 1100 Tanzanian Shillings or USD $0.67 for a RDT compared to the lower unsubsidized price of 500 Tanzania Shillings or USD $0.32 for the subsidized RDT, indicating that a subsidy may not be necessary to encourage testing uptake. Additionally, similar to the Ghana pilot [24], an increase in the purchase of antibiotics among those receiving a negative test result was not observed in this study. The study was also subject to several limitations. A significant pre-intervention difference in parasite-based diagnostic rates between intervention (19%) and control (3%) districts suggests inherent differences in health facility testing uptake that may confound the effect of the intervention. A second limitation was the unforeseen mobility of ADDO dispensers, periodically changing jobs work in different ADDOs during the study period. While dispensers were certified in this study, it was unclear if the certification extended to the ADDO when the dispenser was not present. Dispenser movement complicated follow-up and suggests future consideration for specifying that dispensers and ADDOs be certified, and requiring ADDOs that sell RDTs to have a certified dispenser present. Additional follow-up challenges arose when ADDOs closed temporarily or permanently, or were not reachable for stock delivery or enumeration due to flooded roads and bridges. Also, although dispensers were trained to refer severe and negative cases to the nearest health facility, this study was not resourced to follow the outcomes of these patients. In practice, it is unlikely that all negative cases will complete the referral pathway, underscoring the importance of including diagnosis and treatment of non-malaria febrile illness and recognition of danger signs in ADDO dispenser training. Lastly, the post-intervention survey sampled from ADDOs that participated in the training in the intervention areas, and while these were the majority of the ADDOs in these districts, they are not representative of all ADDOs in the study area. As Tanzania uses the results of this study to inform policy decisions, it will be important to consider how results might vary in different endemic settings and in more urban areas. Expansion of this program will also require evaluation of how best to ensure long-term routine supervision and training, as well as waste management for sharps and cassettes. Finally, a critical challenge to scale-up will be integration of the private retail sector into the routine surveillance system for capturing malaria case data. This information will be imperative for strategic decision-making as malaria prevalence declines across the country.
BODY.CONCLUSIONS:
This pilot study contributes to a growing evidence base that introducing RDTs to the private retail sector in low resource settings can increase parasite-based diagnostic rates for malaria and adherence to test results when dispensers are trained and supervised. The pilot study also showed that RDTs can be introduced under real market conditions; utilizing existing supply chains without subsidizing the cost of the RDT. While the intervention piloted here was limited to a rural setting in Tanzania's specialized ADDO network, it provides a basis for policy decisions on scaling up RDT access across Tanzania to increase parasite-based diagnosis and rational use of ACT through heavily used existing channels. The results presented here support the goals for Tanzania's National Strategic Plan and may have applications in similar settings. | 5,209,819 | {
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TITLE: Potential benefit of bosentan therapy in borderline or less severe pulmonary hypertension secondary to idiopathic pulmonary fibrosis—an interim analysis of results from a prospective, single-center, randomized, parallel-group study
ABSTRACT.BACKGROUND:
No drugs have been approved for the treatment of patients with pulmonary hypertension (PH) secondary to idiopathic pulmonary fibrosis (IPF), particularly those with idiopathic honeycomb lung. This study was conducted to investigate the long-term efficacy and safety of bosentan for PH based on changes in prognosis and respiratory failure.
ABSTRACT.METHODS:
IPF patients with borderline or less severe PH and completely organized honeycomb lung were randomized (1:1) to bosentan or no treatment for PH for 2 years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right cardiac catheterization, and other parameters. An interim analysis was performed, however, following detection of a significant survival benefit favoring bosentan therapy.
ABSTRACT.RESULTS:
Significant differences were noted for the bosentan-treated (n = 12) vs. untreated (n = 12) groups in hospital-free survival (603.44 ± 50.074 days vs. 358.87 ± 68.65 days; hazard ratio [HR], 0.19; P = 0.017) and overall survival (671 days vs. 433.78 ± 66.98 days; HR, 0.10; P = 0.0082). Again, significant improvements were noted for the bosentan-treated group from baseline to month 6 or 12 in several indices in ADL, pulmonary circulation, and %DLCO. Without requiring O2 inhalation, bosentan was associated with no increase but a trend toward a decrease in adverse events and an improvement in respiratory status.
ABSTRACT.CONCLUSIONS:
Bosentan tended to improve prognosis and ADL without worsening respiratory failure in IPF patients with borderline or less severe PH and completely organized honeycomb lung alone.
ABSTRACT.TRIAL REGISTRATION:
This study was registered on December 18, 2010 with UMIN-CTR Clinical Trial as UMIN000004749 to investigate the long-term influence of bosentan on cardiac function, as well as its cardioprotective efficacy and safety, in patients with pulmonary hypertension secondary to concurrent COPD and IPF, respectively.
ABSTRACT.ELECTRONIC SUPPLEMENTARY MATERIAL:
The online version of this article (doi: 10.1186/s12890-017-0523-2) contains supplementary material, which is available to authorized users.
BODY.BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a disorder associated with poor prognosis. Pulmonary arterial hypertension (PAH), which is likely to lead to right heart overload, is also associated with poor prognosis. Patients with IPF are at risk of developing pulmonary hypertension (PH) as the underlying condition worsens or becomes severer, thus further compromising their prognosis [1–8]. However, it remains unclear how long it may typically take for patients with IPF to start developing PH or for its associated influence on cardiac function to become manifest [1]. Given that, once elevated, pulmonary arterial pressure (PAP) becomes irreversible because of established vascular remodeling [1, 9], it appears that efficacious treatment should be started before its onset. Furthermore, it is assumed that cardiac overload starts even before the onset of PH. However, to date, no drugs have been approved for the treatment of PH secondary to respiratory diseases, such as IPF [1]. Drugs specific for PAH, such as bosentan (Tracleer Tablets®), have been reported in some studies to effectively improve PH in patients with respiratory diseases, such as COPD and IPF [1, 10–13]. While the results of randomized controlled studies conducted to date, such as BUILD-1 and BUILD-3 studies [11], appear to argue against the use of bosentan in patients with pulmonary hypertension (PH), these studies involved a wide range of patients from those with fibrotic idiopathic interstitial pneumonia (f-IIP) and fibrotic nonspecific interstitial pneumonia (f-NSIP) to those with highly elevated pulmonary arterial pressure (PAP) and decreased cardiac index (CI), where the presence of multiple risk factors for IPF in these patients may have additively or synergistically contributed to the therapeutic outcomes reported in these studies. Again, the benefit of early intervention with bosentan may not have been sufficiently explored in those with mildly elevated PAP in these trials, while bosentan was indeed shown to be efficacious against IP in a subset of patients in the BUILD-1 study, despite the observation that many patients with IPF are associated with rapidly elevated PAP as well as progression of IPF and that elevated PAP is associated with poor prognosis [7]. Against this background, the present bosentan study focused on IPF patients with completely organized honeycomb lung without any pulmonary (including IP) lesions who chiefly complained of symptoms suggestive of progressive respiratory failure, i.e., progressive dyspnea with minimal IPF activity. Thus, the IPF patients with completely organized honeycomb lung alone were enrolled in this study to ensure that the subjects in this study had pathologically stable IPF and required regular hospital visits for treatment. An interim analysis was performed, however, in patients with borderline or less severe PH (25 mmHg ≤ mean pulmonary arterial pressure [mPAP] at rest <35 mmHg and/or mPAP on effort [mPAPOE] ≥ 30 mmHg), following detection of a greater-than-expected significant survival benefit in patients with borderline or less severe PH treated with bosentan at an early phase of the trial when the number of patients enrolled was still small.
BODY.METHODS.STUDY DESIGN AND METHODS:
This was a prospective, single-center, interventional, parallel, randomized, open-label study.
BODY.METHODS.TARGET PATIENT POPULATION:
This study was conducted in patients with IPF (WHO functional class II, III or IV) who showed no signs of hypoxia during 6-min walk test (6MWT) and therefore had enough functional capacity for ADL and who gave written informed consent to participate in the study.
BODY.METHODS.ELIGIBILITY CRITERIA:
To be included in this study, patients had to fulfill all of the following inclusion criteria but none of the following exclusion criteria:
BODY.METHODS.INCLUSION CRITERIA:
Patients aged 20 years old or older (both sexes)Patients diagnosed at this hospital as having IPF (WHO functional class II, III or IV) without hypoxia at rest or during 6MWT (to exclude those with decreased ADL and dyspnea in daily living associated with hypoxia and to minimize the influence of hypoxic pulmonary vasoconstriction [HPV] as a potential cause of PH associated with decreased partial pressure of oxygen in arterial blood [PaO2]) (PaO2 < 60 mmHg)*.*Including those whose hypoxia (PaO2 < 60 mmHg) had been corrected with long-term oxygen therapy (LTOT)Patients with stable IPF who had not required any change of treatment within 3 months prior to study entry, i.e., those confirmed to have completely organized honeycomb lung and no active inflammatory lesion, such as grand glass opacity (GGO) (chronic IIP based on high-resolution computed tomography (CT) findings for which no effective therapy exists); and who presented to our hospital for the first time with symptoms of progressive respiratory failure and had not received any medical treatment for IPF within 3 months prior to their visit.*Excluding those whose progressive respiratory failure required no treatment for IPF itself and those who had an increased LTOT dose as a minimum requirement for progressive respiratory failure.Inpatients and outpatientsPatients who provided written informed consent to participate in this study
BODY.METHODS.EXCLUSION CRITERIA:
Patients who had received bosentan or any other drug specific for PAH (e.g., phosphodiestetrase type 5 [PDE-5] inhibitors, endothelin receptor antagonists, or prostaglandin analogs) prior to their enrollmentPatients with any disease that could cause right heart overloadPatients with hypoxia during 6MWT (PaO2 < 60 mmHg)*.Excluded were those whose hypoxia (PaO2 < 60 mmHg) had been corrected with LTOT (i.e., those in whom LTOT is in place to ensure PaO2 > 60 mmHg both at rest and during 6MWT, who were deemed equivalent to IPF patients receiving routine therapy in clinical practice to allow them to be monitored for changes in their condition, prognosis and functional capacity for ADL).
Women who were pregnant or might have been pregnant, and who were lactatingPatients with moderate or severe liver disorderPatients receiving treatment with cyclosporine, tacrolimus, or glibenclamideOther patients judged by the investigator to be ineligible for this study (e.g., those with any disease or condition other than IPF that might affect their ADL, such as arrhythmia, LV failure, pulmonary thromboembolism, connective tissue diseases, intervertebral disc herniation, as they were confirmed by history taking, physical examination, chest x-ray, echocardiography [ECG], lung perfusion scintigraphy, and measurements of various parameters conducted during the run-in period).
BODY.METHODS.GROUPING OF PATIENTS:
In order to include those with minimal IPF activity alone, of all patients first diagnosed with IPF at our hospital based on the presence of chronic f-IIP as confirmed by high-resolution CT findings, those whose chief complaints suggested progressive respiratory failure and who were suffering from progressive dyspnea were evaluated for PAP by right heart catheterization (RHC) and ECG, as well as for right heart function by ECG. According to the current diagnostic criteria, if mPAP at rest is <25 mmHg, the patient is not diagnosed as having PH even if the mPAPOE is ≥30 mmHg. In our study, however, this state was defined as borderline PH representing a very mild form of PH; and besides, 25 mmHg ≤ mPAP at rest <35 mmHg was defined as less severe PH. Since the aim of this study was to evaluate the efficacy and safety of early therapeutic intervention with bosentan in PH, borderline PH or PH was diagnosed if mPAP at rest was ≥25 mmHg and/or mPAPOE was ≥30 mmHg and mPAWP was ≤15 mmHg. Moreover, borderline PH or less severe PH was defined as mPAP <25 mmHg and mPAPOE ≥30 mmHg or 25 mmHg ≤ mPAP <35 mmHg; severe PH was defined as mPAP ≥35 mmHg; and non-borderline PH or PH was defined as non-PH (mPAP <25 mmHg and mPAPOE <30 mmHg).
BODY.METHODS.GROUPING OF PATIENTS.DRUG-TREATED AND UNTREATED PATIENTS:
All patients who met the eligibility criteria and gave informed consent to participate in this study were evaluated for PAP and right heart function and those with mPAP at rest ≥25 mmHg and/or mPAPOE ≥30 mmHg were stratified by mPAP: mPAP at rest <35 mmHg vs. ≥ 35 mmHg. Patients in each subgroup were randomly allocated to either bosentan (drug-treated group) or no treatment (untreated group) by the envelope method. Patients diagnosed with non-PH (mPAP at rest <25 mmHg with mPAPOE <30 mmHg) were assigned to the untreated group. The drug-treated group comprised those who were diagnosed at this hospital as having IPF without hypoxia (PaO2 > 60 mmHg) and who gave informed consent to participate in this study after PAP and right heart function assessments. The untreated group comprised those diagnosed at this hospital as having IPF without hypoxia (PaO2 > 60 mmHg) and who gave their informed consent to participate in this study after PAP and right heart function assessments. This group included those with severe PH (mPAP at rest ≥35 mmHg), borderline or less severe PH (25 mmHg ≤ mPAP at rest <35 mmHg and/or mPAPOE ≥30 mmHg), and non-PH (without borderline PH or PH). (Fig. 1; see also Additional file 1).Fig. 1Patient flowchart
An interim analysis was performed, however, in patients with borderline or less severe PH (25 mmHg ≤ mPAP at rest <35 mmHg and/or mPAPOE ≥30 mmHg), following detection of a greater-than-expected significant survival benefit in patients with borderline or less severe PH treated with bosentan, at an early phase of the trial when the number of patients enrolled was still small. The study required that IPF patients be randomized to drug-treated and untreated groups to investigate their clinical course in real-world settings, with no change of treatment allowed including bosentan for 2 years or until their death as a rule, except for minimal symptomatic therapy (including oxygen volume adjustments required to ensure similar oxygen conditions among the patients), which met none of the exclusion criteria.
BODY.METHODS.TARGET SAMPLE SIZE:
See Additional file 2.
BODY.METHODS.OUTCOME MEASURES:
ECG examinations were carried out during the run-in period* and every 6 months thereafter**. Complete two-dimensional, pulsed-wave, color-flow echocardiography was performed using the Toshiba ultrasound system Xario (TOSHIBA MEDICAL SYSTEMS CORPORATION, Tochigi, Japan) as previously described [14–25]. (See also Additional file 3). Doppler measurements were carried out during the run-in period* and every 6 months**. (See also Additional file 3 and Additional file 4: Fig. S1). RHC was carried out during the run-in period* and every 6 months thereafter**. Hemodynamic parameters (systolic PAP [SPAP]; diastolic PAP [DPAP]; mean PAP [mPAP]; systolic PAWP [SPAWP]; diastolic pulmonary capillary wedge pressure [DPAWP]; mean PAWP [mPAWP]; systolic right ventricular pressure [SRVP]; diastolic RVP [DRVP]; mean RVP [mRVP]; systolic right atrial pressure [SRAP]; diastolic RAP [DRAP]; mean RAP [mRAP]; and cardiac output [CO]) and pulmonary vascular resistance (PVR) were measured, with the patient in the supine position, via the internal jugular vein and using a Swan-Ganz continuous cardiac output (CCO) thermodilution flow-directed pulmonary artery catheter (Edwards Lifesciences LLC, USA). Cardiac output was measured by the thermodilution method using a Vigilance hemodynamic monitor (Edwards Lifesciences LLC, USA). Systolic PAP on effort (SPAPOE), diastolic PAP on effort (DPAPOE) and mean PAP on effort (mPAPOE) were measured while patients were clasping and opening both hands repeatedly by putting a full strain on the body. Furthermore, mixed venous blood gas analysis was performed.
BODY.METHODS.SURVIVAL ANALYSIS:
Hospital-free survival and overall survival were determined by the duration of survival from week 0 (start of assessment), i.e., as the date treatment started for the drug-treated group and 2 weeks after RHC for the untreated group. Even for those unable to undergo the periodic assessments due to change of their attending physician, etc., this survival analysis was continued by contacting the patient's current physician to have his/her survival status confirmed. Patients were censored from hospital-free survival if they could no longer continue ambulatory treatment and were admitted to another hospital or if they could no longer present to our hospital for progression of respiratory failure.
BODY.METHODS.ADVERSE EVENTS:
All patients were assessed for adverse events during the run-in period* and every 4 weeks thereafter**, as well as based on their medical records on unscheduled visits to our outpatient clinic. Even for those unable to undergo the periodic assessments due to change of their attending physician, adverse events were assessed by contacting their current physician to have these events confirmed.
BODY.METHODS.OTHER PARAMETERS:
Pulmonary function test (PFT) was carried out during the run-in period* and every 6 months thereafter**. (See also Additional file 3). ADL assessments including exercise tolerance test [26–28] were performed during the run-in period* and every 6 months thereafter**. (See also Additional file 3 and Additional file 5: Figure S2). Those in whom LTOT was in place to ensure adequate oxygen inhalation during 6MWT (deemed equivalent to IPF patients receiving routine therapy in clinical practice to allow them to be monitored for changes in their condition, prognosis and functional capacity for ADL) were assessed for treadmill exercise test (TMET) with LTOT in place. Arterial blood gas (ABG), arterial plasma lactate, brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP were determined during the run-in period and every 6 months thereafter. [29] (See also Additional file 3). Hematology, biochemistry and urinalysis were performed during the run-in period* and every 4 weeks thereafter**. *Run-in period: Within 2 weeks after written informed consent was obtained from each patient. **Every 6 months: Consecutive 6 months with a ± 1-week window counting from week 0 (start of assessment) defined as the date drug treatment started for the drug-treated group and 2 weeks after RHC for the untreated group. However, the periodic assessments not conducted in patients as planned based on the attending physician's judgement were deemed acceptable, unless they met any of the criteria for discontinuation of the study (e.g., pneumonia, etc.) (Fig. 1 and Additional file 6: Figure S3).
BODY.METHODS.STUDY DRUG:
Bosentan was administered, as a rule, according to the approved dosage and administration. Bosentan is to be usually initiated in adults at a dose of 62.5 mg twice daily after breakfast and dinner for 4 weeks and increased to a dose of 125 mg twice daily after breakfast and dinner from week 5 of treatment onwards with the dosage adjusted according to the patient's symptoms and tolerability, but not exceeding 250 mg per day. In this study conducted in routine clinical settings, however, it was acceptable to continue treatment at the initial dosage if deemed by the investigator to be appropriate based on the patient's condition (see also Additional file 7).
BODY.METHODS.CONCOMITANT DRUGS AND THERAPIES:
Drugs allowed for use in the study included drugs intended for the treatment of the underlying disease (IPF) and drugs, other than drugs specific for PAH, for the treatment of PH as required for aggravation of PH. Drugs prohibited for use included cyclosporine, tacrolimus, glibenclamide and other drugs specific for PAH (e.g., PDE-5 inhibitors, endothelin receptor antagonists and prostaglandins) as well as any other investigational drug.
BODY.METHODS.STUDY PERIOD:
The study was conducted for 24 months between September 2010 and September 2022 with patient enrollment lasting until January 2020 (see Additional file 8).
BODY.METHODS.STATISTICAL ANALYSIS:
Data are expressed as the mean ± standard deviation (SD). Changes from baseline in individual outcome measures were compared between drug-treated and untreated patients, and analyzed for statistical significance. Analysis on paired data was performed using Mann-Whitney U test. Changes in trend over time were analyzed using the Residual Maximum Likelihood (REML) or least squares method. All statistical analyses were performed using JMP version 11.2.1 (SAS Institute Inc., Cary, NC). A two-sided P value of <0.5 was considered to indicate a statistically significant change.
BODY.RESULTS.PATIENTS:
This report presents the results of an interim analysis of the IPF patients in this study. A total of 32 IPF patients were enrolled in this study between February 2011 and June 2016, who comprised all the outpatients who had met the study entry criteria. At the time of their initial presentation to our hospital, all patients were confirmed to have chronic fibrotic idiopathic interstitial pneumonia (IIP) based on high-resolution CT findings of completely organized honeycomb lung with basal predominance in bilateral subpleural regions for which no effective therapy exists. Patients chiefly complained of symptoms of progressive respiratory failure. While all patients confirmed to have no progressive pulmonary fibrosis on CT were given detailed explanations as to the potential adverse effects associated with the use of antifibrotics, such as pirfenidone or nitentanib, which has only recently been launched in Japan and indicated for very few patients, as well as the costs due under current health insurance, none were confirmed to have received any treatment specific for IPF (e.g., pirfenidone or nintentanib) within 3 months prior to their enrollment or wished to receive any antifibrotic drug after the first 3 months or later, and none dropped out because of any treatment given, other than symptomatic treatment, for PH as the underlying disease, such as calcium channel blockers. Of these 32 patients, the following 3 patients were excluded from the study: 1 who was found to have cancer during the study, which had probably existed at the time of enrollment (untreated, borderline or less severe PH group), 1 who developed symptoms of disc hernia during the run-in period (non-PH group), and 1 who died from aspiration pneumonia during the run-in period before the start of bosentan therapy (drug-treated, borderline or less severe PH group). The remaining 29 patients who had completed the study or were still on the study treatment were included in the present analyses. Of these 29 patients, 3 (including 1 female) had no borderline PH or PH (non-borderline PH/PH) and the remaining 26 patients with boarderline or less severe PH, or severe PH were randomized to receive or not to receive bosentan therapy. Of these, 13 were in the drug-treated group and the other 13 were in the untreated group, including 1 in each group confirmed to have mPAP at rest ≥35 mmHg (severe PH), and 12 in the drug-treated group (age range, 56–76 years old) and 12 in the untreated group (age range, 51–80 years old) confirmed to have mPAP at rest <35 mmHg (borderline or less severe PH). Patient demographics and characteristics were similar between the untreated, borderline or less severe PH group and the drug-treated, borderline or less severe PH group (Table 1).Table 1Clinical characteristics of subjects with borderline or less severe PH (mPAP <35 mmHg)Untreated borderline or less severe PHDrug-treated borderline or less severe PH
P
*
No. (male/female)12(8/4)12(9/3)0.66Age (y.o.)70.50 ± 7.9766.92 ± 6.450.11Height (cm)160.04 ± 10.11160.87 ± 10.070.84Weight (kg)62.067 ± 12.1754.95 ± 12.720.25No. of patients with LTOT870.67ADL including exercise tolerance testWHO functional class2.67 ± 0.782.83 ± 0.830.78mMRC score2.42 ± 1.0842.33 ± 1.440.98SGRQ score Symptoms56.10 ± 22.8745.78 ± 28.960.52 Activity61.60 ± 22.3555.18 ± 33.210.98 Impact37.53 ± 23.1134.38 ± 22.180.91 Total49.42 ± 21.2743.93 ± 26.410.77SF36 Physical functioning (PF)45.83 ± 21.4160.42 ± 26.410.11 Role physical (RP)38.58 ± 21.9651.058 ± 39.160.56 Bodily pain (BP)72.17 ± 26.3080.00 ± 25.230.45 General health (GH)40.67 ± 18.3446.75 ± 20.0670.49 Vitality (VT)49.34 ± 20.5558.36 ± 29.230.40 Social functioning (SF)56.25 ± 26.3868.75 ± 33.500.35 Role emotional (RE)62.51 ± 30.04867.36 ± 37.690.52 Mental health (MH)63.75 ± 19.6765. 00 ± 27.880.62Right heart cardiography mPAP (mmHg)20.83 ± 5.7521.17 ± 7.730.93 mPAPOE (mmHg)42.67 ± 12.7842.58 ± 8.870.45 mPAWP (mmHg)6.83 ± 3.796.28 ± 3.570.76 mRVP (mmHg)14.42 ± 3.5814.083 ± 6.570.31 mRAP (mmHg)2.50 ± 1.683.00 ± 2.130.45 CO (L/min)4.80 ± 1.125.10 ± 1.270.82 CI (L/min/m2)2.90 ± 0.563.21 ± 0.630.38 PVR (wood)3.12 ± 1.653.022 ± 2.00310.95 PVRI5.073 ± 2.674.58 ± 2.611.00Mixed venous PHv7.39 ± 0.0297.40 ± 0.0260.45 PvCO2 (mmHg)49.34 ± 6.03648.15 ± 4.220.82 PvO2 (mmHg)36.69 ± 3.8937.55 ± 3.930.60 SVO2 (%)68.77 ± 5.4770.53 ± 5.710.66PFT %VC (%)68.34 ± 16.9269.55 ± 22.620.98 FVC (L)2.0033 ± 0.572.087 ± 0.800.86 %DLCO (%)30.72 ± 16.001927.37 ± 23.760.25TTE ET (msec)299.71 ± 55.95263.83 ± 36.160.18 PAAcT (msec)98.67 ± 32.6594.75 ± 11.650.58 AcT/ET0.33 ± 0.0870.37 ± 0.0600.23 PEP (msec)92.71 ± 12.6587.42 ± 18.620.12 ICT (msec)17.083 ± 19.9621.75 ± 21.730.70 IRT (msec)55.71 ± 45.002352.42 ± 36.490.95 ICT + IRT (msec)87.79 ± 64.5472.82 ± 46.340.69 TEI index0.32 ± 0.270.30 ± 0.250.98 TAPSE(cm)2.32 ± 0.472.27 ± 0.550.75 Diastolic RA area (cm2)8.20 ± 3.2110.64 ± 4.910.29 Diastolic RA major axis (cm)4.35 ± 2.00374.20 ± 2.0180.66 Systolic RA area (cm2)4.74 ± 2.105.46 ± 2.600.60 Systolic RA major axis (cm)2.95 ± 0.992.65 ± 0.550.25 Diastolic RV area (cm2)16.090 ± 6.5715.39 ± 7.960.33 Diastolic RV major axis (cm)6.38 ± 1.286.22 ± 1.0980.49 Systolic RV area (cm2)9.27 ± 3.479.38 ± 4.380.64 Systolic RV major axis (cm)4.98 ± 1.424.95 ± 0.890.60 RVEF (%)58.91 ± 12.4551.98 ± 13.290.13Aortic Blood data at rest pH7.41 ± 0.0277.42 ± 0.0220.25 PO2 (mmHg)76.84 ± 10.09182.46 ± 7.930.11 Aortic oxygen saturation (%)95.02 ± 1.5595.85 ± 1.200.12 BNP (pg/ml)29.42 ± 20.2620.76 ± 13.100.34 NT-proBNP (pg/ml)93.33 ± 60.1569.67 ± 48.210.45 LA (mg/dl)11.82 ± 4.08210.00 ± 3.530.33TMET METS3.55 ± 1.893.96 ± 2.540.81Post-TMET Aortic Blood data Post-TMET pH7.34 ± 0.0617.36 ± 0.0690.45 Post-TMET PCO2 (mmHg)46.94 ± 12.2243.017 ± 6.750.66 Post-TMET PO2 (mmHg)54.075 ± 15.9367.23 ± 14.710.18 Post-TMET oxygen-Sat (%)80.35 ± 18.07790.85 ± 4.420.14 Post-TMET BNP (pg/ml)40.20 ± 34.8835.62 ± 46.660.27 Post-TMETNT-proBNP (pg/ml)102.83 ± 67.48108.67 ± 124.950.64 LA post TMET – LA at rest (mg/dl)24.68 ± 20.01222.82 ± 18.880.98 6MWD246.18 ± 104.27296.63 ± 128.00900.31Post-6 MW Aortic Blood data Post-6MWT pH7.39 ± 0.0217.40 ± 0.0390.15 Post-6 MW-PCO2 (mmHg)41.042 ± 8.3242.64 ± 5.420.53 Post-6 MW-PO2 (mmHg)77.20 ± 30.9872.067 ± 15.790.91 Post-TMET Oxygen-Sat (%)92.58 ± 4.1390.00 ± 8.350.69 Post-6 MW-BNP (pg/ml)34.52 ± 25.6625.080 ± 23.950.33 Post-6 MW-NT-proBNP (pg/ml)98.50 ± 75.1380.67 ± 72.410.47 LA post-6 MW – LA at rest (mg/dl)8.60 ± 8.315.42 ± 8.340.14Data presented as mean ± SD
*
P value for Mann-Whitney U test to assess the difference between the untreated and drug-treated patients with borderline or less severe PH
BODY.RESULTS.ADVERSE EVENTS (TABLE .EXACERBATION OF SUBJECTIVE SYMPTOMS OF DYSPNEA (TABLE :
Of the 12 untreated patients with borderline or less severe PH, 7 were confirmed to have experienced exacerbation of subjective symptoms of dyspnea based on the data obtained at the cut-off date, with the time to exacerbation of dyspnea being 152.00 ± 89.94 days (mean ± SD). Of 12 the drug-treated patients with borderline or less severe PH, 3 were confirmed to have experienced exacerbation of dyspnea based on the data obtained at the cut-off date, with the time to exacerbation being 259.00 ± 49.87 days (mean ± SD). Proportional hazard analysis showed that the risk ratio of the drug-treated group to the untreated group was 0.32, but with no significant difference.Table 2Adverse events observed in untreated and drug-treated patients with borderline or less severe PHUntreated borderline or less severe PHDrug-treated borderline or less severe PHExacerbation of dyspnea73Time to exacerbation of dyspnea (mean ± SD) (days)152.00 ± 89.94259.00 ± 49.37Increase of the O2 dose52Time to O2 dose increase (mean ± SE) (days)199.00 ± 132.90,335.00 ± 182.43Decrease of the O2 dose01Hospitalization (hospital-free survival)8 (241.50 ± 192.24)2 (239.002 ± 169.00)Death (survival)7 (309.29 ± 195.13)1 (671)Other adverse events3a
6b
a Gastrointestinal hemorrhage (n = 1), pneumonia (n = 1), and ileus (n = 1)
b Pneumothorax (n = 3), CHF (n = 2), and liver dysfunction (n = 1)
Fig. 2Analysis of survival by adverse event. a Analysis of the time to exacerbation of subjective dyspnea. Among the untreated patients with borderline or less severe PH, the time to exacerbation of dyspnea was 152.00 ± 89.94 days (mean ± SD) in 7 of 12 patients confirmed to have experienced exacerbation of subjective symptoms of dyspnea by the data obtained on the cut-off date. Among the drug-treated patients with borderline or less severe PH, the time to exacerbation of dyspnea was 259.00 ± 49.87 days (mean ± SD) in 3 of 12 patients confirmed to have experienced exacerbation of dyspnea by the data obtained on the cut-off date. Proportional hazard analysis showed that the risk ratio of the drug-treated to untreated groups was 0.58, but with no significant difference noted. The time to exacerbation of dyspnea at the time of analysis was 218.17 ± 35.62 days (mean ± SE) in the untreated group and 290.71 ± 12.036 days in the drug-treated group, but with no significant difference noted. b Analysis of the time to an increase in the dose of O2 (event). Increase of the O2 dose: In the untreated patients with borderline or less severe PH, the time to the dose increase was 199.00 ± 132.90 days (mean ± SD) in 5 of 12 patients confirmed to have required an increase of the dose of O2 by the data obtained on the cutoff date. In the drug-treated patients with borderline or less severe PH, the time to the dose increase was 335.00 ± 182.43 days (mean ± SD) in 3 of 12 patients confirmed to have required an increase of the O2 dose based on the data obtained on the cut-off date. The risk ratio analysis showed that the hazard ratio of the drug-treated to untreated groups was 0.58. The time to O2 dose increase at the time of analysis was 357.71 ± 50.83 days in the untreated group and 438.20 ± 34.61 days in the drug-treated group with no significant difference between the groups, despite the results favoring the drug-treated group. In addition, only 1 drug-treated patient with borderline or less severe PH achieved a decrease of the O2 dose on day 243 due to an improvement of respiratory function. c Hospital-free survival. Of the 12 untreated patients with borderline or less severe PH, 8 were confirmed to have been hospitalized (event) by the data obtained on the cut-off date with the time to hospitalization being 241.50 ± 192.24 days (mean ± SD). Of the 12 drug-treated patients with borderline or less severe PH, 2 was confirmed to have been hospitalized by the data obtained on the cut-off date with the time to hospitalization being 239.002 ± 169.00 days. At the time of survival time analysis, hospital-free survival in the untreated group was 358.87 ± 68.65 days (mean ± SE) (median, 331 days), which was shown to be significantly different from that in the drug-treated group (603.44 ± 50.074) by proportional hazard analysis (hazard ratio [HR] of the drug-treated to untreated groups, 0.10; P = 0.017). d Overall survival. Of the 12 untreated patients with borderline or less severe PH, 7 were confirmed dead (event) by the data obtained on the cut-off date with the time to event being 309.29 ± 195.13 days (mean ± SD); of the drug-treated patients with borderline or less severe PH, 1 was confirmed dead by the data on the cut-off date with the time to event being 671 days. At the time of survival analysis, the time to event in the untreated group was 433.78 ± 66.98 days (mean ± SE), which was significantly different from that in the drug-treated group by proportional hazard analysis (HR of the drug-treated to untreated groups, 0.10; P = 0.0082)
BODY.RESULTS.ADVERSE EVENTS (TABLE .INCREASE OF O:
Of the 12 untreated patients with borderline or less severe PH, 5 were confirmed to have required an increase of the O2 dose based on the data obtained on the cut-off date. Of the 12 drug-treated patients with borderline or less severe PH, 3 were confirmed to have required an increase of the O2 dose based on the data obtained on the cutoff date. The risk ratio analysis showed that the hazard ratio of the drug-treated group to the untreated group was 0.58, with the time to O2 dose increase at the time of analysis being 357.71 ± 50.83 days in the untreated group versus 438.20 ± 34.61 days in the drug-treated group, which was not significantly different despite the fact that the results favored the drug-treated group. Only 1 patient with borderline or less severe PH in the drug-treated group achieved a decrease of the O2 dose on day 243 because of improved respiratory function.
BODY.RESULTS.ADVERSE EVENTS (TABLE .HOSPITAL-FREE SURVIVAL (TABLE :
Of the 12 untreated patients with borderline or less severe PH, 8 were confirmed to have been hospitalized based on the data obtained on the cut-off date. In contrast, of the 12 drug-treated patients with borderline or less severe PH, 2 were confirmed to have been hospitalized based on the data obtained on the cutoff date. At the time of survival time analysis, hospital-free survival was 358.87 ± 68.65 days (mean ± SE) (median, 331 days) in the untreated group, which was significantly different from that in the drug-treated group (603.44 ± 50.074 days) as assessed by proportional hazard analysis (hazard ratio of the drug-treated group to the untreated group, 0.19, P = 0.017; log-rank test, P = 0.019; and Wilcoxon test, P = 0.014).
BODY.RESULTS.ADVERSE EVENTS (TABLE .OVERALL SURVIVAL (TABLE :
Of the 12 untreated patients with borderline or less severe PH, 7 were confirmed dead (event) based on the data obtained on the cut-off date. Of the 12 drug-treated patients with borderline or less severe PH, 1 was confirmed dead with the time to event being 671 days. At the time of survival analysis, the time to event was 433.78 ± 66.98 days (mean ± SE) in the untreated group, which was shown to be significantly different from that in the drug-treated group as assessed by proportional hazard analysis (hazard ratio of the drug-treated group to the untreated group, 0.10, P = 0.0082; log-rank test, P = 0.011; and Wilcoxon test, P = 0.011).
BODY.RESULTS.ADVERSE EVENTS (TABLE .CLINICAL COURSE:
Eight of the 12 untreated patients received LTOT. Of the 12 patients, 1 completed the 2-year treatment period, 2 were still on the study (with one having completed regular examinations up to month 12 and the other up to month 18), and 1 was not available for the periodic assessments from month 18 onwards due to change of the attending physician after change of address. Of the remaining 8 patients, 7 were censored from hospital-free survival analysis due to progression of respiratory failure, including 5 and 1 who were not available for the periodic assessments other than mMRC, 6MWD and TMET from months 6 and 18 onwards, respectively, and were later confirmed dead. One patient was confirmed alive at the time of analysis but was not available for the periodic assessments other than mMRC, 6MWD and TMET from month 12 onwards. The remaining 1 patient developed ileus and was confirmed to have died due to a disease other than lung disease at another hospital and was completely excluded from the periodic assessments from month 6 onwards. As for the periodic assessments with mMRC, TMET and 6MWT, of the 11 patients assessed by mMRC at month 6, 9 each were further assessed at month 12 and 8 were further assessed at month 18, and 7 completed the assessments at month 24, including 1 patient who was assessed at months 18 and 24 by contacting the patient's current physician after change of address. Of the 11 patients assessed by TMET and 6MWT at month 6, 8 were further assessed at month 12, and 7 completed the assessments at months 18 and 24. Seven of the 12 drug-treated patients included in the analysis received LTOT. Four patients completed the study after finishing the assessments at month 48 and 1 of the remaining 8 patients withdrew from the study before month 6 due to hepatic dysfunction. Another patient withdrew from the study due to lung cancer detected on day 518. The last two patients were censored from hospital-free survival analysis due to exacerbation of respiratory failure on days 641 and 303, respectively, with the former confirmed dead on day 671. The remaining 4 patients were still on the study treatment (with 1 having completed regular examinations at baseline alone, 1 up to month 6, 2 up to month 12, and 1 up to month 18).
BODY.RESULTS.LUNG FUNCTION AND RHC.DRUG-TREATED PATIENTS WITH BORDERLINE OR LESS SEVERE PH:
Compared with baseline (Table 1b), significant changes were noted in lung function %DLCO at months 6 and 12 (month 6, +7.011, P = 0.010; month 12, +12.18, P = 0.0025) (See Additional file 9: Figure %DLCO). Compared with baseline (Table 2b), there was a decreasing trend in mPAP at months 6 and 12 although no significant difference was noted (month 6, −2.60, P = 0.098, R = 0.84; month 12, −1.71, P = 0.38, R = 0.83). A similar trend was observed for PVR (month 6, −0.69, P = 0.11, R = 0.88; month 12, −0.41, P = 0.41, R = 0.87). Compared with baseline, there was a significant improvement in mixed venous saturation of oxygen at month 6 (+4.78, P = 0.037, R = 0.45), but no significant change was noted from baseline to month 12. Moreover, significant differences were observed in the drug-treated patients with borderline or less severe PH with regard to changes in mPAP, PVR and PVRI from baseline to month 6 (untreated vs. drug-treated: mPAP, +4.71 vs. -2.60 mmHg, P = 0.0035; PVR, +1.60 vs. -0.69 woods, P = 0.0020) (Fig. 3).Fig. 3Results of RHC. a Comparison of changes in mPAP from baseline to month 6 between untreated and drug-treated patients with borderline or less severe PH. b Comparison of change in PVR from baseline to month 6 between untreated and drug-treated patients with borderline or less severe PH. Significant differences were seen between the untreated and drug-treated patients with borderline or less severe PH with regard to changes in mPAP, and PVR from baseline to month 6 (untreated vs. drug-treated: mean difference in mPAP, 4.71 vs. -2.60 mmHg, P = 0.0035; PVR, +1.60 vs. -0.69 woods, P = 0.0020)
It will be a long time, however, before comparisons of data can be made between the groups for month 12 onwards, with many untreated patients with borderline or less severe PH having been censored from hospital-free survival analysis with an even smaller number of patients available for the periodic assessments. Results for other assessment parameters (See Additional file 10, Additional file 11: Figure ADL, Additional file 12: Figure TTE, and Additional file 13: Figure Arterial blood analysis). Overall, while drug-treated patients with borderline or less severe PH tended to fare better than untreated patients with borderline or less severe PH, it was difficult to draw any conclusion due to the small number of patients currently available for analysis, especially in untreated patients with borderline or less severe PH. Thus, while the study appears to provide potentially valuable findings at this stage, their relevance and/or validity require to be closely examined when the final data of this trial become available.
BODY.DISCUSSION:
Many patients with IPF experience a rapid elevation of PAP as well as progression of IPF [7] and elevated PAP is shown to be associated with poor prognosis [7]. Therapies currently available for slowing the progression of fibrosis, such as pirfenidone, cannot be expected to improve IPF [30]. Besides, for any honeycomb lung that has become completely organized, no realistic treatment options are available, other than symptomatic relief with LTOT, to neutralize the progression of respiratory failure. In addition, it remains largely unclear how IPF and associated PH may interact to influence each other. Again, in agreement with the ATS/ERS/JRS/ALAT Clinical Practice Guideline 2015 that remains inconclusive with regard to the effect of drugs for PAH on IPH except in a subset of cases, recommending dual ERAs in patients with IPF recommended as "worthwhile considerations" and bosentan as "a conditional recommendation against use" [31], our study provided no definite clue as to how IPF and associated PH may interact. Furthermore, while our study did not allow PH and lung fibrosis to be examined for any relationship due to its small sample size, it did show no significant correlation between FVC and mPAP, suggesting that how PH and lung fibrosis interact may not readily lend itself to clarification. Against this background, bosentan was shown to be efficacious in a subset of IIP patients in the BULD-1 study, and this is in contrast to the results of a number of randomized controlled trials [10, 32, 33], including the BUILD-3 and ARTEMIS trials, conducted in a wide range of biopsy-proven IPF patients (where the pathology of IPF studied, including the pathologic activity, varied widely, i.e., those with fibrotic IIP, f-NSIP, elevated PAP and decreased CI), which argued against the use of bosentan in patients with PH and f-IIP. Of note, these studies failed to evaluate bosentan in patients perfectly matched for background IPF, suggesting that early intervention with bosentan in those with mildly elevated PAP may not have been sufficiently explored, while the patient background factors may have additively or synergistically contributed to the unfavorable outcomes reported in these studies. With these considerations in mind, we enrolled patients with completely organized honeycomb lung in this study to ensure that all study subjects were as nearly matched for IPF background as possible and that they had pathologically inactive IPF (i.e., they had no active inflammatory lesion, such as GGO) that would require no change of treatment during the study. Since the subjects of this study were required to regularly visit our hospital, patients who presented to our hospital for the first time with symptoms of progressive respiratory failure were enrolled (those without symptoms of progressive respiratory failure were not eligible for treatment at regular intervals at our hospital and were followed up at some other nearby hospital). The present study included IPF patients with completely organized pulmonary fibrosis alone in an attempt to rule out the potential influence of IPF-associated interstitial inflammation and inter-individual differences in IPF status. As a result, the majority of patients enrolled in the study were found to have borderline to less severe PH. While it remains unclear why these patients comprised the majority, in retrospect, ambulatory patient enrollment may have led to those IPF patients who required no emergency or acute intensive care, i.e., those with only honeycomb lesions accompanied by gradually progressive dyspnea, being included in the study, who could therefore represent a selected segment of the entire IPF population. Thus, the present bosentan study was conducted in IPF patients with progressive dyspnea despite minimal IPF pulmonary lesion activity, thus ruling out the additive or synergistic influence of IPF lesions on progression of dyspnea to unequivocally demonstrate the impact of therapeutic intervention for PH in progressive dyspnea and to investigate treatment-associated pathophysiological changes in cardiac function using ECG, as well as the long-term efficacy and safety of early therapeutic intervention in PH with bosentan, with borderline PH defined as mean PAP on effort (mPAPOE) ≥ 30 mmHg (including mPAP at rest <25 mmHg). At its early phase involving a small number of patients, this study demonstrated a greater-than-expected significant difference in prognosis between bosentan-treated and untreated patients with progressive respiratory failure who were confirmed to have completely organized honeycomb lung. Based on this finding, we performed an ad hoc interim analysis, which demonstrated that bosentan therapy led to a clearly better prognosis in patients with honeycomb lung suffering from symptoms of progressive respiratory failure than that in untreated patients, which was very poor. At the same time, study results reconfirmed that patients with progressive respiratory failure with completely organized honeycomb lung have a really poor prognosis. Although the possible imbalance in patient characteristics between the two groups may have affected the study results, this study adhered to randomization with the envelope method, thus making such possibility rather unlikely. The main limitation of this study is the small number of patients included in the analysis, but this interim report was prepared following detection of a significant difference in prognosis in patients with borderline or less severe PH treated with bosentan when only half the number of patients targeted had completed the study. Again, with this study still at an exploratory stage, we have no sufficient information to determine the sample size, but an earlier bosentan repeated-dose study (AC-052-111 trial) of patients with PAH (WHO functional class III or above) conducted in Japan provided the rationale for the sample size required (i.e., 11 patients required to conduct a two-sided t-test for AUC with two-sided significance level of 5% and 90% power). Given the current state of clinical trials in this field, the sample size of this study appears to be never too small. It is highly likely that the favorable prognosis seen in the bosentan-treated patients with borderline or less severe PH might have been affected by inclusion of those with IPF experiencing a rapid elevation of PAP (not always seen among the untreated patients with borderline or less severe PH undergoing the periodic assessments). It is also possible, however, that rapid PAP elevation may have led to many patients being excluded from periodic assessments, while slowly progressive PAP elevation may have allowed patients to undergo the periodic assessments, although it is difficult to prove one way or the other. Despite this limitation, however, our study has raised the following possibilities. First, targeting patients with completely organized honeycomb lung and symptoms of progressive respiratory failure might help select patients with rapid PAP elevation. Second, the use of bosentan may be associated with improved prognosis in selected patients similar to those included in this study. Moreover, although previous reports have failed to demonstrate a significant difference in prognosis in the entire IPF patient population with any of the drugs tested, as therapeutic options capable of suppressing the pathology of IPF become available in the future, the use of bosentan in combination with any such option might contribute further to improvements in prognosis. In addition, while the study data remain yet to mature at present, the available data demonstrate improvements in exercise tolerance over time in bosentan-treated patients compared with untreated patients thus favoring bosentan therapy, although many untreated patients were censored from hospital-free survival analysis and excluded from the periodic assessments. If these effects on exercise tolerance can be replicated through accumulation of data from continuation of this study, bosentan may have a role to play in protecting against declines in exercise tolerance by working at various levels. Moreover, changes in respiratory conditions among the drug-treated patients suggest that bosentan therapy may have corrected abnormal breath patterns that tended toward hyperventilation. These results suggest a potential role for bosentan in delaying the progression of respiratory failure and that a decrease in respiratory rate from relief of dyspnea may be linked to a trend toward increased PO2, decreased PCO2 and increased PH after exercise tolerance and stress testing, which corresponded to improvements seen in breathing efficiency after stress testing, despite no significant change in 6MWD in which the patients were assessed at the pace each patient felt comfortable. Otherwise, while the study data also suggest improvements in RV function on TTE in patients with borderline or less severe PH treated with bosentan, this finding requires to be examined at the completion of the study (see Additional file 10). Again, while the drug-treated group did not require LTOT or increasing the O2 inhalation dose, the untreated group reached the endpoint of hospital survival in a very short time with progressive dyspnea. Another limitation of the study is that, among the exercises leading to increased PAP during RHC, it included clasping and opening both hands repeatedly with a full strain exerted on the body, which allowed PAP to be monitored but made it rather difficult to continue the exercise during CO measurement thus making PVR, the most critical of all parameters, less amenable to measurement. While the reasons for the observed increases in PAP during exercise in the study can only be surmised, they may include changes in PAP or increases in pulmonary blood flow associated with PVR during exercise [34–36] and intrathoracic pressure associated with straining on the part of the patients being evaluated. A still further limitation of the study is that all patients with lower values of PAP (mPAP <25 or mPAPOE <30) were included in the untreated group, while all patients should have been randomized. Health insurance in Japan made it hardly feasible, however, to design this study as a randomized trial in which patients without PH would also be randomized to bosentan or any other drug specific for PAH. Again, given that patients with IPF might show variable outcomes, e.g., rapid declines, frequent exacerbations, or slow declines, thus representing a heterogeneous population, patients may have had to be enrolled only after their lung function has been shown to be stable for many years. However, it was simply unfeasible to enroll patients only after their lung function had been shown to be stable for some time. Instead, we have further refined the definition of eligible patients as those confirmed to have completely organized honeycomb lung and to have no active inflammatory lesion, such as GGO. In addition, the inclusion criteria initially defined the patient age as ranging between 20 and 40 years old to exclude familial pulmonary fibrosis. Given that this could also exclude IPF, however, the patient age may have been better defined as 40 years old or older and may have led to different outcomes. Indeed, a retrospective analysis of all patients enrolled confirmed that they ranged in age between 51 and 80 years old, which has led us to redefine the patient age as 40 years old or older. While all patients confirmed to have no progressive pulmonary fibrosis on CT were given detailed explanations as to the potential adverse effects associated with the use of antifibrotics, such as pirfenidone or nitentanib, which has only recently been launched in Japan and indicated for very few patients, as well as the costs due under current health insurance, none of these patients had previously received any medical treatment for IPF within 3 months prior to their visit and none wished to receive any antifibrotic after the first 3 months or later. Thus, further study is warranted to investigate whether various treatment options, including combination therapy with bosentan and an antifibrotic, may lead to further improvements in prognosis in these patients.
BODY.CONCLUSIONS:
This was an interim report of our ongoing long-term study conducted to evaluate the effects of bosentan, as a PAH-specific drug, on IPF-associated PH based on detailed data analysis. Despite its limitations, the study appears to suggest that the bosentan-treated group fared remarkably better than the untreated group, while it was thought likely that those without borderline PH or PH receiving no treatment were associated with poor prognosis, and those with borderline PH or PH receiving bosentan therapy were associated with better prognosis. Again, study findings suggest that there exists a subset of IPF patients who might benefit from bosentan therapy with regard to improvements in IPF and prognosis. The authors plan to prepare a final report after accrual of further patients required to complete the study.
BODY.ADDITIONAL FILES:
Additional file 1:Supplementary document on subgroup analysis. Supplementary document on patient grouping. (DOCX 12 kb)
Additional file 2:Supplementary data on determination of sample size. Data included as a basis for sample size determination in this study. (DOCX 17 kb)
Additional file 3:Supplementary document on parameters. Parameters included for evaluation in this study. (DOCX 19 kb)
Additional file 4:Figure S1 Methods for and results of Doppler measurements performed in this study. (PPT 154 kb)
Additional file 5:Figure S2 TMET (Treadmill exercise test) protocol as part of the supplementary document on parameters. (PPTX 54 kb)
Additional file 6:Figure S3 Schedule for evaluation of parameters in this study. (PDF 1240 kb)
Additional file 7:Supplementary information on Guidance for Tracleer Tablets® dosage modification. Guidelines for bosentan dose modification as applied in Japan and used in this study. (DOCX 14 kb)
Additional file 8:Supplementary data on the criteria for discontinuation of the study in individual patients. Criteria for study discontinuation in individual patients used in this study. (DOCX 16 kb)
Additional file 9:Assessment of time-course changes in %DLCO in Drug-treated patients with borderline or less severe PH. A summary of results for %DLCO. (PPTX 117 kb)
Additional file 10:Supplementary results for other parameters. A summary of results for other parameters in this study. (DOCX 18 kb)
Additional file 11:Figure ADL. Comparison of changes in mMRC between drug-treated and untreated patients with borderline or less severe PH; Comparison of changes in TMET between drug-treated and untreated patients with borderline PH or less severe PH. (PPTX 190 kb)
Additional file 12:Figure TTE. Change in PA AcT from baseline to month 12 in drug-treated patients with borderline or less severe PH. (PPTX 61 kb)
Additional file 13:Figure Arterial blood analysis. a. Time-course change in PaO2 at rest in drug-treated patients with borderline or less severe PH; b. Change in post 6MWT aortic pH in drug-treated patients with borderline PH or less severe PH. (PPTX 225 kb)
Additional file 14:Supplementary data on procedures regarding informed consent. Procedures for informed consent. (DOCX 14 kb)
Additional file 15:Supplementary information regarding compensation in case of trial-related injury or death. Compensation or indemnity for injury or death. Scheme for compensation or indemnity for injury or death in this study. (DOCX 14 kb)
Additional file 16:Supplementary information regarding medical expenses. Medical expenses anticipated in this study including those to be borne by subjects. (DOCX 14 kb)
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TITLE: How to avoid discontinuation of antihypertensive treatment. The experience in São Paulo, Brazil
ABSTRACT.OBJECTIVES::
To evaluate the importance of providing guidelines to patients via active telephone calls for blood pressure control and for preventing the discontinuation of treatment among hypertensive patients.
ABSTRACT.INTRODUCTION::
Many reasons exist for non-adherence to medical regimens, and one of the strategies employed to improve treatment compliance is the use of active telephone calls.
ABSTRACT.METHODS::
Hypertensive patients (n = 354) who could receive telephone calls to remind them of their medical appointments and receive instruction about hypertension were distributed into two groups: a) "uncomplicated" – hypertensive patients with no other concurrent diseases and b) "complicated" - severe hypertensive patients (mean diastolic ≥110 mmHg with or without medication) or patients with comorbidities. All patients, except those excluded (n = 44), were open-block randomized to follow two treatment regimens ("traditional" or "current") and to receive or not receive telephone calls ("phone calls" and "no phone calls" groups, respectively).
ABSTRACT.RESULTS::
Significantly fewer patients in the "phone calls" group discontinued treatment compared to those in the "no phone calls" group (4 vs. 30; p<0.0094). There was no difference in the percentage of patients with controlled blood pressure in the "phone calls" group and "no phone calls" group or in the "traditional" and "current" groups. The percentage of patients with controlled blood pressure (<140/90 mmHg) was increased at the end of the treatment (74%), reaching 80% in the "uncomplicated" group and 67% in the "complicated" group (p<0.000001).
ABSTRACT.CONCLUSION::
Guidance to patients via active telephone calls is an efficient strategy for preventing the discontinuation of antihypertensive treatment.
BODY.INTRODUCTION:
Most patients with hypertension do not benefit from treatment.1 Data from NHANES/NCHS 1999–2004 showed that 71.8% of individuals were aware of their condition, 61.4% were under current treatment and 35.1% had it under control.2 Although the percentage of individuals with controlled blood pressure in Brazil is unknown, we estimate it to be low because the percentage of patients with their high blood pressure under control is around 30-35% at outpatient clinics that specialize in hypertension, and these clinics do not represent the national reality.3 Many reasons exist for non-adherence to medical regimens, including adverse drug effects, poor instructions, poor provider-patient relationship, poor memory, a patient's disagreement with the need for treatment or inability to afford medication.4,5 One of the strategies employed to improve treatment compliance is the use of active telephone calls6 to patients through which they are given guidance and treatment questions are answered. Using this strategy, several studies have shown an increase in treatment compliance, a higher percentage of blood pressure control6-8 and a decrease in mortality.9-11 Another strategy that aims at improving treatment compliance is the employment of two low-dose medications. Evidence suggests that the combination of two antihypertensive agents provides a higher percentage of blood pressure control due to complementary mechanisms of action. In addition, this results in better tolerability and consequently, better treatment compliance.12-14 The ASCOT study15 (Anglo-Scandinavian Cardiac Outcomes Trial) has indicated a significant reduction in all causes of mortality with the use of current medications for treating hypertension: calcium channel antagonists and angiotensin-converting enzyme inhibitors. It has also been demonstrated that a high incidence of adverse events may decrease treatment compliance. However, in the LIFE16 study, angiotensin receptor antagonists proved to be better at reducing the risks related to cardiovascular events and they resulted in a lower rate of treatment discontinuation when compared to a beta-blocker. In view of these data, we evaluated the importance of providing guidelines to patients via active telephone calls for blood pressure management and preventing treatment discontinuation in hypertensive patients. We used two treatment regimens with low-dose medications that were offered for free to avoid the influence of financial factors. We opted for one regimen called "traditional" based on diuretics and beta-blockers and another called "current" based on angiotensin II antagonists and calcium channel blockers.
BODY.METHODS:
The study participants were selected at the Hypertension Unit, University of São Paulo General Hospital, Nephrology Division, University of São Paulo School of Medicine. The patients had essential hypertension and were able to receive telephone calls to be reminded of their medical appointments and be given guidance about hypertension. Patients were of both genders, from diverse ethnic backgrounds, over 18 years of age, and had body mass indices below 40 kg/m2. The patients were enrolled in the study after signing a free and informed consent form. The study was approved by the Ethics Committee of the Board of Directors of the University of São Paulo School of Medicine. Patients were excluded on several bases, including blood pressure <140/90 mmHg without antihypertensive medication, secondary hypertension, white-coat hypertension with systolic pressures ≥140 mmHg and/or diastolic pressures ≥90 mmHg at the doctor's office and awake mean systolic pressures <135 mmHg or awake mean diastolic pressures <85 mmHg without antihypertensive medication, malignant hypertension and patients with a previous history of hypersensitivity reaction to the study medications. Other exclusion criteria were as follows: pregnant women or nursing mothers, the presence of liver dysfunction evidenced by the patient's clinical history or by one of the liver function tests (levels twice the normal values for alkaline phosphatase, total bilirubin, aspartate aminotransferase), patients with clinical conditions that might interfere with the total conformity with the study or those who might have an increased risk for participating in the study, patients with a history of alcoholism, drug abuse or mental disorders that might invalidate the free and informed consent or limit the patient's ability to meet the protocol rules and patients who had participated in any other studies involving investigational drugs or drugs already marketed within the previous month before enrollment in this study or concomitantly with this study.
BODY.METHODS.BLOOD PRESSURE MEASUREMENT:
Blood pressure and heart rate measurements were performed on the right upper limb on sitting patients five times by the nursing staff using an appropriately sized cuff with a validated automatic oscillometric device (Dixtal, DX2710, São Paulo, Brazil).17 The mean of the last two measurements was calculated and recorded if the difference between these measurements was less than 4 mmHg. If after the five measurements the difference between the last two was greater than 4 mmHg, the measurement was repeated until the difference between the two measurements was less than 4 mmHg. During the study, blood pressure measurements were always performed in the afternoon by the same nursing staff using the same device. The diagnosis of hypertension was made when the mean values of the last two measurements were as follows: systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg with or without medication at the initial visit (Visit 0). Patients who were receiving antihypertensive medication at the initial visit and had a systolic pressure <140 mmHg or a diastolic pressure <90 mmHg were re-evaluated eight weeks after discontinuation of their medication and introduction of placebo; these patients were included in the study when the mean values included a systolic pressure ≥140 mmHg and/or a diastolic pressure ≥90 mmHg. Controlled blood pressure was defined in two levels as (with the patient in the seated position) a systolic/diastolic pressure less than 140/90 or 120/80 mmHg. All of the patients underwent Ambulatory Blood Pressure Monitoring (ABPM), which was performed with a validated oscillometric device (SpaceLabs 90207, SpaceLabs Inc, Richmond, WA, USA),18,19 five weeks after the start of the placebo to eliminate cases of patients with white-coat hypertension and, in patients who did not receive placebo, to identify the white-coat effect. According to clinical characteristics, the patients were assigned to two groups: a) "uncomplicated"– hypertensive patients without complications and without other concurrent diseases and b) "complicated"- patients with severe hypertension (mean diastolic pressure ≥110 mmHg with or without medication) or comorbidities such as diabetes mellitus, renal failure (serum creatinine >1.4 mg/dL), coronary insufficiency, congestive heart failure or prior history of cerebrovascular accident.
BODY.METHODS.PATIENT RANDOMIZATION:
All patients, from both the complicated and the uncomplicated groups, were open-block randomized to receive active telephone calls ("phone calls" group) or not to receive telephone calls ("no phone calls" group) and to follow two treatment regimens, "traditional" or "current". Thus, after the first visit and randomization, patients from the "phone calls" group were invited to enroll by telephone in a program called "Biosintética Assistance", supported by Biosintética Laboratory. The patients who subscribed started receiving active telephone calls from appropriately trained operators and also started receiving magazines with health-related information, which were sent periodically by mail. There were six contacts by telephone during the study. During phone calls, the patient was reminded to attend the next visit, and he/she was educated about hypertension and any necessary clarifications about his/her treatment. All patients randomized to the "phone calls" group were invited to attend occasional informative lectures with the participation of a multidisciplinary team. At the initial stage of treatment (following eight weeks of treatment with placebo), the "uncomplicated" group received one of the following treatment regimens: a) "traditional" treatment with 6.25 mg 2x/day hydrochlorothiazide and 25 mg 2x/day atenolol; b) "current" treatment with 25 mg 2x/day losartan and 2.5 mg 2x/day amlodipine. If the blood pressure could not be controlled during the visits, the medication doses were doubled or another antihypertensive was added. The "complicated" group did not undergo the treatment period with placebo and was randomized to receive either "traditional" or "current" drug regimens similar to the ones administered to the "uncomplicated" group, though the specifics of each condition were carefully considered. The addition of other antihypertensive agents in the "uncomplicated" group and the specificities of the patient regimens in the "complicated" group were performed according to the guidelines from the V Brazilian Guidelines on Arterial Hypertension.3 All patients were instructed to take their medication every day at 7:00 AM and 7:00 PM, with a variation of up to one hour. A 12-month supply of the necessary medication was supplied to the patients by the physician at the end of the visit at no cost to eliminate the financial factor in this analysis; patients were given enough medication to last between visits. Patients were instructed to bring the remaining pills to their subsequent visits, at which time they were counted by the nursing staff without the patients' knowledge of this procedure. Doctors' visits, preceded by the nursing staff visit, took place every eight weeks for 56 weeks and included measurements of blood pressure, heart rate and weight. The weight was checked with the patient wearing light clothes standing barefoot on a scale (model 2096PP, Toledo do Brasil, São Paulo, Brazil). Study withdrawal was characterized by non-attendance to appointments for up to three months after the scheduled date. Patients who returned to the medical clinic within three months after the scheduled date were allowed to continue in the study and be evaluated in an unscheduled visit. The tests performed during the placebo treatment and after 40 weeks of active treatments included the following: fasting glucose, urea, creatinine, total cholesterol, fractions of cholesterol, triglycerides, uric acid, total bilirubin, creatine phosphokinase (CPK), sodium (Na+), potassium (K+), hemoglobin, thyroid-stimulating hormone (TSH), alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotranferase (ALT) and urinary excretion of sodium in 24 h.
BODY.METHODS.STATISTICAL ANALYSIS:
Data were analyzed using an analysis of variance (ANOVA) according to the factor of controlled or uncontrolled hypertension. P<0.05 was considered statistically significant.
BODY.RESULTS:
The study included 398 patients. Of those, 44 were excluded for the following reasons: a) lack of enrollment in the Biosintética Assistance program (n = 17); b) body mass index >40 kg/m2 (n = 6); c) secondary hypertension (n = 4); d) white-coat hypertension (n = 3); e) white-coat normotension ("masked hypertension") (n = 3); f) alcohol use (n = 2); g) classification error (n = 4); h) refusal to do ABPM (n = 2); i) loss of blood pressure measurements from the first visit (n = 1); j) pregnancy (n = 1); k) death (n = 1). A total of 354 patients were evaluated. There were no statistically significant differences in age, gender, skin color, body mass index, blood pressure or heart rate between the groups classified as: "complicated" (n = 175) and "uncomplicated" (n = 179); "traditional" (n = 176) and "current" (n = 178); "phone calls" (n = 108) and "no phone calls" (n = 246) (Table 1). In addition, no differences were seen in marital status, education or occupation.
BODY.RESULTS.A) CONTROL OF BLOOD PRESSURE:
A marked reduction in blood pressure was seen in patients from both the "complicated" and "uncomplicated" groups (Table 2). The blood pressure was reduced by 19±10/20±14 mmHg in the "uncomplicated" group and by 18±14/22±17 mmHg (systolic/diastolic) in the "complicated" group (p>0.05; n = 354). The "phone calls" and "no phone calls" groups showed significantly lower blood pressures at the end of treatment (p< 0.00001). The "traditional" and "current" groups showed significantly lower blood pressures at the end of treatment (Figure 1). The percentage of patients with controlled blood pressure (<140/90 mmHg) was also high at the end of treatment (74%). On the other hand, the percentage of patients with blood pressure reduced to <120/80 mmHg was only 29%. There was no difference in the percentage of patients with controlled blood pressure between the "phone calls" and "no phone calls" groups or in the reduction of blood pressure and the percentage of patients with controlled blood pressure among the "traditional" and "current" treatments. However, patients in the "phone calls" group (80%) had better blood pressure control than those in the "no phone calls" group (71%), though the difference was not statistically significant. The "uncomplicated" and "complicated" groups had statistically significant differences in the percentage of patients with controlled blood pressure (<140/90 mmHg) (80% vs. 67%, respectively; p<0.000001). At the next to last study visit (visit 7), 90% and 66% of patients had blood pressure measurements <140/90 mmHg in the "uncomplicated" and "complicated" groups, respectively. However, there was no difference in the percentage of patients with blood pressure <120/80 mmHg (31% on the final visit in both groups, Table 3). Among patients with a blood pressure <140/90 mmHg at the final visit, only 3% had received only one type of antihypertensive medication; most patients (56%) received 2 (34%) or 3 (22%) types of antihypertensive medication (Table 4).
BODY.RESULTS.B) TREATMENT DISCONTINUATION:
A significantly lower number of patients in the "phone calls" group quit the treatment compared to the "no phone calls" group (4 vs. 30, respectively; Figure 2). There was no difference in the percentage discontinuation in the "complicated" and "uncomplicated" groups or in the "current" and "traditional" treatment regimens (p>0.05).
BODY.RESULTS.C) TABLET COUNT:
Patients in the groups: "complicated" and "uncomplicated"; "traditional" and "current"; "phone calls" and "no phone calls" did not show statistically significant differences in medication intake, as verified by counting the tablets returned at the visits. Compliance was over 85% at all visits. However, patients in the current + uncomplicated + phone call group had the highest rate of compliance (93%). The lowest rate of compliance occurred in the traditional + uncomplicated + no phone call group (85%) (p>0.05).
BODY.RESULTS.D) BODY WEIGHT:
Blood pressure reductions occurred in the presence of increased body weight (baseline visit: 73±14 kg; final visit: 74±14 kg, p = 0.0008, Table 5).
BODY.RESULTS.E) ADVERSE EVENTS AND LABORATORY TESTS:
Most of the adverse events that occurred during the study were of light or moderate intensity. Patients in the "traditional" group showed significantly more depression symptoms (5 vs. 0) and coughing (30 vs. 4) when compared with patients in the "current" treatment group. On the other hand, patients in the "current" group had a greater number of complaints of dizziness when compared to patients in the "traditional" treatment group (63 vs. 42, respectively). Compared to patients in the "uncomplicated" group, patients in the "complicated" group presented a larger number the following symptoms: abdominal pain (19 vs. 8), sleepiness (32 vs. 10), cough (23 vs. 11), weakness (23 vs. 11) and blurred vision (6 vs. 0). Conversely, compared to patients in the "complicated" group, patients in the "uncomplicated" group presented a larger number of complaints such as pain (74 vs. 53) and headache (80 vs. 59). Patients in the "phone calls" group reported a 34% rate of symptoms, while a 66% rate of symptoms was reported by patients in the "no phone calls" group. The most frequently (>10%) found adverse events were as follows: headache (62.1%), unspecific pain (58.2%), dizziness (45.8%), edema (40.1%), fatigue (15.3%), sleepiness (14.4%), cough (13.3%), precordial pain (13.3%), weakness (11.9%), tachycardia (11.3%), insomnia (10.5%) and paresthesia (10.5%). There were 26 (8%) severe adverse events: death (5), unstable angina (4), acute myocardial infarction (1), transient ischemic attack (1), hypertensive encephalopathy (1), breast cancer (3), bronchospastic crisis (1), cholecystopathy (1), diabetic decompensation (1), syncope (1), nephrectomy (2), trauma (2), peritoneal bypass (1), diarrhea (1) and gastrectomy (1). The results of the laboratory tests performed in the beginning and end of the study are shown in Table 6. There was an increase in the 24-hour urinary sodium excretion from the beginning to the end of the study (120±46 vs. 129±45 mEq/L, respectively; p = 0.000036)
BODY.DISCUSSION:
Adherence to a medication regimen is generally defined as the extent to which patients take medications as prescribed by their health care providers.20 This can be classified into three aspects of the individual's behavior regarding his/her health: 1) take the medication correctly, 2) follow the professionals' instructions related to diets and lifestyle changes and 3) attend medical visits.21 The discontinuation of medication is considered the most serious type of noncompliance with treatment. In our study, the "phone calls" group showed a significantly lower percentage of patients who discontinued treatment compared with the "no phone calls" group. A meta-analysis of randomized studies22 suggested that treatment discontinuation is effectively avoided by contacting the patient using letters, telephone calls or e-mails. Márques Contreras et al.6 evaluated the efficacy of telephone and e-mail intervention for therapeutic compliance among 538 patients with mild to moderate hypertension and verified that the group that received phone calls showed higher compliance rates (96.2%) than the group that was only contacted by e-mail (91.3%) or the group that did not receive any intervention (69.2%). Similar data were found in a controlled study recently conducted by Bosworth et al.7 in which the self-reported medication adherence was shown to increase by 9% in the group that had received behavioral and educational intervention (319 hypertensive subjects) through telephone calls versus 1% in the group that had not received intervention (n = 317). Friedman et al.23, through telephone calls associated with usual medical care for six months, compared hypertensive patients who received their usual medical treatment with those who used a monitoring and counseling system. Participants with compliance below 80% of the prescribed medication prior to enrollment in the study showed better compliance with the treatment when the telephone monitoring system was used than did patients who did not use the system (36% vs. 26%, respectively). On the other hand, participants with a compliance level above 80% prior to enrollment in the study did not show any change in compliance, and compliance was comparable in users and non-users of the telephone monitoring system. In our study, regardless of the group to which they were randomized, patients showed compliance rates above 85% at all visits. However, we do not have data regarding medication compliance before enrollment in the study. It is important to point out that treatment compliance is directly related to mortality. A study conducted by Wu et al.9 randomized 442 non-compliant patients who took five or more medications for chronic illnesses to either receive or not receive telephone counseling. The objective was to investigate the influence of this advice for treatment compliance and patient mortality. The study verified that telephone counseling was associated with a 41% reduction of death risk after two years. These authors used scores to classify the levels of compliance of 1011 patients, and they showed that the lower the level of compliance, the higher the risk of mortality in the long term. The influence of the initial selection of antihypertensive medication in regards to compliance with treatment was evaluated by Monane et al.24 The authors verified that the use of newer antihypertensive agents, such as angiotensin converting enzyme inhibitors and calcium channel antagonists, was associated with a compliance ≥80% when compared with thiazide diuretics in patients with cardiac morbidities and multiple visits to physicians. This may have been the result of better tolerability to newer classes of antihypertensive agents. However, in our study, there was no difference in tolerability between the "traditional" and "current" groups, which could explain the similar compliance rates in both groups. On the other hand, just like in Monane et al.24 we found that fewer patients in the "complicated" group had their blood pressure under control in the final visit (67%), whereas in the next to last study visit, 90% of patients in the "uncomplicated" group and only 66% in the "complicated" group had blood pressure levels below 140/90 mmHg. This may be due to comorbidities and the use of other concurrent treatments. The groups: "complicated" and "uncomplicated"; "traditional" and "current"; "phone calls" and "no phone calls"showed significant reductions in blood pressure from the randomization visit to the final visit, as a high percentage of patients with good blood pressure control (BP <140/90 mmHg) in the total group (74%), regardless of an increase in body weight throughout the study. In our study, the high percentage patients with controlled blood pressure at the end of treatment can be explained by the simple drug regimen, the simple drug acquisition provided by the physician at no cost at the end of each visit, a fixed team of physicians and nurses throughout the study period and the easy access to team members in cases of unexpected occurrences by means of unscheduled visits. We observed that in the next-to-last study visit, the "uncomplicated", "current", "traditional", "phone calls" and "no phone calls" groups had more patients with controlled blood pressure when compared to the last visit. It is possible that during the last visit the patients were worried about continuing the treatment and receiving the medications. Therefore, guidance provided to patients by means of active telephone calls, brochures and group workshops with healthcare professionals is an efficient strategy for reducing treatment discontinuation, the most severe type of noncompliance with treatment.
BODY.DISCUSSION.PERSPECTIVES:
In an attempt to reduce non-adherence to antihypertensive treatment determinants in a developing country, we demonstrated that better blood pressure control was obtained through doctor's visits every two months with the same physician preceded by nursing staff visits with patients receiving all medication necessary for their treatment; this benefit was independent of comorbidities and the type of treatment used. Guidance provided to the patients through active telephone calls, brochures, group workshops with healthcare professionals and donation of all the required medications significantly reduced the treatment discontinuation rates.
BODY.DISCUSSION.SOURCES OF FUNDING:
This study received support from "Biosintetica Assistance" and Biosintética Laboratory, which donated all of the required medication. | 2,974,815 | {
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TITLE: How quick is soon? Early response to continuous positive airway pressure: a randomized controlled trial
ABSTRACT:
BODY.INTRODUCTION:
Numerous studies have confirmed that using non-invasive continuous positive airway pressure (nCPAP) for chronic obstructive pulmonary disease and congestive heart failure improves the respiratory rate, heart rate (HR), and work of breathing. We hypothesize that early application of nCPAP with concomitant medical therapy to patients with acute undifferentiated shortness of breath (SOB) will improve objective measures of respiratory distress. Specifically, early application of nCPAP can improve the tidal volume (TV), end-tidal carbon dioxide (EtCO2) and Rapid Shallow Breathing Index (RSBI), and reduce intubations over the standard of treatment alone in 15 minutes or less.
BODY.METHODS:
Fifty-two patients were randomized equally to either CPAP + standard of care (nCPAP group) or to standard of care (standard group) for acute undifferentiated SOB. nCPAP was applied for 15 minutes. Subject enrollment was randomized and demographic data were recorded upon enrollment. Volumetric measures were obtained by breathing through the EtCO2/Flow sensor for 30 seconds at 5-minute intervals along with vital signs. Inclusion criteria were adults >18 years, with acute respiratory distress, admitted to the resuscitation room of the emergency department, respiratory rate > 25 bpm, SpO2 > 75%, Glasgow Coma Score > 8, HR > 60/min, and systolic blood pressure > 90 mmHg. Exclusion criteria were respiratory arrest and/or cardiac arrest, suspected pulmonary embolism, pneumothorax, myocardial infarction, temperature >38.5°C, or refusal to participate.
BODY.RESULTS:
All tests were two-sided and assessed at the 0.05 type-I error rate. The gender distribution was equal for both groups. There was no difference in baseline characteristics except for age, HR and diastolic blood pressure (P < 0.05). Subjects in the nCPAP group had a greater improvement for various parameters compared with the standard group including TV (0.8 l, 0.3 l), EtCO2 (30 mmHg, 38 mmHg) and RSBI (39, 150), respectively. The nCPAP group also had a shorter hospital and ICU length of stay compared with the standard group (4 vs 5 days, and 2 vs 3 days, respectively). Finally, the rate of intubations was higher in the standard group (n = 8, n = 3) than the nCPAP group (P < 0.01).
BODY.CONCLUSION:
The early application of nCPAP in patients with acute undifferentiated SOB improves their volumetric parameters and vital signs in as early as 5 minutes. This pilot study provides objective support for the notion that early application of nCPAP can lead to measurable improvement in TV, EtCO2, RSBI and reductions in intubations. | 4,088,715 | {
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TITLE: The Effects of Vitamin D Supplementation on Signaling Pathway of Inflammation and Oxidative Stress in Diabetic Hemodialysis: A Randomized, Double-Blind, Placebo-Controlled Trial
ABSTRACT:
Objective: This study was carried out to determine the effects of vitamin D supplementation on signaling pathway of inflammation and oxidative stress in diabetic hemodialysis (HD) patients. Methods: This randomized double-blind placebo-controlled clinical trial was conducted among 60 diabetic HD patients. Subjects were randomly allocated into two groups to intake either vitamin D supplements at a dosage of 50,000 IU (n = 30) or placebo (n = 30) every 2 weeks for 12 weeks. Gene expression of inflammatory cytokines and biomarkers of oxidative stress were assessed in peripheral blood mononuclear cells (PBMCs) of diabetic HD patients with RT-PCR method. Results: Results of RT-PCR indicated that after the 12-week intervention, compared to the placebo, vitamin D supplementation downregulated gene expression of interleukin (IL)-1β (P = 0.02), tumor necrosis factor alpha (TNF-α) (P = 0.02) and interferon gamma (IFN-γ) (P = 0.03) in PBMCs of diabetic HD patients. Additionally, vitamin D supplementation, compared to the placebo, downregulated gene expression of transforming growth factor beta (TGF-β) (P = 0.04), protein kinase C (PKC) (P = 0.001), and mitogen-activated protein kinases 1 (MAPK1) (P = 0.02) in PBMCs of diabetic HD patients. Although not significant, vitamin D supplementation let to a reduction of nuclear factor kappa B (NF-kB) (p = 0.75) expression in PBMCs isolated from diabetic patients compared to the placebo group. There was no statistically significant change following supplementation with vitamin D on gene expression of interleukin (IL)-4, IL-6, and vascular endothelial growth factor (VEGF) in PBMCs of diabetic HD patients. Conclusions: Overall, we found that vitamin D supplementation for 12 weeks among diabetic HD patients had beneficial effects on few gene expression related to inflammation and oxidative stress. Clinical trial registration: IRCT201701035623N101. Registered on January 8, 2017.
BODY.INTRODUCTION:
Increased inflammatory cytokines as a necessary part of chronic kidney disease (CKD) has been identified and associated with cardiovascular disease (CVD), protein-energy malnutrition, all-cause mortality, and decreased glomerular filtration rate (GFR) (Stenvinkel et al., 1999; Akchurin and Kaskel, 2015). Increased biomarkers of inflammation, such as interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were negatively linked to the measures of kidney action and directly with albuminuria (Gupta et al., 2012). Furthermore, various factors, including increased oxygen metabolism, uremic toxicity, increased inflammatory factors, lack of antioxidant vitamins and microelements, and dialysis procedure in patients with CKD would result in oxidative stress (Stepniewska et al., 2015). Prior studies have documented that hypovitaminosis D is very prevalent in individuals with CKD (de Boer, 2008; Cupisti et al., 2015). In a study by Bhan et al. (2010) hypovitaminosis D was reported 50–90% in dialysis subjects. On the other hand, beneficial effects of vitamin D on biochemical variables have reported in hemodialysis (HD) patients (Ibrahim et al., 2015), subjects with type 2 diabetes mellitus (T2DM) (Calvo-Romero and Ramiro-Lozano, 2016) and polycystic ovary syndrome (Maktabi et al., 2017). Few studies have evaluated the effects of vitamin D on gene expression related to inflammation and oxidative stress. Choi et al. (2013) shown significant reductions in gene expression of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in vitamin D-treated rats. In addition, in vitro studies have shown that the release of TNF-α can be inhibited by calcitriol in a dose-dependent fashion (Müller et al., 1992). Another study indicated that vitamin D through vitamin D receptor (VDR) suppressed TNF-α-induced nuclear factor kappa B (NF-κB) activation and IL-6 up-regulation in epithelial cell isolated from transgenic mice and colitis animal model (Liu et al., 2013). However, another study supported no significant changes in TNF-α and IL-6 levels in high-dose vitamin D administration in healthy overweight individuals following a 12-week progressive resistance exercise training program (Carrillo et al., 2012). The molecular mechanism of vitamin D in modulating inflammatory cytokines and oxidative stress are still unclear. Mitogen-activated protein kinases (MAPKs) participate in signaling mechanisms in responses to pro-inflammatory factors as well as NF-κB are thought to play an important function in the regulation of pro-inflammatory cytokines in cellular responses (Baldassare et al., 1999). To our knowledge, data on the effects of vitamin D supplementation on signaling pathway of inflammation and oxidative stress in diabetic HD patients are limited and controversial. The purpose of this study was, therefore, conducted to evaluate the effects of vitamin D supplementation on signaling pathway of inflammation and oxidative stress in diabetic HD patients.
BODY.METHODS.TRIAL DESIGN AND PARTICIPANTS:
This randomized double-blind placebo-controlled clinical trial, registered in the Iranian website for registration of clinical trials as http://www.irct.ir:IRCT201701035623N101, was carried out among 60 diabetic HD subjects aged 18-80 years who were referred to the Akhavan Clinic in Kashan, Iran, from January 2017 to April 2017. This research was carried out in accordance with the Declaration of Helsinki and the Research Ethics Committee of Kashan University of Medical Sciences (KAUMS) approved the study protocol, and informed consent was taken from all subjects. The main exclusion criteria from the study were as follows: taking vitamin D, antioxidant and/or anti-inflammatory supplements such as vitamins E and C, omega-3 fatty acids, and taking immunosuppressive medications within 3 months prior to the enrollment in the study.
BODY.METHODS.STUDY DESIGN:
At first, all patients were randomized into two groups to receive either 50,000 IU of vitamin D or placebo (n = 30 in each group) every 2 weeks for 12 weeks. Vitamin D supplements and placebos were produced by Zahravi Pharmaceutical Company, Tabriz, Iran, and Barij Essence Pharmaceutical Company, Kashan, Iran, respectively. In the current study, we used the above-mentioned dose of vitamin D based on the tolerable upper intake level (4,000 IU/day) of vitamin D (Ross et al., 2011), as well as dosage recommended in previous studies among HD patients (Armas et al., 2013; Mose et al., 2014). Compliance to the vitamin D consumption was evaluated through determination of serum 25 (OH) vitamin D values and asking subjects to return the medication containers. Both dietary 3-day food records [analyzed by nutritionist IV software (First Databank, San Bruno, CA)] and physical activity records were taken at baseline, weeks 3, 6, 9, and 12 of the intervention.
BODY.METHODS.ASSESSMENT OF ANTHROPOMETRIC MEASURES:
Body weight and height were quantified in a fasting status using a digital scale (Seca, Hamburg, Germany) at baseline and after the 12-week intervention. Body mass index (BMI) was calculated by weight and height measurements [weight (kg)/height (m2)].
BODY.METHODS.ASSESSMENT OF OUTCOMES:
Primary outcomes were inflammatory cytokines expression and secondary outcomes were biomarkers of oxidative stress expression. We selected the following inflammatory cytokines and proteins [IL-1β, IL-4, IL-6,TNF-α, interferon gamma (IFN-γ), transforming growth factor beta (TGF-β), protein kinase C (PKC), MAPK1, vascular endothelial growth factor (VEGF) and NF-κB] as they play a very important role in signaling pathways of oxidative stress (Geraldes and King, 2010; Baker et al., 2011; Tanti et al., 2012; Chen et al., 2015).
BODY.METHODS.ISOLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS):
At baseline and endpoint of the intervention, 15 mL samples of fasting blood were taken at reference laboratory of KAUMS, Kashan, Iran. PBMCs were isolated from blood by centrifugation through a Ficoll-Hypaque (Denholm and Wolber, 1991) followed by Percoll. In summary, 10 mL of blood with an equal volume of phosphate-buffered saline (PBS) was mixed (Dagur and McCoy, 2015). Layer diluted blood over Ficoll-Hypaque solution, using 3 parts diluted blood to 2 parts Ficoll-Hypaque and centrifuged 30 min at 500 × g, 25°C. Then, using a sterile Pasteur pipet, carefully collected PBMCs, and located at the interface between the plasma (upper layer) and Ficoll-Hypaque solution (Dagur and McCoy, 2015). Cells to a 50 mL centrifuge tube were transferred, then after adding 10 mL PBS, were centrifuged 10 min at 400 × g, 4°C. The supernatant was discarded and was resuspended cells in 4 mL PBS. Following previous step, 1.65 mL of 10× Hanks balanced salt solution with 10 mL Percoll was mixed. Eight mL Percoll solution with 4 mL mononuclear cells in a silanized 10 × 1.5 cm round-bottom polypropylene tube was mixed (Dagur and McCoy, 2015). Mixing thoroughly by inverting tube three or four times was done. Then, 25 min at 370 × g, 25°C was centrifuged. PBMCs were aspirated by gentle pipetting into a clean test tube. After centrifugation, monocytes appear as a cloudy layer in the top 5 mm of the gradient (Dagur and McCoy, 2015).
BODY.METHODS.RNA EXTRACTION AND REAL-TIME PCR:
To RNA extraction, we used the RNX-plus kit (Cinnacolon, Tehran, Iran). RNA were extracted just after lymphocyte extraction from fresh 5 mL peripheral blood and less than 1 million cells was used for RNA extraction with the trizol reagent (Invitrogen, USA). Following extraction of the total RNAs from each sample, RNA quantification were performed by UV spectrophotometer. Each samples OD 260/280 ratio between 1.7 and 2.1 was intended showing no contamination with both protein and DNA (Dunkley et al., 2008). The isolated RNA was reverse transcribed to cDNA library using moloney murine leukemia virus reverse transcriptase. Gene expression of IL-1β, IL-4, IL-6,TNF-α, IFN-γ, TGF-β, PKC, MAPK1, VEGF, and NF-κB were evaluated by quantitative RT-PCR, using the LightCycler technology (Roche Diagnostics, Rotkreuz, Switzerland) with SYBR green detection and Amplicon Kit (Table 1). Glyceraldehyde-3-phosphate dehydrogenase primers were used as housekeeping gene. To design primers, Primer Express Software (Applied Biosystems, Foster City) and Beacon designer software (Takaposizt, Tehran, Iran) were used. Relative transcription levels were calculated by the method of Pffafi or 2−ΔΔCT. In the current study, we quantified gene expression levels related to inflammation and oxidative stress in PBMCs from diabetic HD patients. PBMCs from venous blood samples are the most available tissue for analysis of gene expression (Mizuarai et al., 2010). In addition, gene expression levels related to inflammation and oxidative stress in PBMCs are more accurate and may provide more valuable information than plasma concentrations (Mizuarai et al., 2010). Few studies have previously assessed gene expression levels of inflammation and oxidative stress in PBMCs from diabetic patients (Xavier et al., 2015; Mazloom et al., 2016). Table 1 Specific primers used for real-time quantitative PCR. Gene Primer Product size (bp) Annealing temperature (C) GAPDH F: GAGTCAACGGATTTGGTCGT 223 58 R: TTGATTTTGGAGGGATCTCG IL1-β F: GATGGCTTATTACAGTGGCAATG 137 59 R: AGTGGTGGTCGGAGATTCG IL-4 F: CTCACAGAGCAGAAGAACAC 221 60 R: TGGTTGGCTTCCTTCACAG IL-6 F: GTAGTGAGGAACAAGCCAGAG 286 60 R: TGACCAGAAGAAGGAATGCC TNF-α F: GAGCCAGCTCCCTCTATTTATG 187 60 R: CTACATGGGAACAGCCTATTGT IFN-γ F: GGTTCTCTTGGCTGTTACTG 250 59.5 R: TGTCTTCCTTGATGGTCTCC VEGF F: TGCAGATTATGCGGATCAAACC 150 58.5 R:TGCATTCACATTTGTTGTGCTGTAG NFK-β F: GCTGAGTCCTGCTCCTTC 202 58 R: GTCTATTTGCTGCCTTGTGG TGF-β F: ACTACTACGCCAAGGAGGTC 250 59 R: CGGTTGCTGAGGTATCGC PKC F: CGTCCTCATTGTCCTCGTAAG 249 59 R: TCATTCCTGCTGGTCAAATCC MAPK1 F: GGAACAGCACCTCCACTATTT 226 60 R: GCCACAATGTCTGCGTATCT GAPDH, glyceraldehyde-3-Phosphate dehydrogenase; IL-1β, interleukin-1β; IFN-γ, interferon gamma; MAPK1, mitogen-activated protein kinases 1; NF-κB, nuclear factor kappa B; PBMCs, peripheral blood mononuclear cells; PKC, protein kinase C; TNF-α, tumor necrosis factor alpha; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor .
BODY.METHODS.RANDOMIZATION:
Randomization assignment was carried out using computer-generated random numbers. Randomization and allocation concealment were conducted by the researchers and participants and were carried out by a trained staff at the clinic.
BODY.METHODS.STATISTICAL METHODS:
The Kolmogorov-Smirnov test was applied to control the normal distribution of variables. Independent sample t-test was used to establish changes in anthropometric measures and dietary intakes between the two groups. To determine the effects of vitamin D administration on inflammation and oxidative stress expression, we used independent sample t-test. P < 0.05 were considered statistically significant. All statistical analyses conducted using the Statistical Package for Social Science version 18 (SPSS Inc., Chicago, Illinois, USA).
BODY.RESULTS:
Sixty diabetic HD patients [vitamin D and placebo (n = 30 each group)] completed the trial (Figure 1). On average, the rate of compliance in our study was high, such that more than 100% of capsules were taken throughout the study in both groups. No side effects were reported following supplementation of vitamin D in diabetic HD patients throughout the study. Potential side effects of vitamin D supplementation monitored by evaluating the serum levels of calcium every month, as well as, monitoring clinical symptoms among participants including, anorexia, nausea, and vomiting. Figure 1Summary of patient flow diagram. Distribution of gender, participants' mean age, height, baseline weight and BMI as well as their change, and years of dialysis of study participants were not statistically different between the two groups (Table 2). Table 2 General characteristics of study participants. Placebo group ( n = 30) Vitamin D group ( n = 30) P a GENDER (%) Male 20 (66.7) 19 (63.4) 0.78 † Female 10 (33.3) 11 (36.6) TYPE OF DIABETES (%) Type 1 2 (6.7) 2 (6.7) 1.00 † Type 2 28 (93.3) 28 (93.3) Smoking (%) 3 (10.0) 3 (10.0) 1.00 † Duration of DM (year) 18.9 ± 6.0 19.1 ± 5.4 0.87 Insulin therapy (%) 30 (100.0) 30 (100.0) 1.00 † Age (y) 60.7 ± 14.3 57.1 ± 13.4 0.31 Height (cm) 162.5 ± 8.0 163.5 ± 8.1 0.65 Weight at study baseline (kg) 71.2 ± 15.7 69.5 ± 11.8 0.65 Weight at end-of-trial (kg) 71.2 ± 15.7 70.1 ± 11.9 0.75 Weight change (kg) 0.008 ± 1.3 0.5 ± 1.3 0.12 BMI at study baseline (kg/m 2 ) 27.0 ± 6.0 26.1 ± 4.5 0.51 BMI at end-of-trial (kg/m 2 ) 27.0 ± 5.9 26.3 ± 4.5 0.61 BMI change (kg/m 2 ) 0.002 ± 0.5 0.2 ± 0.5 0.11 Years on dialysis 3.7 ± 1.0 3.9 ± 1.2 0.56 Cancer (%) 2 (6.7) 2 (6.7) 1.00 † CAD (%) 22 (73.3) 21 (70.0) 0.77 † CVD (%) 5 (16.7) 6 (20.0) 0.73 † Hypertension (%) 28 (93.3) 29 (96.7) 0.55 † Data are means ± SDs . a Obtained from independent t-test . † Obtained from Pearson Chi-square test . CAD, coronary artery disease; CVD, cerebrovascular disease; DM, diabetes mellitus . Considering the 3-day dietary records obtained during the intervention, there was no significant difference in terms of dietary macro- and micro-nutrient intakes between vitamin D and placebo groups (Data not shown). After 12 weeks of intervention, compared to the placebo, vitamin D supplementation significantly increased serum 25-OH-vitamin D (+11.1 ± 4.2 vs. +0.5 ± 3.9 ng/mL, P < 0.001). Results of RT-PCR indicated that compared to the placebo, vitamin D supplementation downregulated gene expression of IL-1β (P = 0.02), TNF-α (P = 0.02), and IFN-γ (P = 0.03) in PBMCs of diabetic HD patients (Figure 2). There was no statistically significant change following supplementation with vitamin D on gene expression of IL-4 and IL-6 in PBMCs of diabetic HD patients. Figure 2Effect of 12-week supplementation with vitamin D or placebo on expression ratio of TNF-α, IFN-γ, IL-1β, IL-4, and IL-6 genes in PBMCs of diabetic HD subjects. P-value was obtained from independent sample t-test. Data are means ± standard deviation. Additionally, vitamin D supplementation, compared to the placebo, downregulated gene expression of TGF-β (P = 0.04), PKC (P = 0.001), and MAPK1 (P = 0.02) in PBMCs of diabetic HD patients (Figure 3). Although not significant, vitamin D supplementation let to a reduction of NF-kB (p = 0.75) expression in PBMCs isolated from diabetic patients compared to the placebo group. We did not observe any significant change following supplementation with vitamin D on gene expression of VEGF in PBMCs of diabetic HD patients. Figure 3Effect of 12-week supplementation with vitamin D or placebo on expression ratio of PKC, MAPK1, TGF-β, NF-κB, and VEGF genes in PBMCs of diabetic HD subjects. P-value was obtained from independent sample t-test. Data are means ± standard deviation.
BODY.DISCUSSION:
We found that vitamin D supplementation for 12 weeks among diabetic HD patients had beneficial effects on few gene expression related to inflammation and oxidative stress. To our knowledge, this is the first report of the effects of vitamin D supplementation on gene expression related to inflammation and oxidative stress in diabetic HD patients. HD subjects are susceptible to several metabolic complications, including increased inflammation and oxidative stress (Kotur-Stevuljevic et al., 2012). Our data demonstrated that vitamin D supplementation for 12 weeks to diabetic HD subjects downregulated gene expression of IL-1β, TNF-α, and IFN-γ compared to the placebo, but did not affect gene expression of IL-4 and IL-6. A study in healthy endurance-trained runners has demonstrated the inverse relationship between vitamin D and TNF-α levels (Willis et al., 2012). Furthermore, in line with our findings, 50 mug/day of vitamin D supplementation for 9 months was able to suppress the production of TNF-α in subjects with congestive heart failure (Schleithoff et al., 2006). 1,25-(OH)2D3 dose-dependently also suppressed the production of IL-α, IL-6, and TNF-α by Escherichia coli lipopolysaccharide-stimulated monocytes (Müller et al., 1992). However, one study has documented no significant changes in TNF-α and IL-6 concentrations in high-dose vitamin D supplementation-healthy overweight populations after 12 weeks (Carrillo et al., 2012). Chronic inflammation in CKD is not only associated with macro- and micro-cardiovascular outcomes, such as atherosclerosis, but is also one of the main players in the progress of malnutrition/protein-energy wasting, which in turn resulted in the description of the malnutrition-inflammation-cachexia syndrome in CKD/ESRD patients (Kalantar-Zadeh, 2005). Hypoalbuminemia result from chronic inflammation and malnutrition is strongly related to mortality in dialysis populations (Kalantar-Zadeh et al., 2005; de Mutsert et al., 2009). Pro-inflammatory factors may directly lead to anorexia via the effect on the brain. Furthermore, inflammatory cytokines, particularly IL-6, may be related to depression in CKD/ESRD patients, which by itself is a predictor of morbidity and mortality (Taraz et al., 2015) and may result in decreasing nutrient intake. Therefore, vitamin D due to its useful effects on inflammatory cytokines may be benefit to decrease clinical and metabolic symptoms in diabetic HD patients. This study demonstrated that vitamin D supplementation for 12 weeks downregulated gene expression of TGF-β, PKC, and MAPK1 in PBMCs of diabetic HD patients, but did not influence gene expression of VEGF and NF-Kβ. Supporting our study, vitamin D administration at a dosage of 50,000 IU/week for 8 weeks in VD-deficient subjects with PCOS significantly decreased the bioavailability of TGF-β1 (Irani et al., 2015). In addition, 1,25-(OH)2D3 decreased gene expression of MAPK phosphorylation in macrophages (Xu et al., 2016). In another study, vitamin D protected human endothelial cells from ionizing radiation induced/oxidative stress by modulating the MAPKs/SirT1 axis (Marampon et al., 2016). Doxercalciferol also significantly decreased PKCα levels suggesting that PKC-mediated cardiac hypertrophy may be related to vitamin D deficiency (Choi et al., 2011). Excessive evidence exists suggesting that MAPK signaling pathways are critical for the synthesis and amplification of inflammatory factors (Carter et al., 1999). Especially, MAPK activation was closely associated with cytokine transcription and translation, which in turn make the target of anti-inflammatory treatment (Kaminska, 2005). However, calcitriol treatment had no significant effect on gene expression of TGF-β in microcardiovascular endothelial cells (Gonzalez-Curiel et al., 2016). In addition, both the low (1 nM) and the high (100 nM) doses of vitamin D3 used in vitro for 48 h did not able to restore the decreased gene expression of PKC isoenzymes in the T cells of systemic lupus erythematosus subjects (Czifra et al., 2014). Oxidative stress in patients with CKD may generate by uremic toxicity, persistent inflammatory state, deficiency of vitamins and microelements, and dialysis procedure itself (Stepniewska et al., 2015). Increased biomarkers of oxidative stress and free radicals in HD subjects are correlated with increased CVD risk and a large number of diseases related to uremia (Taccone-Gallucci et al., 2010).
BODY.CONCLUSIONS:
Overall, we found that vitamin D supplementation for 12 weeks among diabetic HD patients had beneficial effects on some gene expression related to inflammation and oxidative stress. This suggests that vitamin D supplementation may confer advantageous therapeutic potential for HD patients. Further research is needed in other participants and for longer periods to determine the efficacy of vitamin D supplementation.
BODY.LIMITATIONS:
The limitations of our findings include short duration. Long-term interventions might result in better effects in other gene expression related to inflammation and oxidative stress. In addition, due to funding limitations in developing countries, we did not evaluate some gene expression related to insulin and lipid, and reactive oxygen species levels. Further investigations are required to evaluate this outcome. We did not know baseline levels of vitamin D among our participants, therefore, we were not able to comment on their commended dosage of vitamin D by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. This limitation should be considered in the interpretation of our findings.
BODY.AVAILABILITY OF DATA AND MATERIALS:
The primary data for this study is available from the authors on direct request.
BODY.AUTHOR CONTRIBUTIONS:
ZA contributed in conception, data collection and manuscript drafting; HH, ES, HN, AS, MS, FK, and MT contributed in conception, data collection and manuscript drafting; All authors read and approved the final version of the paper.
BODY.AUTHOR CONTRIBUTIONS.CONFLICT OF INTEREST STATEMENT:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 5,801,479 | {
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TITLE: Belatacept-Based Immunosuppression in
ABSTRACT:
This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.
BODY.INTRODUCTION:
Liver transplantation is a life-saving procedure for patients with end-stage liver disease (ESLD) that improves overall survival and quality of life (1,2). Liver transplant (LT) recipients are at increased risk for cardiovascular disease, and chronic kidney disease (CKD; (3–7)). Stage 4 or 5 CKD has been reported in ∼18% of LT recipients by 5 years posttransplant (4) and is associated with increased morbidity and mortality (4–7). Data from 1997 to 2008 in the Organ Procurement Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database showed a threefold increased rate of kidney transplantation in patients who previously received LT (8). While the causes of CKD in LT patients are multifactorial, including pretransplant and peritransplant factors like hepatitis C virus (HCV), diabetes and hepatorenal syndrome, calcineurin inhibitors (CNIs) appear to be significant contributing factors (4,7,9–11). In the OPTN/UNOS analysis, ∼50% of LT patients who received a kidney transplant had a diagnosis consistent with CNI toxicity (8). Thus, there is a need for immunosuppressive regimens that provide efficacy while avoiding the nephrotoxic, cardiovascular and metabolic risks of CNIs in LT recipients. Belatacept, a selective costimulation blocker (12), is designed to provide effective immunosuppression and avoid both renal and nonrenal toxicities associated with CNIs. Results from two phase III clinical trials in kidney transplant recipients found that belatacept-based immunosuppression was associated with similar rates of patient and graft survival, significantly better renal function and an improved cardiovascular/metabolic risk profile versus cyclosporine-based therapy ≤3 years after transplantation (13–17). Higher rates and grades of acute rejection (AR) were observed in belatacept-treated patients receiving standard-criteria donor kidneys (13,15). Posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement, primarily in patients seronegative for Epstein–Barr virus (EBV) at the time of transplant and progressive multifocal leukoencephalopathy (PML) were the most serious adverse events (AEs) reported in belatacept-treated patients (13,14,18). The objective of this exploratory, phase II study was to evaluate the efficacy and safety of belatacept in adult recipients of first LTs from a deceased donor. To identify an optimal immunosuppressive regimen in LT recipients, three belatacept regimens were studied and compared with two tacrolimus regimens. In addition, a follow-up long-term extension (LTE) study (i.e. ≥12 months) was conducted to assess longer-term safety and tolerability. The LTE study was terminated in 2011 (when patients were ∼2 years posttransplant) because of worse patient and graft survival in two of the three belatacept treatment groups. Both the 12-month results and those from the LTE are reported herein.
BODY.MATERIALS AND METHODS.STUDY DESIGN:
This was a randomized, partially blinded, active-controlled, parallel group, multicenter, phase II clinical trial in adult recipients of first LTs (ClinicalTrials.gov: NCT00555321). Three belatacept regimens were studied, representing a stepwise decrease in the level of overall immunosuppression, and compared with the approved immunosuppressive regimen (tacrolimus alone) and the most widely used immunosuppressive regimen (tacrolimus + mycophenolate mofetil [MMF]) in LT. This exploratory study intended to assess the comparability of a belatacept-based regimen with a tacrolimus-based regimen in terms of AR, graft loss and death. Immediately before transplantation, patients were randomized to one of the following treatment groups: (i) basiliximab + belatacept high dose (HD) + MMF; (ii) belatacept HD + MMF; (iii) belatacept low dose (LD) + MMF; (iv) tacrolimus + MMF or (v) tacrolimus alone. Subjects were randomized in a 1:1:1:1:1 ratio using an interactive voice response system with centralized randomization and stratified by HCV status (yes or no) in blocks of five. All patients received corticosteroid therapy for the first 3 months. The trial was fully blinded to patients and study personnel with respect to belatacept dosing regimen (HD or LD) and basiliximab assignment (through the use of placebo infusions), open-label to belatacept or tacrolimus treatment and open-label between the two tacrolimus groups. The study duration was 12 months with an LTE (study was initiated January 22, 2008 and completed May 2, 2011). An external Data Monitoring Committee (DMC) comprising a chair and four members (specialty physicians and one statistician) reviewed emerging safety and efficacy data on a regular basis. The study was conducted in accordance with the Declaration of Helsinki and was consistent with International Conference on Harmonisation Good Clinical Practice and applicable regulatory requirements. The study protocol and amendments were reviewed and approved by the institutional review board/independent ethics committee for each site before initiation of the study (see Table S1 for enrollment by site).
BODY.MATERIALS AND METHODS.PATIENTS AND INTERVENTIONS:
The study population included adults of 18–70 years of age, who were recipients of first LTs from a deceased donor (see Table 1 for additional inclusion and exclusion criteria). Belatacept was administered via intravenous (IV) infusion. Table 1 Study inclusion and exclusion criteria Inclusion criteria Exclusion criteria Adults of 18–70 years of age, who were recipients of first LTs from a deceased donor Donation after cardiac death Informed consent from all patients Living-donor recipients Additional inclusion criteria Split liver recipients Reliable IV access Recipients of organs ABO compatible donor-recipient pairs From donors <12 years or >65 years of age Patients with hepatocellular carcinoma meeting Milan criteria (one nodule ≤5 cm in diameter or three or fewer nodules, with none >3 cm in diameter) With anticipated cold ischemia time >14 h From donors who were positive for HBV or HCV when recipients were negative for HBV or HCV, respectively From donors with known human immunodeficiency virus infection Patients receiving dialysis before LT for ≥2 consecutive weeks before enrollment or who were anticipated to have prolonged dialysis posttransplant Patients with known intrinsic kidney disease (e.g. a urine protein/creatinine ratio >150 mg/g or presence of an abnormal number of red blood cells or granular casts in urine) AND a calculated GFR (cGFR) <40 mL/min/1.73 m 2 body surface area (modified MDRD) within 1 month of enrollment Patients with acute liver failure, hypercoagulable state or malignancy within the previous 5 years (except for nonmelanoma skin cancer cured by local resection or hepatocellular carcinoma as defined above) Patients who were seronegative for Epstein–Barr virus (subsequent study amendment) HBV, hepatitis B virus; HCV, hepatitis C virus; IV, intravenous; LT, liver transplant.
BODY.MATERIALS AND METHODS.PATIENTS AND INTERVENTIONS.HD REGIMENS (GROUPS 1 AND 2):
Belatacept 10 mg/kg was given on days 1 (day of transplant), 3 and 5, and weeks 2, 4, 6, 8, 10, 12, 16, 20 and 24 for the first 6 months and then 5 mg/kg every 4 weeks from months 7–12.
BODY.MATERIALS AND METHODS.PATIENTS AND INTERVENTIONS.LD REGIMEN (GROUP 3):
Belatacept 10 mg/kg was given on days 1, 3 and 5, and weeks 2, 4, 8 and 12 for the first 3 months and then 5 mg/kg every 4 weeks from months 3–12. The belatacept doses in the present study were different from those studied in renal transplant recipients in that an additional belatacept dose was administered on day 3 in all belatacept treatment groups, and one additional dose was allowed for excessive bleeding (>3L) or ascites loss (>4L) during the first 2 weeks following LT. Eight patients in the basiliximab + belatacept HD + MMF group, 9 patients in the belatacept HD + MMF group and 10 patients in the belatacept LD + MMF group received an additional dose of belatacept for bleeding or ascites. Tacrolimus (groups 4 and 5) was administered orally at an initial dose of 0.10–0.15 mg/kg/day after transplantation; doses were adjusted to achieve target trough concentrations between 6 and 12 ng/mL. Basiliximab induction (20 mg IV) was given to patients in group 1 only (belatacept HD regimen) on days 1 and 5. Patients in groups 1 through 4 received MMF at 2 g/day orally, which was later amended to 1 g/day after a case of PML was reported in a patient receiving belatacept HD + MMF. At that time, all but two had received ≥6 months of study treatment. All patients received tapered corticosteroids (Figure 1). Figure 1Patient disposition and dosing. All patients received corticosteroids on days 1–5, which was tapered to ≤10 mg/day by day 30 and ≤5 mg/day by day 90. Thereafter, withdrawal of corticosteroids was at the discretion of the investigator. HD, high dose; LD, low dose; MMF, mycophenolate mofetil. All patients received antiviral prophylaxis for cytomegalovirus (CMV) and herpes simplex virus for ≥3 months posttransplant and for 3 months upon administration of T cell–depleting agents. Additionally, all patients were to receive a 6-month course of prophylaxis for Pneumocystis jiroveci pneumonia.
BODY.MATERIALS AND METHODS.OUTCOMES:
The primary end point was the composite incidence of AR, graft loss and death at 6 months after transplantation. AR was included in the composite end point if it was clinically suspected and proven via biopsy. All biopsies for suspected AR were assessed by a central histopathologist blinded to treatment assignment using the Banff schema for grading of LT rejection and rejection activity index for staging (19). Graft loss was defined as impairment of liver function that resulted in patient death or re-transplantation. Secondary end points included the incidence, severity, treatment and outcome of AR by 12 months; graft loss and death by 12 months; change in renal function over time as determined by measured GFR (mGFR) and calculated GFR (cGFR; MDRD methodology); incidence of HCV recurrence by 12 months, defined as histologic confirmation on liver biopsy scored by the Ishak (modified Knodell) system, a score of ≥5 of 18 on modified histological activity index grading, and a fibrosis score of ≥2 of 6 (20). Incidence rates of cardiovascular and metabolic comorbidities (i.e. posttransplant diabetes mellitus, dyslipidemia and hypertension) and the overall safety of the belatacept-based regimens were also evaluated. Liver allograft biopsies (confirmed by a central pathology laboratory) were obtained at baseline and at 12 months to assess histology. Biopsies were also performed in patients who met protocol-specified criteria for clinical suspicion of AR or HCV recurrence.
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSES:
A statistical analysis plan was prepared prior to unblinding this study. The purpose of the study was to provide initial clinical experience regarding the efficacy and safety of belatacept in LT recipients and identify a belatacept-based regimen with an acceptable composite rate of AR, graft loss and death. Therefore, statistical testing was not prespecified and the study was not powered to demonstrate a difference between treatment groups. A calculated sample size of 50 patients per treatment group was determined to provide initial data regarding safety and efficacy. If the observed primary end point (composite incidence of AR, graft loss and death by 6 months) for a belatacept-based group was 40%, it was estimated that the two-sided 95% confidence interval (CI) of this incidence would extend from 26.4% to 53.6%, which would be within the general range observed in large LT studies that used CNI-based immunosuppression (21,22). Analyses were performed on the intent-to-treat population (i.e. those who were randomized and received a transplant). Most analyses were descriptive in nature, using point estimates and 95% CIs. mGFR was assessed via iothalamate at months 2 (baseline) and 12. cGFR was assessed pretransplant and at 1, 2, 3, 6 and 12 months.
BODY.RESULTS:
A total of 260 patients at 39 centers worldwide were randomized, of whom 250 received a transplant and were treated. A total of 164 patients completed 12 months of treatment (Figure 1). Demographic and baseline characteristics were generally similar across treatment groups (Table 2). The mean age was 54 years, and 46% of patients were HCV-positive. The primary reasons for discontinuing treatment, as defined by the study investigators, were AEs and lack of efficacy in the belatacept groups and AEs in the tacrolimus groups. Table 2 Demographic characteristics of recipients by treatment group Characteristic Basiliximab + belatacept HD + MMF Belatacept HD + MMF Belatacept LD + MMF Tac + MMF Tac (n = 50) (n = 48) (n = 49) (n = 53) (n = 50) Mean age, years 54.0 53.4 55.2 53.0 54.7 Sex, male, % 78 71 63 87 84 Race, % White 88 83 94 93 86 Black 8 6 2 6 4 Cause of ESLD, % Noncholestatic cirrhosis 76 69 67 74 82 HCV-positive, % 46 48 43 47 48 Mean MELD score 22.6 21.1 20.6 24.3 21.6 Hepatorenal syndrome, % 10 10 10 13 6 ESLD, end-stage liver disease; HCV, hepatitis C virus; HD, high dose, LD, low dose; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; Tac, tacrolimus. An imbalance in the frequency of deaths and graft losses in the belatacept LD group early in the study was noted by the DMC. Based on the DMC recommendation, randomization to the belatacept LD group was stopped. Study enrollment, however, was nearly complete (247/250 patients), and patients were permitted to remain on the belatacept LD regimen at the discretion of the investigator. Randomization into the other four treatment groups continued.
BODY.RESULTS.OUTCOMES: COMPOSITE END POINT, DEATH, GRAFT LOSS AND AR.COMPOSITE END POINT:
At the time of the primary analysis at month 6, the incidence rates of the composite end point were higher in the belatacept groups (42–48%) than in the tacrolimus groups (15–38%) (Table 3). This difference was primarily driven by a higher number of AR episodes in the belatacept groups than in the tacrolimus groups. At month 12, patient and graft survival were highest in the tacrolimus + MMF group and lowest in the belatacept LD group. The proportion of patients surviving with a functioning graft was 90%, 83% and 67% in the basiliximab + belatacept HD, belatacept HD, and belatacept LD groups, respectively, and 93% and 88% in the tacrolimus + MMF and tacrolimus groups, respectively. Table 3 Outcomes: composite end point (death, graft loss and AR) by 6 months (primary end point) and 12 months and AR up to month 12 Composite end point Basiliximab + belatacept HD + MMF Belatacept HD + MMF Belatacept LD + MMF Tac + MMF Tac (n = 50) (n = 50) (n = 48) (n = 49) (n = 53) 6 months (primary end point), n (%) 24 (48.0) 20 (41.7) 23 (46.9) 8 (15.1) 19 (38.0) Difference from Tac + MMF, % (95% CI) 32.9 (16.1–49.8) 26.6 (9.6–43.5) 31.8 (14.8–48.5) — — Difference from Tac, % (95% CI) 10.0 (−8.7–29.6) 3.7 (−15.3–23.2) 8.9 (−9.8–28.4) — — AR, n 20 15 15 5 15 Death, n 4 4 6 1 3 Graft loss, n 2 2 6 4 3 Survival with a functioning graft, n (%) 45 (90.0) 43 (89.6) 38 (77.6) 49 (92.5) 45 (90.0) (95% CI) (81.7–98.3) (80.9–98.2) (65.9–89.2) (85.3–99.6) (81.7–98.3) 12 months, n (%) 26 (52.0) 23 (47.9) 26 (53.1) 10 (18.9) 20 (40.0) AR, n 22 16 16 7 15 Death, n 4 7 10 1 4 Graft loss, n 2 2 8 4 4 Survival with a functioning graft, n (%) 45 (90.0) 40 (83.3) 33 (67.3) 49 (92.5) 44 (88.0) (95% CI) (81.7–98.3) (72.8–93.9) (54.2–80.5) (85.3–99.6) (79.0–97.0) AR (centrally read) up to month 12, n (%) Patients with AR 22 (44.0) 16 (33.3) 16 (32.7) 7 (13.2) 15 (30.0) Treated, n/N (%) 12/22 (54.5) 12/16 (75.0) 8/16 (50.0) 5/7 (71.4) 12/15 (80.0) Corticosteroids only, n (%) 12 (24.0) 7 (14.6) 8 (16.3) 4 (7.5) 10 (20.0) Initial lymphocyte-depleting therapy, n (%) 0 (0) 3 (14.6) 0 (0) 0 (0) 0 (0) Grade of AR, n (%) I 15 (30.0) 7 (14.6) 7 (14.3) 6 (11.3) 7 (14.0) II 7 (14.0) 8 (16.7) 8 (16.3) 1 (1.9) 6 (12.0) III 0 (0) 1 (2.1) 1 (2.0) 0 (0) 2 (4.0) Death or graft loss in patients with AR, n 1 1 6 1 1 AR, acute rejection; CI, confidence interval; HD, high dose, LD, low dose; MMF, mycophenolate mofetil; Tac, tacrolimus.
BODY.RESULTS.OUTCOMES: COMPOSITE END POINT, DEATH, GRAFT LOSS AND AR.DEATH:
At the 6-month primary analysis, a higher number of deaths was observed in patients treated with belatacept (basiliximab + belatacept HD [n = 4], belatacept HD [n = 4], belatacept LD [n = 6]) than in those treated with tacrolimus (tacrolimus + MMF [n = 1], tacrolimus [n = 3]). A similar pattern was also observed at 12 months posttransplant (Table 3). The causes of death reported in more than one patient included multisystem organ failure (n = 7), sepsis (n = 7), gastrointestinal bleeding (n = 2) and myocardial infarction (n = 2). In two cases, the cause of death was unknown (Table 4). Table 4 Causes of death Treatment group Age/sex Reported cause of death Study day Basiliximab + belatacept HD + MMF 57/M Sepsis 18 61/M Myocardial infarction 23 49/M Multiple system organ failure 25 56/M Sepsis 127 Belatacept HD + MMF 43/M Sepsis 24 37/M Sepsis 84 62/F Multiple system organ failure 111 47/M Gastrointestinal bleed 147 62/F Unknown 274 58/M Unknown 278 51/M PML 322 Belatacept LD + MMF 65/M Multiple system organ failure 2 59/F Colon perforation 8 48/M Acute hepatic failure 16 63/F Pulmonary failure 21 53/M Sepsis 65 50/M Gunshot injury 117 58/F Multiple system organ failure 202 55/M Multiple system organ failure 208 65/F Multiple system organ failure 339 51/M PTLD 364 Tacrolimus + MMF 54/M Sepsis 168 Tacrolimus 49/M Myocardial infraction 34 52/M Multiple system organ failure 63 46/M Gastrointestinal bleed 68 49/M Sepsis 286 F, female; HD, high dose, LD, low dose; M, male; MMF, mycophenolate mofetil; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disease.
BODY.RESULTS.OUTCOMES: COMPOSITE END POINT, DEATH, GRAFT LOSS AND AR.GRAFT LOSS:
By month 6, numerically fewer cases of death-censored graft loss were reported in the belatacept HD groups (n = 1 each) than in the belatacept LD group (n = 5) and tacrolimus groups (tacrolimus + MMF [n = 3]; tacrolimus [n = 2]). At month 12, a similar pattern was observed. Across treatment groups, ∼50% of graft losses occurred within the first month posttransplant, the main causes of which were primary nonfunction (n = 5) and arterial thrombosis (n = 4).
BODY.RESULTS.OUTCOMES: COMPOSITE END POINT, DEATH, GRAFT LOSS AND AR.ACUTE REJECTION:
Overall, AR (centrally read) was more common in the belatacept groups than in the tacrolimus groups (Table 3). At the month 6 primary analysis, the percent of patients with AR in the basiliximab + belatacept HD, belatacept HD and belatacept LD groups was 40%, 31% and 31%, respectively, versus 9% and 30% for the tacrolimus + MMF and tacrolimus groups, respectively. Most episodes of AR (57–94%) occurred early after transplant (i.e. by month 3) and were mild to moderate in severity (Banff grade I or II). Among patients with AR, ∼50% received treatment for AR in the basiliximab + belatacept HD and belatacept LD groups, while 70–80% received treatment in the other three groups. The majority of patients who were treated for AR received corticosteroids only.
BODY.RESULTS.OUTCOMES: COMPOSITE END POINT, DEATH, GRAFT LOSS AND AR.ANALYSIS BY HCV STATUS:
In HCV-positive patients, the percent with AR by month 6 in the belatacept groups ranged from 33% to 39% versus 12% and 38% for the tacrolimus + MMF and tacrolimus groups, respectively. In patients who were HCV-negative, the percent with AR by month 6 in the belatacept groups was 29–41% versus 7% and 23% for the tacrolimus + MMF and tacrolimus groups, respectively.
BODY.RESULTS.SAFETY:
Serious AEs, including serious infections and malignancies, occurred with a similar frequency across all treatment groups (Table 5). The most commonly reported serious AEs across all groups included pneumonia, sepsis, biliary strictures, cholangitis, pyrexia and acute renal failure. The most common serious infections resulted from CMV, fungal and mycobacterial pathogens. One fatal case of PML occurred ∼6 months after transplantation in a patient receiving belatacept HD and higher than recommended doses of MMF (3–4 g/day for 7.5 weeks). Table 5 Adverse events and events of interest at 12 months Events Patients Basiliximab + belatacept HD + MMF Belatacept HD + MMF Belatacept LD + MMF Tac + MMF Tac (n = 50) (n = 48) (n = 49) (n = 53) (n = 50) HCV at baseline, n 23 23 21 25 24 HCV recurrence, 1 n (%) 14 (60.9) 7 (30.4) 6 (28.6) 13 (52.0) 9 (37.5) Serious adverse events, n (%) 28 (56.0) 29 (60.4) 37 (75.5) 40 (75.5) 35 (70.0) Infections and infestations 11 (22.0) 12 (25.0) 13 (26.5) 12 (22.6) 12 (24.0) Malignancies, n 1 0 2 2 2 PTLD 1 2 0 1 0 0 All infections and infestations, n (%) 32 (64.0) 39 (81.3) 30 (61.2) 31 (58.5) 29 (58.0) Bacterial 5 (10.0) 11 (22.9) 11 (22.4) 6 (11.3) 13 (26.0) Fungal infections 6 (12.0) 9 (18.8) 14 (28.6) 6 (11.3) 5 (10.0) Viral infections 3 10 (20.0) 11 (22.9) 14 (28.6) 9 (17.0) 7 (14.0) CMV 5 (10.0) 4 (8.3) 10 (20.4) 4 (7.5) 1 (2.0) Herpes 3 (6.0) 3 (6.3) 4 (8.2) 3 (5.7) 2 (4.0) Adverse events of nervous system disorders, n (%) 23 (46.0) 19 (39.6) 15 (30.6) 34 (64.2) 34 (68.0) Headache 10 (20.0) 8 (16.7) 5 (10.2) 14 (26.4) 14 (28.0) Tremor 2 (4.0) 2 (4.2) 4 (8.2) 17 (32.1) 13 (26.0) Adverse events of renal and urinary disorders, n (%) Renal failure 1 (2.0) 4 (8.3) 3 (6.1) 5 (9.4) 14 (28.0) Acute renal failure 2 (4.0) 5 (10.4) 2 (4.1) 13 (24.5) 8 (16.0) Renal impairment 0 (0) 1 (2.1) 0 (0) 1 (1.9) 8 (16.0) CMV, cytomegalovirus; HAI, histological activity index; HCV, hepatitis C virus; HD, high dose, LD, low dose; MMF, mycophenolate mofetil; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disease; Tac, tacrolimus. 1 HCV recurrence confirmed histologically by central pathologist; modified HAI grading score ≥5/18 and fibrosis score ≥2. 2 PTLD case occurred after month 12. 3 One case of PML in belatacept HD + MMF. Malignancies were reported in 2–4% of belatacept patients and in 4% of patients receiving tacrolimus-based treatments. Two cases of PTLD were reported in belatacept-treated patients (one in the belatacept LD group at 11 months posttransplant and one in the basiliximab + belatacept HD group after month 12), both of which involved the liver. Neither case involved the CNS; both patients were EBV-seropositive at the time of transplantation. One patient died as a result of PTLD; the other was treated with chemotherapy and is alive with a functioning graft. Overall, most infections were mild or moderate in severity (Table 5); urinary tract infections were the most common. Patients in the belatacept LD group had numerically higher rates of viral and fungal infections (Table 5), most of which were nonserious. A similar proportion of patients across all treatment groups experienced at least one AE. AEs related to neurotoxicity (i.e. headache and tremor) occurred less frequently in patients receiving belatacept-based regimens versus tacrolimus-based regimens (Table 5).
BODY.RESULTS.HCV RECURRENCE:
Approximately 72% (153/212) of patients with a functioning graft at month 12 had biopsies available for evaluation. Recurrence of HCV among patients who were HCV-positive at baseline was higher in the basiliximab + belatacept HD (61%) and tacrolimus + MMF (52%) groups versus the other treatment groups (29–38%) (Table 5).
BODY.RESULTS.RENAL FUNCTION:
Mean cGFR at baseline was 66–80 mL/min. The differences in cGFR between the belatacept-treated patients and tacrolimus-treated patients were observed as early as month 1 and persisted through month 12 (15–34 mL/min/1.73 m2 higher in each belatacept group vs. the tacrolimus groups at month 12) (Figure 2). By month 12 in the intent-to-treat analysis, mean mGFR was 89–93 mL/min in the belatacept HD groups and 71–75 mL/min in the belatacept LD and tacrolimus groups. An on-treatment analysis revealed similar findings at 12 months (mean cGFR was 88 mL/min for basiliximab + belatacept HD; 100 mL/min for belatacept HD; 94 mL/min for belatacept LD; 67 mL/min for tacrolimus + MMF and 62 mL/min for tacrolimus). The proportion of patients with >10 mL/min improvement in cGFR from baseline to month 12 was 47–65% in the belatacept groups versus 12–27% in the tacrolimus groups. Figure 2Mean calculated GFR (MDRD methodology) over time (intent-to-treat analysis, as observed data with no imputation for missing values). All calculated GFR >200 were truncated at 200 mL/min. HD, high dose; LD, low dose; MMF, mycophenolate mofetil.
BODY.RESULTS.CARDIOVASCULAR/METABOLIC PROFILE AT 12 MONTHS:
Systolic and diastolic blood pressures at 12 months were lower among patients receiving belatacept (121–127 mmHg and 75–77 mmHg, respectively) versus those receiving tacrolimus-based regimens (137–138 mmHg and 80 mmHg, respectively). Serum lipids increased from baseline in all treatment groups, with triglyceride levels increasing more in the tacrolimus groups and LDL levels increasing more in the belatacept groups (data not shown). The incidence of new-onset diabetes mellitus (i.e. ≥30 days of treated diabetes in patients without a diagnosis of diabetes before randomization) was somewhat lower in the belatacept HD and LD groups (16% and 14%, respectively) versus patients receiving basiliximab + belatacept HD (36%), tacrolimus + MMF (24%), and tacrolimus (38%).
BODY.RESULTS.PHARMACOKINETICS:
The pharmacokinetics of belatacept in LT recipients was similar to those in kidney transplantation recipients receiving a similar dosing regimen (23). The pattern of minimum belatacept concentration values with the HD and LD regimens in the early posttransplant period were consistent with the differences between the two regimens. Steady-state trough serum concentrations of belatacept in the maintenance phase (during 5-mg/kg dosing) were similar between the HD and LD regimens. Mean serum trough concentrations of belatacept and tacrolimus, and mean daily MMF and steroid doses are shown in Figure 3. Some of the patients who received additional belatacept to compensate for fluid loss went on to experience death or graft loss, but results were mixed and potentially confounded by intra- and postoperative complications. In the overall study population, there was no association between trough belatacept levels and death or graft loss. Figure 3Serum trough levels and mean daily dosing at specified time points. Concentrations of belatacept in human serum were determined using a validated enzyme-linked immunosorbent assay (ELISA) by PPD (Richmond, VA). (A) Mean serum trough levels of belatacept. (B) Mean daily dose of MMF. (C) Mean serum trough levels of tacrolimus. (D) Mean daily dose of steroids. HD, high dose; LD, low dose; M, month; MMF, mycophenolate mofetil; W, week.
BODY.RESULTS.DONOR-SPECIFIC ANTIBODIES:
All treatment groups had patients who tested positive for donor-specific antibodies (DSA) at baseline (Table 6). By 12 months after transplantation, the number of patients with DSA decreased in two belatacept groups (HD and LD), remained the same in two groups (basiliximab + belatacept HD and tacrolimus), and increased in one group (tacrolimus + MMF) (Table 6). There were few cases of de novo DSA in all groups. Table 6 DSA: number of patients with detectable antidonor HLA antibodies Patients with DSA/patients in analysis, n (%) Basiliximab + belatacept HD + MMF Belatacept HD + MMF Belatacept LD + MMF Tac + MMF Tac Baseline DSA (pretransplant) 5/48 (10) 5/46 (11) 8/48 (17) 3/50 (6) 4/49 (8) Total DSA by month 12 5/47 (11) 3/47 (6) 4/43 (9) 8/52 (15) 4/45 (9) De novo DSA 1 by month 12 3/47 (6) 1/47 (2) 1/43 (2) 6/52 (12) 3/45 (7) DSA, donor-specific antibodies; HD, high dose, LD, low dose; MMF, mycophenolate mofetil; Tac, tacrolimus. 1 De novo DSA was defined as appearance of antibody to a new HLA specificity following transplantation.
BODY.RESULTS.LONG-TERM EXTENSION:
Of the 164 patients who completed 1 year of treatment, 145 entered the LTE phase (Figure 4). During the LTE, additional deaths and graft losses were noted in the belatacept HD group (n = 4). Because of the cumulative number of deaths and graft losses in two of the three belatacept groups relative to the tacrolimus groups, the DMC recommended termination of the LTE study. Although a causal relationship to belatacept could not be clearly established, it could also not be rejected. All patients who were currently on belatacept were switched to standard-of-care immunosuppression. Figure 4Patient disposition in LTE. HD, high dose; LD, low dose; LTE, long-term extension; MMF, mycophenolate mofetil. Based on these findings, a comprehensive assessment of the deaths observed in belatacept-treated patients was conducted, and a series of post hoc analyses were performed. Factors evaluated included demographic characteristics, donor age, baseline disease status, mean Model for End-Stage Liver Disease score, and belatacept trough concentrations. Deaths and graft losses were not evenly distributed among the centers. No demographic or disease-related risk factors were predictive of death associated with belatacept, and similarly, no clear explanation for the higher rates of death observed in the belatacept HD and LD groups was identified. Death and graft loss in the subset of patients who were HCV-positive at the time of transplantation were numerically higher in the belatacept groups at month 6 but comparable with the tacrolimus groups at month 12.
BODY.DISCUSSION:
This phase II, randomized, multicenter study was the first clinical trial to explore the use of belatacept in LT recipients. The primary objective was to evaluate the safety and efficacy of belatacept relative to tacrolimus, as reflected by the incidence of AR, graft loss and death in de novo LT recipients. At the conclusion of this study, two of three belatacept groups had higher rates of death and graft loss relative to the standard-of-care control group tacrolimus + MMF. All three belatacept groups also had higher rates of AR, and there was an increase in viral and fungal infections, the majority of which were not serious. Two cases of PTLD and one case of PML were reported in belatacept-treated patients. The two belatacept HD groups had substantially better mGFR than the remaining three groups, while all three belatacept groups had better cGFR. There was also evidence of fewer neurotoxicity events in the belatacept groups. A high rate of discontinuation was observed in the belatacept treatment groups, such that by the time of the 12-month assessment, ∼40% of patients had discontinued assigned belatacept therapy. In contrast to the findings in renal transplant recipients, which showed comparable patient and graft survival relative to the CNI cyclosporine (13–17), this exploratory study in LT recipients demonstrated increased rates of death and graft loss in two of three belatacept groups compared with tacrolimus (different CNI comparator). Multiple factors may account for differences in survival outcomes between kidney transplant and LT recipients, including organ-specific aspects of alloimmune responses (24,25). In the present study, it is notable that basiliximab did not lead to a lower rate of rejection versus placebo in the two belatacept HD groups. There are several hypotheses, including the role of CD28-independent T cells and/or inhibition of regulatory pathways that could explain this observation (26). Further studies are required to understand the mechanism and contribution of these factors to AR in the setting of belatacept therapy. Important nonimmunologic differences include the degree of illness at the time of transplantation, extent of surgical trauma and massive perioperative fluid shifts. Doses of belatacept in this study were higher than those used in the kidney transplant trials, with the assumption that perioperative fluid shifts and fluid losses would necessitate additional belatacept. There was no association between trough belatacept levels and death or graft loss. This was expected, given that there is no exposure–response relationship in the kidney transplant setting, such that therapeutic drug monitoring is not needed with belatacept treatment. While preservation of renal function was a key finding in the pivotal phase III clinical trials of belatacept in renal transplant recipients, the magnitude of the renal function difference in the current study highlights the capacity for native kidneys to recover substantial function following LT in the absence of CNI exposure. The tendency toward more viral and fungal infections observed in belatacept-treated patients raises the possibility of overimmunosuppression in some patients, as observed with regimens that include MMF (27). This finding is somewhat paradoxical, however, given the higher rates of AR in the belatacept groups, which would suggest underimmunosuppression or immunomodulatory effects not yet understood in the context of LT. It is also possible that the management of AR placed patients at risk for subsequent infectious complications. The standard treatment for rejection may have been more intense than was needed in belatacept-treated patients, suggesting that overimmunosuppression may be part of the explanation for the infectious complications. The limited number of patients and events preclude the ability to definitively interpret the relative contributions of overimmunosuppression versus underimmunosuppression. LT recipients are an inherently complex population, with diverse and serious underlying medical concerns that have the potential to adversely affect posttransplant outcomes. Distinguishing the contribution of belatacept alone or an interaction between belatacept and such factors in the context of this phase II study is not feasible. An additional limitation of the study includes the open-label design (belatacept vs. tacrolimus assignments). Findings from this phase II study did not allow for the identification of a safe and effective dose or a regimen for further development of belatacept fulfilling the substantial need for nonnephrotoxic immunosuppressive therapy in LT recipients. | 4,140,547 | {
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TITLE: Evaluation of the functional efficacy of an antioxidative probiotic in healthy volunteers
ABSTRACT.BACKGROUND:
In persons without clinical symptom it is difficult to assess an impact of probiotics regarding its effect on health. We evaluated the functional efficacy of the probiotic Lactobacillus fermentum ME-3 in healthy volunteers by measuring the influence of two different formulations on intestinal lactoflora, fecal recovery of the probiotic strain and oxidative stress markers of blood and urine after 3 weeks consumption.
ABSTRACT.METHODS:
Two 3-week healthy volunteer trials were performed. Open placebo controlled (OPC) study participants (n = 21) consumed either goat milk or by L. fermentum ME-3 fermented goat milk (daily dose 11.8 log CFU (Colony Forming Units). Double blind randomised placebo controlled (DBRP) study participants (n = 24) received either capsules with L. fermentum ME-3 (daily of dose 9.2 CFU) or placebo capsules. The faecal lactoflora composition, faecal ME-3 recovery, effect of the consumption on intestinal lactoflora, and oxidative stress markers of blood (total antioxidative activity; total antioxidative status and glutathione red-ox ratio) was measured.
ABSTRACT.RESULTS:
ME-3 was well tolerated and a significant increase in total faecal lactobacilli yet no predominance of ME-3 was detected in all study groups. Faecal recovery of ME-3 was documented by molecular methods only in fermented milk group, however the significant improvement of blood TAA (Total Antioxidative Activity) and TAS (Total Antioxidative Status) indices was seen both in case of fermented goat milk and capsules", yet glutathione re-ox ratio values decreased only in case of fermented by ME-3 goat milk.
ABSTRACT.CONCLUSION:
The functional efficacy of both consumed formulations of an antioxidative probiotic L. fermentum ME-3 is proved by the increase of the intestinal lactobacilli counts providing putative defence against enteric infections and by reduction of the oxidative stress indices of blood and urine of healthy volunteers. In non-diseased host the probiotic health claims can be assessed by improvement of some measurable laboratory indices of well-established physiological functions of host, e.g. markers of antioxidative defence system.
BODY.BACKGROUND:
Probiotics are defined as live microbial food supplements, which beneficially influence human health [1,2]. Widely accepted probiotics contain different lactic acid producing bacteria of human origin: bifidobacteria, lactobacilli or enterococci. Nowadays the concept of functional foods, incl. probiotic food and dietary supplements implies to their ability to beneficially influence body functions in order to improve the state of well-being and health and reduce the risk of disease [2,3]. The important areas of human physiology that are relevant to functional food science according ILSI (International Life Science Institute) and FUFOSE (The European Commission Concerted Action on Functional Food Science in Europe) are besides others, the modulation of basic metabolic processes and defence against high-grade oxidative stress [4,5]. Human nutrition is clearly associated with oxidative metabolism, which beside production of energy is involved in a number of vital functions of the host. For example, under physiological conditions the reactive species (including peroxyl radicals, nitric oxide radical, superoxide anion) figure a crucial role in primary immune defense of the human body by phagocytic cells against harmful microorganisms [6,7]. On the other hand, a prolonged excess of reactive species is highly damaging for the host biomolecules and cells, resulting in dysbalance of the functional antioxidative network of the organism and leading to substantial escalation of pathological inflammation [8]. By our knowledge, no systematic studies have been performed to approve the functional efficacy of different formulations of probiotic on the antioxidative defence system of a healthy human. In our previous study Lactobacillus fermentum ME-3 (DSM 14241) [9-11], expressed strong antimicrobial activity against Gram-positive and Gram-negative entero- and uropathogens [12,13]. The cells and cell lysate of L. fermentum ME-3 possessed substantial antioxidative potency [14]. In an animal experiment ME-3 suppressed the excessive oxidative stress reaction caused by Salmonella infection in intestinal mucosa and thus improved the gut mucosal antioxidative status [15]. The antioxidative effect of L. fermentum ME-3 on human body oxidative stress markers was confirmed by our pilot study with fermented goat milk [16]. The aim present study was to evaluate the functional efficacy of the probiotic strain L fermentum ME-3 in the human gastrointestinal tract (GIT) of healthy volunteers. The faecal recovery, effect of two different formulations on total faecal lactoflora and oxidative stress markers of blood and urine were compared after 3 weeks consumption.
BODY.METHODS.FORMULATIONS:
The efficacy of two different formulations (experimental fermented goat milk and probiotic capsules) on the human body oxidative stress markers was evaluated. Lactobacillus fermentum ME-3, a probiotic strain of healthy human intestinal origin [17], has been identified by biochemical and molecular methods [9]. The patent application has been submitted to the Estonian Patent Agency (Application No. 0356/01PV) as well as to the International Bureau of World Intellectual Property Organization (WIPO) (Application No. WO03002131) [11]. L. fermentum ME-3 was used as freeze-dried powder in capsulated form and in fermented milk.
BODY.METHODS.FORMULATIONS.CAPSULES:
Gelatine coated capsules were manufactured by the Tallinn Pharmaceutical Company. The freshly prepared probiotic capsules contained 9.0 logs CFU of L. fermentum ME-3 per capsule in addition to 250 mg of saccharose and microcellulose. Identical placebo capsules contained only saccharose and microcellulose. All capsules were stored at +4°C.
BODY.METHODS.FORMULATIONS.SURVIVAL OF ME-3 IN CAPSULE:
Survival of ME-3 in capsule was monitored during 12 months at +4°C. The content of one capsule was dissolved aseptically in 2 ml of 0.9% NaCl solution. The suspension was vortexed, serially diluted and seeded 0.1 ml on de Man-Rogosa-Sharpe (MRS) agar medium (OXOID, U.K.) and incubated 48 hours at 37°C microaerobically (10% CO2). The number of colonies was counted and the viable cell count in capsule was calculated.
BODY.METHODS.FORMULATIONS.EXPERIMENTAL FERMENTED MILK:
Three different lots of experimental fermented goat milk was prepared for the 3-week trial with healthy volunteers in order to establish the health effects of ME-3 consumption. The study group was supplied with fresh product once a week. Experimental fermented milk was prepared as described previously [16] by combining the probiotic strain with two supportive lactobacilli cultures L. plantarum LB-4 and L. buchneri S-15. L. buchneri strain S1-5 decreased the specific taste of the goat milk. L. plantarum LB-4 was included as a strong producer of exopolysaccharides, which gives the fermented milk a cream-like consistence and delightful acidity. The goat milk was inoculated with 2% mixture of Lactobacillus strains and incubated at 37°C for 24 hours. Theproduct, ready to use, was cooled and stored at 4°C.
BODY.METHODS.FORMULATIONS.SURVIVAL OF L. FERMENTUM ME-3 IN FERMENTED GOAT MILK:
To measure the viable cell count of ME-3 in fermented goat milk, samples were taken at the end of fermentation (before cooling the product), and after 24 h, 32 h, 48 h and 7 days from the preparation, when the product was stored at 4°C. The amount of 0.5 ml of the fermented milk was serially diluted in saline and plated on MRS agar medium and incubated for 48 h at 37°C in microaerobic conditions.
BODY.METHODS.DESIGN OF HUMAN VOLUNTEER TRIALS:
Two healthy volunteer (n 45) trials, particularly open placebo controlled (OPC) study and double blind randomized placebo controlled (DBRP) study were carried on to evaluate the functional efficacy of L. fermentum ME-3 in the human body. The inclusion criteria included the wish to participate, no known health problems, and no medical conditions requiring drug therapy, no other yogurts or no special diets. The subjects with a history of GIT disease, food allergy and acute infection, use of any antimicrobial agent within the last month or use of any regular concomitant medication including antioxidant vitamins and anti-inflammatory non-steroidal drugs were excluded. The members of the trial were daily questioned about their general welfare, intestinal function (general welfare, gut gas production, stool frequency) and putative adverse effects. The withdrawal criteria from the trials included acute infections during the study. Reasons for dropout were the unwillingness to proceed with the study or relocation to new area. The blood samples (6 ml) from the antecubital vein, faecal and urine samples were collected before and at the end of all clinical trials. Participants of all trials gave informed consent to the study protocols approved by the Ethical Committee of Tartu University.
BODY.METHODS.DESIGN OF HUMAN VOLUNTEER TRIALS.OPEN PLACEBO CONTROLLED FERMENTED GOAT MILK TRIAL:
The study participants were 5 men and 16 women, mean age 50 years (range 35–60). During three weeks of the trial the study group (3 males and 13 females) consumed daily 150 ml fermented goat milk. The daily dose of probiotic Lactobacillus strain was 11.2 to 11.8 log CFU per person. The control group (1 male and 4 females) consumed the same dose of fresh goat milk.
BODY.METHODS.DESIGN OF HUMAN VOLUNTEER TRIALS.PROBIOTIC CAPSULE TRIAL:
A DBRP study (ISRCTN 53164826) was carried out as follows. The study group consisted of 15 men and 9 women, mean age 52 years (range 40–60) allocated according to their wish to participate and randomly divided by an independent person and computer program for two groups. The study group members (8 males and 4 females) took three probiotic containing capsules (8.4 log CFU per capsule) two times daily (the daily dose 9.2 log CFU) during three weeks. The placebo group (7 males and 5 females) received identical capsules without the probiotic strain. Faecal samples of all participants to assess change in faecal lactoflora and the persistence of the ingested probiotic strain were collected before and at the end of trial. Several laboratory indices of blood and urine were measured before and after the consumption of ME-3. Here we report on changes in human body oxidative stress markers as total antioxidative activity (TAA), total antioxidative status (TAS) and glutathione red-ox ratio (GSH/GSSG) from blood serum.
BODY.METHODS.MICROBIOLOGICAL ANALYSES OF FAECES:
The total count of lactobacilli and the count of L. fermentum were evaluated in faecal samples. The faecal samples were collected at day 0 and 21 in both trials. Samples were kept at -80°C before analyzed. Serial dilutions (10-2–10-9) of the weighed faecal samples were prepared with phosphate buffer (pH 7.2) and 0.05 ml of aliquots was seeded onto MRS agar medium [17]. The plates were incubated at 37°C for 4 days microaerobically in 10% CO2 environment (incubator IG 150, Jouan, France). The catalase negative colonies were selected on the basis of typical for LAB colony morphology, cells microscopy and Gram staining. The count of Lactobacillus species was expressed in log10 colony forming units per gram faeces (log10 CFU/g) and percentage (relative share) in the total count of lactobacilli. The detection level of lactobacilli was a 3.0 log CFU/g faeces. The relative amount of L. fermentum, colonizing the gastrointestinal tract of persons in the study groups was expressed as a proportion of the total count (%), using the Bioquant program [18]). The program gives output data for every microorganism as an absolute count (log10 CFU/g) and their percentage in the total count with its normal values.
BODY.METHODS.AP-PCR TYPING:
The putative ME-3 isolates were typed by arbitrarily primed polymerase chain reaction (AP-PCR). Genomic DNA was extracted from 24 h old cultures, cultivated on MRS agar microaerobically with the QIAamp DNA Mini Kit 50 (QIAGEN GmbH., Hilden, Germany) according to the manufacturers instructions. AP-PCR typing was done with two primers: ERIC1R (5'-ATGTAAGCTCCT GGGGATTCAC-3') and ERIC2 (5'-AAGTAAGTGACTGGGGTGAGCG -3') (DNA Technology A/S, Aarhus, Denmark). A 30 μl volume of reaction mixture consisted of 10 × PCR buffer (Fermentas, Vilnius, Lithuania), 2.5 mM MgCl2 (Fermentas, Vilnius, Lithuania), 200 μM deoxynucleoside triphosphate mixture (dATP, dGTP, dTTP and dCTP, Amersham Pharmacia Biotech, Freiburg, Germany) 0, 60 μg of each primer and 2.5 U Taq DNA Polymerase (Fermentas, Vilnius, Lithuania,) and 5 μl of extracted DNA according to Matsumiya et al. [19]. The PCR mixture was subjected to thermal cycling 35 cycles of denaturation at 95°C for 1 min, annealing at 35°C for 1 min, and extension at 74°C for 2 min, with a final extension at 74°C for 5 min with the PTC-200 thermal cycler (Eppendorf AG, Hamburg, Germany). The PCR products were separated by electrophoresis in a horizontal 2% agarose gel containing 0.1 μl/ml ethidium bromide in Tris-acetic acid-EDTA (TAE) buffer (40 mM Tris, 20 mM boric acid, 1 mM EDTA, pH 8.3) (Bio-Rad Laboratories, Hercules, USA) at constant voltage of 120 V. A 1 kb ladder (GeneRuler, Fermentas, Vilnius, Lithuania) was used as a base pair size marker. The banding patterns of isolates were visualized with UV light and compared with that of L. fermentum ME-3 strain.
BODY.METHODS.MEASUREMENT OF HUMAN BODY OXIDATIVE STRESS STATUS:
Blood serum was analysed for total antioxidative activity TAA, total antioxidative status TAS and glutathione red/ox ratio (oxidized glutathione and reduced glutathione, GSSG/GSH). TAA of the serum was assessed by the linolenic acid test (LA-test) described previously [16]. This test evaluates the ability of the sample to inhibit lipid peroxidation. TAS of the serum was measured with a commercially available kit (TAS, Randox Laboratories Ltd. Ardmore, UK) as described elsewhere [16], water-soluble vitamin E (Trolox) serving as a standard. This method is based on the inhibition of the absorbance of the ferrylmyoglobin radicals of 2,2'-azinobis-ethylbenzothiazoline 6-sulfonate (ABTS+) generated by activation of metmyoglobin peroxidase with H2O2. The cellular oxidative stress markers as total glutathione and oxidized glutathione were measured using the method of Griffith [20] as described elsewhere [16]. The glutathione content was calculated on the basis of a standard curve generated with known concentration of glutathione. Amount of GSH (μg/ml) was calculated as a difference between the total glutathione and GSSG (total glutathione – GSSG). The glutathione red/ox ratio was expressed as GSSG/GSH.
BODY.METHODS.STATISTICAL ANALYSIS:
The computer program Sigma Stat for Windows 2.0 (Jandel Corporation, USA) was applied. The counts of faecal lactoflora were compared by using Student's t-test and Mann-Whitney rank sum test. Changes in oxidative stress markers of blood sera (TAA, TAS and glutathione red-ox ratio) were evaluated by Student's t-test, paired t-test and Mann-Whitney rank sum test. The choice of tests was made automatically according to the distribution of the data. Both microbial and biochemical markers were given as mean and standard deviation. One-way ANOVA test was performed to compare the effect of different formulation on TAA, TAS and faecal lactoflora parameters. Differences were considered statistically significant if the value was p < 0.05.
BODY.RESULTS.SURVIVAL OF ME-3 IN FORMULATIONS:
In capsule after approximately 1-log drop after one week from the production of the capsules, the viable count of the probiotic strain remained stable at the level of 8.4 log CFU per capsule. Additional results have shown at +4°C the stability of the freeze-dried capsulated culture at least 17 months from the production. In fermented goat-milk the cell count of the probiotic strain varied insignificantly from 9.0 to 9.7 log CFU/ml from one preparation to the other. The viable count of ME-3 in the fermented goat milk was found to remain stable at least during 7 days of storage at 4°C.
BODY.RESULTS.HUMAN VOLUNTEER TRIALS:
No dropouts were registered during volunteer trials, yet one participant was withdrawn from the probiotic capsule trial due to acute respiratory viral infection. Besides, no adverse affects in general welfare or changes in GI functionality were assessed during the trial.
BODY.RESULTS.HUMAN VOLUNTEER TRIALS.CHANGES IN TOTAL LAB COUNT:
The consumption of both ME-3 fermented milk and ME-3 capsule significantly increased the total count of lactobacilli in faeces as compared to the initial levels (Fig. 1). In opposite, in the group of volunteers consuming non-fermented goat-milk there was even a decrease in total LAB counts during the 3-week trial and no changes were found in capsule placebo group. Figure 1Increase of total fecal counts of lactobacilli in healthy volunteers consuming of ME-3 in fermented goat milk and probiotic capsule. 1 – Day 0, 2 – Day 21 Significantly different from pre-treatment values (Student's t-test): * p < 0.05; Significantly different from control (Student's t-test): ‡ p = 0.01
BODY.RESULTS.HUMAN VOLUNTEER TRIALS.RECOVERY OF THE PROBIOTIC STRAIN:
In goat milk group L. fermentum as a species appeared in fecal samples of all individuals (n = 16) after consumption of fermented goat milk (Table 1). The AP-PCR confirmed the recovery of ME-3 in the faeces of all study group members (Fig. 2). However, in different trials the administration of ME-3 strain did not lead to the predominance of Lactobacillus fermentum species (Table 1).In the probiotic capsule trial the strain ME-3 was not detectable between L. fermentum isolates by AP-PCR. Table 1 Changes in fecal recovery of L. fermentum during healthy human volunteer trials L. fermentum Groups * Prevalence (%) † Count (log10) ‡ Proportion (%) Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Goat milk trial, ME-3 (n = 16) 25 (4/16) 100 (16/16) 7.0 ± 0.7 7.3 ± 1.4** 21 13 Control (n = 5) - 20 (1/5) - 3.6 - 28 Capsule trial, ME-3 (n = 11) 16.7(2/12) 33.3 (2/12) 4.3 ± 0.5 5.8 ± 1.6 4 9 Placebo (n = 12) 25 (3/12) 16.7 (2/12) 6.3 ± 2.5 8.0 ± 1.6 11 19 * Percentage of subjects with fecal L. fermentum inside the group ** Significantly different from the pre-treatment values (paired t-test): p < 0.001 † Median value ± SD ‡ Proportion of L. fermentum among fecal LAB Figure 2Confirmation for the survival of L. fermentum ME-3 in GIT in subjects receiving ME-3 fermented goat milk by AP-PCR in a horizontal 2% agarose gel. a) From the left: M – DNA 1 kb Ladder, Line 1 -L. bervis ATCC 14869, Line 2 – L. buchneri ATCC 4005, Line 3 – L. reuteri DSM 20016, Line 4 – L. fermentum ATCC 14931, Line 5 – L. fermentum ME-3 b) From the left: M – molecular weight marker, Line 1 ...16 – ME-3 like profiles from feces of goat milk trial study group participants
BODY.RESULTS.HUMAN VOLUNTEER TRIALS.ANTIOXIDATIVE HEALTH EFFECT OF ME-3:
The positive effect on the blood ox stress markers as TAA and TAS was seen in the case of both formulations (Fig. 3). Particularly, the additive increase in goat milk group was 6% and 9% respectively as compared to control group, however only 4% for TAA and 2.5% for TAS in probiotic capsule study group as compared to placebo. Figure 3Effect of ME-3 consumption in fermented goat milk and capsules on human blood oxidative stress markers a) TAA (%) and b) TAS(mmol/l). 1 – Day 0, 2 – Day 21 Significantly different from pre-treatment values: *p < 0.05 (paired t-test); **p ≤ 0.01 (Student's t-test and paired t-test);ME-3 goat milk effect different from the effect of the ME-3 in capsule-form (ANOVA): ‡p ≤ 0.001 The effect of goat-milk consumption on the TAA and TAS values was significantlyhigher (p < 0.001) than by the consumption of the capsulated probiotic (Fig. 3). The decrease of the glutathione red-ox ratio was significant in both groups: the study Group (from 0.15 ± 0.01 to 0.11 ± 0.04 μg/ml, p < 0.01) and control (from 0.14 ± 0.03 to 0.11 ± 0.02 μg/ml, p < 0.01) in the goat milk trial. When the probiotic was consumed in capsulated form, no significant decrease was noticed in the glutathione red-ox ratio.
BODY.DISCUSSION:
Our aim was to evaluate the functional efficacy of the antimicrobial and antioxidative probiotic L. fermentum ME-3 in normal population with variable food intake. First of all the safety of the L. fermentum strain ME-3 was confirmed as no adverse side effects were registered in volunteers. Even relatively high (>1011 CFU) doses of consumed ME-3 had no negative impact on the hosts' general well-being. Lactobacillus fermentum as species, used in various food applications, has a well-established history of safe use and is evaluated as GRAS according to the Food and Drug Administration of the USA [21]. Second, a clear improvement of laboratory indices of antioxidative defence system of a healthy host was documented, using both formulations as fermented by L. fermentum ME-3 goat-milk and probiotic capsules. This effect was simultaneous with the increase of intestinal lactoflora of healthy volunteers even without necessity for faecal recovery of the strain. In the human population, persons without clinical symptoms have still a quite different health status, including stability, capacity and potency of antioxidative defence to counteract sufficiently to oxidative stress-caused adverse effects [7]. If a probiotic is able to exhibit a positive functionality on oxidative stress-related indices, it helps both to stabilize and promote the potency of the whole body antioxidative defence system in subclinical situations without disease symptoms. That in turn may have an impact for lowering the risk of atherosclerotic damage of blood vessels associated with several cardiovascular and neurodegenerative diseases [22-24]. In our study of healthy volunteers for validation of the antioxidative functionality of probiotic, four well-known oxidative stress markers of blood were chosen [25-27]. The state of the lipid fraction (including also LDL) in the antioxidative defence system of the blood is evaluated by TAA. TAS on the other hand reflects more the antioxidativity of the water-soluble fraction of the human blood. Among the measured blood sera markers both the TAA and TAS values were also improved in the two different study groups. However, there was found a significantly lower improvement of TAA and TAS values in cases of capsule than fermented goat-milk where the recovery of the strains was assessed by AP-PCR. Similarly, the reduction of the glutathione red-ox ratio was detected after the consumption of fermented by ME-3 goat-milk but not with the capsule. The crucial non-enzymatic cellular antioxidant is GSH [28] present in the millimolar range mainly in the red blood cells, liver, pancreas, kidneys, spleen, eyes, lungs and intestinal cells [29]. The oxidized form of glutathione becomes even at low concentrations toxic, and therefore in the cells the glutathione red-ox ratio is kept as low as possible. In the case of inflammation this balance is shifted towards the oxidized form, indicating non-physiological intracellular oxidative stress. Thus, our study shows that there is a good association between the mode of formulation of probiotic and expression of its functional properties inside the healthy host. The antioxidative potential of the food supplement containing ME-3 was excellent, as reisolates of the strain from capsule expressed significantly higher TAA in comparison with the base values of the strain in vitro (data not shown). Unexpectedly, the shifts in the antioxidativity markers in blood serum of participants of the probiotic capsule trial were less pronounced in comparison with ME-3 fermented goat milk. Particularly, the explanation for more expressed positive shifts in oxidative stress markers of volunteers of the fermented goat milk trial could be due to the synergistic effect of the probiotic and the substrate. Milk is not just a carrier for the probiotic Lactobacillus strain, but contains natural "lactogenic" factors like lactose, minerals, vitamins and other components that enhance the metabolic activity of ingested probiotic strain in GIT. Both fermented goat milk and goat milk elevated the values of TAA and TAS The goat milk contains different biomolecules (e.g. casomorphins, lactorphins, casokinins, etc) having certain antioxidative properties, which can contribute to consumers' plasma antioxidative capacity [30-36]. This was proved by some antioxidative effect also in persons consuming non-fermented goat milk. However, the elevation these indices were remarkably more expressed in the fermented goat milk group, thus the goat milk fermentation with L. fermentum ME-3 results in additive increase of total antioxidativity. Therefore, the provisional FAO regulations [37] suggesting the need for health claims by specified formulations of probiotic seem to be of the utmost importance. Additionally, in our study with experimental fermented milk the average daily dose of L. fermentum ME-3 being 11.5 logs CFU was clearly higher than that of capsule (max 9.5 log CFU). It is possible that the dose excesses the amount of bacteria necessary for interacting with intestinal mucosa and the unattached lactobacilli are excreted with faeces. The finding of Saxelin and colleagues confirmed that the faecal recovery of the probiotic strain started from the consumption of more than 9.0 log CFU daily doses of capsulated LGG [38]. To our surprise, in the present study the similar dose did not result in faecal recovery of the strain. It is possible that the ME-3 strain germinated mainly in some upper parts of intestinal tract where the advantageous conditions for survival and metabolic activity of probiotic lactobacilli were present. Using molecular tools, Marteau et al. showed that lactobacilli figuring only 7% of faecal microflora performed up to 30% of microbial communities in human colon [39]. If administered in lower quantities as in case of capsule trial, ME-3 did not reach the detectable level in faecal samples. Yet, its presence in gut was proved by the positive antioxidative health effect in blood but not in urine. Therefore it is understandable that the higher load of metabolically active probiotic bacteria in goat-milk resulted also in their faecal recovery and the highest impact on the oxidative stress indices. Moreover, in our study the positive impact of ME-3 consumption on the host lactoflora was proved by the increase of faecal lactobacilli counts in all participants of human volunteer studies. In experimental settings the high counts of intestinal lactobacilli have been shown as an important defensive factor against enteric infections [40,41]. Though up to now the period of consumption of probiotics has not been defined, the 3-week ingestion of fermented goat-milk and capsule seemed enough for reaching the aims. It is important to mention that after consumption of ME-3, a strain with high antagonistic activity, neither the species nor the strain predominated among total lactoflora. This shows a well-granted microbial balance inside the gut, which cannot be disturbed by high load of probiotic bacteria. Apparently, the interconnected advanced metabolism of large gut microbiota keeps the proportions of different species quite stable. Some other investigators have obtained similar results showing the proportional increase of different microbial populations (bifidobacteria, coliforms) after administration of Lactobacillus sp. probiotic [42,43]. Thus, the functional efficacy of different formulations of anti-infectious and antioxidative probiotic L. fermentum ME-3 were proved both by the increase of the lactobacilli counts providing putative defence against infectious agents in gut and by reduction of the oxidative stress indices of blood and urine of healthy volunteers. Further, studies evaluating the efficacy of ME-3 as adjunct to conventional therapy in patients with atherosclerotic damages and a high-grade oxidative stress are ongoing.
BODY.CONCLUSION:
In non-diseased host, the probiotic health claims can be assessed by improvement of some measurable laboratory indices of well-established physiological functions of organism. In our case, the possibility for augmentation of the antioxidative defence system by the probiotic L. fermentum ME-3 in normal population can be proposed.
BODY.COMPETING INTERESTS:
Marika Mikelsaar, Mihkel Zilmer, Tiiu Kullisaar, Heidi Annuk (Hynes) and Epp Songisepp are sharing the Estonian patent application: no. EE 2001 00356 29.06.01 and International Patent application: no. WO03002131.
BODY.AUTHORS' CONTRIBUTIONS:
Epp Songisepp, and Pirje Hütt have been in charge of the microbiological analysis. The former has been also in charge of analyzing the results and writing of the manuscript. Jaak Kals was responsible for performance and management of the volunteer trials. Tiiu Kullisaar has been in charge of the biochemical analysis and writing the manuscript. Mihkel Zilmer has conducted the biochemical estimations and writing the manuscript. Reet Mändar has been in charge of the molecular analysis and revising the manuscript. Marika Mikelsaar is the main conductor of the L. fermentum ME-3 research; for this paper she has been in charge of the clinical trial design and writing the manuscript. | 1,198,254 | {
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TITLE: Efficacy and Safety of a Lidocaine Gel in Patients from 6 Months up to 8 Years with Acute Painful Sites in the Oral Cavity: A Randomized, Placebo-Controlled, Double-Blind, Comparative Study
ABSTRACT:
Lidocaine is a well-accepted topical anaesthetic, also used in minors to treat painful conditions on mucosal membranes. This randomized, double-blind, placebo-controlled study (registered prospectively as EudraCT number 2011-005336-25) was designed to generate efficacy and safety data for a lidocaine gel (2%) in younger children with painful conditions in the oral cavity. One hundred sixty-one children were included in two subgroups: 4–8 years, average age 6.4 years, treated with verum or placebo and 6 months–<4 years, average age 1.8 years, treated only with verum. Pain reduction was measured from the time prior to administration to 10 or 30 minutes after. In addition, adverse events and local tolerability were evaluated. In group I, pain was reduced significantly after treatment with verum compared to placebo at both time points. In group II, the individual pain rating shift showed statistically significant lower pain after treatment. Only seven out of 161 patients reported an adverse event but none were classified as being related to the study medication. The local tolerability was assessed as very good in over 97% of cases. For painful sites in the oral cavity, a 2% lidocaine gel is a meaningful tool for short-term treatment in the paediatric population.
BODY.1. INTRODUCTION:
The use of medicinal products in younger children, even if approved and accepted for decades in adults and older children, often takes place with some uncertainties on the parents' or physician's site. Younger patients not only are smaller and have less weight but also have at least partly different pharmacokinetic characteristics [1]. Although for topically applied and locally acting medicinal products the potential negative consequences of use are considered less important, controlled in-use-data is highly appreciated. Clinical trials according to accepted rules represent the highest standard of clinical evaluation to prove efficacy and safety but are difficult to perform in younger patients for various reasons [2]. Ethical aspects are more critical and also the design of a study is more demanding, for example, choice of reliable efficacy criteria, especially if laboratory tests or noninvasive measurements are not suitable. Pain perception shows a high degree of individual variation in intensity, onset, and degree of toleration [3]. In patients not reliably able to specify pain perception, due to their age, it can be very difficult to measure whether a pain medication was successful, especially when the pain is mostly moderate and local. Lidocaine is a well-established and approved local anaesthetic alone and in combination used in a variety of topically applied preparations, mostly as medicinal product [4]. It is also used to treat painful oral conditions in children, like aphthous ulcers, blisters, teething, or gingivitis. The objectives of this randomized, double-blind, placebo-controlled, phase IV study were to determine the efficacy and safety of a gel with 2% lidocaine in children from 6 months up to 8 years with painful conditions in the oral cavity as a meaningful tool for short-term treatment in the paediatric population. The verum preparation used is available in Germany for short-term, symptomatic treatment of pain on the oral mucosa, on the gums, or on lips. The dosing recommendation for children is up to 4 times daily as a pea size piece of gel (approximately 0.2 g gel or 4 mg lidocaine hydrochloride).
BODY.2. PATIENTS AND METHODS:
This randomized, double-blind, placebo-controlled, single-centre, phase IV clinical trial (EudraCT number 2011-005336-25) was initiated after approval by the responsible ethics committee of the Medical Chamber of the German Federal State of Thuringia and by the German National Health Authority (BfArM). The study was conducted in accordance with the World Medical Association Declaration of Helsinki 2013, the Guidelines of ICH Good Clinical Practice (GCP) as well as the requirements of German national drug and data protection laws. All patients and their parents or legal guardians were given sufficient time and necessary information to consider the benefits and risks of involving the children in the clinical trial before written informed consent was obtained and before assent was sought from the child. Two different age groups (I: 4–8 years and II: 6 months–<4 years) were included. Children with painful site/s in the oral cavity aged 4 years or older were randomly assigned to be treated either with verum or with placebo, whereas children younger than 4 years were only treated with verum.
BODY.2. PATIENTS AND METHODS.2.1. STUDY MEDICATION, DOSAGE, AND ADMINISTRATION:
The 2% lidocaine gel (commercially available as Dynexan Mundgel, Kreussler Pharma, Germany) and the placebo preparation (identical composition without lidocaine, both products filled in identical 20 mg tubes to guarantee blindness) were locally applied once by or under supervision of a member of the study staff to the painful site/s as a pea size amount of gel (0.2 g gel) corresponding to 4 mg lidocaine hydrochloride in case of verum. The whole study took place at a clinical trial facility, specialized in conducting clinical studies with children. Different patient recruitment arrangements, like advertisements in the local newspaper, referrals by paediatricians, and distribution of flyers, were performed to enlarge the number of suitable patients, after obtaining approval by the ethics committee and health authority.
BODY.2. PATIENTS AND METHODS.2.2. PAIN MEASUREMENT:
The painful sites were defined as open breaks of the oral mucosa, lips, or tongue as a symptom of a variety of mild diseases, or trauma, for example, bites, aphthous ulcer, mouth blisters, cold sores, partial gingivitis, hand-foot-mouth disease, herpes simplex, teething, and trauma from dental braces. The primary efficacy variable was the pain reduction from T1 (prior to administration) to T2 (10 ± 5 min after application) as assessed by the Wong-Baker FACES Pain Rating Scale (Figure 1). This scale is a self-report measure used to assess the intensity of children's pain. The rating scale was used, because of its suitability for children from 3 years of age on as well as its appropriateness in pre- or nonverbal children. Children were instructed to indicate their pain by pointing to one of the faces. If the child was not old enough and/or not able to use this scale, the assessment of the children's pain by the parents on the same scale was used instead. A secondary efficacy variable was pain reduction from T1 (prior to administration) to T3 (30 ± 10 min after application, Wong-Baker FACES Pain Rating Scale). This "mixed" analysis of children's and parents' assessments was performed to consider the child's assessment as often as possible according to the protocol and statistical analysis plan (SAP). To investigate whether this approach was reliable, an additional analysis was performed with assessments of the same person (either child, if available from T1 and T2 (or T3), or parent, if the child's assessment was missing at one or two points of time). Additionally, assessment of satisfaction (5-point verbal rating scale with "very unsatisfied," "somewhat unsatisfied," "slightly satisfied," "satisfied," and "very satisfied") and assessment of local tolerability by the investigator ("poor," "moderate," "good," and "very good") were evaluated.
BODY.2. PATIENTS AND METHODS.2.3. SAMPLE SIZE ESTIMATION:
Sample size calculation was performed within a parametric test scenario. In age group I, a sample number of 64 subjects per treatment arm was considered sufficient to obtain reliable data (assumptions: difference to be detected: one scale point, alpha-level: 0.05, power: 80%, and standard deviation: two scale points). For age group II, a sample size of 32 patients was chosen. In order to recruit 160 evaluable patients, about 222 subjects were planned to be screened, due to an assumed screening failure rate of 15% and a drop-out rate of 15%.
BODY.2. PATIENTS AND METHODS.2.4. STATISTICAL ANALYSES:
The statistical analysis was conducted in compliance with the ICH E9 Note for Guidance on Statistical Principles for Clinical Trials. The efficacy variables were analysed by using the Mann-Whitney U test (differences between groups) and the Wilcoxon test (differences within groups, changes over time), whereby the null hypothesis of no difference between both groups was tested. To evaluate the robustness of results, additional analyses were applied (ANCOVA with baseline values as covariable and sensitivity analyses with several variants of assessments, e.g., using parents' instead of children's assessments). All analyses were performed using Statistical Analysis System software, version 9.2 or higher (SAS Institute Inc., Cary, NC, USA).
BODY.3. RESULTS:
Study data were collected between May 21st, 2012, and June 14th, 2014, from 129 patients (age group I) and additional 32 patients (age group II). Within age group I, 63 patients were treated with 2% lidocaine gel (verum) and 66 patients with placebo. No patient dropped out of the study (Figure 2).
BODY.3. RESULTS.3.1. BASELINE PATIENT CHARACTERISTICS:
In age group I, 54 male (verum N = 30, placebo N = 24) and 75 female subjects (verum N = 33, placebo N = 42) were included. In age group II, both genders were equally distributed (16 male and 16 female patients). The average age in group I was 6.4 ± 1.4 years, ranging from 4.0 to 8.9 years. In age group II, the mean average age was 1.8 ± 0.9 years, ranging from 6 months to 4.0 years. Except for one Black and one Latvian-Korean patient, all other patients were Caucasians. In age group I aphthous ulcer (36.0%) and in age group II teething (63.6%) were the main cause of painful sites (Table 1). The mean average size of the painful sites was 19.9 ± 15.7 mm2, ranging from 5 mm2 to 150 mm2. Gingiva and/or oral mucosa were affected in the majority of cases (age group I: 92.7%, age group II: 81.6%), whereas lips or tongue were involved in the remaining cases. The parents in age group I often reported grouching (20.2%), changes in behaviour (24.1%), and poor feeding (26.0%), whereas in age group II weeping (14.2%), crying (13.5%), grouching (18.4%), and sleepiness (18.4%) were often reported.
BODY.3. RESULTS.3.2. PAIN ASSESSMENT:
The self-rating by the children of age group I could be used in 107 cases (verum N = 53, placebo N = 54) at T1 (prior to administration) and in 109 cases (verum N = 57, placebo N = 52) at T2 (10 ± 5 min after application). The assessments by parents were used in 22 cases at T1 and in 20 cases at T2, because of children's lack of ability to rate their pain properly or showing signs of unwillingness or lack of concentration. For the secondary efficacy parameter (change of pain rating from T1 to T3 (30 ± 10 min after application)), the self-rating by the children was analysed in 108 patients (verum N = 56, placebo N = 52) at T3. The assessments by parents were used for 21 patients at T3.
BODY.3. RESULTS.3.3. EFFICACY RESULTS:
On average (median) pain has been reduced by 2.0/5 (verum) versus 1.2/5 (placebo) (Table 3). Nonparametric analysis (Mann-Whitney U test) of treatment related difference in pain assessment yielded a statistical significance (p < 0.001) of the observed effect in favour of the 2% lidocaine gel (verum). A similar result (p < 0.002) was achieved also for the measurement of pain reduction from T1 to T3. These results were reassured also if the assessment of the same person (either child or parent) was evaluated at both endpoints. The children's satisfaction as assessed by parents on a 5-point verbal rating scale one hour after administration tends to yield a higher proportion of verum patients showing satisfaction, although observed differences compared to placebo arm did not reach a statistical significance at α = 0.05 level (χ
2-Test including age group II subjects: p value = 0.060; χ
2-Test age group I only: p value = 0.259). Age group II (aged <4 years) patients were all treated with lidocaine 2% gel (verum). In order to assess the efficacy, the individual shift in pain rating had been evaluated. There were no patients with a worsening of pain, 4 patients (12.5%) without a change, 13 patients (40.6%) with an improvement of one, 7 patients (21.9%) of two, 5 patients (15.6%) of three, and 3 patients (9.4%) of four categories in pain rating on T2 compared to T1 (Table 3). This improvement in pain rating was even more pronounced at T3, with 16 patients (50%) indicating "No Hurt," 13 patients (40.6%) indicating "Hurts Little Bit," and 3 patients (9.4%) indicating "Hurts Little More" (Table 2). The observed ratings consequently showed statistically significant reduction of pain (Wilcoxon signed rank test results; T2: p value < 0.0001 and T3: p value < 0.0001).
BODY.3. RESULTS.3.4. SAFETY EVALUATION:
Seven out of 161 patients (4.4%) reported in total 7 adverse events (worsening of hand-mouth-foot disease, stomach ache, minimal lesion of the upper lip after a fall, bronchitis, single loose bowels, stabbing pain mouth due to aggravating hand-mouth-foot disease, and laceration of the gingiva due to a fall). Two adverse events were registered in each treatment arm in age group I and three adverse events in age group II after verum application (no placebo patients treated). None of these adverse events were assessed as related to study drug. For most patients (post study examination: 97.5%; one day after the study day: 98.1%) the local tolerability has been rated as "very good."
BODY.4. DISCUSSION:
In general, clinical studies with younger patients are more difficult to conduct not only because of the regulatory situation, but also because of the lower motivation of the children and their parents to participate and less ability of the young patients to understand the study principles [2, 5]. For minor to moderate and usually short-lasting pain situations, the psychological strain is weak, which affects the willingness to participate in a placebo-controlled clinical study, because the benefit seems not to be substantially relevant. Pain perception in children as a primary efficacy criterion is ambitious and the choice of a suitable method is important [6–8]. Most children aged 4-5 years or older can provide meaningful self-reports of pain intensity, depending on training and provision with age-appropriate tools. Children younger than 4-5 years have a tendency to use only the extremes of a scale. Other response sets or biases include giving the same answer to all questions and responding in an upward or downward sequence to successive questions. Pain rating may be affected by their perception of the consequences of the rating, for example, reward for being brave and fear of getting a syringe. Many other cognitive, social, and cultural factors influence pain ratings (e.g., previous experiences, temperament, presence of an audience, and family and community norms for pain expressions) making them idiosyncratic and difficult to interpret [6]. The assessment of efficacy criteria in studies investigating moderate pain relies on the self-assessment of pain. Patient independent criteria, like lab test or ultrasound, cannot be used. Topically applied locally acting medicinal products are more difficult to investigate than systemically acting products. Self-healing properties and placebo effects are presumably higher. For local skin or mucous membrane defects, the placebo formulations by themselves may have a healing or protecting effect. To solve these and other obstacles, we performed this study in a clinical trial facility and not in private practices, made sufficient patient enrolment possible with a variety of recruitment arrangements, excluded younger patients from the possibility to receive a placebo, and used an accepted pain rating scale for children, the Wong-Baker FACES Pain Rating Scale [9]. The participating children were trained and asked by the blinded study personnel in a language the child is familiar with. Additionally, to substitute and fortify the child assessment, the parents or legal guardians were asked to indicate on the same scale, how they consider the child's pain. More than 80% of children in group I (4–8 years) were able to rate pain by themselves whereas for the remaining children self-reporting could not be used. It is interesting that on average children in this age group rated their pain slightly lower than their parents. However, it should be realized that comparing the child's face with the expression on the faces picture is indirect rating and may be sensitive to bias. As expected and anticipated in age group II mostly only the parents' assessment of how they consider the level of the children's pain before and after administration could be evaluated. These children were too young to allow the use of the pain scale. The medicinal product used in this study is authorized and on the market in Germany and France for many years. In Germany, it can be applied to children without age restriction. In a recently published clinical study in patients between 6 years and 15 years with pain because of clamp placement, oral trauma, or aphthous ulcers, the identical medicinal product (also due to regulatory circumstances called a cream in France) showed significant superiority compared to the respective placebo formulation [10]. In the present study, significant superiority could be measured in children even down to 4 years of age. Additionally descriptive efficacy and safety data in children between 6 months and below 4 years were obtained, including patients with teething pain, one of the major sources of oral pain in children up to 2 years of age. Lidocaine alone or in combination with another local anaesthetic is a well-known product for local pain reduction [11, 12]. In different clinical studies conducted with children, the efficacy of topically applied lidocaine could be demonstrated [13–16]. But not in every study could the expected positive outcome be achieved, like in a recent study with children from 6 months up to 8 years suffering from acute infectious ulcerative mouth conditions analysing the effect of a 2% lidocaine viscous solution in comparison to a placebo on the amount of ingested fluid within 60 minutes of administration [17]. At least such an efficacy criterion seems questionable to judge the effectiveness of lidocaine. Seven out of 161 subjects (4.4%) reported in total 7 adverse events (in age group I 2 adverse events in the verum and the placebo arm each, in age group II 3 adverse events after verum treatment and no patients treated with placebo). None of these adverse events were assessed as study drug related, clearly demonstrating the safety of the product.
BODY.5. CONCLUSIONS:
The 2% lidocaine gel, as successfully tested in our clinical trial in comparison to a placebo gel with the same composition without lidocaine, is an adequate tool to reduce or prevent pain on the oral mucosa or gingivae, like bites, aphthous ulcers, mouth blisters, cold sores, gingivitis, hand-foot-mouth disease, dental braces, or teething in younger children. | 4,677,000 | {
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TITLE: A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β
ABSTRACT.BACKGROUND:
Long-acting β2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma.
ABSTRACT.METHODS:
This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC).
ABSTRACT.RESULTS:
Abediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 μg had similar magnitude of peak FEV1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV1 AUC 0–6, 0–12, and 0–24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate.
ABSTRACT.CONCLUSIONS:
Abediterol 0.625–2.5 μg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.
ABSTRACT.ELECTRONIC SUPPLEMENTARY MATERIAL:
The online version of this article (doi:10.1186/1471-2466-14-176) contains supplementary material, which is available to authorized users.
BODY.BACKGROUND:
The use of β2-adrenergic agonist bronchodilators in combination with inhaled corticosteroids (ICSs) to manage the symptoms of asthma is recommended by Global Initiative for Asthma (GINA) guidelines [1]. Currently licensed bronchodilators include salbutamol, a short-acting β2-adrenergic agonist (SABA) administered as required [2], salmeterol and formoterol, two long-acting β2-adrenergic agonists (LABAs) administered twice daily in combination with an ICS [3, 4], and the recently licensed vilanterol, a LABA administered once daily in fixed-dose combination with the ICS fluticasone furoate [5]. There is ongoing interest to develop once-daily medications to further simplify treatment regimens and improve patient compliance [6]. Abediterol is a novel, once-daily LABA in clinical development as a fixed-dose combination with an ICS for the treatment of asthma and chronic obstructive pulmonary disease (COPD) [7]. Abediterol displays high affinity for β2-adrenoceptors, plus a higher functional selectivity for β2-adrenoceptors over β1-adrenoceptors than formoterol, indacaterol, vilanterol and olodaterol in cellular models [7–9]. The potency of abediterol is also higher than salmeterol and indacaterol in isolated human bronchi and, in addition to these two LABAs, vilanterol and olodaterol in animal models [7, 10]. Abediterol has a rapid onset and prolonged duration of action [7, 10]. A Phase II clinical trial in patients with asthma provided results that were consistent with the preclinical data; abediterol resulted in significant improvements in lung function at 5 min post-dose that were greater than improvements seen with salmeterol, and significant bronchodilation was sustained up to 24 h post-dose [11]. These characteristics make abediterol an ideal candidate for once-daily dosing. Moreover, abediterol has a favorable cardiovascular safety and tolerability profile: in anesthetized dogs, abediterol had a lesser effect on heart rate compared with salmeterol, formoterol, and indacaterol at concentrations that produced comparable bronchodilation [7, 12]. In early phase clinical trials, doses of abediterol ≤10 μg were safe and well tolerated and did not demonstrate any clinically relevant effects on heart rate in healthy subjects [13], patients with asthma [14], or patients with COPD [15]. Drug regulatory authorities have concerns that excessively high LABA doses may cause unacceptable side effects [16]. The trough forced expiratory volume in 1 s (FEV1), measured 24 h after dosing, is an important endpoint to assess once-daily LABA efficacy [16]. The maximum effect achieved soon after dosing, otherwise known as the 'peak' effect, is also of interest for efficacy and safety reasons. A very high peak effect may indicate high levels of acute drug exposure that could predispose patients to β-agonist-mediated side effects, such as cardiovascular adverse events, when receiving chronic treatment [17]. Moreover, the ideal pharmacologic characteristic of a once-daily LABA is a low 'peak to trough ratio', ensuring relatively stable lung function throughout the day [18]. The peak effect of salbutamol is well characterized, and causes acute bronchodilation without safety concerns. The bronchodilator response following single-dose administration of salbutamol (4 x 100 μg) is commonly used as one of the diagnostic tests for asthma, as recommended by a joint European Respiratory Society (ERS)/American Thoracic Society (ATS) taskforce [19]. This effect is, therefore, a reasonable benchmark for a novel LABA to achieve and this degree of acute bronchodilation is considered clinically meaningful. A major regulatory agency recommended that the peak effects of abediterol should be compared to those of salbutamol to guide dose selection for further clinical trials in order to avoid a dose that induces a much greater degree of bronchodilation than is necessary for clinical effectiveness, which could increase the potential for safety concerns during chronic treatment. We report a placebo-controlled, dose-ranging, crossover study comparing the acute bronchodilator effects of abediterol to salbutamol in patients with persistent stable asthma. The primary aim of the study was to investigate the peak bronchodilatory effect of abediterol versus placebo and to confirm it was in the same range as that of salbutamol. The full profile of lung function over 24 h, including the trough FEV1, was also measured. The goal of this study was to enable the selection of abediterol doses for future long-term clinical trials, based on a peak effect similar to that of salbutamol 400 μg metered dose inhaler (MDI), coupled with a trough effect compatible with a 24-h duration of action. This trial design was a specific recommendation by a major regulatory agency.
BODY.METHODS.STUDY DESIGN:
This was a Phase IIa, randomized, double-blind, double-dummy, 6-way crossover, single-dose, multicenter, dose-ranging study conducted between August 2011 and January 2012. The study was conducted in two sites in the UK and seven in Germany. The study protocol was approved by an independent ethics committee in each country (see Additional file 1) and complied with the Declaration of Helsinki and the International Conference on Harmonisation and Good Clinical Practice guidelines. Patients provided written, informed consent. Following a screening visit and a 12–16 day run-in period to assess clinical stability, participants were randomized to 1 of 6 treatment sequences according to a balanced Williams design for crossover studies (1:1:1:1:1:1). Block randomization was performed by the Sponsor, using a computer-generated schedule to assign a treatment sequence to each patient randomization number. The block size and randomization schedule were not communicated to investigators. Patients received abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg (administered as four inhalations with 100 μg per inhalation), or placebo (at 09:00 h ±1 h) at each visit, with a washout period of 7–14 days. A follow-up telephone call to assess safety was made approximately 2 weeks following the final treatment visit or premature discontinuation. Abediterol and placebo to abediterol were administered via a multidose dry powder inhaler (Genuair®). Salbutamol and placebo to salbutamol were administered via a pressurized MDI (VentolinTM EvohalerTM). In order to preserve study blinding, independent, trained personnel prepared the medication, delivered the device to patients, and collected the device following inhalation.
BODY.METHODS.PATIENTS:
Eligible participants were men or women aged 18–70 years with a clinical diagnosis of persistent asthma (according to GINA guidelines) for ≥6 months prior to screening. Eligible patients had an FEV1 >60% and ≤85% of the predicted normal value, with an FEV1 reversibility ≥12%, and an absolute increase in FEV1 of ≥200 mL over their baseline value following inhalation of salbutamol 400 μg at screening. Comparable FEV1 measurements were required at screening and pre-dose at each visit in order to ensure there were no carry-over effects from previous treatment periods (limit of variability ±20%). At enrollment, all patients were using only an ICS to control their asthma, and had been on a stable dose and regimen for at least 4 weeks prior to screening, up to the equivalent of 1600 μg/day of beclometasone dipropionate, and had not previously been exposed to abediterol. Exclusion criteria included: a smoking history within the past 6 months or >10 pack-years; presence or history of relevant pulmonary disease or any other clinically relevant disease or abnormality as judged by the investigator; difficult-to-treat asthma; any respiratory tract infection ≤6 weeks prior to screening; hospitalization or emergency room treatment for asthma ≤3 months prior to screening; treatment with β2-antagonists; and positive laboratory tests for illicit drugs. The use of anticholinergics, SABAs (other than salbutamol), LABAs, continuous oral or parenteral corticosteroids, methyl-xanthines, cromolyn sodium, nedocromil, leukotriene modifiers, anti-immunoglobulin E, β1-blocking agents, and other investigational drugs was prohibited during the study. Patients using prohibited medications underwent up to 6 weeks' washout before the screening visit. Salbutamol pressurized MDI (100 μg/puff) was the only reliever medication permitted and was used on an as-needed basis and avoided 6 h prior to and during a treatment visit unless absolutely necessary.
BODY.METHODS.EFFICACY ASSESSMENTS:
Pulmonary function tests were conducted at screening, pre-dose, and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 23, 24, and 36 h post-dose at each treatment visit using standardized spirometers at each investigational site (eResearchTechnology, Philadelphia, PA, USA). Prior to the first spirometry measure, the technician demonstrated the procedure and allowed the patient two practice attempts. At each study time point, the maneuvers were repeated until three technically adequate measurements were made according to ERS/ATS guidelines for acceptability and repeatability [20], with a maximum of eight attempts allowed.
BODY.METHODS.SAFETY AND TOLERABILITY ASSESSMENTS:
Treatment-emergent adverse events (TEAEs), including serious adverse events, were recorded throughout the study and follow-up period. A physical examination was performed at screening and at 36 h post-dose following the last treatment period (Visit 6), and blood pressure and 12-lead electrocardiogram measures were made at screening, pre-dose, and at 0.75, 2, 6, 24 h post-dose for each treatment period, and 36 h post-dose at Visit 6. Clinical laboratory tests (blood chemistry, hematology, urinalysis, and a serum pregnancy test) were performed at screening and at 36 h post-dose at Visit 6. Blood glucose and serum potassium levels were assessed at screening, pre-dose, and at 4, 24 h post-dose for each treatment period, and 36 h post-dose at Visit 6.
BODY.METHODS.STATISTICS:
The primary efficacy endpoint was change from baseline in peak FEV1 (defined as the highest FEV1 value observed within 4 h of the administration of the investigational medicinal product [IMP]) on Day 1. Secondary endpoints included change from baseline in peak forced vital capacity (FVC) on Day 1, trough FEV1 (defined as the highest average of the maneuvers performed at 23–24 h post IMP administration) and FVC on Day 2, change from baseline in FEV1 and FVC at each time point up to 36 h post-dose, and change from baseline in normalized FEV1 area under the curve (AUC; defined as the area between baseline FEV1 and the FEV1 curve, from 0 to × hours divided by × hours) at 0–6, 0–12, and 0–24 h post-dose. In accordance with the GINA guidelines, a change in FEV1 of 200 mL was considered clinically relevant [1]. A population of 48 patients was necessary to achieve 80% power to detect a 150 mL change from baseline in peak FEV1 for any dose of abediterol compared with placebo. Assuming a 15% withdrawal rate, the protocol required at least 54 patients to be randomized. All reported efficacy assessments were analyzed in the intention-to-treat population, defined as all randomized patients who took at least one dose of the IMP (placebo, abediterol, or salbutamol) and had at least one baseline and one post-dose FEV1 value for at least one treatment visit. Safety analyses are reported in the safety population, which consisted of all randomized patients who took at least one dose of the IMP. All statistical analyses were performed using Statistical Analysis System (SAS Institute Inc., Cary, NC, USA) version 9.1.3 software. Efficacy variables were analyzed using an analysis of covariance model for crossover designs, with fixed-effect factors of sequence, treatment, and period, patient within sequence as a random effect, and baseline FEV1 or FVC as a covariate, as appropriate. Between-treatments comparisons were performed by means of contrasts on the treatment factor. The difference between treatments was estimated by the difference between the least squares means. Statistical comparisons between active treatments and placebo were two-sided hypothesis tests with a significance level of 0.05.
BODY.RESULTS.STUDY POPULATION:
A total of 115 patients were screened, with 62 patients randomized (40/62 [64.5%] male, mean age 40.9 ± 11.2 years). Patient demographics are presented in Table 1. A diagram of patient flow is presented in Figure 1. All 62 patients were included in the intention-to-treat and safety populations. One protocol violation occurred when a patient was inadvertently given the treatment scheduled for Visit 6 at Visit 5, and vice versa. Data for this patient were analyzed according to the treatments received. Four patients withdrew or were discontinued from the study: two due to inability to comply with the study schedule, one who did not fulfill stability criteria, and one for unknown reasons (patient did not return for the premature discontinuation visit).Table 1
Patient demographics at baseline: safety population
Patients (N = 62)Age, mean no. years (SD)40.9 (11.2)Male gender, n (%)40 (64.5)Race, n (%) White58 (93.5) Other4 (6.5)Cigarette smoking status, n (%) Former smoker21 (33.9) Never smoked41 (66.1)Smoking history, mean no. pack-years (SD)4.6 (3.3)Asthma duration, mean no. years (SD)25.5 (13.2)Asthma severity, n (%) 60% ≤ FEV1 < 80% of predicted46 (74.2) FEV1 ≥80% of predicted16 (25.8)Bronchial reversibilitya, mean % (SD)21.3 (8.2)FEV1 absolute reversibilityb, mean L (SD)0.568 (0.261)
acalculated as 100 x (FEV1 [post-bronchodilator] – FEV1 [pre-bronchodilator]/FEV1 [pre-bronchodilator]); bcalculated as FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator).FEV1, forced expiratory volume in 1 s; SD, standard deviation.Figure 1
Diagram of patient flow.
BODY.RESULTS.EFFICACY:
Mean baseline FEV1 values were similar across all treatment periods, ranging from 2.63 L to 2.69 L. The full profile of lung function after each treatment is shown in Figure 2. The onset of action of abediterol was rapid, with significant bronchodilation compared with placebo observed at the first study time point (15 min) post-dose (p < 0.0001 for all doses of abediterol versus placebo, Figure 2a). All doses of abediterol produced significantly greater improvements in peak FEV1 from baseline compared with placebo (p < 0.0001 for all doses, Table 2), and the magnitude of effect of abediterol 0.625, 1.25, and 2.5 μg was not significantly different from salbutamol 400 μg (Figure 3, Table 3). Least squares means differences in change from baseline in peak FEV1 versus placebo were 0.274, 0.322, 0.371, and 0.405 L for abediterol 0.313, 0.625, 1.25, and 2.5 μg, respectively, and 0.353 L for salbutamol 400 μg (Table 3). Median time to peak FEV1 was 3 h post-dose for abediterol (all doses), 2 h post-dose for placebo, and 1 h post-dose for salbutamol 400 μg.Figure 2
Change from baseline in FEV
1
over time. Data are presented as least squares means with 95% confidence intervals: a) p < 0.0001 versus placebo for salbutamol and all doses of abediterol at all time points; b) p < 0.0001 for all doses of abediterol 0–24 h post-dose and abediterol 1.25 and 2.5 μg 36 h post-dose versus placebo, p = 0.002 and p = 0.01 for abediterol 0.313 and 0.625 μg, respectively, at 36 h post-dose versus placebo. FEV1, forced expiratory volume in 1 s. Table 2
Change from baseline in pulmonary function parameters (L): intention-to-treat population
Placebo N = 59 Salbutamol 400 μg N = 58 Abediterol 0.313 μg N = 60 Abediterol 0.625 μg N = 60 Abediterol 1.25 μg N = 60 Abediterol 2.5 μg N = 61 Peak FEV 1
0.202 (0.045) 0.555**** (0.045) 0.477**** †† (0.045) 0.524**** (0.045) 0.573**** (0.045) 0.608**** (0.045) Trough FEV 1
a
-0.054 (0.039) -0.076 (0.039) 0.166**** †††† (0.039) 0.205**** †††† (0.039) 0.278**** †††† (0.039) 0.346**** †††† (0.039) Normalized FEV 1 AUC 0–6
0.088 (0.039) 0.347**** (0.039) 0.354**** (0.038) 0.403**** † (0.038) 0.461**** †††† (0.038) 0.496**** †††† (0.038) Normalized FEV 1 AUC 0–12
0.063 (0.040) 0.219**** (0.040) 0.348**** †††† (0.039) 0.393**** †††† (0.039) 0.455**** †††† (0.039) 0.496**** †††† (0.040) Normalized FEV 1 AUC 0–24
0.007 (0.039) 0.100** (0.039) 0.282**** †††† (0.039) 0.321**** †††† (0.038) 0.390**** †††† (0.038) 0.446**** †††† (0.039) Peak FVC 0.222 (0.034) 0.361**** (0.034) 0.317** (0.034) 0.329*** (0.034) 0.361**** (0.034) 0.380**** (0.034) Trough FVC a
-0.028 (0.035) -0.065 (0.035) 0.094** †††† (0.035) 0.050* †† (0.035) 0.111*** †††† (0.035) 0.120*** †††† (0.035) Data are least squares means (standard error).
a trough values are the mean of the 23 and 24 h post-dose measurements. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 versus placebo; † p < 0.05, †† p < 0.01, †††† p < 0.0001 versus salbutamol 400 μg (analysis of covariance). AUC, area under the FEV 1 curve; FEV 1 , forced expiratory volume in 1 s; FVC, forced vital capacity. Figure 3
Change from baseline in peak FEV
1
at Day 1. Data are presented as least squares means ± standard error: p < 0.0001 versus placebo for all doses of abediterol and salbutamol 400 μg; **p < 0.01, ***p < 0.001, ****p < 0.0001 (analysis of covariance). FEV1, forced expiratory volume in 1 s. Table 3
Comparison of peak FEV
1
for abediterol versus placebo and abediterol versus salbutamol
Least–squares mean difference (standard error) 95% confidence interval Abediterol 2.5 μg vs. placebo 0.405 (0.027) 0.353, 0.458 Abediterol 1.25 μg vs. placebo 0.371 (0.027) 0.318, 0.424 Abediterol 0.625 μg vs. placebo 0.322 (0.027) 0.269, 0.375 Abediterol 0.313 μg vs. placebo 0.274 (0.027) 0.221, 0.327 Salbutamol 400 μg vs. placebo 0.353 (0.027) 0.299, 0.406 Abediterol 2.5 μg vs. salbutamol 400 μg 0.0529 (0.0270) -0.0002, 0.1061 Abediterol 1.25 μg vs. salbutamol 400 μg 0.0181 (0.0269) -0.0350, 0.0711 Abediterol 0.625 μg vs. salbutamol 400 μg -0.0308 (0.0269) -0.839, 0.0223 Abediterol 0.313 μg vs. salbutamol 400 μg -0.0783 (0.0269) -0.1313, -0.0253 Data included for comparisons of all doses of abediterol with placebo and with salbutamol. Statistically significant increases in FEV1 were sustained at 24 h post-dose compared with placebo (p < 0.0001 for all doses of abediterol 0–24 h post-dose, Figure 2b). Abediterol significantly improved trough FEV1 from baseline compared with placebo (p < 0.0001 for all doses; Figure 4). Least squares means differences in change from baseline in trough FEV1 versus placebo were 0.219 L (95% CI 0.136, 0.302), 0.259 L (95% CI 0.176, 0.342), 0.332 L (95% CI 0.249, 0.415), and 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313, 0.625, 1.25, and 2.5 μg, respectively (Table 2). The effects of salbutamol on FEV1 were not sustained after 6 h post-dose, as expected for a SABA (Figure 2b).Figure 4
Change from baseline in trough FEV
1
at Day 2. Data are presented as least squares means ± standard error: p < 0.0001 versus placebo for all doses of abediterol; **p < 0.01, ***p < 0.001, ****p < 0.0001 (analysis of covariance). FEV1, forced expiratory volume in 1 s. Change from baseline in normalized FEV1 AUC0–6, FEV1 AUC0–12, and FEV1 AUC0–24 was significantly higher for all doses of abediterol versus placebo (p < 0.0001 for all, Table 2), with dose-related effects observed. The change from baseline in normalized FEV1 AUC0–6 was significantly greater for abediterol 0.625–2.5 μg versus salbutamol 400 μg (p < 0.05, Table 2).
BODY.RESULTS.EFFICACY.FVC:
Mean baseline FVC values were comparable across treatment periods, ranging from 4.23 L to 4.30 L. Abediterol produced significantly greater change from baseline in peak FVC compared with placebo (p < 0.01 for all doses, Table 2). The change from baseline in peak FVC was similar to that observed with salbutamol. Additionally, abediterol significantly improved trough FVC from baseline compared with placebo (p < 0.05 for all doses, Table 2). All doses of abediterol significantly (p < 0.05) increased FVC versus placebo up to 24 h post-dose except for the 0.625 μg dose at 12 and 23 h.
BODY.RESULTS.SAFETY AND TOLERABILITY:
The percentage of patients experiencing TEAEs was similar across all treatment groups (Table 4). Most TEAEs were mild to moderate in intensity, no patient discontinued the study due to a TEAE, and there were no serious adverse events or deaths. The most common TEAEs were headache and nasopharyngitis, reported by 41.9 and 27.4% of patients, respectively. The percentage of patients that experienced at least one treatment-related TEAE was <10% for all doses of abediterol, and was similar to that of salbutamol and placebo. No clinically significant changes in serum glucose or potassium concentrations were observed over time in any of the treatments groups (Table 5). Minor variations in heart rate over time were observed for all treatment groups, including placebo; none were considered to be dose related or clinically relevant (Table 5). There were no clinically relevant changes in clinical laboratory tests, blood pressure, or electrocardiogram parameters.Table 4
TEAEs occurring in ≥2% of patients in any treatment group: safety population
Number (%) of patients reporting TEAEsPlacebo N = 59Salbutamol 400 μg N = 58Abediterol 0.313 μg N = 60Abediterol 0.625 μg N = 60Abediterol 1.25 μg N = 60Abediterol 2.5 μg N = 61Total N = 62Any TEAE16 (27.1)12 (20.7)18 (30.0)16 (26.7)18 (30.0)23 (37.7)51 (82.3) Headache7 (11.9)6 (10.3)4 (6.7)7 (11.7)8 (13.3)7 (11.5)26 (41.9) Nasopharyngitis1 (1.7)08 (13.3)3 (5.0)4 (6.7)2 (3.3)17 (27.4) Chest discomfort2 (3.4)01 (1.7)002 (3.3)5 (8.1) Wheezing1 (1.7)2 (3.4)1 (1.7)01 (1.7)04 (6.5) Oropharyngeal pain01 (1.7)01 (1.7)03 (4.9)4 (6.5) Cough2 (3.4)001 (1.7)003 (4.8)TEAE, treatment-emergent adverse event.Table 5
Change in clinical safety parameters from pre-dose values following treatment: safety population
Placebo N = 59Salbutamol 400 μg N = 58Abediterol 0.313 μg N = 60Abediterol 0.625 μg N = 60Abediterol 1.25 μg N = 60Abediterol 2.5 μg N = 61Serum glucose (mmol/L) 4 hours post-dose-0.37 (0.56)-0.24 (0.55)-0.19 (0.71)-0.27 (0.70)-0.16 (0.94)-0.23 (0.74) 24 hours post-dose0.01 (0.38)0.00 (0.33)0.13 (0.51)0.06 (0.62)0.11 (0.45)0.15 (0.59)Serum potassium (mmol/L) 4 hours post-dose-0.01 (0.36)-0.09 (0.38)-0.01 (0.35)0.10 (0.37)0.02 (0.36)-0.04 (0.35) 24 hours post-dose-0.02 (0.37)0.04 (0.34)0.05 (0.33)0.15 (0.32)0.04 (0.28)0.05 (0.38)Heart rate (bpm) 0.75 h post-dose-0.6 (9.1)2.0 (10.1)-0.7 (6.1)-0.8 (7.5)-1.5 (9.0)-0.8 (6.2) 2 h post-dose-3.4 (8.7)-1.0 (8.0)-2.0 (6.6)-3.4 (8.1)-4.3 (8.4)-3.2 (6.7) 6 h post-dose5.1 (10.2)7.2 (7.7)6.2 (7.1)6.2 (8.0)6.4 (9.8)5.3 (7.2) 24 h post-dose-2.1 (9.8)-1.9 (8.0)-1.6 (6.7)-0.8 (8.4)-0.9 (8.7)-0.6 (7.6)Data are mean (standard deviation).bpm, beats per minute.
BODY.DISCUSSION:
In this study, abediterol 0.313, 0.625, 1.25, and 2.5 μg provided clinically and statistically significant improvements in peak bronchodilation versus placebo in patients with persistent, stable asthma. Abediterol doses ≥0.625 μg also caused bronchodilation compatible with once a day administration, as improvements in trough FEV1 >250 mL compared with placebo were observed. The peak bronchodilatory effect of abediterol was similar to that of salbutamol 400 μg for all doses ≥0.625 μg. A mean increase in peak FEV1 >200 mL is considered clinically relevant in asthma [1]. This magnitude of change was exceeded for all doses of abediterol, including the lowest dose, 0.313 μg. The primary objective of this study was to define abediterol doses that caused peak bronchodilation similar to salbutamol, the most widely prescribed SABA [21]. High doses of β2-agonists may increase the degree of bronchodilation but also can cause excessive systemic side effects through systemic absorption [22]. However, the current study demonstrates that the doses of abediterol from 0.625 to 2.5 μg induce acute bronchodilation similar to salbutamol, and therefore treatment with higher doses may not be warranted. Significant bronchodilation compared with placebo was achieved with a range of abediterol doses from 0.313 to 2.5 μg, consistent with the high potency of abediterol demonstrated in preclinical studies that suggested a potential for significant bronchodilation in vivo[7]. Abediterol has higher potency than formoterol, salmeterol, indacaterol, olodaterol, and vilanterol in anesthetized guinea pigs [7, 10] as well as higher potency than salmeterol and indacaterol with comparable potency to formoterol in isolated human bronchi [7]. Based on the results of this preliminary dose-ranging study and the guidelines published by Chowdhury et al. [16], the clinically effective dose in asthma is considered most likely to be in the range of 0.625–2.5 μg. Significant bronchodilation compared with placebo was observed for salbutamol and all doses of abediterol at the first-assessed time point (15 min) post-dose; this indicates a rapid onset of action for both salbutamol and abediterol. Salmeterol and formoterol, both twice-daily LABAs, are widely used as maintenance therapy in COPD and asthma due to their longer durations of action compared with salbutamol [6, 18]. In clinical studies in patients with asthma, the onset of action of formoterol 24 μg is consistently faster than that of salmeterol 50 μg, with a median onset of action of 3.6 min compared with 31.0 min in one study [23, 24]. In vitro experiments in isolated human bronchi suggest that the onset of action of abediterol is faster than salmeterol and is not significantly different from formoterol and indacaterol [7]. The prolonged duration of action of abediterol, with significant improvements in trough FEV1, normalized FEV1 AUC0–24, and trough FVC relative to placebo, and significant bronchodilation maintained up to 36 h post-dose is consistent with the results of previous clinical studies in healthy subjects and patients with COPD or asthma [11, 13, 25]. For example, a recent Phase II clinical study in patients with COPD demonstrated that abediterol 2.5, 5, and 10 μg achieved >200 mL increases in FEV1 at 24 h, and that this bronchodilatory effect was greater than that of indacaterol 150 μg, and the duration of action was similar [25]. Taken together, these results are compatible with a once-daily dosing regimen in asthma and COPD. The convenience of once-daily dosing is likely to improve compliance in patients with asthma, leading to better patient outcomes [26, 27], as shown in various studies, including that of Wells et al. whereby once-daily ICS led to improved compliance in patients with asthma compared with ICS administered multiple times daily [28]. LABA monotherapy treatment is contra-indicated in asthma; co-administration with an ICS is mandated, preferably as a fixed-dose combination to reduce the risk of monotherapy administration. Development of once-daily LABAs for use in fixed-dose combinations with once-daily ICS is important for simplifying treatment regimens and, therefore, helping improve patient compliance and general asthma management. The safety and tolerability profile of abediterol in this study is comparable to that reported in other studies in the abediterol development program [11–13, 25]. Single doses of abediterol 0.313–2.5 μg were safe and well tolerated, and the TEAEs were consistent with the known safety profile of β2-agonists.
BODY.CONCLUSION:
Abediterol 0.625–2.5 μg demonstrated a peak bronchodilatory response similar to that of a high dose of salbutamol (400 μg) at very low doses, and showed a clear dose–response relationship. Abediterol is a promising new, highly potent, LABA with a sustained duration of action and a favorable safety and tolerability profile. These results suggest that further studies are warranted to further evaluate the efficacy and safety of abediterol in combination with ICS in both asthma and COPD.
BODY.ELECTRONIC SUPPLEMENTARY MATERIAL:
Additional file 1:
Independent Ethics Committees (IEC).
(DOCX 17 KB) | 4,320,624 | {
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TITLE: Assessing Calcium Intake in Postmenopausal Women
ABSTRACT.INTRODUCTION:
Because foods fortified with calcium are increasingly available, the calcium content of calcium-fortified foods may not be adequately captured in traditional assessments of dietary intake, such as dietary records analyzed with commercially available software. The primary objective of our study was to design and test a calcium-focused food frequency questionnaire (CFFFQ) including foods naturally rich in calcium and calcium-fortified foods. Secondary objectives were to review calcium sources and adequacy of intake in black and in white postmenopausal women.
ABSTRACT.METHODS:
We studied a convenience sample of 46 black and 139 white postmenopausal women (mean [SD] age 69.4 [5.8] years). Subjects completed a multiple-pass interview for 24-hour recall of foods eaten and the 46-item CFFFQ.
ABSTRACT.RESULTS:
The correlation between measures for total daily calcium intake was moderately strong (r = 0.53, P < .001). The CFFFQ estimated greater total daily calcium intake than did the 24-hour recall (mean [SD], 1,021 [624] mg/d vs 800 [433] mg/d, P < .001). As daily calcium intake increased, the 24-hour recall increasingly underreported calcium (r = 0.41, P < .001) compared with the CFFFQ. Cross-tabulation and Χ2 analyses found that the CFFFQ had greater specificity for lower calcium intakes. For calcium classified by food groups, there was moderate correlation for dairy (r = 0.56, P < .001) and fruits (r = 0.43, P < .001). The CFFFQ overestimated mean total calcium compared with the 24-hour recall by 221 mg/d (P < .001), including within racial groups (195 mg/d for black women, P = .04, and 229 mg/d for white women, P < .001). Dairy was the primary calcium source for both groups (55% of intake for black women and 57% of intake for white women).
ABSTRACT.CONCLUSION:
The CFFFQ can be used to identify postmenopausal women with inadequate calcium intakes (<800 mg/d) and to identify key sources of dietary calcium. Older black women consume less daily calcium than do older white women.
BODY.INTRODUCTION:
As the prevalence of osteoporosis continues to increase, interventions targeting modifiable risk factors receive more emphasis from researchers, clinicians, and public health professionals. Although many nutrients are important to bone health, interventions largely focus on calcium intake (1). Clinicians often prescribe a calcium supplement but pay limited attention to dietary sources of calcium intake (2,3). Other interventions may target only dairy calcium (4,5). However, calcium fortification of foods broadens the possible sources of calcium so that adequate calcium intake may be achieved through a diverse diet. Sources of dietary calcium may differ across cultures and ethnicities according to food preferences and tolerances. For example, blacks and Asians have a higher prevalence of lactose intolerance, which may lead to reduced dairy intake, but also have cultural food preferences, including not drinking milk at meals, that affect calcium intake (6). White women eat more cheese and drink more milk than do black or American Indian women (7). However, research specifically targeting calcium intake and food source is scarce. Previous research from our group investigating the role of socioeconomic status on calcium intake determined that black women consumed fortified grain products more frequently than did white women (8). Because fortified foods are increasingly available (9), the calcium content of calcium-fortified foods may not be adequately captured in traditional assessments of dietary intake, such as dietary records analyzed with commercially available software. The primary aim of this study was to develop and evaluate the feasibility of a calcium-focused food frequency questionnaire (CFFFQ) that incorporates both natural and fortified sources of calcium. Because determining calcium intake has become more difficult as food fortification has become more common, this study compared 2 methods: an interview for 24-hour recall of calcium intake and the CFFFQ. Although supplements can be an important source of calcium, this project focused on food-derived calcium. Secondary aims were to compare food source of calcium between black and white women aged 60 years or older and evaluate the adequacy of calcium intake as assessed using the 24-hour recall and the CFFFQ. Postmenopausal women were studied because they are at high risk for osteoporotic fractures (1).
BODY.METHODS.PARTICIPANTS:
In 2005, we recruited a convenience sample of postmenopausal women aged 60 to 80 years who were enrolled in a parent study in the Urbana-Champaign area of Illinois (10) (assessing body composition, bone health, physical activity, physical function, and self-efficacy) to complete additional nutritional assessments. Exclusion criteria for the parent study were neurologic illness, orthopedic limitations, or cognitive limitations that precluded completion of all study testing procedures. All those in the parent study were invited to participate in the current study of evaluation of calcium intake. The human subjects institutional review board of the University of Illinois approved the research protocol, and all participants completed an informed consent form before data collection began.
BODY.METHODS.CALCIUM INTAKE:
The CFFFQ and a self-reported 24-hour recall were completed on the same day to assess calcium intake and food source. The CFFFQ is a 46-item food frequency survey focusing on calcium-rich foods. Foods on the questionnaire were chosen based on calcium content and those found in previous studies to be commonly consumed. Foods on the CFFFQ were categorized and presented according to representative food groups: dairy (6 foods), foods with dairy (5 foods), fruits (6 foods), vegetables (3 foods), grains (10 foods), meats (8 foods), and other foods (8 foods) (Appendix). Inclusion of fortified foods was based on availability for purchase in area grocery stores (both local and chain stores). Fortified foods were noted as such on the CFFFQ. A standard portion size was included for each specific food item. Participants entered quantity of food relative to daily, weekly, monthly, or yearly consumption. "Not eaten" was given as an option. We entered foods and servings into a database (Microsoft Access 2003, Redmond, Washington) that calculated calcium content on a daily basis. Double entry was used for quality assurance. Participants met with researchers to complete the 24-hour recall. The researchers used a multiple-pass interview style to elicit complete information (11). Foods from the 24-hour recall were categorized into the same food groups as on the CFFFQ and were then entered in Nutritionist Pro version 2.3 (First DataBank, San Bruno, California) to obtain calcium values per day.
BODY.METHODS.STATISTICAL ANALYSIS:
We analyzed the data by using SPSS version 14.0 (SPSS, Inc, Chicago, Illinois). On the basis of the findings of the Kolmogorov-Smirnov test, the primary variables of interest were not normally distributed. Nonparametric tests were subsequently used to evaluate group or intake assessment differences (Spearman rank correlation and Mann-Whitney). We assessed the adequacy of calcium intake by comparing these 2 assessment methods to two-thirds of the Institute of Medicine's (12) adequate intake amount (used to determine inadequate intake) for women aged 51 years or older. Comparison of the adequacy classification as a measure of specificity of each calcium intake method was completed by using cross-tabulation to demonstrate the relationship between the 2 variables. Chi-square analysis was performed on the cross-tabulated variables. Significance was defined as α = .05.
BODY.RESULTS:
Of 245 eligible women from the parent study, 185 chose to participate in our study. Of the 185, 46 were black (mean [SD] age, 68.0 [4.85] years) and 139 were white (70.0 [6.0] years).
BODY.RESULTS.COMPARISON OF CFFFQ TO 24-HOUR RECALL:
Calcium from the CFFFQ was significantly correlated with 24-hour recall for all food groups (P < .001) except for vegetables (P = .08) (Table 1). Estimates obtained with the 24-hour recall method were significantly lower than CFFFQ estimates of total daily calcium, dairy, foods with dairy products, fruits, and vegetables (Table 2). The CFFFQ estimate of mean total calcium compared with the 24-hour recall was higher by 221 mg/d (P < .001), including within racial groups (195 mg/d for black women, P = .04, and 229 mg/d for white women, P < .001). There was no significant difference between the CFFFQ and 24-hour recall methods for calculated calcium intake for grains, meats, and "other" foods. This pattern was consistent for the total group and for black and white women separately (Table 2). The Bland-Altman plot illustrates the lack of agreement between methods of assessment for total daily intake (Figure). The positive correlation between the lack of agreement (error score on the Y-axis) and the daily intake indicates that for increasing levels of daily calcium intake, the 24-hour recall of calcium intake increasingly underestimated calcium intake compared with the CFFFQ (r = 0.41, P < .001). Figure.Scatterplot of agreement between the calcium-focused food frequency questionnaire (CFFFQ) and an interview for 24-hour recall of calcium intake. Estimated calcium difference is the difference in calcium intake found between the CFFFQ and the 24-hour recall. Average calcium intake is the average of calcium intake between the 2 methods. Open circles represent white women (n = 139) and closed circles represent black women (n = 46). The parallel solid and the broken lines represent the mean difference (2 SD) for all participants (221 [528] mg).The figure shows the lack of agreement between the 2 methods of assessing total daily intake. P < .001, r = 0.41.
BODY.RESULTS.CALCIUM ADEQUACY ASSESSMENT:
The prevalence of inadequate intake (<800 mg) was 56% (n = 103) using the 24-hour recall and 45% (n = 83) using the CFFFQ method. Examining the cases where intake would be inadequate as measured by both tools, 64 (35%) women would be classified as having inadequate calcium intake. However, 39 (21%) women whose intake would be classified as adequate by the CFFFQ would be classified as inadequate by the 24-hour recall method. Only 19 (10%) who would be classified as having inadequate intake by the CFFFQ would have adequate intake as classified by the 24-hour recall. Compared with the self-reported 24-hour recall, the CFFFQ indicates more specificity for lower intakes.
BODY.RESULTS.COMPARISON OF INTAKE AND SOURCE BETWEEN BLACK AND WHITE WOMEN:
Regardless of dietary assessment method used, white women had higher calcium intakes than black women. When using the CFFFQ, white women reported consuming approximately 43% more calcium than did black women (mean [SD] 1,104 [632] mg for white women vs 768 [531] mg for black women, P < .001). When using the 24-hour recall method, mean calcium intake for white women was approximately 52% higher than intake for black women (875 [429] mg vs 573 [365] mg, P < .001). From the CFFFQ, the primary calcium source was dairy products (55% for black women and 57% for white women). White women obtained more calcium (630 [423] mg) from dairy than did black women (424 [373] mg, P < .004). Grains were the second highest calcium source, although grains provided a much lower percentage than dairy (13% of total calcium for each racial group). Calcium from grains primarily came from fortified foods. Dairy was also the primary calcium source when the 24-hour recall data were analyzed, and a significant difference in mean (SD) dairy calcium intake between racial groups was found (243 [273] mg for black women, 444 [360] mg for white women, P < .001).
BODY.DISCUSSION:
Calcium intake has received increased attention in the last decade because of its role in bone health and as a modifiable risk factor for osteoporosis. The number of calcium-fortified food products being developed and marketed has increased substantially (9). Although labeling for "excellent" (>200 mg/serving) and "good" (100-200 mg/serving) sources of calcium are regulated by the Food and Drug Administration, there is no federal regulation regarding which foods can be fortified with calcium or the degree of fortification (13). Together, these factors make discerning calcium intake difficult for researchers, clinicians, dietitians, and consumers. The primary findings of this study are that the CFFFQ identifies low calcium intakes and identifies key sources of calcium, including calcium-fortified foods. Other studies have included either no calcium-fortified foods (14-18), calcium-fortified mineral water (19), calcium-fortified juice alone (20), calcium-fortified juice and a grain product (21), or did not provide details regarding the inclusion of calcium-fortified foods in the assessment tool (5,7,22-26). In contrast, the CFFFQ is unique in providing 14 fortified food choices, including 1 in fruits, 8 in grains, and 5 in "other" food categories. Fortification of foods can contribute greatly to total calcium intake. From our data, inclusion of calcium-fortified foods in the diet has the potential to increase total daily calcium intake by 1,000 mg or more. Because calcium fortification of food products is not federally regulated, food items being fortified and levels of fortification vary at the discretion of the manufacturer. The lack of regulation may hinder the role that these foods can play in dietary calcium intake by affecting the consistency of the calcium content of the product. The second unique feature of this study is the categorization of calcium intake estimates into food groups. Although total calcium intake is the primary focus in nutritional assessment studies, the effectiveness of nutrition education and osteoporosis interventions can be enhanced by focusing on calcium intake from the food groups the participants usually get their calcium. This information can be used to design more realistic and targeted nutrition education messages. In our study, the largest percentage of total calcium for both white and black women came from dairy, followed by grains and fruits. Although the grain category contained several fortified food items, the fruit category contained only 1 fortified food item. Even though consumption of fortified foods was assessed, dairy was still the primary calcium source found in this study. An analysis (15) of food intake from the US Department of Agriculture's 1994-1996, 1998 Continuing Survey of Food Intakes by Individuals (CSFII) found that dairy contributed 42% of total calcium intake. A higher percentage of dairy contribution would have been expected from that study because it included no competing calcium-fortified foods. In addition, the CSFII reported 21% of total calcium from calcium-rich mixed foods (ie, foods with 2 or more items with calcium such as sandwiches or pizza). In our study, this category contributed only 4% to 5%. Ward et al (21) also reported that most calcium intake was derived from dairy, but a comparable calcium-rich mixed foods group is not identified. The food frequency assessment tool used by Ward et al (21) also ranked the fruits and vegetables group and grains as contributing 11% to 15% of total calcium, whereas the diet records used in the study estimated this contribution at 6% to 13%. Cook et al (15) included no calcium-fortified foods, and the Ward et al (21) study was limited to calcium-fortified juice and 2 grain products. There is a scarcity of information in the literature regarding calcium intake for black and white women. In our study, mean total calcium intake among black women did not meet the adequate intake value whereas it did among white women. Other studies conclude that calcium intake is greater in white women than black women (27,28). However, an article published from the parent study of our study using the same CFFFQ found no difference in total, daily, dietary, or supplemental calcium (8). In that analysis, black and white women were matched on age, socioeconomic status, and education level (n = 33 per group). The findings suggest that racial differences in calcium intake are somewhat influenced by socioeconomic status and education level. Similarly, a comparison between black, white, and American Indian women also reported no significant difference in dietary calcium between black and white women (7). In our study, grains were the second-highest calcium source for both black and white women. Grains are predominately calcium-fortified sources. This is consistent with findings from our previous work, which determined that dairy was the greatest source of calcium but more for white women, whereas black women consumed greater amounts of calcium-fortified grains (8). The prominent role of calcium-fortified foods in these studies reinforces the need for these sources to be carefully evaluated when measuring calcium intake.
BODY.DISCUSSION.LIMITATIONS:
The values from the CFFFQ were typically higher than those from the 24-hour recall, with the exception of vegetables and "other" foods. This finding may be due in part to the limitations of using a 24-hour recall. Women may have identified foods in the CFFFQ but did not happen to consume those foods on the specific day of the recall, except for vegetables. However, Chee et al (24) found a similar trend in comparing a calcium-rich food frequency questionnaire with a 3-day diary for postmenopausal Malaysian women. Assessing dietary intake by any method has inherent limitations. Validating food frequency questionnaires can be complicated without biomarkers for comparison. Because most nutrients do not yet have reliable biomarkers, 24-hour recalls or food records are the usual standard instruments. Correlations between these methods are considered adequate within the range of 0.4-0.7 (29). Although most of the correlations between total calcium and calcium from food groups when comparing CFFFQ to 24-hour recalls are significant, only total calcium intake, dairy calcium intake, and fruits fall within this acceptable statistical range. Differences in reported calcium intake when comparing the CFFFQ and 24-hour recall could be attributed to a lack of consumer awareness of calcium fortification when responding to the 24-hour recall and a positive respondent bias on the CFFFQ. For example, participants could have responded more positively concerning calcium-fortified foods if consumption of that food was seen as a positive health behavior. Because calcium-fortified foods can essentially double calcium intake, consumer awareness of their own calcium-fortified food product consumption and interviewer probe for each of these food items are essential for an accurate estimate of calcium intake. To assist both the researcher and clinician, software for dietary assessment needs to be updated to include the calcium-fortified foods. Several food frequency questionnaires that assess calcium intake have shown strong correlation with food actually consumed (19,22-25,30,31). However, many studies report correlations but no difference between means or report findings regarding only total calcium intake and not calcium intake by individual food groups. In addition, many rapid assessment tools include either no or limited sources of calcium-fortified foods, and these foods may or may not be probed for on 24-hour recalls.
BODY.DISCUSSION.CONCLUSIONS:
Our results suggest that the CFFFQ could be used to determine inadequate intakes of calcium. Primary calcium sources for all women were dairy followed by grains, and calcium intake was higher in white women than in black women. The CFFFQ can be used to more accurately identify calcium intakes and usual calcium source, which is of interest because of the increasing availability of calcium-fortified foods. Calcium-fortified sources can go unreported in 24-hour recalls and diaries, leading to an underestimation of calcium intake. When 24-hour recalls are used to assess and quantify calcium intake, researchers and clinicians need to clarify with clients whether the foods they ate were fortified. The CFFFQ may be used to better quantify calcium intake, including both natural and fortified sources. Accurate assessment of calcium is critical in evaluating bone health risks. This information can aid in the development of effective interventions to increase calcium intake. | 2,774,638 | {
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TITLE: Cluster Randomized Trial of Text Message Reminders to Retail Staff in Tanzanian Drug Shops Dispensing Artemether-Lumefantrine: Effect on Dispenser Knowledge and Patient Adherence
ABSTRACT:
Artemisinin combination therapies are available in private outlets, but patient adherence might be compromised by poor advice from dispensers. In this cluster randomized trial in drug shops in Tanzania, 42 of 82 selected shops were randomized to receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL). Eligible patients purchasing AL at shops in both arms were followed up at home and questioned about each dose taken. Dispensers were interviewed regarding knowledge of AL dispensing practices and receipt of the malaria-related text messages. We interviewed 904 patients and 110 dispensers from 77 shops. Although there was some improvement in dispenser knowledge, there was no difference between arms in adherence measured as completion of all doses (intervention 68.3%, control 69.8%, p [adjusted] = 0.6), or as completion of each dose at the correct time (intervention 33.1%, control 32.6%, p [adjusted] = 0.9). Further studies on the potential of text messages to improve adherence are needed.
BODY.INTRODUCTION:
Patient adherence to treatment is an important step in ensuring the effectiveness of artemisinin-based combination therapies (ACTs) for malaria.1 Incomplete adherence to recommended treatment can result in poor clinical outcomes, undermine the effectiveness of case management as a tool for malaria control, and may contribute to the selection of drug-resistant malaria parasites.2,3 ACTs are first-line treatment of Plasmodium falciparum malaria in the public sector of most malaria-endemic countries, with patient adherence reported to range widely from 39% to 100%.4,5 Many patients seek care for malaria in the private retail sector.6–9 The proportion of private sector clients obtaining ACTs has increased over time as ACTs have become more widely known, and their price has fallen, particularly in settings where they have been subsidized by programs such as the Affordable Medicines Facility-malaria (AMFm).10 Although access to effective antimalarials in the private sector may have increased, drug sellers may not always provide patients with appropriate doses or advice, raising concerns about patient adherence, though evidence is very limited. Only five studies have specifically assessed patient adherence to antimalarials obtained in the private retail sector.11–15 Of these, ACTs were used only in one study by Cohen and others (2012)11 in Uganda, which reported 66% of patients seeking care from drug shops were adherent. As ACTs become more available in the private sector, it becomes increasingly important to understand patient adherence and the effects of interventions intended to improve adherence. Supporting interventions, such as shopkeeper training, have previously succeeded in increasing the proportion of patients who receive and complete the recommended dose of non-ACT antimalarials,13,16 but such interventions have yet to be tested on a national scale or applied to ACTs. Mobile phones are a promising tool for the delivery of healthcare interventions as coverage of mobile networks and handset ownership increases.17–19 Text messaging, the least expensive mobile phone function, has been used in malaria control settings for commodity monitoring, disease surveillance, and pharmacovigilance.20 In addition, a trial in public health facilities in Kenya21 showed that 6 months of text message reminders improved public health workers' management of pediatric malaria by 24% points immediately after the intervention, and the improvements were sustained for at least 6 months after the intervention was withdrawn. The text message reminders were well accepted by health workers,22 inexpensive, and cost-effective.23 Given the concerns over inadequate patient adherence to ACTs delivered through the private retail sector, and the potential benefit of text-message interventions to enhance adherence, we designed and completed a cluster randomized trial in southern Tanzania to assess the effect of text message reminders to drug shop workers on patient adherence to artemether-lumefantrine (AL). We also evaluated the effect of text messages on dispenser knowledge and advice. The private retail sector in Tanzania is an important source of treatment of malaria,24,25 and ACT availability in such outlets increased after the implementation of AMFm in 2010. Another key intervention in Tanzania's private sector has been the creation of accredited drug dispensing outlets (ADDOs) by the Tanzania Food and Drug Administration (TFDA) to improve regulation of drug shops and quality of medicines. ADDOs are drug shops that have been upgraded through a process of training and certification and are allowed to sell a limited number of prescription-only drugs, including some antibiotics and ACTs.26,27
BODY.METHODS.STUDY SETTING.:
The study was conducted in Mtwara, a rural region in southeastern Tanzania with 35.5% of the population in the lowest national wealth quintile.28 Prevalence of malaria among children 6–59 months of age in Mtwara was 17.4% in the 2011–2012 HIV/AIDS and Malaria Indicator Survey29 and 23% in a survey of patients seeking treatment at private drug shops.30 AL has been recommended as the first-line treatment of malaria since 2004, although it was not available in public health facilities until 2006. The recommended treatment regimen is six doses of AL over 3 days, with 1–4 tablets (20 mg artemether/120 mg lumefantrine) per dose depending on the weight/age band. National guidelines state that the second dose should be taken 8 hours after the first dose, followed by the remaining doses morning and evening of the second and third days.31 In Mtwara, ADDO accreditation commenced in 2006, and officially only accredited drug stores are allowed to function. In reality, a large number of non-accredited shops exist because of a lack of training, unpaid fees, or administrative delays. These shops are tolerated by regulating authorities and considered "prospective ADDOs." Before AMFm, ACTs were not commonly available in ADDOs in Mtwara, and dispenser training on ACTs was limited, but ACT availability significantly increased after AMFm implementation, with 88% of ADDOs stocking ACTs in Mtwara in August 2011.32 To support AMFm roll out, TFDA offered a 1 day refresher training that included treatment of malaria with ACTs to dispensers with previous nursing training in Mtwara in August 2011.
BODY.METHODS.SAMPLE SIZE CALCULATIONS.:
We based the sample size for this two arm cluster randomized trial on data from the public sector in Tanzania, where patient adherence to AL was 65–98%(Khatib R, unpublished data).33–35 We assumed lower adherence to AL obtained at ADDOs in Mtwara (60%) and powered the study to detect a 15% point increase in the intervention arm. We wanted to recruit a small number of patients per cluster to reduce the potential bias caused by increasing community awareness of the study's objectives. Assuming a coefficient of variation of 0.25, 80% power, 5% significance, and 20% loss to follow-up, 13 patients from 36 outlets in each arm were required, a total of 468 patients per arm.
BODY.METHODS.SELECTION OF STUDY ADDOS.:
In May 2012, we conducted a census of all drug shops in Mtwara (ADDOs or prospective ADDOs). Data were collected on the characteristics of owners and dispensers, ACT stocks and sales, and global positioning system (GPS) coordinates. ADDOs were excluded from the sampling frame if they had sold fewer than five antimalarial treatments in the previous week, no dispensers used a mobile phone, the shop was located on the border with Mozambique or was not accessible, or the owner refused to participate (Figure 1). The final sampling frame consisted of 131 ADDOs. The 82 ADDOs were selected sequentially at random, with any ADDOs within 400 m of a selected ADDO, or any ADDOs where staff from a selected ADDO also worked, removed from the sampling frame. The selected ADDOs were then stratified by location in urban or rural wards, and the intervention was randomly allocated to 29 of 57 urban ADDOs and 13 of 25 rural ADDOs. Figure 1.Consort-like style flow diagram of trial.
BODY.METHODS.INTERVENTION DESIGN.:
We designed seven content messages about advice that dispensers should provide when dispensing AL (Figure 2). The messages were derived from the government refresher training booklet and reflected the recommended practices for dispensing AL. Messages were pilot tested in ∼20 ADDOs in a semi-urban district outside of Dar es Salaam. Dispensers at these ADDOs were sent each potential message in turn and asked to explain their understanding of the meaning and relevance of each message. Dispensers were also asked if they would find receipt of the messages helpful, how often they would like to read the messages, and whether complementary components such as quotes or questions would encourage reading. Phrasing and frequency of the messages were adjusted based on feedback received during the pilot. Figure 2.Content of text messages sent to dispensers in the intervention arm. Before sending the first message, the 42 ADDOs in Mtwara randomized to the intervention arm were visited to invite participation and collect an updated list of mobile numbers for all dispensers. Messages began in July 2012 and were sent in random order once per day Monday–Friday for the first 4 weeks, followed by once per day Monday, Wednesday, and Friday for the next 10 weeks. Messages were written in Swahili and scheduled in advance on an automated platform, with each message paired with a different complementary component each time to promote interest. Complementary components consisted of inspirational quotes or proverbs or, once per week, a quiz question on message content that earned correct respondents free air time (500 TSH or $.30). Over the 14-week period, 49 messages were sent to each of 60 dispensers, and detailed delivery reports were kept for each message.
BODY.METHODS.DATA COLLECTION.:
From September through November 2012, dispensers at ADDOs in the intervention and control arms were visited by study supervisors and given a standard introduction about study objectives. To limit patients' awareness of our primary interest in adherence, which could have led to a biased assessment, dispensers were told we were studying how patients chose to treat fever and would visit some, but not all, patients at their homes. They were asked to fill out a registration form for all patients purchasing any treatment of fever, including the day and time of their ADDO visits, the patients' names, the drugs purchased, and a description of where the patients lived. Dispensers were provided with blister packs of AL that they could then sell to patients needing treatment of malaria. Study staff visited ADDOs every day to check and collect registration forms for 1–3 weeks, or until 12–15 patients purchasing AL were registered if quicker. Eligible patients who obtained AL were identified from the registration forms and assigned patient identification numbers (recorded on follow-up forms). Patients were followed up ∼68–72 hours after their ADDO visit, according to a predefined schedule, and all attempts to locate and interview patients were recorded. Where written informed consent was given, patients or their caregivers were asked about demographic and socioeconomic characteristics, treatment-seeking history, illness symptoms, detailed information about each dose of AL taken and the advice provided by the ADDO dispenser. Blister packs were requested for a pill count, and blood samples were collected for a blood smear and a malaria rapid diagnostic test (mRDT) (Pf-specific from ICT Diagnostics, Cape Town, South Africa). Blood smears were stained in the field and transported to the Ifakara Health Institute, where they were double-read by two microscopists blinded to results from each other and the mRDT, with discrepant results read by a third microscopist. Adherence was defined in two ways.5 Patients were considered to have "verified completed treatment" if they reported taking all doses by the time of the follow-up visit and a pill count verified that no pills remained in the blister pack, if available. The second, more stringent definition included a time component, based on patient reports of the time each dose was taken using the Swahili times of day: "alfajiri" (early morning), "asubuhi" (morning), "mchana" (afternoon), "jioni" (evening), "usiku" (night), and "usiku sana" (late night). Patients were considered to have "verified timely completion" if they took the second dose at the Swahili time of day corresponding with 8 hours after the first dose, and then took each of the remaining doses at the Swahili time of day corresponding with 12 hours after the previous dose, verified by the absence of pills in the blister pack. For ease of reading, we hereafter refer to these definitions as "completed treatment" and "timely completion." After completion of patient interviews, dispensers working at the study ADDOs were interviewed on ADDO characteristics, demographics, receipt of study text messages, and advice they would give to patients when dispensing AL. To assess knowledge corresponding with message content, we used an open-ended question, e.g., "I would like to ask about which advice you think you should provide to a person of any age taking treatment for malaria. For the following topics (e.g., "when to take the second dose" or "what to do with the pills if the patient feels better," etc.) tell me if advice on this topic is important or not, and if so, what advice you would provide." Responses were recorded verbatim and evaluated by the study leader using predetermined criteria based on message content.
BODY.METHODS.DATA ENTRY AND ANALYSIS.:
All patient and dispenser interview data were collected using personal digital assistants, and data extracted from study forms (census, registration, and follow-up forms) were double entered into Microsoft Access databases (Microsoft Corp., Redmond, WA). Data were analyzed in Stata 11.0 (Stata Corporation, College Station, TX). Primary outcomes were analyzed by intention-to-treat. Comparison of adherence was based on a t test of the proportion adherent in each cluster. A list of potentially important confounders was identified a priori consisting of ADDO accreditation certificate, number of customers purchasing ACTs in the previous week, dispenser medical qualification, dispenser training on ACTs, patient age, and patient education. Adjustment for variables on this list found to be unbalanced between arms was performed by fitting a logistic regression model to the individual data and performing analysis on the aggregated residuals, as described by Bennett and colleagues.37
BODY.METHODS.ETHICS.:
All questionnaires, consent forms, and other study documents were translated into Swahili and piloted before use. Written informed consent was collected from dispensers before census, patient registration and interview, and from patients or their caregivers prior to interview. The study protocol was approved by the ethical review boards of Ifakara Health Institute and London School of Hygiene and Tropical Medicine. The Centers for Disease Control and Prevention (CDC) investigators provided technical assistance in design and analysis but were not engaged in data collection. The trial is registered with Current Controlled Trials, ISRCTN83765567.
BODY.RESULTS:
Figure 1 shows the trial profile. Of the 82 randomized ADDOs, 37 from the control arm and 40 from the intervention arm participated in the study. The number of registered patients eligible for follow-up was 537 in the control arm and 518 in the intervention arm, with ∼15% of patients in each arm lost to follow-up. Most outlets were in urban wards (70% in both arms), had a single dispenser, and had at least some ACTs in stock on the day of interview (Table 1). Of 51 dispensers in the control arm and 59 in the intervention arm, ∼80% in both arms were female and had a low-level medical qualification, mostly nurse assistants (Table 2). Though low in both arms, more ADDOs in the control arm compared with the intervention arm were able to show an accreditation certificate (43% versus 20%, respectively). However, the difference in the percentages of dispensers that had received training on ACTs was not as pronounced (69% in the control arm versus 60% in the intervention arm), though the median year of training was more recent in the control arm (2011 versus 2009). Characteristics of patients were well balanced between arms (Table 3). A high percentage of patients (36% in the control arm and 38% in the intervention arm) had sought care before attending the study ADDO, with most patients going to a kiosk or general shop and only 7% of patients in the control arm and 4% in the intervention arm going to a public health facility. Approximately 90% reported symptoms of fever or headache, and approximately half had upset stomachs or nausea. Based on an mRDT taken at the time of follow-up, 28% in the control arm and 25% in the intervention arm tested positive, with only 1.4% and 1.6%, respectively, testing positive by study blood smear. (Some degree of discrepancy is expected because of the persistence of HRP2 detected by the mRDT.) Seventy percent of dispensers received at least 75% of the text messages. The median percentage of messages received was 86%, with 20% of dispensers receiving no messages (Figure 3). Table 4 presents results of the dispenser interviews on knowledge of advice to provide patients when dispensing AL. Dispensers in the intervention arm reported slightly better knowledge of the correct AL regimen for adults in the intervention arm compared with the control arm (90% versus 78%; adjusted prevalence ratio [aPR] = 1.2 (95% confidence interval [CI]: 0.95, 1.5); p [adjusted] = 0.0748), though knowledge of the correct regimen for a child aged four weighing 20 kg was lower than for adults in both arms (75% versus 64%; aPR = 1.2 [0.85, 1.7]; p [adjusted] = 0.2). Dispenser knowledge was considerably higher in the intervention arm than the control arm on advice to take AL with fatty food (60% versus 20%; aPR = 3.4 [95% CI: 1.6, 7.1]; p [adjusted] < 0.0001) and to continue to take AL if minor side effects occur (68% versus 43%; aPR = 1.6 [95% CI: 1.0, 2.4]; p [adjusted] = 0.0188). However, surprisingly high dispenser knowledge (87–99%) was recorded in both arms on advice to complete treatment even if feeling better, advice to return to the ADDO or go to a health facility if the condition worsens, and advice to take the second dose after 8 hours (Table 4). Knowledge on advising patients to take a replacement dose in case of vomiting within half an hour of taking a dose was lower (55% versus 50%), with no difference observed between arms. Figure 3.Percentage of text messages received by dispensers in the intervention arm. Table 5 shows that ∼60% of patients in both arms reported being told how to take AL correctly, with similar percentages reporting being told to take the second dose after 8 hours and to complete treatment even if feeling better, indicating that dispensers were providing some advice even in the absence of the intervention. However, no differences were found between control and intervention arms for any piece of advice. Less than 5% of patients in both arms reported being told about vomiting, side effects, or taking AL with fatty food, and < 10% in both arms took the first dose of AL at the ADDO. There was no difference in patient adherence between arms (Table 6). Completed treatment was 70% in the control arm and 68% in the intervention arm (adjusted risk ratio [aRR] = 0.96 [95% CI: 0.82, 1.1]; p [adjusted] = 0.6), with a similar percentage of patients adherent to each of the four age-appropriate blister packs and no important differences between arms. The mean number of doses taken by non-adherent patients was four in both arms, and the most common reported reasons for non-adherence included planning to take the medication later, forgetting to take the tablets, feeling better, and other reasons (Figure 4). Timely completion was much lower, with 33% of patients in both arms taking all doses at appropriate times. A per protocol analysis, excluding patients attending ADDOs where at least one dispenser did not receive any messages, had no impact on results. Figure 4.Reasons given by patients/caretakers for not completing treatment.
BODY.DISCUSSION:
We have reported results from a cluster randomized trial of a text message intervention directed at drug shop dispensers to improve patient adherence to ACTs in Tanzania. The intervention increased dispenser knowledge of some components of advice to provide patients when dispensing AL, but knowledge of other components was already very high in the absence of the intervention. The improvements in knowledge did not translate into an increase in information patients reported receiving, even though patients commonly reported receiving some advice. There was no difference in adherence of patients to the ACT regimen between the arms. Adherence by completed treatment was < 70% to ACTs obtained from ADDOs, comparable to the 66% adherent by the same definition in the study by Cohen and others (2012)11 in the private retail sector in Uganda. However, timely completion was only 33% in our study, indicating that even patients who complete treatment may do so with poor adherence to the recommended schedule. Both of these results are comparable to reported adherence to ACTs obtained from public health facilities, where studies under real life conditions have found adherence of 64–77% for completed treatment verified by pill count and 39–75% for timely completion verified by pill count,5 including one study from Tanzania.35 Two other studies from public health facilities in mainland Tanzania using different definitions and methods have reported higher adherence (88.3% and 90%).33,34 Although the text message intervention targeting dispensers was not effective at improving patient adherence, there was a marked increase in dispenser knowledge of advising patients to take AL with fatty foods or milk and to continue AL even if minor side effects occurred. However, knowledge in both arms was surprisingly high, particularly on advising patients to take the second dose after 8 hours, to complete treatment even if feeling better, and to seek further care if the condition worsens. This could reflect the recent ADDO trainings in Mtwara, raising the possibility that the intervention's impact could have been different in the absence of recent training. Knowledge did not necessarily result in the provision of advice, even though some advice was provided. For example, 98% of dispensers in both arms knew it was important to advise patients to complete treatment even if feeling better, but only 60% of patients reported receiving this advice. Other advice was much less commonly provided, with < 5% of patients in both arms reporting being advised on what to do in case of minor side-effects or vomiting, even though dispenser knowledge of this advice was much higher. This may be because the dispensers did not deem the advice helpful to their business or to the patients, as it could heighten a negative perception about the effects of their products. Dispensers may have also perceived that clients were in a hurry or not receptive to advice. Alternatively, patients or caretakers may not have recalled the advice given to them several days before. Exit interviews or mystery shopper surveys may have been useful in assessing whether advice was communicated, but these methods also have limitations, such as greater potential for a Hawthorne effect and ethical challenges. We intentionally avoided telling dispensers that the purpose of our study was to improve patients' adherence. Although dispensers receiving text messages were aware that the content focused on advising patients about the correct use of AL, we did not mention the objective to dispensers in either arm to avoid this information being relayed to patients, who might then change their behavior because they expected their adherence to be monitored.5 However, if this intervention were to be scaled up outside the study context, one might include greater emphasis on adherence and its value in communications with dispensers, which might in turn increase the likelihood that they would provide appropriate advice. The evaluation of patient adherence relied on self-reported data from patients or their caregivers, which may be subject to recall and social desirability bias. We inspected blister packs for the 80% of patients who could provide them and identified only 10 patients (1%) that had reported completing all doses but had pills remaining. On the other hand, patients may have removed pills from the packaging to consume at a later time. Even though Swahili times of day, based on sunrise and sunset, were used to assess timely completion, patients or their caregivers may not have remembered when each dose was taken or may have provided the expected responses to avoid being seen as negligent. A similar text message intervention targeting health workers in public health facilities in Kenya found significant improvements in health worker case management of pediatric malaria.21 The primary outcome measure by Zurovac and colleagues included completion of four treatment tasks (e.g., prescribing AL) and at least four of six dispensing and counseling tasks, of which the biggest improvements were seen in giving the first dose at the health facility and advising patients to take the second dose after 8 hours, take each dose after a meal, and what to do in case of vomiting. Although we found strong evidence in the intervention arm of improved dispenser knowledge of advice to take each dose with a fatty meal, we recorded high dispenser knowledge in both arms of advice to take the second dose after 8 hours and no difference between arms in knowledge of advice on what to do in case of vomiting. We also recorded < 10% of patients in either arm taking the first dose of AL at the ADDO, even though drinking water was available at many ADDOs. The contrasts between our findings and those of Zurovac and colleagues could reflect the private drug shop setting, as we found patients' relatives often seek care at ADDOs on behalf of patients, in contrast to public health facilities where patients themselves must be present for a clinical exam. Health workers in public health facilities may also be more accustomed to taking on advisory roles than dispensers in private drug shops and less concerned with making a profit.37 Interventions involving training of dispensers in the private retail sector, although limited in number, have improved dispenser knowledge across a range of diseases and settings, but the impact of improved knowledge on dispenser and patient behavior has been mixed.37,38 Even fewer studies have reported effects of an intervention targeted at retail dispensers on patient adherence to antimalarial drugs. One study from 1998–2001 in Kilifi, Kenya found that trained shopkeepers were willing to take on an advisory role, resulting in both increases in advice and the proportion of patients taking adequate doses of chloroquine and sulfadoxine pyrimethamine or sulfadoxine-pyrimethamine.14 Although receiving instructions has been associated with patient adherence to antimalarials in several studies in the public and private sectors,11,39,40 other factors might also influence patient adherence, including patient education, higher socioeconomic status, treatment-seeking behavior, understanding the instructions, knowledge and perceptions of the illness or of the drug, and satisfaction with information received or with the drug.5 The private retail sector is likely to continue to be an important source of treatment of malaria and there is a need to maximize patient adherence to ACTs. Given the effectiveness of text message reminders on health worker case management in Kenya and the low cost of this intervention, there is potential for further evaluations of text message interventions targeted at dispensers in the private retail sector to improve dispenser knowledge, advice provided, and patient adherence, particularly in settings where dispensers have not received recent training on malaria. Such interventions should ensure message content addresses gaps in dispenser knowledge and would benefit from additional research on dispenser readiness to provide advice, and client receptivity to their advice. There should also be further consideration of how best to design the evaluation so that dispensers are motivated to communicate the importance of adherence without biasing study results. The double gap between dispenser knowledge and providing advice and then patients receiving advice and being adherent may also call for other interventions to enhance adherence. Text message reminders to patients have been shown to be a low-cost approach to improve patient adherence to antiretroviral therapy for HIV41–43 and have been used in two recent studies to increase patient adherence to malaria test results and treatment (Goldberg J, unpublished data).44 However, scaling up a text message intervention targeted at malaria patients in Tanzania would require an increase in personal mobile phone use among patients most at risk of malaria,45 as only about half of the households in rural areas own a mobile phone,29 and the phone may be shared among household members. In contrast, nearly all dispensers censused in Mtwara regularly used at least one mobile phone. Other interventions that have been shown to improve patient adherence to antimalarial drugs include packaging and community education.46 ACTs are now mostly available in factory packaged unit dose packs blister packs with illustrated instructions, therefore additional room for improvement may be limited. One possible modification could be improved instructions in local languages. Community education through communication campaigns could be helpful in emphasizing the importance of taking all doses, but it may be challenging to communicate the details of when and how to take each dose to the general population. Finally, the introduction of mRDTs in the private sector might have positive implications for patient adherence, especially if also combined with dispenser advice.5
BODY.CONCLUSION:
Text message reminders improved some aspects of dispenser knowledge of advice to provide to patients when dispensing AL in the private sector. However, patients in the intervention arm were not more likely to report receiving improved advice and did not have higher adherence than patients in the control arm. Adherence to AL among patients in both arms was suboptimal, highlighting the need for studies evaluating other interventions to improve adherence to ACTs obtained in the private retail sector. | 4,183,415 | {
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TITLE: Effects of transcranial direct current stimulation on temperature and pain perception
ABSTRACT:
Transcranial direct current stimulation modifies cortical excitability and in consequence some cerebral functions. In the present study we aimed to elucidate whether tDCS could affect temperature and pain perceptions in healthy subjects testing different stimulation parameters. A total of 20 healthy subjects were studied by means of quantitative sensory testing. Two different experiments were performed. First, we studied the effects of 15 minutes 2 mA anodal transcranial direct current stimulation applied over left M1 and parietal cortex in two separated sessions. Then, we tested the effects of 5 minutes tDCS over M1 by means of a sham controlled design to optimize the possibility to study minimal effects of tDCS using different polarities (cathodal and anodal) and intensities (1 and 2 mA). 2 mA anodal tDCS, when applied for both 15 and 5 minutes over the motor cortex, increased cold perception threshold. Conversely, motor cortex cathodal tDCS modulated cold perception threshold only when 1 mA intensity was used. M1-tDCS can modify the temperature perception; these effects are polarity and intensity dependent. As stimulation intensity seems critical to determine the effects, we suggest that for clinical application strong anodal tDCS (>1 mA) or weak cathodal tDCS (<2 mA) should be used for pain control.
BODY.INTRODUCTION:
Treatment of chronic pain (CP) is often difficult and satisfactory pain control is not always achieved. However, invasive motor cortex stimulation (MCS) and non-invasive brain stimulation (NIBS) techniques have emerged as a potential therapy and have been reported to be highly successful in a proportion of treated patients1. However, although MCS is generally effective in pain relief, a conspicuous number of patients are not-responders. A high number of not-responders is unwanted and favours the expansion of the less expensive NIBS techniques over the neurosurgical techniques. Non-invasive methods of brain stimulation, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are able to induce long lasting effects within the human motor cortex2–4 and have been used to treat pain. Anodal tDCS over primary motor cortex (M1) promotes an increase in cortical excitability, while cathodal tDCS induces a reduction of cortical excitability5, furthermore it was shown that the longer the duration of tDCS, the longer the induced after-effects6, 7. As far as it concerns cathodal tDCS, increasing intensity from 1 mA to 2 mA can switch motor cortex excitability inhibition into excitation8. Also, as intensity increases, the induced electric field goes deeper into the brain so that it is conceivable that the orientation and distance of the axonal or dendritic-somatic axis with respect to the electrical field could affect the resulting biological and clinical effects unexpectedly9. Finally, it is important to consider that little variations of electrode size area, shape, or placement (montage) can strongly influence the "diffusion" of the current and the geometry of the induced DC fields into the brain10–13. Many prior studies have evaluated the effects of tDCS on different temperature and pain perception in healthy volunteers. A list of the most relevant works on this issue is given in Table 1
14–21. It should be noted a great divergence across studies about the effects of tDCS on the studied parameters. For this reason further research is warranted.Table 1Most relevant papers about the effects of tDCS on temperature and pain perception in healthy volunteers.ArticlePolarityStimulation Intensity and durationEvaluation protocolResultsTargetBorckardt et al.14
Anodal Sham HD-tDCS2 mA, 20 minutesQSTAnodal HD-tDCS decreased heat and cold perception thresholds with no effects on heat pain threshold and just a small effect on cold pain thresholdM1Bachmann et al.15
Anodal Cathodal Sham1 mA, 15 minutesQSTCathodal tDCS increased cold perception thresholdM1Grundmann et al.16
Anodal Cathodal Sham1 mA, 15 minutesQSTCathodal tDCS increased cold detection thresholds in both hands and warm detection thresholds only in the contralateral handS1Zandieh et al.17
Anodal Cathodal Sham2 mA, 15 minutesCold Pressor TestAnodal tDCS led to increment in pain thresholdM1Jurgens et al.18
Anodal Cathodal Sham1 mA, 15 minutesQSTNeither anodal nor cathodal tDCS significantly were able to change somatosensory and pain perceptionM1Mylius et al.20
Anodal Cathodal Sham2 mA, 20 minutesQSTAnodal tDCS led to an increase of tolerance to heat painDLPCCsifcsak et al.21
Anodal Cathodal Sham1 mA, 10 minutesLaser evoked potentials (LEP)Cathodal tDCS significantly reduced the amplitude of N2 and P2M1Boggio et al.22
Anodal Sham2 mA, 5 minutesPeripheral electrical stimulation (PES)Anodal tDCS of M1 increased both perception and pain thresholds, whilst stimulation of the DLPFC increased pain threshold only.M1 DLPC V1
Quantitative sensory testing (QST) is a standardized method that allows the evaluation of temperature and pain perceptions by means of different kinds of thermal stimuli (warm, hot inducing pain, cold and cold inducing pain) thus providing information about each of the physiological pathways involved22–24. More in detail, QST provides the opportunity for assessment for Aδ-fibres and C-fibres that are involved respectively in temperature cold and warm perception and nociception (cold pain and hot pain)25–27. To elucidate whether tDCS could affect temperature and pain perceptions in healthy subjects, we performed a double-blind study in which we evaluated the effects of 15 min 2 mA-tDCS on temperature and pain perception as measured by QST: we chose this tDCS protocol since it is commonly used to obtain pain relief in clinical applications28. In order to disclose a possible site-specificity of tDCS effects we applied the neuromodulatory protocol over M1 and parietal cortex (Pcor). Moreover, in a separate experimental session, we tested the effects of a very short tDCS protocol (5 min, cathodal and anodal, M1) by using a placebo-controlled double blind study to disclose the polarity and intensity dependency of the effects of tDCS on thermal and pain perceptions. Contemporary, by means of these experiments, we aimed to test which QST parameters can be used as a biomarker of the effects of tDCS, possibly to be used in future study about its application in pain treatment.
BODY.METHODS.SUBJECTS:
Ten healthy volunteers (7 women, 3 men, mean age 31.9 ± 4.9 (SD) years, range 27–41 years) were studied by applying anodal tDCS 2 mA for 15 minutes over two different cerebral targets, M1 and Pcor. Moreover, eleven healthy volunteers (9 women, 2 men, mean age 31.5 ± 7.5 (SD) years, range 24–39 years) were studied with a very short duration tDCS protocol using a sham controlled design. Just one subject participated in both experimental protocols. All subjects gave informed consent prior to participation; the study was approved by the Ethical Committee for Clinical Research (Toledo, Spain) and was conducted in accordance with the Declaration of Helsinki.
BODY.METHODS.EXPERIMENTAL DESIGN:
Subjects were seated in a comfortable chair, with their arms and the whole body at rest. Sensory testing was evaluated prior to, immediately after, and 25 minutes after tDCS (times pre, post 0, and post 25, respectively). See Figure 1 for a schematic representation of the experimental protocols. The experimental protocols were randomly administered across the subjects and were separated by at least one week. The entire testing algorithm (temperature perception testing and pain thresholds) lasted for an average time of 12 minutes.Figure 1Schematic representation of the experimental setup.
BODY.METHODS.MOTOR CORTEX LOCALIZATION: TRANSCRANIAL MAGNETIC STIMULATION:
Transcranial magnetic stimulation (TMS) was performed with a Magstim 200 magnetic stimulator (Magstim Company, Whiteland, Dyfed, UK) and a figure-of-eight magnetic coil (diameter of one winding, 70 mm; peak magnetic field, 2.2 Tesla). The magnetic stimulus had a biphasic waveform with a pulse width of about 300 μs. During the first phase of the stimulus, the current in the center of the coil flowed towards the handle. The coil was placed tangentially on the scalp inducing a posterior-anterior current in the brain. We determined the optimal position for activation of the right first dorsal interosseous (FDI) by moving the coil in 0.5 cm steps around the presumed motor hand area of the left motor cortex. The site where stimuli of slightly suprathreshold intensity consistently produced the largest motor evoked potentials (MEPs) with the steepest negative slope in the target muscle was marked as the "hot spot".
BODY.METHODS.PARIETAL CORTEX LOCALIZATION:
To localize the optimal position of the electrodes to stimulate parietal cortex, we used as reference the motor hand area of the right first dorsal interosseus (FDI) localized by TMS (hot spot) and moving 2 cm posteriorly in the parasagittal direction29.
BODY.METHODS.EXPERIMENT 1: COMPARING THE EFFECTS OF THE ANODAL TDCS OVER THE MOTOR AND PARIETAL CORTICES:
We tested the effects of a protocol similar to those commonly used to obtain pain relief in clinical applications28 (anodal tDCS, 15 min, 2 mA, M1 or Pcor) on two different cortical targets. With this experiment, we tested if there are effects on QST parameters that can be used as a biomarker of the effects of the tDCS. Furthermore, we tested the effects over the parietal cortex as some studies suggest that this target can be used for pain control23. It should be noted that this experiment was developed to test if Pcor stimulation is effective in obtaining pain control and changes in temperature perception in healthy humans. We compared this site of stimulation to a commonly used protocol in pain treatment (Anodal tDCS 15 min over M1) and for this reason we did not use, in this first experiment, sham stimulation as a control condition. All the subjects underwent two different experimental sessions: (1) anodal motor cortex tDCS, 2 mA, 15 minutes, (2) anodal parietal cortex tDCS 2 mA, 15 minutes. Following the skin preparation to reduce impedance, saline-soaked sponge electrodes (5 × 7 cm) were positioned over the motor/parietal cortex and contralateral orbit, using the hot spot (for motor cortex stimulation) or 2 cm posteriorly in the parasagittal direction (for sensory cortex stimulation) as the center of the cortical electrode. Stimulation was applied for 15 min at a current of 2 mA (8 s phade in/phade out for a total stimulation time of 916 s). The current intensity and duration were within the established safety limits30. For anodal tDCS, the anode was positioned above the motor cortical representation of the right FDI while the cathode was placed above the contralateral orbit.
BODY.METHODS.EXPERIMENT 2: PLACEBO-CONTROLLED STUDY ON POLARITY AND INTENSITY EFFECTS OF TDCS OVER THE MOTOR CORTEX:
In Exp 1, we used the M1 stimulation (commonly used protocol in pain treatment) as a control for the Pcor stimulation. As we demonstrated that Pcor stimulation was inefficient in obtaining a significant change in any studied parameters (see results), in Exp 2 we tested the polarity and stimulation intensity dependence of the effects of M1 stimulation. Thus, in Exp 2 we added a sham tDCS as a control condition, cathodal tDCS to test also a different polarity and two different stimulation intensities to test (1 mA and 2 mA). We tested the effects of a very short tDCS protocol (5 min) using a sham controlled design to optimize the possibility to study minimal effects of tDCS over the motor cortex of different polarities (cathodal and anodal) and intensities (1 and 2 mA). For this, we evaluated how tDCS applied to the motor cortex for 5 min was able to induce a change in sensory and pain perception, as measured by QST. This study was sham-controlled. All the subjects underwent five different experimental sessions: (1) anodal tDCS of 1 mA; (2) anodal tDCS of 2 mA; (3) cathodal tDCS of 1 mA; (4) cathodal tDCS of 2 mA; (5) sham tDCS. Following the skin preparation to reduce impedance, saline-soaked sponge electrodes (5 × 7 cm) were positioned over the motor cortex and contralateral orbit12, using the hot spot identified with TMS as the center of the cortical electrode. Stimulation was applied for 5 min at a current of 1 mA or 2 mA (8 s phade in/phade out for a total stimulation time of 316 s). The current intensity and duration were within the established safety limits30. Sham stimulation involved the same electrode placement and duration as the real conditions; however the constant current was delivered for only 30 s. Most subjects experienced a mild tingling sensation at the site of electrode contact that was independent of polarity and usually subsided after a period of a few seconds. For anodal tDCS and sham stimulation, the anode was positioned above the motor cortical representation of the right FDI while the cathode was placed above the contralateral orbit. For cathodal tDCS the opposite montage was used.
BODY.METHODS.QUANTITATIVE SENSORY TESTING:
QST was conducted by using a Thermal Sensory Analyzer TSA 2001-II (MEDOC, Ramat Yishai, Israel)31, 32. This device uses computer controlled Peltier elements to heat or cool a contact plate in the thermode to the desired temperature. The thermode area was 3 cm × 3 cm (9 cm2). The entire thermode stimulating surface was placed in contact with the skin-testing site and secured by a Velcro band without stretch. Cold and warm thresholds were measured by stimulating right thenar eminence. The initial resting temperature of the thermode was 32 °C and the rate of the temperature change was 0.5 °C/s down or up for cold and warm trials, respectively. Stimulus magnitude was defined in each trial as the difference between the final temperature and the resting temperature of the thermode. Room temperature was controlled and kept between 23–24 °C.
BODY.METHODS.WARM AND COLD THRESHOLD DETERMINATION:
The method of levels (MLE) was used, because its measurements have been shown not to be influenced by reaction time33. A single stimulus of predetermined magnitude was presented and the subject indicated, after the cessation of the stimulus, whether it was felt or not. The initial stimulus step size was predetermined at a step of 3 °C (above or below the starting temperature of 32 °C). Subsequently, stimuli were decreased by intermediate steps of 1 °C, until the subject gave a negative response. The subsequent stimuli were increased or decreased by fine search steps of 0.3 °C. The direction changed according to the response, increasing for negative response (not felt), decreasing for positive response (felt). Null stimuli were randomly included. Four negative responses were required, after fine search had begun, to terminate the test. Threshold was determined by taking the mean of all results during the fine search step. Thresholds were expressed as the difference of the obtained value with respect to the starting temperature of 32 °C.
BODY.METHODS.HEAT AND COLD PAIN THRESHOLD DETERMINATION:
Cold pain thresholds were measured over five trials by decreasing the temperature at a rate of 1 °C/s until the subject indicated that the temperature became painful. The threshold for heat pain was measured over five trials in which the temperature was increased until the stimulus was perceived as painful. Pain thresholds were determined by taking the average of the five successive trials. Thresholds were expressed as the difference of the obtained value respect to the starting temperature of 32 °C. The order of heat and cold detection and pain threshold measurements was randomised across participants.
BODY.METHODS.STATISTICAL ANALYSIS:
Cold and warm thresholds and cold and heat pain thresholds in baseline condition were compared using unpaired t test. For this comparison only the baseline cold and warm thresholds obtained for anodal (2 measures) and cathodal (2 measures) and sham stimulation protocols have been averaged. The cold and warm perception threshold values were computed across subjects for both real and sham conditions and for the three time points (baseline, post 0 and post 25). For the experiment 1, the effects of motor and sensory cortex 15 minutes tDCS on thermal thresholds (warm and cold) and pain thresholds (hot and cold) were evaluated by means of three-way mixed model ANOVA with TIME (baseline, post 0 and post 25) as within-subject factor and LOCATION (M1 and Pcor) and MODALITY (cold perception, warm perception, cold pain and hot pain) as between-subjects factors, followed – in case of a significant interaction– by four separate two-way repeated-measures follow-up ANOVAs (TIME and LOCATION) for each studied modality. Again, when a significant interaction was found, two separate one-way repeated measures follow-up ANOVAs (TIME) were performed for each LOCATION. When significant main effects or interactions were found, Tukey's honest significant difference test was used for post-hoc comparisons. In the experiment 2, we evaluated the effects of 5 minutes anodal tDCS, cathodal tDCS and sham stimulation when two different intensities were used (1 and 2 mA). To achieve this, we performed two separate three-ways mixed model ANOVAs for 1 mA and 2 mA stimulations whit MODALITY (warm perception, cold perception, heat pain and cold pain) and STIMULATION (anodal, cathodal and sham) as between-subjects factors and TIME (baseline, post 0 and post 25) as a within-subjects factor, followed – in case of a significant interaction – by four separate two-way repeated-measures follow-up ANOVAs (TIME and STIMULATION) for each studied modality. Again, when a significant interaction was found, other three separate one-way repeated measures follow-up ANOVAs (TIME) were performed for each STIMULATION. When main effects or interactions were found, Tukey's honest significant difference test was used for post-hoc comparisons.
BODY.RESULTS:
As previously reported by other authors using QST17, 24 baseline cold threshold was lower than warm threshold (0.68 ± 0.35 °C vs 0.92 ± 0.49 °C, p = 0.008 unpaired t test) (Fig. 2). Baseline cold pain threshold was higher than heat pain threshold (21.1 ± 5.2 °C vs 14.4 ± 2.1 °C, p < 0.001 unpaired t test) (Fig. 2).Figure 2Temperature perception thresholds and pain threshold at baseline condition. Thresholds were expressed as the difference of the obtained value with respect to the starting temperature of 32 °C.
BODY.RESULTS.EXPERIMENT 1:
At baseline, cold perception threshold, warm perception threshold, cold pain threshold and heat pain threshold did not differ between the 2 experimental sessions (paired t-tests, p > 0.5). 2 mA anodal tDCS, when applied for 15 min over the motor cortex, induced a change only in cold perception threshold but not in the other studied parameters (one-way follow-up ANOVA for cold perception: F(2,18) = 3,68; p = 0.046)). In details, 15 minutes 2 mA anodal tDCS induced a significant increase in cold perception thresholds immediately after the end of the stimulation (p = 0.039) (see Fig. 3).Figure 3Temperature perception thresholds and pain thresholds for warm (hot) and cold perception (Anodal tDCS 15 min 2 mA over motor and sensory cortex). Error bars are standard deviations. *p < 0.05.
Moreover, 2 mA anodal tDCS when applied over the Pcor for 15 minutes induced no significant changes in all the studied parameters (one-way follow-up ANOVA for cold perception: F(2,18) = 3,33; p = 0.058), we only observed a tendency to increase the cold perception (Baseline vs Post 25; p = 0.058).
BODY.RESULTS.EXPERIMENT 2:
At baseline, cold perception threshold, warm perception threshold, cold pain threshold and heat pain threshold did not differ between the 5 experimental sessions (paired t-tests, p > 0.5). Cold perception threshold was significantly modulated by tDCS (one-way follow-up ANOVA for cold perception: F (2,20) = 4,60; p = 0.022). Particularly, when 1 mA was used, cathodal tDCS was able to increase cold perception threshold at 25 minutes after the end of the stimulation (p = 0.018) (see Fig. 4).Figure 4Temperature perception thresholds for warm and cold perception (anodal, cathodal and sham stimulation, tDCS 5 min 1 and 2 mA over motor cortex). Error bars are standard deviations. *p < 0.05.
Anodal and sham 1 mA tDCS were able to change none of the studied parameters, and cathodal 1 mA tDCS was not able to change warm perception threshold, cold pain threshold and heat pain threshold. When the intensity of tDCS was set at 2 mA, the only modality of stimulation able to increase cold perception threshold was anodal tDCS (one-way follow-up ANOVA for cold perception: F (2,20) = 7,46; p = 0.004)). Particularly, cold perception threshold was significantly increased at 25 minutes after the end of the stimulation (p = 0.003) (Fig. 5 left upper panel).Figure 5Temperature pain thresholds for hot and cold perception (anodal, cathodal and sham stimulation, tDCS 5 min 1 and 2 mA over motor cortex). Error bars are standard deviations. *p < 0.05.
BODY.DISCUSSION:
The present study shows that motor cortex 2 mA-anodal tDCS, applied for both 5 min and 15 min, increased cold perception thresholds. Moreover the absence of effects when stimulating a non-motor cortex such as Pcor were demonstrated by applying 2 mA-anodal tDCS for 15 min. Hitherto, a single session of 15 min of anodal tDCS at 2 mA delivered over the motor or parietal cortex was unable to modulate pain perceptions. Moreover, when anodal tDCS was delivered with a smaller intensity (1 mA) and for 5 minutes, no effects on temperature and pain perceptions were found. As far cold perception concerns, our findings are in line with previous studies. Indeed, Borckardt and co-workers, using a high definition tDCS montage, found that 20 min tDCS delivered at an intensity of 2 mA modified heat and cold sensory perception when anodal stimulation was used while no effects were found in heat pain threshold and just a small effect on cold pain threshold14. More in details, they reported that after stimulation lower temperatures were required to detect a change induced by cold stimuli. Furthermore, higher temperatures were required to detect a change induced by warm stimuli. On the other hand, we did not find any effects on the warm perception and cold and hot pain perception. Moreover another study described that 2 mA anodal stimulation of the primary motor area can be utilized to alleviate cold pain perception17. However it should be considered that these groups found some effects on pain and this discrepancy respect our data could be due to the use of HD-tDCS14 that is characterized by a different spatial profile of induced brain current flow. On the other hand, Zandieh et al. (2012) evaluated the effects of 2 mA tDCS over cold pain threshold by using cold pressor test, so that the different evaluation methodology could have accounted for the slight different results17. In addition, it should be considered that the effects induced by tDCS are considerably affected by the presence of a large inter-subject variability as it was shown by similar studies using other forms of non-invasive brain stimulation34. In this light, the differences between our results and those from other groups could be also influenced by this large intersubjects variability and by the relatively little size of the studied cohorts. Our data also suggest that anodal tDCS increases cold perception threshold by a dose-dependent mechanism in which intensity bigger than 1 mA is required. Furthermore we also observed that 5 minutes 1mA-cathodal tDCS applied over M1 significantly increased cold perception threshold, while no effects were found when using sham stimulation. This result was similar to the effects of 2mA-anodal tDCS. It should be noted that we found positive results only when tDCS was applied over M1 and not over Pcor. Since our main results consist in the modulation of not painful perception (i.e. cold perception), it could be expected that Pcor location was the most effective site of application. However Craig et al. found that the application of innocuous cold stimuli activates insula and not primary somatosensory cortex. Nevertheless, painful heat and cold stimuli activated the contralateral anterior cingulate cortex, contralateral primary motor, primary sensory cortex (S1), bilateral secondary sensory cortex, midinsular cortex, thalamus, and cerebellum35. Furthermore, functional neuroimaging also disclosed remote and widespread effects of tDCS and rTMS when focally applied to the primary motor or premotor cortex through fibres that project to remote cortical or subcortical structures involved in cognitive-emotional or discriminative aspects of sensorial experience and pain3, 36: thus it is not surprising that the stimulation of M1 is crucial in the modulation of thermal perception thresholds. It is important to keep in mind that the tDCS we used cannot be considered "strictly" focal. Indeed, due to the large size of the tDCS electrodes (35 cm2) and the montage we used, it cannot be ruled out that when tDCS electrodes are placed over M1, the tDCS stimulation can affect also the parietal cortex (and vice versa). Indeed, a non focal effect of tDCS over M1 may spread to Pcor. This seems not to be the case, at least using the polarity (anodal) and the parameters we used here, as tDCS delivered over Pcor is less effective in modulating temperature sensory perception than M1 stimulation. Hitherto, we found a tendency to increase in the cold perception threshold after 2 mA anodal tDCS over Pcor (similar to the effects of M1 stimulation) that can be explained (may be not exclusively) by a spreading of the currents towards the M1. Another interesting point from our results is that also 5 min cathodal stimulation induced an increase in cold perception threshold. Other groups found similar results, for example Bachmann et al.15 reported that cathodal stimulation of the primary motor area reduced sensitivity of A-fibers to somatosensory input (cold detection thresholds)15. Also, effects of the stimulation of the left S1 on thermal perception were found, with cathodal tDCS increasing cold detection thresholds in both hands and warm detection thresholds only in the contralateral hand16. In both cases tDCS was delivered at 1 mA intensity and cathodal stimulation was the most efficient when compared with anodal or sham stimulation. Furthermore it should be considered that the net effect of motor cortex stimulation may be a mixed effect, as cathodal tDCS may also exert a "facilitatory effect" by deactivating inhibitory interneurons37 thus, hypothetically explaining the similar effects induced by cathodal and anodal tDCS in the present study. We found no effect over pain thresholds. Ihle et al.,38, developed a study using functional imaging to explore the underpinnings of the previously suggested antinociceptive effects of tDCS over the motor cortex38. They found that neither cathodal nor anodal tDCS over the left M1 (1 mA, 15 minutes) significantly changed cortical nociceptive processing as a response to a heat pain paradigm when compared with sham stimulation. Only contrasting the interaction between responses to anodal and cathodal stimulation, It was found a substantial polarity-specific differences of regional brain activation after painful stimulation: anodal stimulation induced a decrease of regional Cerebral Blood Flow (rCBF), whereas cathodal stimulation resulted in an increase of rCBF in the hypothalamus, inferior parietal cortex, inferior parietal lobule, anterior insula, and precentral gyrus contralateral to the stimulation site38. In sum, here we suggest the importance of evaluating the most efficient combination of intensity/polarity and site of stimulation for better results, since at the best of our knowledge this is the only work evaluating different intensities, polarities and cortical targets in the same study. As far as the parietal cortex stimulation, we found only mild effects. We cannot exclude that longer stimulation sessions or repeated sessions may have an effects on temperature perception. More studies would be done to better clarify these considerations. We are aware that the findings obtained from healthy subjects have to be cautiously transferred to the patients. On the other hand, the effects of neuromodulation techniques in physiological conditions need to be understood before to think the multiple mechanisms that can condition the clinical response of the patients suffering for pain and sensory disturbances. We can conclude that tDCS delivered over the motor cortex can modify the temperature perception and that these effects are polarity and intensity dependent. As stimulation intensity seems critical to determine the effects, we suggest that for clinical application strong anodal tDCS (>1 mA) or weak cathodal tDCS (<2 mA) should be used for pain control (in the attempt of reducing inconsistencies). | 5,462,761 | {
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TITLE: Custodiol - N versus Custodiol: a prospective randomized double blind multicenter phase III Trial
ABSTRACT:
BODY.BACKGROUND/INTRODUCTION:
HTK-Solution (Custodiol) is a well-established cardioplegic and organ preservation solution. We currently developed a novel HTK based solution Custodiol-N which includes iron chelators to reduce oxidative injury as well as L-arginine, to improve endothelial function.
BODY.AIMS/OBJECTIVES:
In the present first-in-human study, Custodiol-N was compared with Custodiol in patients undergoing elective coronary bypass surgery.
BODY.METHOD:
The study was designed as prospective randomized double blind non-inferiority trial. Primary end-point was area under the curve (AUC) of creatine kinase MB (CKMB) within the first 24 hours after surgery. Secondary endpoints included, peak CKMB and troponin-T and AUC of troponin-T release, cardiac index, cumulative catecholamine dose, ICU-stay and mortality. All values are given as mean ± SD, p < 0.05 was considered as statistically significant.
BODY.RESULTS:
Early termination of the trial was performed per protocol as the primary non-inferiority end point was reached after inclusion of 101 patients. Patient characteristics, medical history, operation and cross-clamp times did not differ between the groups. CKMB AUC (878 ± 549 vs. 778 ± 439 h*U/l, non-inferiority p < 0.001) and Troponin-T AUC (12990 ± 8347 vs. 13498 ± 6513 h*pg/ml, non-inferiority p < 0.001) was similar in both groups. Although the trial was designed for non-inferiority, peak CKMB (52 ± 40 vs. 41 ± 30 U/l, superiority p < 0.002) was significantly lower in the Custodiol-N group. Cardiac index, catecholamines ICU-stay and mortality (1 death in the control group) was similar in both groups.
BODY.DISCUSSION/CONCLUSION:
This study shows that Custodiol-N is safe and provides similar cardiac protection as the established HTK-Custodiol solution. The significantly reduced peak CKMB levels in the Custodiol-N group may implicate a beneficial effect on ischemia/reperfusion injury in the setting of coronary bypass surgery. | 4,693,888 | {
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TITLE: Continued stabilization of trabecular metal tibial monoblock total knee arthroplasty components at 5 years—measured with radiostereometric analysis
ABSTRACT.BACKGROUND AND PURPOSE:
The trabecular metal tibial monoblock component (TM) is a relatively new option available for total knee arthroplasty. We have previously reported a large degree of early migration of the trabecular metal component in a subset of patients. These implants all appeared to stabilize at 2 years. We now present 5-year RSA results of the TM and compare them with those of the NexGen Option Stemmed cemented tibial component (Zimmer, Warsaw IN).
ABSTRACT.PATIENTS AND METHODS:
70 patients with osteoarthritis were randomized to receive either the TM implant or the cemented component. RSA examination was done postoperatively and at 6 months, 1 year, 2 years, and 5 years. RSA outcomes were translations, rotations, and maximum total point motion (MTPM) of the components. MTPM values were used to classify implants as "at risk" or "stable".
ABSTRACT.RESULTS:
At the 5-year follow-up, 45 patients were available for analysis. There were 27 in the TM group and 18 in the cemented group. MTPM values were similar in the 2 groups (p = 0.9). The TM components had significantly greater subsidence than the cemented components (p = 0.001). The proportion of "at risk" components at 5 years was 2 of 18 in the cemented group and 0 of 27 in the TM group (p = 0.2).
ABSTRACT.INTERPRETATION:
In the previous 2-year report, we expressed our uncertainty concerning the long-term stability of the TM implant due to the high initial migration seen in some cases. Here, we report stability of this implant up to 5 years in all cases. The implant appears to achieve solid fixation despite high levels of migration initially.
BODY:
Swedish Knee Arthoplasty Register data suggest that uncemented tibial components have worse survivorship than cemented components (Knutson and Robertsson 2010). However, more recent data from Australia have suggested that modern uncemented designs have a similar cumulative revision rate to that of cemented components (Graves et al. 2004). With recent improvements in biomaterials, the potential for improved longevity using uncemented implants is once again being explored. Trabecular metal (Zimmer, Warsaw, IN) is a new material available for use in uncemented total knee arthroplasty. It is a porous biomaterial with morphology and mechanical properties resembling those of trabecular bone (Bobyn et al. 1999a,b, Zardiackas et al. 2001, Levine et al. 2006, Balla et al. 2010). In a previous paper, we presented the 2-year implant migration results of the trabecular metal tibial monoblock component using radiostereometric analysis (RSA) (Dunbar et al. 2009). The results of that study showed high initial migration in 9 out of 28 of the tibial components, with apparent stabilization occurring after 1 year in all cases. These results reflected the results of a similar RSA study on the same implant, performed at another center (Henricson et al. 2008). In addition, in the 2-year report we also documented apparent deformation of the tibial base plate, which occurred in 5 of the cases of high migration (Dunbar et al. 2009). The implications of the high degree of migration and plate deformation for long-term survival are not known. In a subset of the patients enrolled in the study, we also performed RSA for measurement of inducible displacement between 2 and 4 years. The results of this study showed that the trabecular metal component had the lowest inducible displacement ever reported in the literature, indicating excellent stability (Wilson et al. 2010). The results of these 3 studies supported the hypothesis that these components were achieving adequate bone in-growth for long-term survival (Henricson et al. 2008, Dunbar et al. 2009, Wilson et al. 2010). However, longer follow-up is necessary to determine whether the early stability of these implants is durable. In this paper, we present the 5-year longitudinal RSA results from the original cohort of patients randomized to receive either the Nexgen LPS monoblock (trabecular metal) tibial component (Zimmer) or the cemented NexGen Option Stemmed tibial component (Zimmer) (Dunbar et al. 2009).
BODY.PATIENTS AND METHODS:
70 subjects with severe osteoarthritis were randomized to receive either the Nexgen LPS monoblock (trabecular metal) tibial component (Zimmer, Warsaw, IN) or the cemented NexGen Option Stemmed tibial component (also Zimmer). Surgery was performed by 4 experienced consultant knee surgeons using a standardized protocol: posterior cruciate ligament resection, patellar resurfacing with a cemented inlay component, cementing of the femoral component, and RSA marker placement of 0.8mm beads. 4–6 tantalum markers were placed around the periphery of the polyethylene component; a median of 10 tantalum markers were inserted into the proximal tibia. The postoperative protocol was standardized with the use of continuous passive motion as tolerated, and patients were allowed full weight bearing immediately. No drains were used. At the 5-year postoperative time point, patients were contacted and asked if they would consent to continued participation in the study. Written informed consent was obtained from patients who had verbally agreed to participate, when they arrived for their 5-year follow-up RSA examination. This was in accordance with requirements of our Institutional Ethics Review Board. The knee was placed above a uniplanar calibration box (Medis Specials, Leiden, the Netherlands) and simultaneous digital stereo radiographs were taken with the X-ray tubes oriented obliquely. Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores were obtained at 5 years. Full details of the original study design can be found in the previously published article (Dunbar et al. 2009). The original 2-year study was registered at ClinicalTrials.gov (NCT00405379).
BODY.PATIENTS AND METHODS.RADIOSTEREOMETRIC ANALYSIS:
RSA data analysis was performed using commercial software (MB-RSA; MEDIS, Leiden, the Netherlands). All translations and rotations were calculated to comply with the standards presented by Valstar et al. (2005). Rigid-body translations and rotations of the prosthesis were calculated about a coordinate system centered at the volumetric center of the implant, with axes aligned with the anatomical directions. The maximum total point motion of the tibial component for each case was calculated using fictive markers to standardize the calculations in cases where the prosthesis bead placement was not uniform for all subjects (Nilsson and Karrholm 1993, Nilsson et al. 1999, Valstar et al. 2005). The limit of rigid body fitting was a maximum of 0.2 mm for the tibial segment and 0.2 mm for the prosthesis segment. The condition number did not exceed 40 at any follow-up, indicating adequate distribution of beads in the rigid body (Valstar et al. 2005). The accuracy of the RSA system was assessed with a standard phantom study protocol. Accuracy was represented as half of the average width of the 95% prediction interval in a regression analysis of true and measured translations of a phantom. Precision was evaluated with double examination analysis, and represented as the 95% confidence interval of the measurements from 11 double clinical examinations performed at the postoperative follow-up. The marker configuration model-based RSA technique (Kaptein et al. 2005) was used to solve the occluded marker problem in cases where less than 3 beads were matched in an examination at follow-up. Marker configuration models were also used to test for bead loosening and possible deformation of the trabecular metal base plate. At the 2-year follow-up, implants were classified as being "stable" (< 0.2 mm MTPM between 1 and 2 years' follow-up) or as being "at risk" of early aseptic loosening (> 0.2 mm MTPM between 1 and 2 years' follow-up) (Ryd et al. 1995). Implants categorized as "at risk" at 2 years were re-evaluated, and if found to have less then 0.3 mm of motion between 2 and 5 years, they were considered to have stabilized. Implants considered to be "at risk" at 2 years with greater than 0.3 mm of motion between 2 and 5 years were still considered to be "at risk". Implants classified as being "stable" at 2 years but which showed more than 0.3 mm of motion between 2 and 5 years were classified as being "at risk". 0.3 mm was chosen as the threshold for migration over 3 years by extrapolating the 0.2 mm between 2-year follow-up periods, originally described as the modified continuous migration (MCM) criteria by Ryd et al. (1995).
BODY.PATIENTS AND METHODS.STATISTICS:
Analysis of variance was used to test for differences in age, body mass index (BMI), and subjective measures between implant groups. Maximum total point motion measurements were not normally distributed; therefore, the Kruskal-Wallis test was used to investigate differences in maximum total point motion between implant groups at 5 years. Analysis of variance was used to test for differences in translations and rotations between groups at 5 years. Fisher's exact test was used to investigate differences in proportions of implants found to be "at risk" between groups, and Wilson's procedure was used to calculate the 95% confidence intervals of this proportion. There were 8 primary outcome metrics (maximum total point motion, 3 translations, 3 rotations, and proportion of implants at risk). A Bonferroni correction for multiple comparisons was used, giving a significance level of p < 0.006.
BODY.RESULTS.STANDARD OUTCOMES AND FOLLOW-UP:
All standard outcome measures for the 45 patients in this study are given in Table 1. Originally, 37 patients were randomized to receive the trabecular metal component and 33 received the cemented component. Age and BMI were similar in the 2 groups at the time of admission. There were no differences in subjective measures (WOMAC) between implant groups at any follow-up point. Table 1. Subject demographics and WOMAC scores. Only matched WOMAC data from earlier follow-ups are included. Values are mean (SD) Trabecular metal Cemented p-value (n = 27) (n = 18) (ANOVA) Sex, M/F 10/17 8/10 Age 60 (8) 61 (9) 0.7 Body mass index 32 (5) 34 (5) 0.2 WOMAC preoperatively 51 (20) 44 (18) 0.2 WOMAC at 6 months 22 (23) 18 (20) 0.5 WOMAC at 12 months 15 (16) 14 (22) 0.9 WOMAC at 24 months 13 (16) 15 (14) 0.6 WOMAC at 60 months 18 (18) 19 (18) 0.8 For the 5-year follow-up, 45 patients could be reached and were willing to participate. There were 27/28 of the trabecular metal subjects and 18/21 cemented subjects with 2-year data recruited. The reasons for loss to follow-up for the other 25 patients are documented in Figure 1 and it happened mainly in the first two years of follow-up. Of the patients with a high degree of prosthesis migration in the original study, all 9 were recruited to the 5-year follow-up. All but 3 of the patients originally recruited to the study are still being followed by the operative surgeon, and there have been no revisions to date. The three patients who were exceptions had left the province. Figure 1.Consolidated Standards of Reporting Trials (CONSORT) flow diagram.
BODY.RESULTS.RSA RESULTS:
The accuracy of the RSA system was 0.025 mm, 0.025 mm, 0.063 mm, and 0.026 mm for the x-, y-, and z- directions and maximum total point motion, respectively. The precision of the RSA system was 0.07 mm, 0.07 mm, and 0.11 mm for x-, y-, and z- translations, 0.16°, 0.15°, and 0.12° for x-, y-, and z- rotations, and 0.10 mm for maximum total point motion. At the 2-year follow-up, there were no subjects "at risk" in the trabecular metal group (0/28). At the 5-year follow-up, none of the trabecular metal components were found to be "at risk". At the 2-year follow-up, there were 4 subjects "at risk" in the cemented group (4/21). At the 5-year follow-up, 1 of the cemented components "at risk" was lost to follow-up, 2 stabilized (0.09 mm and 0.07 mm of movement between 2 and 5 years) and 1 continued to migrate (0.35 mm of movement between 2 and 5 years). 1 of the cemented implants found to be stable at 2 years migrated an additional 0.42 mm and was classified as being "at risk". However, retrospectively, this implant had somewhat anomalous 2-year data (0.64 mm, 0.45 mm, and 0.87 mm at 1, 2, and 5 years), where the difference between 1 year and 5 years would make the implant appear stable (0.23 mm in 4 years) but the difference between 2 years and 5 years would make the implant appear to be continuously migrating (0.42 mm in 3 years). The condition number and mean errors for this subject were within normal limits. All other implants that were found to be stable at 2 years migrated less than 0.3 mm between the 2- and 5-year follow-up, and were still classified as stable. The proportion of "at risk" components at 5 years was 2 of 18 (0.11, 95% CI: 0.03–0.33) in the cemented group and was 0 of 27 (95% CI: 0.0–0.13) in the trabecular metal group (p = 0.2). At the 5-year follow-up, there was no difference in MTPM between the cemented group and the trabecular metal group (p = 0.9) (Table 2 and Figure 2). MTPM values for individual subjects are shown in Figure 3. Compared to the cemented components, the trabecular metal tibial components had more subsidence (p = 0.001) (Table 2). Table 2. Summary of radiostereometric analysis (RSA) data by group and follow-up 6-month follow-up 12-month follow-up 24-month follow-up 60-month follow-up p-value a TM Cemented TM Cemented TM Cemented TM Cemented (n=30) (n=24) (n=29) (n=23) (n=28) (n=21) (n=27) (n=18) Mean maximum total point motion (range) 0.85 (0.07–3.11) 0.54 (0.12–1.99) 0.87 (0.12–3.25) 0.57 (0.16–1.87) 0.92 (0.06–3.40) 0.65 (0.18–2.12) 0.98 (0.16–3.11) 0.79 (0.06–2.16) 0.9 Lateral/medial translation (SD) –0.02 (0.13) 0.01 (0.14) –0.02(0.13) –0.00(0.14) –0.01 (0.14) 0.02 (0.16) –0.02 (0.16) 0.01 (0.26) 0.7 Superior/inferior translation (SD) –0.34 (0.31) 0.00 (0.08) –0.34 (0.34) –0.01 (0.11) –0.35 (0.35) –0.03 (0.10) –0.38 (0.37) –0.04 (0.11) 0.001 Anterior/posterior translation (SD) 0.02 (0.12) 0.02 (0.29) 0.03 (0.13) 0.06 (0.18) 0.02 (0.12) 0.09 (0.18) 0.01 (0.12) 0.08 (0.29) 0.3 Anterior/posterior tilt (SD) –0.33 (0.73) 0.02 (0.43) –0.40 (0.80) –0.02 (0.30) –0.39 (0.80) –0.05 (0.40) –0.45 (0.90) –0.11 (0.26) 0.1 Internal/external rotation (SD) 0.19 (0.38) –0.15 (0.47) 0.15 (0.39) –0.14 (0.44) 0.19 (0.45) –0.08 (0.60) 0.17 (0.45) 0.04 (0.82) 0.5 Varus/valgus tilt (SD) –0.05(0.72) 0.07 (0.32) –0.11 (0.73) 0.06 (0.32) –0.10 (0.75) 0.06 (0.33) –0.12 (0.73) –0.02 (0.20) 0.6
a 5-year results only Figure 2.Maximum total point motion (MTPM) (mean and standard deviation) according to the duration of follow-up in the trabecular metal and cemented groups. Lines joining data points do not indicate continuous measurement but are included to show the pattern of migration. Figure 3.Individual maximum total point motion (MTPM) according to the duration of follow-up in the trabecular metal group (blue) and the cemented group (red). Lines joining data points do not indicate continuous measurement but are included to show the pattern of migration. At the 2-year follow-up, 9 subjects in the trabecular metal group had shown very high migration in the first 6 months postoperatively (> 1.0 mm). All of these implants migrated less than 0.2 mm between 1 and 2 years and were not considered to be "at risk" At 5 years, all of these implants continued to show stability with an average change in MTPM of 0.10 mm over the 3 years between follow-ups. Using the marker configuration models, independent bead motion was detected in 5 of the high-migration cases, between the postoperative and 6-month follow-up examinations. The error of fit of the model marker was reduced dramatically (0.103 mm to 0.0466 mm on average) when the bead in question was removed from the analysis. The position of the bead with respect to that of the bead in the model was inferior, indicating that the motion was not due to loose beads, which would have traveled radially. The magnitude of independent bead motion was from 0.3 mm to 0.5 mm in all 5 cases. At the 5-year follow-up, there was no change in the position of the independently moving bead—indicating that the deformation of the base plate was permanent.
BODY.DISCUSSION:
In the original 2-year report on these patients, we expressed our uncertainty concerning the long-term stability of the trabecular metal tibial implant due to the high initial migration seen in some cases. Subsequent to this, we have found stability of this implant up to 5 years and migration below the level of detection of our system in all cases. This implant appears to achieve solid fixation despite high initial levels of migration. The one cemented implant that was originally classified as being stable at 2 years but which appeared to be continuously migrating between 2 and 5 years was an unusual finding. We believe that due to random error, the MTPM of this subject was underestimated at 2 years, leading to a spurious finding of continuous migration between 2 and 5 years. However, this patient will continue to be monitored closely in the clinic. The mechanism that results in high early migration and subsequent stabilization is unknown. Previous work (Bellemans 1999) suggested that uncemented components can migrate extensively early after implantation and still form a robust interface with bone. However, migrations of such high magnitude (> 2.5 mm) are more typically associated with continuous migration (Grewal et al. 1992). In our work, all of the initially high migration stabilized by 1 year, suggesting that long-term stability can be achieved even in cases of quite extensive migration. Furthermore, our previous inducible displacement study on this patient group included subjects with a high degree of early migration, and all showed a low degree of inducible displacement (Wilson et al. 2010). Low inducible displacement suggests that bone ingrowth has occurred, and is inconsistent with fixation characterized by fibrous encapsulation. One possible explanation for this novel behavior may be related to the mechanical properties of the trabecular metal material. Due to its low elastic modulus, the trabecular metal monoblock component may deform, allowing areas of the implant that were well fixed initially to remain stable and achieve ingrowth of bone instead of lifting off as the contralateral side sinks into the bone. In support of this, we did measure permanent deformation of the trabecular metal tibial base plate in some of the high-migration cases (Dunbar et al. 2009). The most important limitation of this study was the small sample size. With only 37 patients randomized to the trabecular metal arm of the study, and of these only 27 being willing to participate in the 5-year follow-up, our ability to draw firm conclusions about the risk of revision in patients with this implant is somewhat limited. Another limitation is the modular nature of the cemented components. As the polyethylene was the part of the implant marked with RSA beads, any motion of the polyethylene component with respect to the tibial base plate would be detected as migration of the implant. It is possible that this contributed to the migration detected in some of the cemented cases. However, the monoblock construction of the trabecular metal implant makes motion between the polyethylene and base plate unlikely and less of a concern in that group. | 3,278,655 | {
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TITLE: Clinical evaluation of the AutoPulse automated chest compression device for out-of-hospital cardiac arrest in the northern district of Shanghai, China
ABSTRACT.INTRODUCTION:
Whether the AutoPulse automated chest compression device is worthy of clinical use for out-of-hospital cardiac arrest (OHCA) remains controversial. A prospective controlled study was conducted to evaluate the effect of AutoPulse versus manual chest compression for cardiopulmonary resuscitation (CPR) of OHCA patients in the northern district of Shanghai, China.
ABSTRACT.MATERIAL AND METHODS:
A total of 133 patients with OHCA who were treated at the Emergency Medical Center of the Tenth People's Hospital Affiliated with Tongji University between March 2011 and March 2012 were included. The patients were randomly assigned to the Manual CPR (n = 64) and AutoPulse CPR groups (n = 69) in accordance with the approach of chest compression received. The primary outcome measure was return of spontaneous circulation (ROSC), and the secondary outcome measures included 24-h survival rate, hospital discharge rate, and neurological prognosis at hospital discharge.
ABSTRACT.RESULTS:
The ROSC rate of patients with OHCA was significantly higher in the AutoPulse CPR group than in the Manual CPR group (44.9% vs. 23.4%; p = 0.009). The 24-h survival rate of OHCA patients was significantly higher in the AutoPulse CPR group than in the Manual CPR group (39.1% vs. 21.9%; p = 0.03). The hospital discharge rate of the patients with OHCA was significantly higher in the AutoPulse CPR group than in the Manual CPR group (18.8% vs. 6.3%; p = 0.03). The proportion of patients with OHCA and a cerebral performance category score of 1 or 2 points at hospital discharge was higher in the AutoPulse CPR group than in the Manual CPR group, but the difference was not statistically significant (16.2% vs. 13.4%, p = 1.00).
ABSTRACT.CONCLUSIONS:
Use of the AutoPulse increases CPR success and survival rates in patients with OHCA, but its ability to improve cerebral performance requires further evaluation.
BODY.INTRODUCTION:
High-quality cardiopulmonary resuscitation (CPR) is of great importance to cardiac and cerebral resuscitation [1–3]. However, chest compression often fails to meet relevant guidelines in terms of depth, frequency, and compression/relaxation time [4, 5]. Manual chest compression is not ideal for blood perfusion in most patients. Even when chest compression is performed by a highly trained individual, the generated cerebral blood flow is only 30–40% of the normal level and the cardiac blood supply is only 10–20% of the normal level [6]. Thus, finding a proper automated chest compression device to replace manual chest compression is necessary. The AutoPulse (ZOLL Circulation, Sunnyvale, CA, USA) is a chest compression device that was approved by the U.S. Food and Drug Administration for CPR in patients who suffer from cardiac arrest (CA) in 2001, and was approved in China by the China Food and Drug Administration in 2007. The AutoPulse is an electrical chest compression device that functions through the compression and relaxation of a load-distributing band connected to a hard board using an electric motor. The operation procedure of the AutoPulse was as follows: first, all clothing was removed from the patient, who was then placed on the hard board following the indicating line; next, both ends of the load-distributing band were fixed with a buckle to the front chest of the patient through the armpit; and finally, the device was started and the load-distributing band was automatically tightened to fit patients of different sizes. The default setting was as follows: compression strength, to reduce the patient's chest volume by 20%; and compression frequency, 80 times/min. The device was designed with continuous and 15:2 compression modes; in the latter case, compressions were performed 15 times and then paused for 3 s in each run, allowing for ventilation of the patient twice. In this research, the 15:2 compression mode was used. However, the compression frequency and two compression modes were fixed and could not be adjusted. Animal studies have shown that compared to ordinary CPR, AutoPulse-assisted CPR improved cardiac and cerebral hemodynamics as well as neurological prognosis [7, 8]. A human study showed that compared to manual chest compression, the AutoPulse significantly increased the coronary blood flow [9]. In a retrospective study, the return of the spontaneous circulation (ROSC) rate was significantly improved in patients in the AutoPulse CPR group compared to those in the Manual CPR group [10]. A large-scale multi-center prospective study found that compared with patients in the Manual CPR group, those of the AutoPulse CPR group had significantly higher rates of ROSC, hospital admission, and hospital discharge [11]. Earlier research indicated that the AutoPulse was a good choice for clinical use in patients after CA. However, a large-scale multi-center prospective controlled study found that compared with patients of the Manual CPR group, those of the AutoPulse CPR group had a decreased 4-h survival rate (28.5% vs. 29.5%; p = 0.74) and hospital discharge rate (5.8% vs. 9.9%; p = 0.6) with significantly poor neurological prognosis [12]. Because of the contradictory results from similar studies, whether the AutoPulse is worthy of clinical use in CPR for patients after CA requires more comprehensive evaluation. On the basis of the above-mentioned studies and Lerner's experience [13], we enhanced the control over the emergency treatment procedure and the professional level of emergency care personnel to minimize various interferences during the research. A prospective controlled study was designed to comprehensively evaluate the effect of the AutoPulse versus manual CPR for OHCA in the northern district of Shanghai, China. The results will provide valuable clinical evidence for the use of the AutoPulse to provide CPR for patients after OHCA.
BODY.MATERIAL AND METHODS.STUDY DESIGN:
The study was designed as a single-center, prospective, randomized, controlled clinical trial. This clinical trial was reviewed and approved by the ethics committee of the Tenth People's Hospital in Shanghai. The inclusion criterion was: patients with OHCA who were admitted to the Emergency Medical Center of our hospital between March 2011 and March 2012. The exclusion criteria were: pregnant females, trauma patients, patients with advanced cancer, or patients aged < 14 years or > 90 years old (Figure 1). Figure 1Flow of participants in trial There are 10 ambulances in our Emergency Medical Center, which were encoded from number one to number ten optionally, then five numbers were randomly produced by a computer. The ambulances with the five numbers were equipped with an AutoPulse. The ambulances with or without the device were used in turn to visit the patients. After pre-hospital emergency treatment, all patients were sent to the Emergency Department of the Tenth People's Hospital Affiliated with Tongji University, which has an intensive care unit (ICU) and the corresponding advanced life support technologies. The patients or their families were informed of this research and signed informed consent prior to emergency treatment or after admission to the emergency room. The follow-up was terminated for patients who refused to participate in this research. All emergency personnel were familiar with this device as well as the 2010 American Heart Association (AHA) CPR guidelines. The personnel were familiar with our study design and research procedure.
BODY.MATERIAL AND METHODS.RESEARCH PROCEDURE:
The unified regimen was as follows: the emergency personnel arrived at the scene and connected the monitor to determine the cardiac rhythm. In the case of ventricular fibrillation or pulseless ventricular tachycardia, defibrillation was performed immediately. If stable ROSC was achieved after defibrillation, then the patient was excluded from the research. If the patient failed to establish stable ROSC or the initial cardiac rhythm was not ventricular fibrillation or pulseless ventricular tachycardia, then the use of the AutoPulse was determined by the presence of this device in the ambulance. In the absence of an AutoPulse, manual chest compression was performed immediately; in the presence of an AutoPulse, 1 person performed manual chest compression while another two persons prepared the device. Endotracheal intubation was conducted simultaneously with balloon-assisted ventilation consisting of 100% oxygen. When the AutoPulse was in place, the patient was placed on the hard board in a supine position. The load-distributing band was connected and fixed as described above. The device was then started to deliver 15 compressions followed by two balloon-assisted ventilations in each run. Patients who met the inclusion criterion were included in the study. For these patients, an end-tidal carbon-dioxide (etCO2) module was connected to the intubation. Changes in the etCO2 level were monitored and recorded. Chest compression was performed on the patient continuously until ROSC was achieved or death was announced by the emergency personnel. Surviving patients were sent to the emergency room for further treatment, where chest compression was performed in the same way. Patients who demonstrated ROSC before or after admission to the emergency room were changed to a ventilator for ventilation assistance. The ventilator was operated in a mode of volume control ventilation (tidal volume, 8 ml/kg; inspired oxygen concentration, 100%). Vasoactive drugs, antiarrhythmic drugs, a defibrillator [14], and the chest compression rate of the Manual CPR group were used or performed strictly following the 2010 AHA CPR guidelines. The ROSC status of patients admitted to the emergency room was recorded. Patients who achieved ROSC were admitted to the ICU, where physicians and nurses were not allowed to know whether the patient had been treated with an AutoPulse. The following changes in patient condition were continuously recorded: 24-h survival rate, hospital discharge rate, and neurological prognosis at hospital discharge. Neurological prognosis was assessed in all patients achieving ROSC using Cerebral Performance Category (CPC) scores, which was repeated in those who survived at 24 h and once again in patients at the time of hospital discharge. Patients with multiple CPC scores were analyzed with data from the last scoring.
BODY.MATERIAL AND METHODS.STATISTICAL ANALYSIS:
Statistical analysis was performed using SPSS 13.0 statistical software (SPSS Inc, Chicago, IL, USA). Measurement data are expressed as mean ± standard deviation, while enumeration data are described using the number of cases (percentage). Basic and CPR data of the patients were compared as follows: measurement data using the t test and enumeration data using the χ2 or Fisher's exact probability test. Associations between treatment groups and all end points were analyzed using the χ2 test. Values of p < 0.05 were considered statistically significant.
BODY.RESULTS:
A total of 133 patients were included in this clinical trial. During the treatment, no patients were changed from the AutoPulse to manual CPR and vice versa. Patients' gender, age, and weight in the Manual CPR and AutoPulse CPR groups are listed in Table I. Weight was provided by the family of the patient or estimated by the researcher. There were no significant differences in the above indicators between the two groups (p > 0.05), nor were there significant differences detected in the witness (59.4% vs. 66.7%, p = 0.38) or composition of the cardiac rhythm types (p = 0.32).
Table I Comparison of basic patient characteristics between the Manual CPR and AutoPulse CPR groups Parameter Manual CPR ( n = 64) AutoPulse CPR ( n = 69) P -value Male 44 (68.8) 50 (72.5) 0.64 Age, mean ± SD [years] 64.2 ±12.6 62.6 ±14.9 0.53 Weight, mean ± SD [kg] 68.4 ±8.9 67.3 ±8.1 0.47 Witness 38 (59.4) 46 (66.7) 0.38 Cardiac rhythm: 0.32 Ventricular fibrillation/pulseless ventricular tachycardia 8 (12.5) 9 (13) Pulseless electrical activity 20 (31.3) 31 (44.9) Asystole 32 (50.0) 24 (34.8) Others 4 (6.3) 5 (7.2) Data are presented as number (percentage) unless otherwise specified; mean values were compared using the t test, while percentages were compared using the χ 2 or Fisher test.
Table II compares the CPR data of patients between the Manual CPR and AutoPulse CPR groups. There were no statistically significant differences in the number of patients receiving CPR before the arrival of professional emergency personnel between groups (25.0% vs. 27.5%, p = 0.70), the duration from the emergency call to the arrival of emergency care personnel (11.5 vs. 11.7 min, p = 0.70), or the total duration of CPR (33.4 vs. 19.6 min, p = 0.21) between groups. In the AutoPulse CPR group, the average device preparation time was 3.4 ±1.0 min. The rates of epinephrine and defibrillation utilization during CPR did not differ statistically significantly between the two groups (87.5% vs. 76.8%, p = 0.10 and 20.3% vs. 15.9%, p = 0.51, respectively). However, patients in the AutoPulse CPR group had significantly higher etCO2 than those of the Manual CPR group (22.3 vs. 16.1 mm Hg, p < 0.05). Also, the 1-h return of spontaneous breathing (ROSB) rate was significantly higher in patients in the AutoPulse CPR group than in the Manual CPR group (24.6% vs. 10.9%, p = 0.04).
Table II Comparison of patient resuscitation characteristics between the Manual CPR and AutoPulse CPR groups Variable Manual CPR ( n = 64) AutoPulse CPR ( n = 69) P -value CPR before arrival of emergency care personnel 16 (25.0) 19 (27.5) 0.74 Duration from call to arrival of emergency care personnel, mean ± SD [min] 11.5 ±3.1 11.7 ±2.8 0.70 Total CPR time [min] 33.4 (15.1) 19.6 (19.3) 0.21 AutoPulse preparation time, mean ± SD [s] * NA 52 ±23 Epinephrine 56 (87.5) 53 (76.8) 0.1 Defibrillation 13 (20.3) 11 (15.9) 0.51 EtCO 2 [mm Hg] 16.1 (5.4) 22.3 (6.1) < 0.001 1-h return of spontaneous ventilation 7 (10.9) 17 (24.6) 0.04 Data are presented as number (percentage) unless otherwise specified; mean values were compared using the t test, while percentages were compared using the χ 2 or Fisher test. * Time to apply the AutoPulse and thus terminate manual chest compressions, which was exactly the time to place the patient on the hard board, connect and fix the load-distributing belt, and start the AutoPulse device. The patients' clinical prognostic features are shown in Table III. In terms of the primary endpoint, the ROSC rate was significantly higher in the AutoPulse CPR group than in the Manual CPR group (44.9% vs. 23.4%; p = 0.009). In terms of the secondary endpoint events, the 24-h patient survival rate was significantly higher in the AutoPulse CPR group than in the Manual CPR group (39.1% vs. 21.9%; p = 0.03). Similarly, the hospital discharge rate was significantly higher in the AutoPulse CPR group than in the Manual CPR group (18.8% vs. 6.3%; p = 0.03). The neurological prognosis results are shown in Table IV. In the Manual CPR group, 13.4% of the ROSC patients were scored as CPC 1 or CPC 2 vs. 16.2% in the AutoPulse CPR group. Despite a relative increase in the latter group, there was no statistically significant difference (p = 1.00).
Table III Comparison of patient clinical prognosis between the Manual CPR and AutoPulse CPR groups Parameter Manual CPR AutoPulse CPR P -value ROSC 15 (23.4) 31 (44.9) 0.009 24-h survival 14 (21.9) 27 (39.1) 0.03 Hospital discharge 4 (6.3) 13 (18.8) 0.03 Table IV Comparison of CPC scores of patients between Manual CPR and AutoPulse CPR groups CPC score * Manual CPR ( n = 15) AutoPulse CPR ( n = 31) P -value 1 1 (6.7) 2 (6.5) 1.00 # 2 1 (6.7) 3 (9.7) 3 4 (26.7) 5 (16.1) 4 0 (0) 1 (3.2) 5 9 (60.0) 20 (64.5) Data are presented as number (percentage) unless otherwise specified; mean values were compared using the t test, while percentages were compared using the χ 2 or Fisher test. * CPC scoring of all ROSC patients # comparison of the ratio of patients scored as CPC 1 or CPC 2 in ROSC patients at hospital discharge between AutoPulse CPR and Manual CPR groups. With regard to complications, there was a lack of detailed data for comparison of injuries between groups. This is because an autopsy was refused by the families of all patients due to Chinese tradition. As required by patient condition, bedside X-ray examinations were performed upon admission to the emergency room; additionally, all deceased patients were subjected to bedside X-ray examination. The results showed that the incidence of rib fracture was 6.7% in the AutoPulse group (4/60), slightly higher than that in the Manual CPR group (4.8%, 3/63), but the difference was not statistically significant (p = 0.71). Due to the following condition of the illness, 6 patients (two in the Manual CPR group and four in the AutoPulse CPR group) underwent abdominal computed tomography (CT) examinations, in which no abdominal organ injuries were found.
BODY.DISCUSSION:
Studies have shown that the increased circulating blood flow in CPR is closely related to the success rate of resuscitation [2]. Animal studies in a porcine model of CA confirmed that the AutoPulse generated better blood circulation than manual chest compression [7, 8]. Similar conclusions were obtained in a number of human studies [9, 15, 16]. A retrospective study found that the ROSC rate of patients with CA was significantly higher in those treated with the AutoPulse than in those treated with manual CPR [10]. A recent multi-center prospective study compared the effects of the AutoPulse CPR versus manual CPR, which found that at one of the medical centers, the survival rate of patients in the AutoPulse group declined from 19.6% to 4% after the implementation of an updated experimental program with delayed use of the AutoPulse (p = 0.024); at the other medical centers, the 4-h survival rate at the primary endpoint was significantly higher in the AutoPulse CPR group than in the Manual CPR group (p = 0.008) [17]. The earlier studies confirm that the AutoPulse plays a positive role in CPR and that stable effective blood circulation is a key factor of CPR success. Our study found that the 1-h ROSB rate was significantly higher in the AutoPulse CPR group than in the Manual CPR group. Basic research has shown that the respiratory center is located in the medulla oblongata and that even a few minutes of ischemia and hypoxia injury can cause irreversible brain damage. Thus, the higher ROSB rate indicates that patients treated with the AutoPulse achieved better cerebral blood supply and that the AutoPulse is superior to manual CPR for improving cerebral blood flow. Additionally, we found that the etCO2 level was significantly higher in the AutoPulse CPR group compared to the Manual CPR group. Under normal physiological conditions, the etCO2 level is determined by CO2 production, pulmonary alveoli ventilation capability, and pulmonary blood flow. When CA occurs, CO2 is continuously generated in vivo. The major influencing factors of CO2 discharge into the lung are CO2 transmission speed and volume from the peripheral tissues (CO2-generating site) to the lung, which depend on the pulmonary blood flow. Thus, if the ventilation remains constant, then the etCO2 level changes reflect cardiac output changes as well as the effect of CPR. In recent years, several studies have reported that etCO2 can be used as a noninvasive monitoring indicator for CPR that is related to prognosis [18, 19]. The 2010 AHA CPR guidelines clarify that during CPR of patients with CA, etCO2 can be used as a physiological parameter to indicate the cardiac output and myocardial perfusion, which helps to optimize the quality of chest compression. Together our results indicate that the AutoPulse is superior to manual CPR for improving cardiac blood flow. Thus, we consider that better cardiac and cerebral blood circulation achieved by mechanical chest compression compared to manual chest compression is the main reason for the high success rate of CPR with the use of AutoPulse. Additionally, uninterrupted chest compression in a patient by an AutoPulse even during delivery may be another important factor contributing to the high ROSC rate [1–3]. The importance of continuous chest compression was emphasized by the 2010 AHA CPR guidelines. A recent study showed that in the helicopter emergency medical service, the ROSC rate was significantly higher in the AutoPulse CPR group than in the Manual CPR group, mainly because the former strategy achieved sustained chest compression during transportation [20]. A simulation study on a human body suggested that compared to manual chest compression, the AutoPulse achieves more sustained and stable chest compression during transportation [21]. From the occurrence of CA to emergency room admission, patients need to be carried for transportation at least twice. In this process, manual chest compression will inevitably be interrupted, whereas the AutoPulse can avoid this problem. Although AutoPulse preparation requires time (average 52 s in our study), it may bring more benefit by continuous chest compression during transportation than the potential risks that arise from CPR interruption during device preparation. Cerebral resuscitation remains a major problem in medical science [22, 23]. A large-scale clinical trial showed that only 27% of adults achieved good recovery of neurological function after CPR [24]. Therefore, the ability of the AutoPulse in improving cerebral resuscitation and neurological function recovery should be of concern. Despite the above statement, patients seem to have better cerebral blood supply in the AutoPulse CPR group than in the Manual CPR group. Animal experiments also demonstrated that compared to manual CPR, AutoPulse-assisted CPR more significantly improved the neurological prognosis in a porcine model of CA. However, it is disappointing that we observed no statistically significant difference in neurological prognosis between the AutoPulse CPR and Manual CPR groups. In terms of complications, there is evidence that compared to manual CPR [25], AutoPulse-assisted CPR increases the risk of organ damage [26–28]. In particular, Truhlar [29] proposed that caution should be taken in the use of AutoPulse in thrombolysis to avoid hemorrhage in the abdominal cavity. Because none of the patients' families consented to an autopsy, we have no detailed data for comparative analysis of relevant organ damage between the two groups. However, bedside X-ray films were taken in all patients upon admission to the emergency room, showing that the incidence of rib fractures was slightly lower in the AutoPulse CPR group than in the Manual CPR group. Thereafter, 6 patients were subjected to abdominal CT examination as required by their condition, and none had abdominal organ damage. Because not all patients underwent the above checks, we could not conclude that the AutoPulse is safer than manual CPR in terms of rib fracture and abdominal organ injury or that there is no difference between the risks of organ damage between the AutoPulse and manual CPR. It is worth noting that a recent study using a porcine model of ventricular fibrillation indicated that manual chest compression is advantageous compared to the AutoPulse for improving hemodynamic parameters [30]. A retrospective comparative study by Jennings [31] found that compared to conventional CPR, AutoPulse-assisted CPR improves the hospital admission rate but reduces the hospital discharge rate of patients with OHCA. Whether the AutoPulse can improve the prognosis of patients with OHCA remains controversial. Considering previous studies [12, 13] and the characteristics of the emergency medicine in the Shanghai area, we used a prospective, randomized, controlled method in this study. On the basis of the previous studies [11, 12] and the characteristics of emergency medicine, ROSC was chosen as the primary outcome measure, and 24-hour survival, discharge rate and discharge neurologic prognosis were chosen for secondary outcome measures. The parameters of etCO2, defibrillation, use of epinephrine, etc, were also analyzed in the results. Due to the uncertain time and places of cardiac arrest onset, it was difficult to achieve complete randomization for the research. Hallstrom et al. [12] assigned the patients to two groups randomly according to the emergency medical services (EMS) station with or without the AutoPulse. However, it was impossible for us to follow because our study was performed in a single emergency medicine center. So we finally equipped half of the ambulances with an AutoPulse randomly by using a computer. It may be the most relevant method to achieve randomization as far as possible. This prospective study has brought new findings at both the primary and secondary endpoints of clinical events. Data comparison showed that the ROSC, 24-h survival, and hospital discharge rates of patients with OHCA were significantly higher in the AutoPulse CPR group than in the Manual CPR group. However, in the final neurological prognosis, there was no statistically significant advantage in patients with OHCA within the AutoPulse CPR group. Our work represents the first prospective controlled study regarding the clinical use of the new chest compression device AutoPulse for CPR of patients with OHCA in China. The results are of guiding value for application of this device worldwide, especially in China's Emergency System. The major limitations of our study are as follows: 1) the small sample size may lead to a biased conclusion; and 2) it is difficult to achieve complete randomization based on the grouping method for the ambulance visiting mode because of the particularity of pre-hospital emergency treatment. Due to our present finding that the AutoPulse can improve the ROSC and 24-h survival rates of patients with OHCA, a multi-center prospective study has been designed for in-depth research in China. In conclusion, in Shanghai's Emergency Medical System in the northern district, AutoPulse CPR is superior to manual CPR for increasing resuscitation success and survival rates in patients with OHCA. This device also improves cardiac and cerebral blood circulation in patients but has no significant positive effect on their neurological prognosis. Thus, we conclude that the AutoPulse is worthy of clinical use but that its application prospects require further comprehensive evaluation. | 4,889,691 | {
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TITLE: Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population
ABSTRACT:
Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61–6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia.
BODY.INTRODUCTION:
Preeclampsia affects 2–7% of pregnancies [1], [2]. Diagnosed as new onset hypertension and proteinuria after 20 weeks gestation [1], [2], preeclampsia is a leading cause of maternal [3] and fetal [4] morbidity and mortality. Oxidative stress (including low antioxidant levels) and angiogenic imbalance are believed to contribute to preeclampsia [5], [6], [7]. No intervention has been proven to prevent preeclampsia. Vitamin C and E lowered preeclampsia incidence by 60% in a pilot randomized controlled trial (RCT) in high-risk women [8]. Unfortunately, this effect was not confirmed in subsequent RCTs involving high [9], [10], [11], [12], [13] or low-risk women [13], [14], [15]. Although the discordant effects in large and small populations are likely due to reduced power in small studies, differences might also be explained by increased heterogeneity in large multicenter studies obscuring a responsive subset of women. The phenotype of the antioxidant [16] and pro-angiogenic [17] protein haptoglobin (Hp) predicts cardiovascular disease risk, and responsiveness to Vitamin E [18], [19], [20] or C and E [21] in some non-pregnant populations. We examined whether Hp phenotype might influence preeclampsia risk, or identify a subset of women who responded to vitamin supplementation. Hp stimulates angiogenesis [17] and acts as a powerful antioxidant by clearing free hemoglobin following hemolysis [16]. Hp's two different α alleles (α1, α2) give rise to three genetically determined phenotypes (1-1, 2-1 and 2-2) [16]. Size and structural differences (Figure 1) lead to functional differences between phenotypes [16]. Hp 1-1 is a stronger antioxidant [16], whereas Hp 2-2 is more angiogenic [17]. Less is known about the function of Hp 2-1, a highly variable heterodimer which is not commercially available. Hp 2-1 individuals have no Hp 2-2, very little Hp 1-1, and large amounts of the 2-1 forms which are structurally very different from Hp 1-1 or 2-2 [16]. 10.1371/journal.pone.0060479.g001Figure 1Hp phenotypes by Native and SDS PAGE.Panel A: Hp phenotyping of Hb-supplemented serum by Native PAGE on a 6% gel. Hp 2-2 (Lane 1) is a heterodimer with a series of slow moving bands. Hp 1-1 (Lane 4) is a homodimer with one fast moving band. Hp 2-1 (Lanes 2, 3, 5) has a band between the Hb/Hp 1-1 and Hb/Hp 2-2 bands, and several slow-moving bands in the same region as the Hb/Hp 2-2 bands. Panel B: In the rare Hp 2-1 M phenotype, a modification of the Hp α2 allele leads to overproduction of the fast migrating Hp 1-1 band, relative to the slower migrating Hp 2-1 bands. This results in a stronger Hb/Hp 1-1 band, and weaker Hb/Hp 2-1 bands, than in Hp 2-1. Panel C: Hp phenotyping of serum by SDS PAGE on a 12% gel. The Hp β band is common to all phenotyes. The presence of the Hp 1 and 2 alleles is indicated by the α1 and α2 bands, respectively. We chose to examine Hp phenotype and preeclampsia for three reasons. First, Hp's antioxidant and pro-angiogenic properties depend on phenotype [17], [22], [23]. Oxidative stress and reduced angiogenesis contribute to preeclampsia [5], [6]. In our recent case-control study, Hp 2-1 was associated with increased preeclampsia risk in non-hispanic white women, but not in black women [24]. We sought to confirm these findings in a larger cohort while extending the existing literature to include Hispanics. Second, any potential effect of Hp phenotype on preeclampsia risk or treatment response would affect a significant number of women. Hp 1-1, 2-1 and 2-2 are all common in whites, blacks and Hispanics (prevalences of 16%-50%) [25]. Third, Hp phenotype predicts cardiovascular disease risk, and responsiveness to Vitamin E [18], [19], [20] or C and E [21] in other non-pregnant populations. Hp 2-2 diabetics are twice as likely to have a cardiovascular event as Hp 1-1 and 2-1 diabetics [18], [21], [26]. Vitamin E supplementation eliminates this increased risk in Hp 2-2 diabetics, but has no effect in Hp 1-1 or 2-1 diabetics [18], [19], [27]. In contrast, Vitamin C may be harmful in Hp 2-2 diabetics as oxidation of Vitamin C may exacerbate pre-existing oxidative stress [28]. In post-menopausal women with coronary artery disease, Vitamin C and E decreased coronary artery diameter in Hp 2-2 diabetic women [21]. This harmful effect was not universal, as Vitamin C and E benefited Hp 1-1 women by significantly increasing coronary artery diameter [21]. We sought to determine whether Hp phenotype was associated with serious complications of pregnancy-associated hypertension (PAH) or preeclampsia in white, black or Hispanic women. We also examined whether Hp phenotype might influence responsiveness to antioxidant vitamins in preventing preeclampsia. Based on our previous findings, we hypothesized that Hp 2-1 would be associated with increased preeclampsia risk in white women, but not in black women. We also posited that phenotype would affect treatment response although directionality was difficult to predict based upon data from non-pregnant populations.
BODY.MATERIALS AND METHODS.POPULATION:
This was a secondary analysis of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network double-blind, multicenter RCT (NCT 00135707) in which 10,154 nulliparous, low risk women received daily doses of 400 IU of vitamin E and 1000 mg of vitamin C, or placebo, from 9-16 weeks gestation until delivery. The trial was conducted at 16 centers in the US between 2003 and 2008. Full details of the study were reported previously [14]. The trial was conducted in accordance with the Declaration of Helsinki of the World Medical Association. All subjects provided written, informed consent before participating. Hp phenotyping was performed at the University of Pittsburgh (Institutional Review Board approval PRO10010368).
BODY.MATERIALS AND METHODS.OUTCOMES:
The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes (aspartate aminotransferase ≥100 U per liter), elevated serum creatinine (≥1.5 mg/dl), thrombocytopenia (<100,000 platelets/mm3), eclampsia, fetal growth restriction (<3rd centile adjusted for sex and race/ethnicity), medically indicated preterm birth before 32 weeks due to PAH, or fetal death after 20 weeks gestation, or neonatal death. Hypertension was diagnosed using blood pressure measurements obtained during or after 20 weeks gestation, excluding intraoperative and intrapartum systolic blood pressures. Severe PAH was defined as a systolic blood pressure of 160 mm Hg or more, or a diastolic blood pressure of 110 mm Hg or more on two occasions 2 to 240 hours apart, or a single severely elevated blood pressure measurement that led to treatment with antihypertensive medication. Mild PAH was defined as systolic pressure between 140 and 159 mm Hg or a diastolic pressure between 90 mm Hg and 109 mm Hg on two occasions 2 to 240 hours apart. Mild preeclampsia was defined as mild PAH with proteinuria documented within the 3 days preceding or following the elevated blood pressure measurement. Proteinuria was defined as protein excretion ≥300 mg/24 hours, a dipstick urinary protein ≥2+, or protein:creatinine ≥0.35 in the absence of a 24-hour urine sample. Early onset preeclampsia was defined as preeclampsia requiring delivery before 37 weeks gestation. Severe preeclampsia was defined as preeclampsia with either severe PAH or protein excretion 35 g/24 hours, or as mild PAH with oliguria (<500 ml urine/24 hours), pulmonary edema (confirmed by radiography), or thrombocytopenia (<100,000 platelets/mm3).
BODY.MATERIALS AND METHODS.DESIGN:
The RCT included 10,154 women, of whom 2,434 were enrolled in a nested prediction cohort. The RCT design specified that secondary analyses requiring blood be conducted in the prediction cohort, as these women consented to extra blood collection for prediction and pathophysiology studies. If additional subjects were required, investigators could obtain samples from the 7,720 women not in the prediction cohort, in whom very little blood was collected. We needed samples from all white, black, and Hispanic women with preeclampsia in the RCT to detect a 2-fold increase in preeclampsia risk in Hp 2-1, compared to Hp 1-1, in each racial group (α = 0.05; Power: 83% white, 96% black, 98% Hispanic). We determined Hp phenotype in the prediction cohort; then added a case-control cohort composed of women who were not in the prediction cohort. The case-control cohort allowed us to capture all cases without phenotyping 5,500 additional controls. Cases in the case-control cohort included all women with preeclampsia, the primary outcome, or both (n = 703 cases) who were not in the prediction cohort. We selected 2 controls per case (n = 1,406) [29], matched for center and race/ethnicity (Figure 2). 10.1371/journal.pone.0060479.g002Figure 2Study Flow Chart.Subjects lost to follow-up include 183 women who miscarried, one subject whose data were removed at the patient's request, and one subject whose data were removed at the institutional review board's request.
BODY.MATERIALS AND METHODS.HP PHENOTYPING:
Hp phenotyping was performed as described previously [24], [30]. Serum samples (5 μl) supplemented with human hemoglobin (Sigma-Aldrich, St. Louis, MO) were phenotyped by hemoglobin-Hp complex peroxidase activity on native polyacrylamide gel electrophoresis (PAGE). Hemolyzed samples and samples with low Hp concentrations were phenotyped by Western blot following sodium dodecyl sulfate (SDS) PAGE of 1 to 6 μl of serum. Proteins from native and SDS gels were transferred to a polyvinylidene fluoride (PVDF) membrane (Millipore, Billerica, MA). SDS PAGE was followed by Western blotting with primary (1∶5,000, Polyclonal Rabbit Anti-Human Haptoglobin, DakoCytomation, Carpinteria, CA) and secondary (1∶25,000, Goat anti-Rabbit IgG horseradish peroxidase, Millipore) antibodies. Membranes were stained for peroxidase activity (SuperSignal West Pico Chemiluminescent Substrate, Fisher Scientific, Pittsburgh, PA) and imaged (FlouroChem Q System, Cell Biosciences, Santa Clara, CA). Hp phenotypes were identified by banding patterns of the Hp-hemoglobin complexes (native PAGE, Figure 1) or the Hp α1 and α2 alleles (SDS PAGE).
BODY.MATERIALS AND METHODS.PLASMA ASCORBATE:
Blood was collected in vials containing metaphosphoric acid, and frozen at −80 C [31]. Plasma ascorbic acid was measured by high performance liquid chromatography in the Molecular Epidemiology and Biomarker Laboratory (University of Minnesota) as described previously [31].
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
The prediction and case-control cohorts were analyzed separately (statistical methods in Data S1); then pooled to maximize power. In the pooled analysis, sampling weights were applied to reduce potential bias arising from an overrepresentation of women with the primary outcome (but not preeclampsia) in the control group for preeclampsia analyses, and an oversampling of women with preeclampsia (but not the primary outcome) in the control group for primary outcome analyses. Patients from the prediction cohort were assigned a weight of one. Cases and controls were assigned a sample weight defined as the inverse of their probability of selection [32]. Sample weights included a post-stratification adjustment for race/ethnicity. Baseline characteristics were compared using the t-test for continuous variables and the Rao-Scott chi-square test [33] for categorical variables. Logistic regression models were constructed to assess the multivariable association between Hp phenotype and the incidence of each outcome, adjusting for variables that were associated with Hp phenotype in univariate analyses. Odds ratios and 95% confidence intervals were estimated from unconditional survey logistic regression models. Taylor series replicate weights were created to estimate standard errors and p values in the weighted analyses. Model covariates included randomization group, and demographic variables that differed between women with the Hp 1-1, 2-1 and 2-2 phenotypes (age, self-reported vitamin use, education level, diastolic blood pressure at screening). The weighted analysis gave similar results to an unweighted analysis (i.e. samples were not weighted by the post-stratification sample weights; data not shown). Results were considered to be statistically significant at α = 0.05 with no adjustment for multiple comparisons [34]. All p values are 2-sided. SAS Version 9.2 (SAS Institute Inc.) and STATA (StataCorp, 2011 Stata Statistical Software: Release 12, College Station, TX, StataCorp LP), using procedures appropriate for sample-weighted data, were used for all analyses.
BODY.RESULTS.COHORTS:
We phenotyped 2,393 of the 2,434 women in the prediction cohort (Figure 2), excluding 40 women who miscarried, and one who had no samples collected. The case-control cohort included all remaining subjects who developed the primary outcome only (severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death) (n = 190), preeclampsia only (n = 280), or the primary outcome and preeclampsia (n = 233), and 1,406 controls matched for center and race/ethnicity. Women in the prediction cohort entered the study at an earlier gestational age (11.4±1.1) than women in the case-control cohort (14.0±2.0). Results of separate analyses for the prediction (Data S1; Tables S1, S2) and case-control cohorts (Data S1; Tables S3, S4, S5, S6, S7) are presented in Data S1. Results for the pooled cohort are described below.
BODY.RESULTS.SUBJECTS:
The pooled dataset included 1,008 Hp 1-1, 2,129 Hp 2-1 and 1,261 Hp 2-2 women. Ninety-six women had the rare 2-1 M phenotype, which results from a modification of the α2 allele [16]. These women were excluded from subsequent analyses. There were 1,840 white women, 1,392 black women, 1,188 Hispanic women, and 74 women of "Other" race.
BODY.RESULTS.WEIGHTING:
The weighted sample included 2,201 Hp 1-1 women, 4,840 Hp 2-1 women, 2,760 Hp 2-2 women, and 146 Hp 2-1 M women. The weighted cohort accurately reproduced the demographic characteristics of the original sample (Table S8). Demographic characteristics in the weighted cohort were not significantly different between the placebo and vitamin groups.
BODY.RESULTS.SUBJECT CHARACTERISTICS:
As expected, race/ethnicity differed between women with the Hp 1-1, 2-1, 2-2 and 2-1 M phenotypes (Table 1). The phenotype distribution for each race/ethnicity was similar to previous reports (Table 1, S9) [25]. Hp phenotype groups did not differ with respect to pre-pregnancy BMI, blood pressure at randomization, smoking, history of a previous pregnancy, or family history of preeclampsia (Table 1). Subsequent analyses were adjusted for characteristics that differed between the Hp 1-1, 2-1 and 2-2 groups (race/ethnicity, age, education, vitamin use). Analyses were also adjusted for diastolic blood pressure at randomization, which differed between phenotype groups in the prediction cohort (Table S10) but not in the pooled cohort. The white and other groups were pooled for race/ethnicity adjustments, as phenotype prevalence in the other group was most similar to whites (Table S9). 10.1371/journal.pone.0060479.t001 Table 1 Subject Characteristics for the Weighted Pooled Cohort by Hp phenotype. Subject Characteristics Hp 1-1 (n = 2,201) Hp 2-1 (n = 4,840) Hp 2-2 (n = 2,760) Hp 2-1 M (n = 161) p Age – years 22.4±4.9 23.6±5.1* 24.0±5.1* 20.2±3.7* ,†,‡
<0.01 Gestational age at randomization – week 13.4±2.1 13.3±2.0 13.4±2.1 13.0±2.5 0.48 Race or ethnicity - % within phenotype NA White 618 (28%) 2,142 (44%) 1,408 (51%) 3 (2%) Black 779 (35%) 1,059 (22%) 542 (20%) 132 (82%) Hispanic 779 (35%) 1,555 (32%) 724 (26%) 25 (6%) Other 25 (1%) 84 (2%) 86 (3%) 1 (<1%) Pre-pregnancy body mass index - kg/m 2
25.3±6.1 24.9±5.4 25.0±5.6 26.6±8.7 0.20 Smoked during pregnancy – n (%) 352 (16%) 721 (15%) 515 (19%) 23 (15%) 0.12 Education - years 12.2±2.9 12.7±2.7* 13.1±2.6* ,†
12.0±2.0 †,‡
<0.01 Prenatal/multivitamin use prior to randomization – n (%) 1,517 (69%) 3,759 (78%)* 2,194 (79%)* 132 (82%)* <0.01 Previous pregnancy – n (%) 520 (24%) 1,084 (22%) 731 (26%) 33 (21%) 0.16 Family history of preeclampsia – n (%) 319 (14%) 634 (13%) 341 (12%) 18 (11%) 0.64 Blood pressure at entry (9-12 weeks) Systolic – mm Hg 108±10 108±10 108±10 110±9 0.23 Diastolic – mm Hg 65±8 65±8 65±8 64±9 0.25 Values are mean ± SD or n (%). Abbreviations: NA; not applicable. Statistical comparisons for race/ethnicity were not performed, as cases and controls were matched for race/ethnicity. Significant difference (p<0.05) from: *Hp 1-1, † Hp 2-1, ‡ Hp 2-2.
BODY.RESULTS.PRIMARY OUTCOME AND PREECLAMPSIA RISK:
Hp phenotype was not significantly associated with the risk of the primary outcome, preeclampsia, severe preeclampsia, or early onset preeclampsia in white/other, Hispanic or black women (Table 2). Women of "other" race comprised 4% of the white/other group, and results were not different when these women were excluded (data not shown). The relationship between Hp phenotype on early onset preeclampsia approached statistical significance (p = 0.06) in Hispanics. 10.1371/journal.pone.0060479.t002 Table 2 Outcomes according to race/ethnicity and Hp phenotype in the weighted pooled cohort. Outcome Weighted Cases (n) Hp 2-1 † OR (95% CI) Hp 2-2 † OR (95% CI) White/Other Primary Outcome *
216 0.87 (0.56, 1.35) 0.92 (0.58, 1.45) Preeclampsia 222 0.98 (0.62, 1.54) 1.18 (0.74, 1.88) Severe Preeclampsia 90 1.30 (0.65, 2.62) 1.31 (0.64, 2.69) Early Onset Preeclampsia 58 0.96 (0.41, 2.22) 1.40 (0.61, 3.22) Late Onset Preeclampsia 163 0.98 (0.59, 1.64) 1.10 (0.65, 1.87) Black Primary Outcome 243 1.26 (0.90, 1.76) 1.00 (0.66, 1.51) Preeclampsia 237 1.03 (0.74, 1.45) 0.92 (0.61, 1.38) Severe Preeclampsia 115 1.14 (0.73, 1.80) 0.88 (0.49, 1.55) Early Onset Preeclampsia 74 1.18 (0.67, 2.07) 0.95 (0.48, 1.88) Late Onset Preeclampsia 163 0.97 (0.66, 1.44) 0.90 (0.56, 1.46) Hispanic Primary Outcome 116 0.79 (0.49, 1.29) 0.85 (0.47, 1.54) Preeclampsia 217 0.77 (0.53, 1.12) 0.74 (0.46, 1.19) Severe Preeclampsia 76 0.71 (0.40, 1.24) 0.67 (0.32, 1.40) Early Onset Preeclampsia 42 0.41 (0.20, 0.86) 0.53 (0.21, 1.37) Late Onset Preeclampsia 175 0.90 (0.60, 1.37) 0.82 (0.49, 1.39) Hp 1-1 was the reference group for odds ratios. Hp phenotype was determined in 1,573 black women, 1,164 Hispanic women, and 1,432 women of white or other race. Each observation was weighted to reflect the pregnancy outcomes and racial distribution of the full cohort. * The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Abbreviations: OR, odds ratio; CI, confidence interval. † Adjusted for group (treatment vs. placebo), race/ethnicity, age, education, vitamin use and diastolic blood pressure at randomization.
BODY.RESULTS.TREATMENT RESPONSE:
Vitamin C and E supplementation did not prevent the primary outcome or any form of preeclampsia among white/other, black or Hispanic women of any Hp phenotype after adjusting for vitamin use, age, education, and diastolic blood pressure at randomization (data not shown). In Hispanics, the effect of vitamin supplementation differed between Hp phenotype groups for preeclampsia (Hp phenotype*treatment group: p<0.01) and late onset preeclampsia (p = 0.02), but not for severe (p = 0.06) or early onset preeclampsia (p = 0.10). Vitamin supplementation significantly increased preeclampsia (odds ratio (OR) 3.30; 95% confidence interval (CI) 1.61-6.82, p<0.01, Table 3) and late onset preeclampsia risk (3.01; 1.38-6.57, p<0.01) in Hispanic Hp 2-2 women. This adverse effect was not seen in Hp 1-1 or 2-1 Hispanics (p>0.05), or in white/other or black women of any phenotype. 10.1371/journal.pone.0060479.t003 Table 3 Odds ratios for effect of treatment in Hispanic women in the weighted pooled cohort. Outcome Phenotype OR (95% CI) *
p *
Preeclampsia Hp 1-1 0.71 (0.39, 1.29) 0.27 Hp 2-1 0.95 (0.61, 1.50) 0.83 Hp 2-2 3.30 (1.61, 6.82) <0.01 Late Onset Preeclampsia Hp 1-1 0.70 (0.36, 1.35) 0.29 Hp 2-1 1.02 (0.63, 1.66) 0.92 Hp 2-2 3.01 (1.38, 6.57) <0.01 * Adjusted for vitamin use, age, education and diastolic blood pressure at randomization. Increased preeclampsia risk in Hispanic Hp 2-2 women was specific to the large quantities of vitamins C and E in study supplements. Prenatal/multivitamin use at randomization was not associated with an increased risk of preeclampsia (2.17; 0.53-8.71, p = 0.27) or late onset preeclampsia (2.85; 0.57–14.36, p = 0.20) in Hispanic Hp 2-2 women receiving placebo. Low rates of prenatal/multivitamin use at randomization (43% in Hispanics vs. 91% in non-Hispanics, Table S10) are unlikely to explain why the adverse effect of supplementation in Hp 2-2 women was only seen in Hispanics. Hispanic 2-2 women who were not taking prenatal vitamins at randomization had a smaller increase in preeclampsia risk with supplementation than Hispanic 2-2 women who were taking prenatal vitamins at randomization (2.01; 0.80–5.01, p = 0.14 vs. 7.83; 2.01–30.53, p<0.01, Table 4). 10.1371/journal.pone.0060479.t004 Table 4 Odds ratios for treatment effect in Hispanic Hp 2-2 women according to prenatal/multivitamin use at randomization. Outcome Vitamin Use at Randomization OR (95% CI) *
p *
Preeclampsia Yes 7.83 (2.01, 30.53) <0.01 No 2.01 (0.80, 5.01) 0.14 Late Onset Preeclampsia Yes 8.23 (1.64, 41.28) 0.01 No 1.91 (0.73, 5.00) 0.18 * Adjusted for age, education and diastolic blood pressure at randomization.
BODY.RESULTS.HP PHENOTYPE, PRENATAL/MULTIVITAMIN USE AT RANDOMIZATION, AND PLASMA ASCORBATE:
Hp phenotype influences plasma ascorbate concentration [35], providing a potential mechanism by which Hp phenotype might influence treatment response to vitamin C and E. We examined the relationship between Hp phenotype and plasma ascorbate in a pre-planned analysis. Plasma ascorbate was measured at the pre-randomization screening visit in 264 women with known Hp phenotypes. Plasma ascorbate was lower in women who were not taking a prenatal/multivitamin at randomization (n = 34) compared to those who were (n = 230) (p = 0.02 for main effect, Table 5). Statistical comparisons within phenotype groups were not conducted, as the number of women who were not taking prenatal/multivitamins at randomization within each phenotype group was very small. Hp phenotype was not significantly associated with plasma ascorbate (p = 0.73). The interaction between Hp phenotype and vitamin use at randomization was not significant (p = 0.32). Plasma ascorbate was only measured in six Hispanic Hp 2-2 women; therefore we could not determine whether supplementation had a different effect on plasma ascorbate in this group. 10.1371/journal.pone.0060479.t005 Table 5 Plasma ascorbate concentrations according to Hp phenotype and prenatal/multivitamin use at randomization. Hp Phenotype Not Taking Prenatal/multivitaminsat Randomization Taking Prenatal/multivitaminsat Randomization All 8.4 (7.2, 9.5) (n = 34) 9.9 (9.4, 10.3) (n = 230)* 1-1 9.3 (7.4, 11.3) (n = 12) 9.6 (8.6, 10.5) (n = 48) 2-1 8.0 (6.3, 9.6) (n = 16) 9.8 (9.2, 10.4) (n = 126) 2-2 7.4 (4.7, 10.1) (n = 6) 10.2 (9.3, 11.1) (n = 56) Plasma ascorbate at the pre-randomization study visit was measured in a subset of 264 patients with known Hp phenotype. The vitamin and placebo groups were pooled, as study treatment had not yet started. Women not taking a prenatal vitamin at randomization had lower plasma ascorbate than women taking prenatal/multivitamins at randomization (*p = 0.02). Statistical comparisons within phenotype group were not conducted due to the small number of women not taking prenatal/multivitamins at randomization. Values are mean (95% confidence interval) in mg/L.
BODY.DISCUSSION:
Hp phenotype was not associated with the risk of the primary outcome (a composite of PAH and serious adverse outcomes in the mother, her fetus or neonate) or any type of preeclampsia in white, black or Hispanic women. Moreover, daily vitamin C and E supplementation did not prevent the primary outcome or preeclampsia in women of any Hp phenotype. Supplementation increased the risk of preeclampsia and late onset preeclampsia by 3-fold in Hispanic Hp 2-2 women.
BODY.DISCUSSION.HP PHENOTYPE AND THE RISK OF PREECLAMPSIA AND SERIOUS COMPLICATIONS OF PAH:
We found no relationship between Hp phenotype and the primary outcome or preeclampsia risk in white, black or Hispanic women. This study has two key strengths. First, it extends the existing literature by including large numbers of black and Hispanic women. Previous studies focused on predominantly white, non-Hispanic women [24],[36],[37],[38]. Studies examining the relationship between Hp phenotype and preeclampsia risk in different racial groups were recently recommended [39]. Second, this is the largest study of non-Hispanic white women completed to date, and was adequately powered to detect the difference that we observed in our previous case-control study [24]. This is particularly important, as the heterogeneous results and small sample sizes of previous European studies suggests that spurious findings may be common. At the time we initiated this investigation, two small, underpowered European studies had reported that preeclampsia risk was not different [38] or increased [36] in Hp 1-1 white women. Adequately powered studies [39], and studies in North American women, were needed. An Israeli study subsequently reported a 50% reduction in preeclampsia risk among Hp 1-1 women, compared to Hp 2-1 and 2-2 [24], [30], [37]. Our larger case-control study suggested that Hp 1-1 was only protective when compared to Hp 2-1, and not Hp 2-2 [24]. Unfortunately, we were unable to confirm this finding in the present cohort. However, we did confirm our previous preliminary data [24] suggesting that there was no relationship between Hp phenotype and preeclampsia risk in black women in a large adequately powered cohort. The trend (p = 0.06) towards an increased risk of early onset preeclampsia in Hp 2-1 and 2-2 Hispanics was likely a spurious result due to the small number of cases (n = 42).
BODY.DISCUSSION.HP PHENOTYPE AND VITAMIN C AND E:
Accumulating evidence suggests that preeclampsia and later life cardiovascular disease are intimately linked. These conditions share several risk factors (i.e. black race, obesity, diabetes) and pathophysiological processes (inflammation, oxidative stress, endothelial dysfunction, and impaired angiogenesis) [40], [41]. The American Heart Association recently recognized preeclampsia as a cardiovascular disease risk factor [41]. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations, particularly in diabetics [18], [19], [21], [26]. Uncomplicated pregnancy is an insulin resistant state [42], and gestational diabetes [43] and Type 1 diabetes [44] increase preeclampsia risk. Therefore, we examined the potential for Hp phenotype to influence the effectiveness of vitamin C and E in preventing preeclampsia and serious complications of PAH. Daily vitamin C and E did not prevent preeclampsia or serious complications of PAH in low risk primiparous women of any Hp phenotype. Supplementation actually increased preeclampsia risk by 3-fold in Hispanic Hp 2-2 women, however the mechanism requires further investigation. This effect was not explained by the strikingly lower prevalence of vitamin supplementation at randomization in Hispanics. Hispanic women have an increased risk of the metabolic syndrome and diabetes, conditions associated with oxidative stress [45]. Platelet volume, a marker of accelerated platelet turn over, was increased in Hispanic women compared to white or black women in the prediction cohort [46]. Accelerated platelet turnover could indicate low-grade intravascular coagulation and subsequent mild chronic hemolysis. The resulting oxidative stress would be worse in Hp 2-2 women due to the low antioxidant capacity of this phenotype. We speculate that supplementation may have exacerbated pre-existing oxidative stress, and therefore preeclampsia risk, in Hispanic Hp 2-2 women by increasing ascorbate radical formation. A definitive explanation will be sought in future studies. Supplementation increased the risk of late onset preeclampsia, but not early onset preeclampsia, in Hp 2-2 Hispanics. This could reflect pathophysiological differences between these conditions or lower power due to fewer cases of early onset preeclampsia. Several factors could explain the difference between our results and previous research in other populations [18], [19], [21], [26]. First, cardiovascular disease studies suggest that vitamin E alone has different effects from vitamin C and E combined [18], [19], [27]. Vitamin C and E can be beneficial or harmful, depending on Hp phenotype [27]. Coronary artery diameter increased following vitamin C and E supplementation in Hp 1-1 post-menopausal women with coronary artery disease. However, the pro-oxidant effects of vitamin C [28] combined with the reduced antioxidant capacity of Hp 2-2 may have contributed to accelerated coronary artery narrowing in diabetic Hp 2-2 post-menopausal women taking vitamins C and E [21]. Oxidative stress increases in pregnancy [40], suggesting that a similar mechanism could be active in Hp 2-2 pregnant women. In partial support of this hypothesis, we observed a 3-fold increase in preeclampsia risk in Hp 2-2 Hispanic women receiving vitamin C and E. The original RCT combined vitamins C and E, an approach used in cardiovascular disease prevention trials [47], [48], [49] that was successful in small clinical trials. Therefore, we cannot determine whether vitamin E or C alone would have been efficacious. However, the absence of a beneficial treatment effect in women of any Hp phenotype makes this possibility unlikely. Second, previous studies focused primarily on Type 2 diabetics [18], [19], [21], [26], however women with pre-existing diabetes were excluded from the current study. Insulin resistance increases during pregnancy, and 3% of women in the trial developed gestational diabetes [42]. The most extensively studied mechanism by which vitamin E reduces cardiovascular disease risk in Type 2 diabetes is by preventing the HDL dysfunction caused by cross-linking with glycosylated hemoglobin [28]. Hypothesizing that a similar mechanism might be active in Type 1 diabetes, members of our study team assessed the potential for Hp phenotype to modify the effectiveness of vitamin C and E in preventing preeclampsia in women with Type 1 diabetes [30]. Unfortunately, supplementation was not effective in preventing preeclampsia in women with Type 1 diabetes of any Hp phenotype [30]. Trials in Type 2 diabetics have not been conducted. Third, despite the similarities between preeclampsia and cardiovascular disease, there are also critical differences. Preeclampsia only occurs in pregnancy, and is proposed to result from an interaction between materials released by the placenta, and maternal constitutional characteristics that are largely cardiovascular risk factors [40]. It may be that transient exposure to insults in young women cannot be equated to years of chronic exposure to cardiovascular risk factors in older women.
BODY.DISCUSSION.CONCLUSIONS:
In contrast to our hypothesis, our secondary analysis of a large RCT indicates that Hp phenotype does not influence preeclampsia risk, or identify a subset of nulligravidas for whom vitamins C and E would reduce preeclampsia risk in white, black or Hispanic women. Vitamins C and E supplementation may increase preeclampsia risk in Hispanic Hp 2-2 women, but due to the limitations of secondary analysis, this finding requires verification.
BODY.SUPPORTING INFORMATION:
Data S1
Supplemental Data. Supplemental data file containing methods and results for separate analyses of prediction cohort and case-control cohort, and an appendix listing members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.(DOC)Click here for additional data file. Table S1
Prediction cohort subject characteristics. Values are mean ± SD or n (% within phenotype). Significant difference (p<0.05) from: *Hp 1-1, †Hp 2-1, ‡Hp 2-2.(DOC)Click here for additional data file. Table S2
Outcomes according to Hp phenotype in the prediction cohort. *Adjusted for treatment group (vitamins vs. placebo), age, race/ethnicity, education, vitamin use prior to randomization, and diastolic blood pressure at randomization. †The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclamptic seizure, fetal growth restriction, medically indicated preterm birth or perinatal death.(DOC)Click here for additional data file. Table S3
Subject Characteristics for Subjects not in the Prediction Cohort, and in the Weighted Case-Control Cohort. Values are mean ± SD or n (%).(DOC)Click here for additional data file. Table S4
Case-control cohort weighted subject characteristics. Values are mean ± SD or n (%). Abbreviations: NA; not applicable. Statistical comparisons for race/ethnicity were not performed, as cases and controls were matched for race/ethnicity. Significant difference (p<0.05) from: *Hp 1-1, †Hp 2-1, ‡Hp 2-2.(DOC)Click here for additional data file. Table S5
Outcomes according to Hp phenotype and race/ethnicity in the case-control cohort. Hp 1-1 was the reference group for odds ratios. Hp phenotype was determined in 769 black women, 579 Hispanic women, and 716 women of white or other race. Each observation was weighted to reflect the pregnancy outcomes and racial distribution of the full cohort, excluding women in the prediction study (3,170 white/other women, 1,839 black women, 2,459 Hispanic women). Abbreviations: OR, odds ratio; CI, confidence interval. *Adjusted for group (treatment vs. placebo), race/ethnicity, age, education, vitamin use and diastolic blood pressure at randomization †Significantly different from 1, p<0.05.(DOC)Click here for additional data file. Table S6
Interaction between Hp phenotype and treatment in case-control cohort. *Adjusted for vitamin use, age, education and diastolic blood pressure at randomization(DOC)Click here for additional data file. Table S7
Odds ratios for the effect of treatment in Hispanic women in the case-control cohort. *Adjusted for vitamin use, age, education and diastolic blood pressure at randomization(DOC)Click here for additional data file. Table S8
Subject Characteristics for the Original Study and the Weighted Pooled Cohort Values are mean ± SD or n (%). *Values for the 9,969 women with known pregnancy outcomes in the original study. Women who were lost to follow-up (n = 183) were excluded. Weights for this analysis were based on race/ethnicity and pregnancy outcome, therefore these women were not eligible to be selected for the pooled cohort analysis.(DOC)Click here for additional data file. Table S9
Hp phenotype prevalence by race in the weighted pooled cohort Values are n (% within race).
(DOC)Click here for additional data file. Table S10
Subject Characteristics for Hispanic vs. non-Hispanic Women in the Weighted Pooled Cohort. Values are mean ± SD unless otherwise indicated.(DOC)Click here for additional data file. | 3,616,124 | {
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TITLE: The Effect of Yellow Tinted Intraocular Lenses on the Result of Frequency Doubling Perimetry after Cataract Surgery
ABSTRACT.PURPOSE:
To investigate the effect of yellow tinted intraocular lenses (IOLs), implanted in the bag after phacoemulsification, on the result of frequency doubling technique (FDT) perimetry.
ABSTRACT.METHODS:
For 68 eyes of 52 patients, an IOL was implanted in the bag after phacoemulsification. The patients were categorized into three groups according to the type of implanted IOLs used. IOLs were selected randomly among two types of yellow IOLs (Acrysof SN60WF IOL, Hoya YA60BBR IOL) and a clear IOL was used as a control. A FDT Humphrey matrix was performed 2 months after the surgery. The mean deviation (MD) and pattern standard deviation (PSD) among these three groups was analyzed using Mann-Whitney U-test.
ABSTRACT.RESULTS:
Two months after the procedure, there was no significant difference between each of the three groups: the clear IOL and Hoya YA60BBR IOL (MD, p = 0.21; PSD, p = 0.27), the clear IOL and Alcon SN60WF IOL (MD, p = 0.11; PSD, p = 0.22), and the Hoya YA60BBR IOL and Alcon SN60WF IOL (MD, p = 0.33; PSD, p = 0.56).
ABSTRACT.CONCLUSIONS:
When interpreting the result of the FDT after cataract surgery, the color and type of IOLs used should not be considered.
BODY:
The cornea absorbs light with a wavelength below 295 nm and the crystalline lens absorbs light with a wavelength below 400 nm. Therefore, the human retina is protected from short-wavelength light. After cataract surgery with the implantation of a clear intraocular lens (IOL), the retina is now exposed to short-wavelength light. Consequently, yellow intraocular lenses have emerged as a blue blocker. From recent studies, it has been revealed that blue-light filtering IOLs may have protective effects against exudative age related macular degeneration [1]. Frequency doubling technique (FDT) perimetry is a well-known procedure used for glaucoma screening. Threshold tests potentially may identify glaucomatous defects sooner than other methods. The FDT stimulus predominantly stimulates the Magnocellular pathway, which is primarily involved in motion and flicker detection and represents about 10% of all retinal ganglion cells. The FDT perimeter (Welch Allyn, Skaneateles Falls, NY; Humphrey Instruments, San Leandro, CA, USA) uses a vertical sine wave grating of low spatial frequency (0.25-0.50 cycle/degree) that undergoes counterphase flickering at a high-temporal frequency (12-25 Hz). The contrast of the stimulus is modified in each location to calculate threshold sensitivity [2]. Some reports demonstrated the effect of cataracts on FDT perimetry, suggesting a significant improvement in mean deviation (MD) without a significant change in pattern standard deviation (PSD) after cataract surgery with clear IOLs [3,4]. In this study, we compared the effect of IOLs between each of the three groups (the clear IOL, Alcon Acrysof IQ SN60WF [Alcon, Fort Worth, TX, USA], and Hoya YA60BBR [Hoya Co., Tokyo, Japan]) with the result of FDT perimetry.
BODY.MATERIALS AND METHODS:
We prospectively included 68 eyes of 52 patients who underwent cataract surgery and intraocular lens implantation with otherwise normal eye findings. Informed consent was obtained from each patient before enrollment in the study. All the procedures conformed to the tenets of the Declaration of Helsinki. Fifty-two patients had cataract surgery under similar preoperative conditions using the same phacoemulsification technique with the Infinity machine and Ozil system (Alcon). All the surgeries were performed without complications by the same surgeon (CKJ). The operated eye was randomized to receive an AcrySof IQ IOL (Alcon), a Hoya YA60BBR IOL, or a conventional clear IOL (OII Biovue3; BioVue, Ontario, CA, USA) in the capsular bag. Postoperatively, all patients were given gatifloxacin 0.3% (Gatiflo, Handok pharmaceuticals, Seoul, Korea) and prednisolone acetate 1% (Pred Forte; Allergan, Irvine, CA, USA), 4 times a day for 30 days. After 30 days, the application of the two eyedrops was decreased to by twice a day for 30 days. Patients with diabetes mellitus, poor cooperation, glaucoma (diagnosed by intraocular pressure, visual field exam, optic nerve morphology, and retinal nerve fiber layer findings), complicated cataracts and any negative events resulting from cataract surgery were excluded from the study. Routine postoperative ocular evaluations (visual acuity, refraction, IOP measurements, etc.) were carried out at each visit to avoid the bias of low visual acuity on perimetry. FDT perimetry was performed with a FDT Humphrey matrix (Carl Zeiss Meditec, Dublin, CA, USA). The FDT 24-2 threshold test was performed following the same procedure for eyes with clear or yellow IOL implantations with the refractive error fully corrected, two months after the operation. The global indices obtained by FDT were MD and PSD. The data was analyzed with the nonparametric Mann-Whitney U-test or Kruksal-Wallis test using a 5% significance level by SPSS ver. 13.0 (SPSS Inc., Chicago, IL, USA).
BODY.RESULTS:
A total of 52 people were enrolled in the study (28 men and 24 women). The mean age was 63.2 ± 11.5 years old (range, 52 to 78 years). Demographics are shown in Table 1. There were no significant differences among three IOL groups with respect to visual acuity and spherical equivalence in the preoperative and postoperative phase (Table 2). The results of FDT perimetry testing are shown in Figs. 1, 2, and 3. There were no statistically significant differences for MD and PSD between the clear IOL and Hoya YA60BBR IOL groups (MD: clear IOL, -5.09 ± 4.72 Db; Hoya YA60BBR IOL, -3.68 ± 3.83 dB; p = 0.21 / PSD: clear IOL, 4.26 ± 2.45 dB; Hoya YA60BBR IOL, 3.81 ± 1.99; p = 0.27, Mann-Whitney U-test). There were no statistically significant differences for MD and PSD the clear IOL and Alcon SN60WF IOL groups (MD: clear IOL, -5.09 ± 4.72 dB; Alcon SN60WF IOL, -2.47 ± 2.61 dB; p = 0.11 / PSD: clear IOL, 4.26 ± 2.45 dB; Alcon SN60WF IOL, 3.28 ± 1.23 dB; p = 0.22, Mann-Whitney U-test). No statistically significant differences were observed between the two types of yellow IOL groups (MD: Hoya YA60BBR, -3.68 ± 3.83 dB; Alcon SN60WF, -2.47 ± 2.61 dB; p = 0.33 / PSD: Hoya YA60BBR, 3.81 ± 1.99 dB; Alcon SN60WF, 3.28 ± 1.23; p = 0.56, Mann-Whitney U-test).
BODY.DISCUSSION:
FDT perimetry is barely affected by refractive errors. Therefore, it is more useful for glaucoma screening than the standard automated perimetry. In this study, FDT perimetry was used for comparing the effect of the colors of IOLs. No significant difference of postoperative visual acuity and spherical equivalence between each of three groups place greater accuracy on the results from FDT perimetry in this study. Another report by Ueda et al. [5] showed that there was no significant difference between clear and yellow IOLs for either MD or PSD. They compared the Hoya VA60BB (clear IOL) with Hoya YA60BB (yellow IOL). The results from FDT perimetry were also not influenced by the color of the IOL. In this study, the results from FDT perimerty of the conventional clear IOL and yellow tinted IOL were not significantly different. The two yellow tinted IOLs used in this study were Hoya YA60BBR and Alcon SN60WF. They are similar in many aspects. Both of the IOLs have hydrophobic acrylic optics with similar size (optic diameter 6 mm) and similar refractive index (YA60BBR, 1.51; SN60WF, 1.55). These blue-blockers absorb short wavelength light for retinal protection, but also absorb different ranges of wavelength. Hoya YA60BBR mainly absorbs lights in the range of 400-450 nm, while Alcon SN60WF absorbs light in the 400-500 nm wavelength range [6,7]. However, in this study, the different spectral transmittance between the two types of yellow tinted IOLs did not affect the results of FDT perimetry. Therefore, FDT perimetry results after cataract surgery can be interpretated without giving regard to the type of yellow tinted IOL used. FDT perimetry predominantly stimulates the magnocellular pathway by using frequency doubling illusions. Rod cells may transit signals to the lateral geniculate body through the magnocellular pathway of ganglion cells. This theory was suggested by three articles. As repoted by Lee et al. [8], rod inputs were much more apparent in magnocellular pathway cells. Purpura et al. [9] stated that the Magnocellular pathway is the predominant conveyor of information of spatial contrast to the visual cortex in the mesopic and scotopic illuminations. Sun et al. [10] reported that rod threshold areas are inferred to be mediated by the magnocellular pathway. As a result, we can assume that a frequency doubling illusion predominantly stimulates rod cells. Sensitivity of cones and rods varies in some conditions. First, the illuminance level determines the level of activity of photoreceptors. Rods are more active photoreceptors in scotopic conditions. Secondly, rod cells are more sensitive than cone cells in short wavelength light. Stabell and Stabell [11] suggested that the "rod color" is blue. Therefore, if a short wavelength blue ray light was blocked by the yellow tinted IOL, we can assume that the result of FDT perimetry would be altered. There was no significant difference in the result of FDT perimetry between conventional clear and yellow tinted IOLs. According to a previous report by Ueda et al. [5], this lack of a significant difference was explained through findings from a report by Antonio and associates that compared clear IOLs with yellow IOLs with respect to contrast sensitivity. At different spatial frequencies, contrast sensitivity exhibits similar values in patients implanted with clear and yellow tinted IOLs. The contrast sensitivity test predominantly activates the cone pathway, so this process may be mainly mediated by P-cell pathway. This is owed to the test condition: which consists of photopic conditions and requirements of the ability for high spatial frequency and fine visual discrimination. Although FDT perimetry determines contrast sensitivity for detecting frequency doubling stimulus, it is not sufficient to completely explain the process. Frequency doubling illusion has low spatial and high temporal frequency, so it selectively stimulates the magnocellular pathway. There are two considerations to explain why there are no significant differences in the result of FDT perimetry. First, the rod pathway has convergence pattern. In the case of the rod system, the convergence of preceding neurons to the ganglion cell is enormous and consist of 75,000 rods going through 5,000 rod bipolar cells to 250 AII amacrine cells to a single alpha ganglion cell [12]. Though the sensitivity of the rod cells are decreased due to the blocking short wavelength light, some population of rods can activate this pathway and transmit signals to the magnocellular pathway. Second, the testing condition of FDT perimetry is not a scotopic condition. In FDT perimetry, ambient room illumination was dim, and background luminance of the monitor was 45 cd/m2. Therefore, it is a mesopic condition. In scotopic conditions, only rod cells are active photoreceptors. Cone cells are also active photoreceptors in mesopic conditions. This means that cone cells are able to mediate visual signals in FDT perimetry. This study has several limitations that included the absence of preoperative FDT perimetry data, the small number of cases, and the absence of concurrent standard automated perimetry. A larger number of cases, more than 100 cases in each group, could make a difference in the findings between each group, or confirm the result seen in this study. Therefore, further studies are needed to make up for these points in the future. In conclusion, there were no significant changes in the result of FDT perimetry after cataract surgery between clear and yellow IOLs. When interpreting the results of FDT perimetry, the color and type of IOLs do not need to be taken into account. | 3,039,191 | {
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"There were no statistically significant differences for MD and PSD between the clear IOL and Hoya YA60BBR IOL groups (MD: clear IOL, -5.09 ± 4.72 Db; Hoya YA60BBR IOL, -3.68 ± 3.83 dB; p = 0.21 / PSD: clear IOL, 4.26 ± 2.45 dB; Hoya YA60BBR IOL, 3.81 ± 1.99; p = 0.27, Mann-Whitney U-test). There were no statistically significant differences for MD and PSD the clear IOL and Alcon SN60WF IOL groups (MD: clear IOL, -5.09 ± 4.72 dB; Alcon SN60WF IOL, -2.47 ± 2.61 dB; p = 0.11 / PSD: clear IOL, 4.26 ± 2.45 dB; Alcon SN60WF IOL, 3.28 ± 1.23 dB; p = 0.22, Mann-Whitney U-test). No statistically significant differences were observed between the two types of yellow IOL groups (MD: Hoya YA60BBR, -3.68 ± 3.83 dB; Alcon SN60WF, -2.47 ± 2.61 dB; p = 0.33 / PSD: Hoya YA60BBR, 3.81 ± 1.99 dB; Alcon SN60WF, 3.28 ± 1.23; p = 0.56, Mann-Whitney U-test).",
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TITLE: Antibiotic use during pregnancy: a retrospective study of prescription patterns and birth outcomes at an antenatal clinic in rural Ghana
ABSTRACT.BACKGROUND:
Babies are increasingly being exposed to antibiotics intrapartum in the bid to reduce neonatal and maternal deaths. Intrapartum antibiotic exposure, including even those considered safe in pregnancy, have been associated with childhood obesity and compromised immunity. Data on the extent of antibiotic use, safety and its impact on birth outcomes and neonatal health in Sub-Saharan Africa is very limited. This study sought to ascertain the extent of antibiotic use in pregnancy and its effects on birth outcomes in a rural hospital in Ghana.
ABSTRACT.METHODS:
The study was a retrospective randomized study of mothers who delivered babies in a rural hospital between 2011 and 2015 in Ghana. A total of 412 mother/baby records out of 2100 pre-selected met the inclusion criteria of the study. Indicators of neonatal health used were birthweight, Apgar score, incidence of birth defects.
ABSTRACT.RESULTS:
Sixty five percent of pregnant women were administered antibiotics at some stage during pregnancy. Beta Lactam antibiotics accounted for more than 67% of all antibiotics prescribed. There was a statistically significant association between antibiotic exposure and pregnancy factors such as stage of pregnancy, parity and mode of delivery but not with socio-economic status of the mother. Intrapartum antibiotic exposure did not significantly affect the birthweight, incidence of congenital birth defect and mean Apgar scores. After adjusting for method of delivery, however, perinatal antibiotic use (24 h to delivery) was associated with lower mean Apgar scores. Birth weight was affected significantly by maternal socio-economic factors such as age and marital status.
ABSTRACT.CONCLUSION:
Sixty five percent of women attending the antenatal clinic received antibiotics. Intrapartum antibiotics did not affect early markers of neonatal health such as birthweight, congenital birth defect and mean Apgar scores. However, antibiotic use less than 24 h to delivery was associated with a decrease in mean APGAR score.
BODY.BACKGROUND:
There has been a sturdy increase in global antibiotic prescription and consumption [1]. Several concerns have been raised about irrational use of antibiotics and its subsequent impact on drug resistance and cost of healthcare. Furthermore, the role that human microbiota, believed to account for the greater part of human body weight, plays in programming the immunity and metabolism of an individual has re-emphasized the need to regulate use of antibiotics [2]. Pregnancy presents with significant risk of complications which may lead to morbidity and mortality for mother-baby pairs. Globally, more than 50% of neonatal deaths occur in Sub-Saharan Africa because of infections and limited health resources [3, 4]. To manage the complications associated with pregnancy and motherhood, many medicines are employed. Antibiotics remain important in pregnancy and may be second to only iron and food supplement [5]. Due to limited health resources, such as laboratories to carry-out culture and sensitivity test, the extent of exposure of pregnant women and babies to antibiotics and the effects on their health may be underestimated. There have been several attempts to promote rational antibiotic use partly because of the risk of drug resistance, increased cost of healthcare, as well as the risk of teratogenicity in the developing foetus [6, 7]. However, recent studies have shown that there may be other insidious risk associated with antibiotic use in pregnancy independent on safety profile, mechanism of action or even class the of antibiotic [2]. For instance it is well documented that Caesarian birth or intrapartum antibiotic exposure contributes adversely to childhood obesity and compromised immunity of the baby [8, 9]. Unlike classical teratogenesis, these effects occur indirectly through alterations of the maternal microbiota without the agent necessarily crossing the placenta to affect the tissues of the foetus. Neonatal Health and Birth outcome is highly dependent on maternal health, nutrition and socio-economic factors. The use and choice of antibiotic during pregnancy depends primarily on maternal factors such as health, nutrition, mode of delivery and socio-economic factors. These maternal factors influence the indicators used to estimate birth outcomes and neonatal health such as birth weight, APGAR scores, and incidences of birth defects. To able to understand the full extent and effects of intrapartum antibiotics on mother and babies, there is a need to elucidate the complex interplay between maternal health, mode of delivery and socio-economic status and neonatal health. A key point in the millennium development goals is reducing maternal and neonatal mortality. To date there is little clinical data on the trends of antibiotic use during pregnancy and its effects on neonatal health from sub-Saharan Africa. Using Birth weight, APGAR scores, and incidences of birth defects as indicators of birth outcomes and early neonatal health and survival, this study examines the use of antibiotics during pregnancy, its effects on birth and neonatal health and as well as the effects of other maternal factors on antibiotic use in a rural health facility in Ghana.
BODY.METHODS.STUDY AREA:
Seventh-Day Adventist Hospital, Dominase is a 45 bed capacity hospital located in Dominase about 19 km off the Kumasi–Cape coast highway. The hospital has an obstetrics and gynaecology unit which runs an antenatal clinic with a resident gynaecologist, pharmacist and several midwives and nurses. To limit the impact of un-prescribed and undocumented antibiotic usage, the area chosen was predominately rural with no existent pharmacy. Furthermore, the National Health Insurance Scheme of Ghana runs a "capitation policy" where patients choose a particular primary health care facility for their needs without paying out of pocket. Patients who visit any other facility aside the allocated facility have to pay to access healthcare. This discouraged the tendency for mothers from seeking health services from other facilities as well as reduce self –medication. This is of particular importance because antibiotics can be obtained without prescription in Ghana.
BODY.METHODS.STUDY DESIGN:
The design was a retrospective descriptive study. The primary source of data was prescriptions generated and recorded in patient medical records filed in the hospital between January 2011 and December 2015.
BODY.METHODS.SAMPLING METHOD:
Folder numbers of all live babies born in the hospital between January, 2011 and September, 2015 were retrieved from the registration book at the maternity unit. Five hundred folder numbers were selected for each of the 5 years from the registration book using systematic sample, making a total of 2500 folders. The contents of 2100 folders were available for the study. Each folder of mother-baby pairs was subsequently screened using the inclusion and exclusion criteria. A total of 412 mother-baby pairs met the selection criteria. The Inclusion criteria included;The mother should have attended at least three ANC at the hospital after confirmation of pregnancy either by ultrasonography or Human Chorionic Gonadotrophic (HCG) detection method.Should have delivered a live singleton baby at the facility.
The exclusion criteria included;Twin gestationsDeliveries of referral cases from other hospitals
BODY.METHODS.STATISTICAL ANALYSIS:
Data obtained from the medical records were transferred unto a data capture form, the secondary data was later collated, scrutinized and analysed using IBM Statistical package for Social Sciences (SPSS) version 21. Pearson Chi-square test was used to analyze categorical variables. Relative risk and Odds ratio were used as a measure of the degree of association between an event (outcome) and comparable groups. Students T- test and One way analysis of variance (one-way Anova) were used to analyze the difference in mean values between a set of comparable groups or values. Bonferroni was used as the post hoc test after one- way Anova. A p-value less than 0.05 was considered statistically significant.
BODY.METHODS.POTENTIAL CONFOUNDERS:
The study assumed that antibiotic prescribed was synonymous with exposure which is not always the case. Because of the rural nature of the setting the hospital dispensary dispenses most of the medications prescribed at the same facility. This reduces the inconvenience of patients moving to city centers for their prescribed medicines. The dose prescribed, the duration of therapy and the frequency of administration were not taken into consideration. The design of the study could not totally account for possible out-of- hospital antibiotic use. The choice of a rural community with few chemical shop outlets and no pharmacy was expected to reduce this potential confounder. The National Health Insurance Scheme runs a "capitation policy" where a patient chooses one primary health care facility for their needs. The policy also reduces patients moving from one hospital to another because if a patient visits another hospital they have to pay hospital charges. This reduces attrition and tendency for self- medication.
BODY.RESULTS.SOCIODEMOGRAPHIC DATA:
The biodata recorded were mothers' age at birth, gravida, marital status, occupational status and religious affiliation. Mothers' age at birth ranged from 13 to 44 years with a mean age of 26.3 ± 6.40 years. Most of the pregnant women were between 20 and 30 years, married and average number of gravida of 3.07 ± 2.03. (Table 1).Table 1Socio-demographic characteristics of participantsFrequencyPercentMarital statusMarried30482.2Single6617.8Mothers age at birth≥195613.720–3025161.4≤3110224.9OccupationFarmer12634.3Trader7821.3Student4311.7Teacher82.2Seamstress277.4Hairdresser5113.9Nurse3.8Unemployed277.4Othersa
41.0Religious affiliationChristian33391.2Muslim246.6Traditional82.2GRAVIDA1–321268.8≤ 49631.2Total412100.0
aOthers include sprayer, baker, secretary and army officer
BODY.RESULTS.PREVALENCE OF ANTIBIOTIC EXPOSURE:
About two out of three women (65.8%, n = 271) attending ANC clinic in the hospital were treated with an antibiotic at a point during pregnancy. There was no association between the socio-economic status of a woman, i.e., marital status, occupation, age etc. with the odds of being treated with antibiotics. However antibiotic use was associated multiple gravida and Cesarean section. The odds ratio for antibiotic exposure during Caesarean were 13.8 times higher (95% CI, 5.9–32.5, K = 55.47) than that for women who delivered vaginally. There was an association (p < 0.001) between antibiotic exposure with advance in stage of pregnancy (Fig. 1). Most exposures (79.0%) were third trimester exposures. In fact 42.4% all antibiotic treatments occurred within 24 h to delivery and about 84% of these women went through Caesarean section. First trimester exposures accounted for just 16.6%. Furthermore 4.40% women received antibiotics in all three trimesters. Interestingly, 5.5% went through gestation and Caesarian without receiving any antibiotics at all (Table 2).Fig. 1Antibiotic use during pregnancy during the different stages of pregnancy. 12 respondents received antibiotics at all stages of pregnancy. 141 did not received antibiotics at all. 13 received during the 1st and 2nd trimesters only. 47 received antibiotics during the 2nd and 3rd trimesters only. 14 respondents received during the 1st and 3rd trimesters only. 141 respondents were treated during the 3rd trimester
Table 2Antibiotic exposure in pregnant women of different socio economic class and mode of deliveryAntibiotic exposureYesNo TotalStatisticsMarital statusMarried197(64.8%)107(35.2%)304
P = 0.77,DF = 1,Single44(66.7%)22(33.3%)66k = 0.83,OR = 0.97Age of mother at birth≥ 1932(57.1%)24(43.9%)43
P = 0.357, DF = 220–30167(66.5%)8(33.5%)238K = 2.058≤ 3169(67.6%)33(32.4%)96OccupationEmployed182(64.6%)105(37.4%)126
P = 0.61, K = 10.06Student27(62.8%)16(37.2%)43Unemployed19(70.4%)8(29.6%)27ReligionChristian219(65.8%)114(34.2%)333
P = 0.368, K = 1.99Muslim15(62.5%)9(37.5%)24DF = 2Traditional5(62.5%)3(37.5%)8GRAVIDA1–3117(60.9%75(39.1%)192
P = 0.066, K = 3.38≤467(72.0%)26(28.0%)93DF = 1 OR = 0.83Method of deliveryC. SectioN104(94.5%)6(5.5%)110
P < 0.001,K = 55.47Vaginal167(55.3%)135(44.7%)302DF = 1 OR =13.8Total
271(65.8%)
141(34.2%)
412
Prevalence of antibiotic use in pregnancy showed a steady increase of 54.8% in 2013 to a peak of 77.8% in 2015.
BODY.RESULTS.CLASSES OF ANTIBIOTICS PRESCRIBED:
Beta lactams antibiotics i.e. cephalosporins and penicillins accounted for more than 67% of antibiotics used whilst metronidazole was used in 24% of pregnant women. Quinolones and sulphonamide/trimethoprim represented about of 2.1% antibiotics prescribed. Cephalosporins, penicillins and metronidazole showed a steep rise in use from first trimester to third trimester (Fig. 2). Macrolide use diminished as pregnancy progressed. Use of quinolones and co-trimoxazole however declined to zero in third trimester. 60% of the patients were given antibiotic because of a urinary tract infection, 12% due to respiratory tract infections, 14.3% as premedication for caesarean section. Other minor reasons included gastroenteritis (5.5%), premature rapture of membranes (2.8%), pelvic inflammatory disease (1.7%) and unspecified indications (3.7%).Fig. 2Classes of antibiotic use and the trimester of exposure
BODY.RESULTS.SAFETY AND APPROPRIATENESS IN PREGNANCY:
The FDA classifications for the drugs prescribed in the study fell into classes B, C and D with classes A and X antibiotic not prescribed. Most of the drugs fell into category B with 96.6% followed by C and D with 2.9% and 0.5% respectively. It was observed that some antibiotics were prescribed without due justification i.e. there was drug –diagnosis mismatch and this constituted 3.5% of all prescriptions issued.
BODY.RESULTS.INTRAPARTUM ANTIBIOTIC EXPOSURE AND BIRTH OUTCOMES.ANTIBIOTIC EXPOSURE AND BIRTHWEIGHT:
The mean birthweight of babies who delivered at the facility was 2.96 ± 0.56 kg. Intrapartum antibiotic treatment did not affect mean birthweight. Similarly there was no statistically significant relationship between mode of delivery and birthweight. Generally, there was a direct relationship between mothers' socio-economic status and birthweight. Babies born of single mothers had lower birthweights compared to those born of married mothers (p < 0.001, F = 12.74) (Table 3).Table 3Effect intrapartum antibiotic exposure on weight at birthBirth WeightNMean ± SDMarital statusMarried298
3.02 ± 0.56
***
Single652.75 ± 0.53Age group≥1955
2.75 ± 0.48
***
20–302422.95 ± 056≤311003.10 ± 0.57Occupational statusEmployed287
3.00 ± 0.57
*
Student432.75 ± 0.58Unemployed273.00 ± 0.47ReligionChristian3242.98 ± 0.57Muslim232.82 ± 0.48Traditional82.88 ± 0.52GRAVIDA1–3206
2.87 ± 0.51
***
4 And Above953.08 ± 0.57Mode of deliveryCeasarian section1032.96 ± 0.59Vaginal delivery2972.96 ± 0.55Antibiotic exposureYes2612.96 ± 0.58No1392.97 ± 0.53Results represented as mean ± SD. * means p < 0.05, ***p < 0.001
BODY.RESULTS.INTRAPARTUM ANTIBIOTIC EXPOSURE AND BIRTH OUTCOMES.ANTIBIOTIC EXPOSURE AND APGAR SCORES:
There was no statistically significant relationship between antibiotic prescription during pregnancy and mean Apgar scores (i.e. 8.242 ± 1.3 vs 8.32 ± 1.62 (p = 0.414, F = 1.59)). However when mothers were treated with antibiotics in less than 24 h to parturition, there was a statistically significant decrease in mean Apgar than those not treated with antibiotics i.e. (7.86 ± 1.72 vs 8.4 ± 1.30 p = 0.002, F = 13.65) after adjusting for the effects of the mode of delivery. Babies born naturally had mean Apgar scores statistically higher than those born by Caesarean section i.e. 8.42 ± 1.23 vs 7.86 ± 1.87(p = 0.003, F = 8.98). Younger mothers, unmarried women and mothers with less gravida had significantly higher mean Apgar scores compared with older (p = 0.046), married (p = 0.018) and higher gravida (p = 0.034) mothers respectively (Table 4).Table 4Effect intrapartum antibiotic exposure on mean APGAR scoreAPGAR Scores
N
Mean ± SDMarital statusMarried282
8.26 ± 1.37
*
Single628.69 ± 0.90Age groups≤1953
8.60 ± 1.10*
20–302328.41 ± 1.28≥31938.10 ± 1.43Occupational statusEmployed2728.32 ± 1.32Student418.40 ± 1.25Unemployed258.48 ± 0.95ReligionChristian3118.33 ± 1.34Muslim218.43 ± 1.15Traditional19.00 ± 0.00GRAVIDA1–3200
8.54 ± 1.22
*
≥4888.20 ± 1.27Mode of deliveryCeasarian section100
8.03 ± 1.67
**
Vaginal delivery2818.47 ± 1.11Antibiotic exposureYes2488.30 ± 1.30No1338.47 ± 1.26Perinatal antibiotic exposureYes104
7.96 ± 1.70
**
No2778.51 ± 1.07Results represented as mean ± SD. *means p < 0.05, **p < 0.01
BODY.RESULTS.INTRAPARTUM ANTIBIOTIC EXPOSURE AND BIRTH OUTCOMES.ANTIBIOTIC EXPOSURE AND CONGENITAL BIRTH DEFECT:
Six birth defects were seen in the study representing 1.5% of all deliveries i.e. Cleft lip, mega cephalous, cleft palate and webbed feet. Intrapartum antibiotic exposure irrespective of trimester of exposure was not associated with any significant risk of birth defect (RR = 1, P = 0.97). There was no statistically significant association between marital status (p = 0.94), mothers age at birth (p = 0.361), occupation (p = 0.630), parity (p = 0.94) and religion (p = 0.49) and birth defects. Females had relatively higher odds ratio of incidence of birth defects than males. i.e. 2.2% vs 1.0% (OR = 2.2, P = 0.343, 95% CI).
BODY.DISCUSSION:
The study was design to ascertain the prevalence antibiotic prescription among pregnant women attending ANC. About 65.8% of pregnant women were exposed to an antibiotic at some point during pregnancy. This figure was higher than an earlier report of about by 59.9% in the eastern region of Ghana [10] as well as the WHO/International Network for the Rational Use of Drugs figures. Women who went through Caesarean section were more likely to receive antibiotics to control wound infection and endometritis [11, 12]. Risk of antibiotic exposure was highest in the last trimester but it corresponded with the increased incidence of respiratory tract infections, urinary tract infections and gastritis during third trimester. This is of a concern because acquisition of specific foetal immunity begins in the third trimester and it is highly dependent on microbiome which can be altered by antibiotics [9, 13]. Most of the antibiotic used are classified as safe in pregnancy by the FDA. Macrolides though safe, directly stimulate the motilin receptors inducing Gastro-intestinal discomfort which may be undesirable in pregnancy [14, 15]. Anatomically the uterus sits directly on the urinary bladder and so increase in weight of the uterus as pregnancy advances exerts a proportional pressure on the bladder and stomach leading to increased incidence of UTI, gastritis and heartburns [16, 17]. Babies exposed to intrapartum antibiotics had mean weights slightly lower than those unexposed. A study by Vidal et al., (2013) [8] reported a similar pattern and it was further observed that such babies quickly gained much more weight after delivery leading to obesity in childhood. This study also noted a strong association between mother's socio-economic factors and birthweights as has been reported elsewhere [18–20]. This may be due to economic stability, marital support etc [18, 21, 22]. Babies born to Mothers who received antibiotics less than 24 h to delivery or subsequently had caesarean birth had lower mean Apgar scores much even after adjusting for other confounding factors. This correlates with other reports in which babies born vaginally had much higher Apgar scores at 5 min compared to caesarean born [23]. Older mothers or women with higher gravida had babies with mean Apgar scores lower than younger mothers or women with less gravida. A total six birth defects (15 per 10,000 live births) were recorded in this study. This figure was similar to other prevalence birth defects reported other authors [24].
BODY.CONCLUSION:
65% of pregnant women received antibiotics at some stage during pregnancy. Antibiotic use did not affect mean birth weight, APGAR score or incidence of birth defects. However, antibiotic use less than 24 h to delivery was associated with a decrease in mean APGAR score. | 5,551,012 | {
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TITLE: A randomized trial of a lifestyle intervention in obese endometrial cancer survivors: quality of life outcomes and mediators of behavior change
ABSTRACT.BACKGROUND:
To examine the effects of a 6 month lifestyle intervention on quality of life, depression, self-efficacy and eating behavior changes in overweight and obese endometrial cancer survivors.
ABSTRACT.METHODS:
Early stage endometrial cancer survivors were randomized to intervention (n = 23) or usual care (n = 22) groups. Chi-square, Student's t-test and repeated measures analysis of variance were used in intent-to-treat analyses. Outcomes were also examined according to weight loss.
ABSTRACT.RESULTS:
Morbidly obese patients had significantly lower self-efficacy, specifically when feeling physical discomfort. There was a significant improvement for self-efficacy related to social pressure (p = .03) and restraint (p = .02) in the LI group. There was a significant difference for emotional well-being quality of life (p = .02), self-efficacy related to negative emotions (p < .01), food availability (p = .03), and physical discomfort (p = .01) in women who lost weight as compared to women who gained weight. Improvement in restraint was also reported in women who lost weight (p < .01).
ABSTRACT.CONCLUSION:
This pilot lifestyle intervention had no effect on quality of life or depression but did improve self-efficacy and some eating behaviors.
ABSTRACT.TRIAL REGISTRATION:
; NCT00420979
BODY.BACKGROUND:
Endometrial cancer is the most common gynecologic cancer in the United States and obesity is the most significant risk factor for development of the disease [1]. A recent prospective study reported that 68% of women with early endometrial cancer were obese which is markedly increased compared to older reports [2-5]. Adding to this escalation is the increased rate of obesity in the female population (18.1%) [6]. When assessing obesity associated cancers, it appears that endometrial cancer patients are the most morbid as most have stage I disease yet are at significant risk for premature death [7]. While the impact of weight on cancer recurrence does not appear to be a factor in endometrial cancer, obese endometrial cancer survivors have a higher mortality from causes not related to cancer [8]. Endometrial cancer survivors have numerous co-morbidities related to their obesity which include hypertension (HTN), diabetes mellitus (DM), cardiovascular disease (CVD), osteoarthritis (OA) and pulmonary disease [5]. Improving medical co-morbidities through weight management in survivors may lead to improved overall quality of life and survival. Differences in quality of life (QOL) between obese and non-obese endometrial cancer survivors are related to physical health. In a prospective examination of QOL, general health status, and obesity in women with early stage endometrial cancer, [9] women with a body mass index (BMI) less than 30 (non-obese) had increased physical QOL scores. There was also an inverse relationship between the global physical health composite score and BMI; with higher BMI associated with a declining physical QOL score. A recent cross-sectional survey of Canadian endometrial cancer survivors revealed that those patients with morbid obesity had a QOL score three times lower than women with a normal BMI [10]. This suggests that if weight is decreased, survivors QOL may be improved. What is unknown is the effect a survivorship lifestyle intervention trial may have on QOL, psychological health and eating behavior. We have previously reported the effects of a six-month lifestyle intervention on weight loss, exercise behavior, and nutrient intake changes in overweight and obese endometrial cancer survivors [11]. We found that a lifestyle intervention program in obese endometrial cancer survivors is feasible and efficacious – resulting in sustained behavior change and weight loss over a one year period. The present query was conducted in order to examine the intervention's effect on QOL outcomes, depression, self-efficacy and eating behavior, possible mediators of behavior change. We hypothesized that a lifestyle intervention program would improve these outcomes in obese endometrial cancer survivors. We also conducted an exploratory analysis comparing women who lost weight with women who gained weight.
BODY.METHODS.STUDY DESIGN & PATIENT RECRUITMENT:
The study was a prospective randomized controlled trial comparing a lifestyle intervention (LI) consisting of exercise and nutritional counseling with cognitive-behavior modification to usual care (UC) in overweight and obese endometrial cancer survivors. An invitation letter was sent to women included in the cancer registry from the Ireland Cancer Center at University Hospitals Case Medical Center diagnosed with stage I-II endometrial cancer from 2001–2004. The 6 month intervention was delivered to the LI group while the UC group received only an informational brochure outlining the benefits of proper nutrition and physical activity. Institutional review board approval was granted and informed consent and authorization to use protected health information (HIPAA) was obtained from all patients prior to study procedures. Feasibility, eligibility criteria, and details of the intervention have been published elsewhere [11]. Randomization assignment was stratified by BMI (<40 versus ≥ 40). Prior analysis revealed that demographics and clinical characteristics were equivalent between groups [11].
BODY.METHODS.INTERVENTION PROGRAM:
The counseling protocol was administered by the study registered dietitian (RD), primary investigator (PI), and psychologist. It followed a stepwise, phased approach using strategies outlined by social cognitive theory, indicating that the optimal intervention for a major behavior change should focus on establishing short-term goals, and enabling the person to build self-efficacy [12-16]. The intervention covered topics related to nutrition and exercise and met weekly for six weeks, biweekly for one month, and monthly for 3 months. Participants were contacted by the RD either by phone, email, or newsletter every week that the group did not meet. The psychologist met with the group during 2 of the 11 sessions and topics included cognitive and behavioral self-management strategies for weight loss and stress management. The PI met with both LI and UC participants at 3, 6 and 12 months.
BODY.METHODS.MEASURES:
Patient demographic and clinical data was obtained at baseline and prior to randomization. QOL and self-efficacy were assessed at baseline and at 3, 6, and 12 months. Eating behavior and depression was assessed only at baseline and 12 months. QOL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G), a valid and reliable questionnaire evaluating physical, functional, family-social, and emotional well-being domains [17,18]. A fatigue subscale (-F) and an endometrial symptom subscale (-En) were also used [19,20]. Functional status was measured with the SF-36, a comprehensive short-form survey designed to measure functional health and well-being [21]. Depression was measured by the Beck Depression Inventory (BDI) which is well-validated and frequencly used in lifestyle research studies [22]. Self-efficacy, an individual's judgement regarding his/her ability to perform certain behaviors, was measured with the Weight Efficacy Life-Style (WEL) questionnaire. This scale specifically evaluates self-efficacy judgments specific to eating behaviors in five situational factors: negative emotions, food availability, social pressure, physical discomfort, and positive activities [23,24]. This measure has evidenced adequate psychometric properties, including internal consistency coefficients ranging from 0.76 to 0.90 [23]. Eating behavior was measured by the Three-Factor Eating Questionnaire (TFEQ), a self-assessment questionnaire developed to measure cognitive and behavioral components of eating [25,26]. Responses are aggregated into three scales, cognitive restraint, disinhibition and hunger. Cognitive restraint is designed to measure dietary restraint, that is, control over food intake in order to influence body weight and body shape. Disinhibition measures episodes of loss of control over eating, while the hunger scale is concerned with subjective feelings of hunger and food cravings. Higher numbers reflect increased restraint, decreased tendency to overeat in the presence of disinhibitors (i.e. stress, mood, alcohol) and decreased perception of hunger. All three subscales have demonstrated high internal consistency and reliability [27,28]. Patient anthropometric data including weight, waist circumference, and BMI were measured at all time points manually by the study dietitian. BMI was computed as patient weight in kilograms divided by the square of their height in meters. Participants were categorized according to World Health Organization guidelines: < 18.5 (underweight), 18.5 to 24.9 (healthy weight), 25.0 to 29.9 (overweight), Class I – 30.0 to 34.9, Class II – 35.0–39.9, and Class III or morbid obesity ≥ 40.0 kg/m2 [29].
BODY.METHODS.STATISTICAL ANALYSES:
Patient demographic, clinical variables and baseline values were compared between groups and by BMI (25.0 – 39.9 versus ≥ 40) by use of independent samples t-test or chi-square test for proportions. Primary analysis used repeated measures analysis of variance (ANOVA) with the 3, 6 and 12 month data as outcomes and the appropriate baseline measurement as a covariate to test for the main effect of group (LI versus UC, intention-to-treat analyses) on QOL outcome measures (FACT-G; physical, functional, social, emotional well-being, fatigue and endometrial subscales) and self-efficacy (WEL; negative emotions, food availability, social pressure, positive activities, physical discomfort). Change (from baseline to 12 months) in eating behavior (TFEQ) and depression measures were compared using paired samples t-test for each group and independent samples t-test for the difference in change between groups. Missing data for participants who did not complete all study assessments was handled according to the last and next method or previous row mean method as recommended by Engels et al [30]. Imputation was done on between 15–19% of values for the various QOL and eating behavior measures. The percentage of missing data for these measures was less than that imputed for weight values as some patients opted to mail these surveys back as data were self-report. Data were also analyzed using last observation carried forward and completers only approaches. There were no substantive differences among the three approaches and thus we present results of the first approach only. QOL outcomes were also examined according to whether patients lost weight or their weight remained stable/gained over the course of the year as an ancillary stratified analyses. We were interested in examining if QOL outcomes differed between these two groups as there were some women in the UC group who lost weight and likewise women in the LI group who did not lose weight [31]. SPSS for Windows (version 14.0) was used for statistical analyses (SPSS Inc., Chicago, IL). Approximately 25 patients per group were needed to provide 80% power to detect a difference between groups in mean weight change from baseline to twelve months of 5 kg (11 pounds) or greater, representing approximately 5% weight loss for an obese female (alpha = 0.05, two-sided, SD = 5.0) [32]. Five percent weight change is considered clinically relevant and a recommended goal for weight loss over 6 months [33,34]. Weight change was the primary endpoint of this feasibility trial and the study was powered based on this endpoint. In addition, 25 patients/group were needed to detect a large standardized effect size (d = 0.80) with power of 0.80 and a two-tailed alpha of 0.05. A large standardized effect size on the FACT-G is approximately 10 points based on a standard deviation of 12 and exceeds the 7 point MID identified for this scale [18,35].
BODY.RESULTS:
Forty-five patients were enrolled; 23 were randomized to the LI group and 22 to the UC group. In summary, most patients were Caucasian with an average age of 55 years. As reported previously, at 12 months, the LI group lost 3.5 kg compared to a 1.4 kg gain in the UC group (p = .02) and increased their exercise by 16.4 metabolic equivalents (METS) compared to a decrease of 1.3 METS in the UC group (p < .001) [11]. Average time since diagnosis was 2 years and mean BMI was 42.3 kg/m2 [11]. Fifty-three percent (24/45) of participants reported being very overweight during the previous ten years and 15/45 (33%) reported being moderately overweight. Patients with a BMI > 40 had increased abdominal obesity with a mean (SD) waist circumference of 125.6 (15.9) cm as compared to those with a BMI < 40 (mean 98.5 cm (8.2), p < 0.01). Waist/hip ratio did not differ between morbidly obese and BMI < 40 patients (mean 0.84 (SD = .07). Co-morbidities related to obesity (hypertension, diabetes, CVD, arthritis and metabolic syndrome) were common in these patients [11]. Five patients had prior bariatric surgery prior to enrollment (LI; 4, UC: 1) with surgeries performed 3–6 years before the study began.
BODY.RESULTS.BASELINE DIFFERENCES BASED ON BODY MASS INDEX:
Baseline QOL (FACT-G, SF-36), BDI, WEL and TFEQ scores did not differ between the LI and UC groups. However significant differences were observed when patients were categorized according to BMI (Table 1). Total QOL (FACT-G) was not significantly lower in morbidly obese women [BMI ≥ 40: 78.0 (SD = 14.4) vs. BMI < 40: 83.7 (SD = 11.4); p = 0.14], however the difference was consistent with minimally important differences (5–6 points) [18]. SF-36 physical composite score was decreased in morbidly obese women (p = 0.04). At baseline 7/45 (15%) patients reported mild depressive symptoms, and 4/45 (9%) reported moderate depressive symptomatology. Beck depression score did not differ according to BMI (Table 1). Table 1 Quality of life, depression, self-efficacy and eating inventory scores at baseline (n = 45) Variables Overall (n = 45) Body mass index < 40 (n = 23) Body mass index ≥ 40 (n = 22) p value * Quality of Life FACT-G (0–108) 80.1 (12.1) 83.7 (9.6) 78.0 (14.1) 0.14 Physical well-being (0–28) 23.9 (3.2) 24.8 (3.2) 23.2 (3.3) 0.12 Social well-being (0–24) 16.5 (3.1) 16.6 (2.6) 16.5 (3.2) 0.90 Emotional well-being (0–24) 18.6 (4.1) 19.4 (3.9) 17.9 (4.4) 0.27 Functional well-being (0–28) 21.2 (5.4) 22.9 (4.0) 20.4 (5.4) 0.10 Endometrial (0–64) 53.5 (5.8) 52.8 (5.0) 54.6 (6.6) 0.32 Fatigue (0–52) 37.9 (9.7) 40.2 (9.7) 36.2 (9.8) 0.19 Physical composite score, SF36 43.9 (10.7) 47.1 (8.7) 40.6 (11.7) 0.04 Mental composite score, SF36 50.0 (10.9) 50.6 (9.8) 49.3 (12.2) 0.70 Beck depression inventory (0–63) 10.3 (7.9) 8.8 (6.5) 11.4 (9.0) 0.29 Weight self-efficacy Negative Emotions (0–36) 18.8 (10.8) 20.4 (9.7) 15.5 (10.4) 0.12 Food Availability (0–36) 18.3 (9.3) 20.0 (8.8) 15.4 (8.9) 0.09 Social Pressure (0–36) 24.2 (8.7) 25.0 (7.2) 22.3 (9.7) 0.31 Physical Discomfort (0–36) 26.5 (8.3) 28.8 (5.8) 23.4 (9.4) 0.03 Positive Activities (0–36) 24.3 (7.3) 25.5 (5.0) 22.3 (8.5) 0.15 Total (0–180) 112.1 (36.8) 119.6 (26.7) 98.8 (39.0) 0.05 Three-factor eating questionnaire Restraint (0–21) 10.3 (4.9) 12.8 (4.4) 7.5 (3.8) < 0.01 Disinhibition (0–16) 7.9 (3.6) 7.3 (3.8) 9.2 (3.0) 0.10 Perceived Hunger (0–14) 5.6 (3.4) 5.6 (3.4) 6.3 (3.6) 0.50 * Independent samples Student's t-test. Data are presented as the mean (standard deviation) FACT-G, Functional Assessment of Cancer Therapy-General; SF-36, Short-form Medical Outcomes Survey In regards to eating patterns, morbidly obese patients had significantly lower self-efficacy when feeling physical discomfort and decreased total self-efficacy (WEL) score. Restraint on the TFEQ questionnaire was decreased in patients with BMI > 40 as compared to BMI < 40.
BODY.RESULTS.EFFECTS OF THE LIFESTYLE INTERVENTION (INTENTION-TO-TREAT ANALYSIS):
Repeated measures ANOVA with baseline measurements as a covariate and 3, 6 and 12 months as outcomes revealed no group (LI versus UC) effects for QOL outcomes (Table 2). There was a significant group effect for self-efficacy related to social pressure and restraint improved in the LI group. The UC group had a significant change in depression from baseline. Change scores for depression or TFEQ, compared by independent samples t-test, however did not differ by group. Table 2 Effects of the lifestyle intervention on QOL and clinical outcomes (intention-to-treat analysis) Variables Baseline 3 mos 6 mos 12 mos Group effect P* Primary Quality of life outcome FACT-G (0–108) 0.37 Lifestyle intervention 80.6 (12.7) 81.1 (14.0) 82.4 (14.5) 80.1 (14.2) Usual care 79.5 (13.1) 80.1 (15.5) 81.8 (13.2) 82.2 (14.9) Secondary QOL outcomes Physical well-being (0–28) 0.84 LI 23.9 (3.4) 23.6 (4.3) 24.0 (4.4) 23.3 (4.3) UC 23.9 (3.0) 23.3 (4.5) 24.2 (4.1) 23.7 (4.1) Functional well-being (0–28) LI 21.3 (5.2) 22.0 (5.6) 22.0 (5.7) 21.2 (6.2) 0.44 UC 21.0 (5.7) 22.0 95.6) 22.0 (5.0) 22.0 (6.1) Emotional well-being (0–24) LI 18.3 (4.4) 19.1 (4.5) 19.3 (4.5) 18.8 (4.5) 0.98 UC 18.9 (3.9) 19.2 (4.0) 19.5 (4.1) 20.0 (3.7) Social/family well-being (0–28) LI 17.2 (2.7) 16.6 (3.0) 17.2 (2.7) 16.9 (2.6) 0.17 UC 15.7 (3.3) 15.6 (3.4) 16.3 (3.0) 16.6 (3.4) Fatigue (0–52) LI 37.5 (10.3) 38.5 (11.3) 39.2 (11.6) 38.5 (11.1) 0.99 UC 38.2 (9.2) 39.0 (10.4) 39.2 (11.5) 40.0 (9.3) Endometrial subscale (0–64) LI 54.4 (5.4) 54.9 (6.7) 55.5 (6.8) 55.0 (6.7) 0.46 UC 52.3 (6.2) 51.9 (6.9) 52.6 (6.9) 53.6 (6.2) Weight self-efficacy Negative emotion (0–36) 0.87 LI 17.0 (10.4) 21.7 (9.8) 23.1 (9.7) 21.9 (9.1) UC 19.9 (10.8) 24.9 (9.9) 22.8 (10.0) 23.9 (10.9) Food Availability (0–36) 0.49 LI 17.5 (8.5) 23.1 (8.9) 23.2 (9.9) 22.4 (10.1) UC 18.8 (10.3) 23.6 (9.8) 21.0 (9.5) 23.2 (9.9) Social pressure (0–36) 0.03 LI 23.9 (8.1) 28.2 (7.0) 28.4 (7.5) 27.9 (7.9) UC 23.9 (9.3) 26.1 (8.5) 23.3 (8.0) 26.0 (7.3) Positive activities (0–36) LI 23.2 (5.7) 27.5 (4.8) 27.8 (4.2) 27.3 (4.6) 0.10 UC 25.1 (8.5) 27.5 (8.1) 24.9 (7.7) 27.9 (5.0) Physical discomfort (0–36) 0.38 LI 25.8 (8.4) 28.5 (7.1) 29.1 (6.6) 29.7 (6.7) UC 26.8 (8.2) 29.1 (6.5) 27.6 (6.7) 29.0 (6.4) Total (0–180) 0.19 LI 107.4 (31.5) 129.1 (30.4) 131.5 (31.7) 129.3 (31.3) UC 114.5 (40.9) 131.1 (39.4) 119.6 (37.7) 130.0 (35.6) Beck depression inventory LI 9.7 (6.8) - - 8.6 (7.2) 0.16 UC 10.6 (8.9) - - 8.3 (7.4) 0.02 Three-factor eating questionnaire Restraint (0–21) - - LI 10.0 (4.8) - - 11.9 (5.1) 0.02 UC 10.3 (5.2) 11.1 (4.9) 0.24 Disinhibition (0–16) - - LI 8.8 (2.8) - - 8.4 (3.3) 0.44 UC 7.1 (4.1) 7.0 (4.1) 0.68 Hunger (0–14) - - LI 6.2 (3.3) 6.0 (2.7) 0.67 UC 5.1 (3.6) 4.2 (2.6) 0.13 Data are presented as the mean (standard deviation). LI (n = 23), UC (n = 22) * p value for repeated measures ANOVA with baseline measurement as covariate and 3, 6 and 12 months as outcomes or paired samples t-test (eating inventory and Beck depression inventory) Abbreviations: QoL, quality of life; FACT-G, Functional Assessment of Cancer Therapy-General; SF-36, Short-form Medical Outcomes Survey; BDI, Beck Depression Inventory; WEL, weight efficacy lifestyle; TFEQ, three-factor eating questionnaire; BMI, body mass index
BODY.RESULTS.ASSOCIATION BETWEEN WEIGHT LOSS AND OUTCOMES (EXPLORATORY ANALYSIS):
Table 3 presents an ancillary analysis for QOL, self-efficacy, depression and eating behavior outcomes. For this analysis we compared women who lost weight (WL; n = 21) versus those whose weight was the same or who gained weight (WG; n = 24) from baseline to twelve months. There was a significant effect (WL versus WG) for emotional well-being QOL, self-efficacy related to negative emotions, food availability, and physical discomfort as the WL group had higher scores. For self-efficacy related to negative emotions, there was a mean increase of 8.9 in women who lost weight versus 0.6 in those whose weight was stable/gained. Similarly, for self-efficacy related to food availability and physical discomfort, the weight loss group had an increase of 7.9 and 5.3 versus 1.9 and 1.0 in women who did not lose weight. Women who lost weight had improvement in depression (2.3 versus 1.2) and TFEQ restraint score (2.8 versus 0.1). Women who lost weight also had a lower disinhibition score at 12 months. Group differences for change in TFEQ restraint score were observed using independent samples t-test for comparison of change scores between WL and WG (p = .01), but not for depression. Table 3 Effects of weight loss on QOL and clinical outcomes (ancillary analyses) Variables Baseline 3 mos 6 mos 12 mos Group effect P* Primary QoL outcome FACT-G 0.26 WL 81.4 (14.0) 83.5 (15.7) 84.8 (14.7) 82.3 (15.4) WG 78.9 (11.7) 78.1 (13.3) 79.8 (12.6) 80.1 (13.8) Secondary QoL outcomes Physical well-being (0–28) 0.79 WL 24.7 (3.3) 24.5 (4.6) 24.7 (4.7) 24.2 (4.8) WG 23.1 (3.0) 22.5 (4.0) 23.5 (3.7) 22.8 (3.5) Functional well-being (0–28) WL 21.9 (5.6) 22.8 (5.3) 23.3 (5.0) 21.9 (6.1) 0.65 WG 20.5 (5.2) 21.2 (5.8) 20.8 (5.4) 21.2 (6.2) Emotional well-being (0–24) WL 18.2 (4.3) 20.0 (4.1) 20.0 (4.3) 19.5 (4.2) 0.02 WG 18.9 (4.0) 18.4 (4.2) 18.9 (4.2) 19.3 (4.1) Social/family well-being (0–28) WL 16.6 (3.2) 16.2 (3.4) 17.0 (2.8) 16.7 (2.8) 0.98 WG 16.4 (3.0) 16.0 (3.0) 16.5 (2.9) 16.8 (3.2) Fatigue (0–52) WL 39.0 (10.2) 41.6 (10.5) 41.4 (12.1) 42.0 (10.5) 0.07 WG 36.9 (9.3) 36.3 (10.5) 37.3 (10.7) 36.9 (9.5) Endometrial subscale (0–64) WL 54.3 (6.6) 54.3 (7.7) 55.2 (8.1) 55.5 (6.9) 0.55 WG 52.8 (5.1) 52.7 (6.2) 53.1 (5.7) 53.3 (5.9) WEL Negative emotions (0–36) < 0.01 WL 16.7 (10.9) 24.3 (10.5) 25.6 (9.3) 25.6 (9.7) WG 20.0 (10.3) 22.4 (9.5) 20.5 (3.3) 20.6 (9.8) Food Availability (0–36) 0.03 WL 16.5 (10.4) 24.0 (9.6) 23.8 (9.9) 24.4 (10.4) WG 19.5 (8.3) 22.8 (9.0) 20.7 (9.4) 21.4 (9.4) Social pressure (0–36) 0.20 WL 25.2 (9.2) 28.4 (7.5) 28.1 (7.5) 29.1 (7.2) WG 22.7 (8.1) 26.1 (8.0) 23.9 (8.2) 25.2 (7.6) Positive activities (0–36) 0.10 WL 23.0 (7.9) 27.5 (6.2) 27.5 (5.3) 27.8 (5.0) WG 25.1 (6.5) 27.5 (6.9) 25.4 (7.0) 27.4 (4.6) Physical discomfort (0–36) WL 25.5 (9.2) 29.6 (7.0) 30.0 (6.9) 30.8 (7.1) 0.01 WG 27.0 (7.4) 28.1 (6.5) 26.9 (6.2) 28.0 (5.7) Total (0–180) <0.01 WL 106.9 (37.4) 133.8 (36.0) 135.0 (33.8) 137.6 (33.9) WG 114.3 (35.5) 126.9 (33.9) 117.4 (34.4) 122.6 (31.4) Beck depression inventory WL 9.3 (7.0) - - 7.0 (6.5) 0.03 WG 10.9 (8.8) - - 9.7 (7.9) 0.14 TFEQ Restraint (0–21) WL 10.1 (4.5) - - 12.9 (4.2) <0.01 WG 10.2 (5.4) - - 10.3 (5.3) 0.74 Disinhibition (0–16) WL 7.8 (3.0) - - 6.9 (3.3) 0.05 WG 8.1 (4.1) - - 8.4 (4.1) 0.48 Hunger (0–14) WL 6.1 (3.8) - - 5.1 (2.5) 0.21 WG 5.3 (3.1) - - 5.1 (3.1) 0.51 Data are presented as the mean (standard deviation). WL, n = 21; WG, n = 24 * p value for repeated measures ANOVA with baseline measurement as covariate and 3, 6 and 12 months as outcomes or paired samples t-test (eating inventory and Beck depression inventory) Abbreviations: QoL, quality of life; FACT-G, Functional Assessment of Cancer Therapy-General; SF-36, Short-form Medical Outcomes Survey; BDI, Beck Depression Inventory; WEL, weight efficacy lifestyle; TFEQ, three-factor eating questionnaire; BMI, body mass index
BODY.DISCUSSION:
Lifestyle interventions are necessary for survivorship in obese endometrial cancer patients as they are at risk for premature death not due to cancer but secondary to poor cardiovascular health. The majority of patients in this study were morbidly obese and had lower physical health-related scores. The lifestyle intervention did not have any effect on global QOL outcomes, however self-efficacy, emotional well-being and certain eating behaviors improved with weight loss. Although the intervention was efficacious in promoting weight loss, the lack of influence on QOL was contrary to the hypothesis. It may be that a longer intervention, greater weight loss or increased exercise is needed to improve QOL. Functional, and psychological-related changes may require a longer term investment in a healthy lifestyle before reaching significance. Social cognitive theory [36] is a well-established explanation of health behavior change, and is frequently utilized in dietary and physical activity lifestyle interventions [37-39]. Social cognitive theory explains health behaviors in terms of reciprocal relationships between behavior, personal factors and environmental influences. The power of circumstance, of being diagnosed with endometrial cancer, can potentially launch new life courses, change a person's perception of their environment, improve health behavior-related expectations and influence reciprocal determinism. Thus, endometrial cancer patients may be amenable to a "teachable moment." Self-efficacy is the social cognitive theory concept that represents one's judgment about her ability to successfully engage in a particular behavior and overcome barriers to achieve change [36]. Toobert et al performed a lifestyle intervention trial in women with CVD and found that fat intake decreased as their self-efficacy scores increased [40]. This research and those of our collaborators supports self-efficacy as a theoretical model and a possible mediator to improve lifestyle change in the obese [41,42]. We found increased self-efficacy as related to negative emotions, food availibiltiy and physical discomfort in those women who lost weight during the year. In addition, self-efficacy scores at twelve months remained increased, six months after the intervention had concluded. In terms of eating behavior, restraint was also improved in patients who lost weight. Weight losers, however had a lower disinhibition score, indicating an increase likelihood to overeat in the presence of disinhibitors. This was an unexpected finding and may indicate that there are still certain triggers that are evident and more attention to these is possibly needed. Different populations including endometrial cancer survivors, may need more intense interventions in order to change morbid patterns [24]. Limitations of this study include its small sample size, and lack of racial heterogeneity. There was a greater number of patients in the intervention group who had a prior history of bariatric surgery. These patients may have better self-efficacy and eating behavior patterns that could influence results though the number of patients is too small to make any conclusions. However, the findings should trigger clinicians to focus on positive lifestyle change, improving self-efficacy and decreasing co-morbidity in endometrial cancer survivors. An additional limitation was potential contamination of the control group, as depression improved in the control group over time. This may have been influenced by all study patients participating in an orientation meeting, in addition to meeting with the principal investigator at the 3 measurement time points. It may be that simple increased physician contact (without teaching) can improve outcome measures. Others have questioned whether improving QOL could be attributable to the increased attention (or increasing self-efficacy) given to cancer patients involved in exercise interventions [43]. QOL may improve temporally as patients experience more years of survivorship and travel farther from the challenging time of diagnosis. In addition, we can also hypothesize that the weight loss observed was not large enough to see a change in QOL. However, given that this was a feasibility study the results are helpful in designing a future intervention trial.
BODY.CONCLUSION:
This pilot lifestyle intervention had no effect on quality of life, or depression but did improve self-efficacy and restraint. A substantial amount of endometrial cancer survivors are surviving their cancer, however, they are succumbing to other diseases correlated with obesity. The Gynecologic Oncology Group is considering adding QOL measures to their next large prospective endometrial cancer trial with long term follow up. Future directions will also consist of the measurement of 5 year outcomes in this study population [44]. Goals of upcoming projects are to decrease co-morbidity and increase overall survival in endometrial cancer survivors.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
VVG, HG, MBK, JJ, EL and KC conceived of the study, and participated in its design and coordination. VVG, HG, and MBK implemented the study and were responsible for day to day conduct of the study. VVG, HG, and KC analyzed the data. VVG, HG, and KC drafted the manuscript; MBK, JJ and EL provided critical review. All authors read and approved the final manuscript. | 2,656,477 | {
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TITLE: Absorption, Metabolism and Excretion of Cranberry (Poly)phenols in Humans: A Dose Response Study and Assessment of Inter-Individual Variability
ABSTRACT:
The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.
BODY.1. INTRODUCTION:
Several clinical trials have showed the beneficial effects of cranberry intake on human health [1,2,3,4,5,6,7]. However, while in vitro studies have shown dose-response effects of cranberry (poly)phenols on the inhibition of microbial invasion of gut and bladder epithelial cells [8,9] and in the cytotoxicity of ovarian cancer cells [10], very few human dose-response studies have been conducted. Howell et al. reported an ex vivo dose-dependent effect on E. coli anti-adhesion in urine after cranberry consumption [11], and more recently, cranberry powder intake has demonstrated a dose-dependent effect on reducing urinary tract symptoms in men [12]. However, dose-response studies with cranberry interventions that report improvements in human health not related to the urinary tract are scarce. We recently reported a dose-dependent enhancement in endothelial function after cranberry juice intake [13], while other works did not reveal any improvement in endothelial function or blood pressure after different doses of quercetin-3-O-glucoside, a flavonoid present in cranberries, although an increase in quercetin circulating metabolites was reported [14]. To the best of our knowledge, few works have investigated plasma (poly)phenol dose-response profiles after intake of (poly)phenol-rich foods. A statistically significant increase was seen in the maximum concentration (Cmax) and area under the curve (AUC) of pelargonidin-glucuronide, pelargonidin-3-O-glucoside and cyanidin-3-O-glucoside after increasing amounts of strawberry powder, which were correlated with insulin response and inflammatory markers [15]. However, not all (poly)phenols seem to follow a linear dose response. After green tea consumption, the sum of catechins detected in plasma did not follow a linear dose response, despite the fact that (-)-epicatechin and (-)-epigallocatechin gallate increased their plasma concentration proportionally with the dosage intake [16]. These results suggested an apparent saturation mechanism which was also reported for some plasma (poly)phenols after wild blueberry consumption [17]. We have previously reported that improvements in endothelial function after cranberry consumption correlated with plasma levels of phenolic metabolites, mostly deriving from phase II metabolism [13]. In this work, we evaluate whether the plasma and urine levels of 60 phenolic metabolites found after consumption of cranberry juice with five different (poly)phenol concentrations follow a dose response and we calculate the extent of their inter-individual variability.
BODY.2. MATERIALS AND METHODS .2.1. CHEMICALS:
Sulfates and glucuronides of (poly)phenol standards were obtained from Toronto Research Chemicals (Toronto, ON, Canada). Kaempferol-3-O-ß-d-glucuronide was obtained from Extrasynthese (Genay, France). The 1-methylpyrogallol-O-sulfate, 2-methylpyrogallol-O-sulfate, 4-methylcatechol-O-sulfate, 4-methylgallic-3-O-sulfate, catechol-O-sulfate, pyrogallol-O-1-sulfate, pyrogallol-O-2-sulfate and vanillic acid-4-O-sulfate were kindly provided by Dr Claudia Nunes dos Santos and Dr Rita Ventura, and their synthesis has been described elsewhere [18]. The 2-, 3- and 4-hydroxyhippuric acids were purchased from Enamine (Kiev, Ukraine). Remaining compounds were obtained from Sigma-Aldrich Co. (Steinheim, Germany). Acetic acid was from Carl Roth (Karlsruhe, Germany) and Oasis HLB μElution plates (2 mg sorbent per well, 30 μm) were from Waters (Eschborn, Germany). Milli-Q system (Merck KGaA, Darmstadt, Germany) ultrapure water was used. Unless otherwise stated, all chemicals and reagents were obtained from Sigma-Aldrich Co. (Steinheim, Germany).
BODY.2. MATERIALS AND METHODS .2.2. HUMAN STUDY :
The study protocol has been described previously [13]. In brief, ten healthy young individuals with ages between 18 and 35 years old participated in a cross-over randomized double-blinded control-matched clinical trial which was registered under the NIH [19] ClinicalTrials.gov website (NCT02517775). All procedures involving human subjects were approved by the University of Düsseldorf Research Ethics Committee (ref: 14-012) and all procedures were performed following the Declaration of Helsinki guidelines. Volunteers were instructed to follow a low-polyphenol diet and exclude berry intake for 24 h prior to each visit. Volunteers were fasted for at least 12 h prior to each intervention to reduce background diet interference as much as possible. During the study day, the same low (poly)phenol meal was giving to all volunteers together with the test drink, and no other food or drink was allowed until after 8 h post-consumption, except for water ad libitum. Participants consumed cranberry juice containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols (TP) in a random order with 1 week wash out. On the study day whole blood was collected at 0, 1, 2, 4, 6, 8 and 24 h and urine was collected 0–8 and 8–24 h after intake. Plasma was obtained by centrifuging whole-blood collected in EDTA-containing vacutainers for 15 min at 1800 g for at 4 °C; plasma samples were spiked with 2% formic acid. Ascorbic acid was added to the urine containers (3.75 g/2 L) and acidification with formic acid until pH 2.5 was achieved. Urine containers were kept in opaque cool bags with ice blocks. Plasma and urine aliquots were stored at −80 °C until analysis.
BODY.2. MATERIALS AND METHODS .2.3. (POLY)PHENOL ANALYSIS IN PLASMA:
Plasma was analyzed with a previous validated μ-SPE coupled with UPLC-Q-TOF-MS that allowed for high-throughput [20]. Briefly, 600 μL of plasma were centrifuged at 15,000× g for 15 min at 4 °C and 350 μL of the supernatant was diluted (1:1) with phosphoric acid 4% and spiked with taxifolin (50 nM) as an internal standard. 600 μL were loaded on a 96 well μ-SPE HLB plate, washed with 200 μL of water and 200 μL of 0.2% acetic acid and finally eluted with 60 μL of methanol. Extracted and concentrated plasma samples were analyzed with an Agilent 6550 iFunnel Accurate-Mass Quadrupole Time-of-Flight Mass Spectrometer (Q-TOF MS) (Agilent, Waldbronn, Germany) after separation on a 1290 Infinity UPLC system (Agilent, Waldbronn, Germany) using a Zorbax Eclipse Plus RRHD column 2.1 mm × 50 mm, 1.8 μm (Agilent, Waldbronn, Germany). The mobile phase consisted of 0.1% HCOOH (solvent A) and acetonitrile with 0.1% HCOOH (solvent B). The elution profile (flow rate of 0.4 mL/min) started at 1% solvent B and increased to 10% after 5 min, to 25% at 8 min and to 99% at 9.1 min. The percentage of solvent B was held constant for 0.9 min. The Q-TO-MS parameters were as follows: Negative mode, gas temperature 150 °C, gas flow 20 L/min, nebulizer 25 psig, sheath gas temperature 350 °C, sheath gas flow 12 L/min and Vcap 3000 V. Data were analyzed and processed using Mass Hunter Workstation Quantitative and Qualitative Analysis software (version B.06.00, Agilent, Waldbronn, Germany).
BODY.2. MATERIALS AND METHODS .2.4. DATA TREATMENT AND STATISTICAL ANALYSIS:
The maximum plasma concentration (Cmax) and time needed to reach it (Tmax) and AUC of time vs. concentration (calculated using a trapezium method) were calculated using the PKSolver add-in software for Microsoft Excel [21]. Linear regression analysis was performed between (poly)phenol amount from each juice and the average AUC, giving a regression equation and r2 values. All statistical analysis was performed using GraphPad Prism V6. Significance was defined as p < 0.05.
BODY.3. RESULTS.3.1. PLASMA KINETICS OF CRANBERRY (POLY)PHENOLS:
A total of 60 compounds in plasma were identified and quantified post-consumption of cranberry juice containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols, as we have previously reported for the juice containing 787 mg of (poly)phenols [22]. These included cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Full details of the plasma kinetic profiles can be found in Supplementary Tables S1 and S2. In summary, plasma concentrations varied from low nM to mid μM. The maximum concentration in plasma (Cmax) ranged from 1–31,269 nM (after 409 mg TP), 1–263,152 nM (after 787 mg TP), 2–115,012 nM (after 1238 mg TP), 12–267,355 nM (after 1534 mg TP) and 5–390,606 nM (after 1910 mg TP). The highest Cmax for juices was achieved for 3-(4-hydroxyphenyl) propionic acid, followed by hippuric acid and catechol-O-sulfate. The time to reach Cmax (Tmax) varied depending on the metabolite and depending on the amount of (poly)phenols in the juice (Supplementary Figure S1). The level of TP in cranberry juice seemed to impact the Tmax of individual metabolites, for example the Tmax for 3-(4-hydroxyphenyl) propionic acid varied between 7.2 h (409 mg TP juice) and 13.8 h (787 mg TP juice). The AUC of the plasma concentration against the time plot was calculated for each metabolite between 0 and 24 h and was between 2–3,119,972 nM*h (caffeic acid and 3-(4-hydroxyphenyl) propionic acid at 409 mg TP), 1–2,274,346 nM*h (caffeic acid and hippuric acid at 787 mg TP), 2–1,609,708 nM*h (caffeic acid and 3-(4-hydroxyphenyl) propionic acid at 1238 mg TP), 1–390,606 nM*h (caffeic acid and 3-(4-hydroxyphenyl) propionic acid 1534 mg TP) and 5–2,467,256 nM*h (chlorogenic acid and 3-(4-hydroxyphenyl) propionic acid at 1910 mg TP). The compounds with a higher AUC for each dose were hippuric acid > catechol-O-sulfate > 2,3,dihydrobenzoic acid > phenylacetic acid.
BODY.3. RESULTS.3.2. PLASMA DOSE RESPONSE :
The linear dose response for each plasma metabolite was assessed and of the 60 identified metabolites, 14 (poly)phenol metabolites displayed a linear dose-response curve (r2 ≥ 0.89) in plasma (Figure 1) with slopes significantly different from zero (p < 0.05): caffeic acid 4-O-ß-d-glucuronide and quercetin-3-O-ß-d-glucuronide displayed r2 > 0.98, while ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid and syringic acid exhibited r2 > 0.90. Vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate and isoferulic acid 3-O-sulfate had r2 values of almost 0.90. The sum of the (poly)phenol metabolites also exhibited a modest but significant (p > 0.05) correlation of r2 = 0.74 when plotted vs. (poly)phenol content in the interventions. Linear regression analysis was performed between the TP level in the intervention and the AUC of each class of compounds. The AUC for flavonols produced the highest r2 (0.97, p < 0.001), followed by the valerolactones (r2 = 0.89, p < 0.005), benzoic acids (r2 = 0.85, p < 0.01), cinnamic acids (r2 = 0.72, p < 0.05), phenylacetic acids (r2 = 0.71, p < 0.05), benzaldehydes (r2 = 0.65, p < 0.05); hippuric acids, pyrogallols, and catechols did not show a linear dose response.
BODY.3. RESULTS.3.3. INTER-INDIVIDUAL VARIABILITY:
The coefficient of variation (CV) expressed as a percentage was calculated for Cmax and AUC for each individual plasma metabolite after consumption of juice containing 787 mg TP; the %CV was used to assess the inter-individual variability after consumption of the juice (Figure 2). The CV of the AUC for the total (sum of all 60) metabolites was 53% and the CV for Cmax was 51%. The CV for the Cmax varied between 43% for dihydroferulic acid 4-O-sulfate and 216% for vanillic acid. The CV for the AUC varied between 48% for 4-hydroxybenzaldehyde and 163% for 1-methylpyrogallol-O-sulfate.
BODY.3. RESULTS.3.4. URINARY RECOVERY:
The same 60 (poly)phenol metabolites quantified in plasma were quantified in urine. Urinary excretion of (poly)phenol metabolites over the 24 h period post cranberry juice consumption is shown in Figure 3. Between 38 and 48 mg total urinary metabolites were excreted post-consumption of the five juices with varying TP content. The mean percentage recovery varied between 10.1% for the juice containing 406 mg TP down to 2.1% for the juice containing the highest TP content (1910 mg). The juice containing the least TP (409 mg) had a higher percentage excretion compared to all the other juices (p < 0.001). A positive, linear dose response for total excretion over 24 h of each urinary metabolite was assessed and of the 60 identified metabolites, 12 (poly)phenol metabolites displayed a positive linear dose-response curve (r2 ≥ 0.66) in urine with slopes significantly different from zero (p < 0.05); they were: 2,3-dihydrobenzoic acid (r2 = 0.79), 2,4-dihydrobenzoic acid (r2 = 0.77), dihydrocaffeic-3-O-sulfate (r2 = 0.66), ferulic-O-4-sulfate (r2 = 0.89), o-courmaric acid (r2 = 0.72), quercetin-3-O-ß-d-glucuronide (r2 = 0.89), 2,5-dihydroxybenzoic acid (r2 = 0.80), chlorogenic acid (r2 = 0.72), p-coumaric acid (r2 = 0.90), sinapic acid (r2 = 0.85), benzoic acid (r2 = 0.99), isoferulic acid (r2 = 0.74). The sum of (poly)phenol metabolites did not exhibit a linear dose response (r2 = 0.32, p = 0.25) when plotted vs. (poly)phenol content in the interventions.
BODY.4. DISCUSSION:
In this study, we quantified 60 poly(phenol) metabolites in plasma and urine after consumption of cranberry juice containing five differing amounts of (poly)phenols. Other than previous work by our group where the same 60 metabolites were quantified in a single concentration of cranberry juice [22], this is a much larger number of metabolites than usually reported after cranberry juice consumption [23,24,25]. Further, here we present quantities of glucuronidated and sulfated metabolites in addition to the methylated and native metabolites, unlike many of the previous works looking at cranberry (poly)phenol metabolites. This study demonstrates that the most abundant plasma (poly)phenol metabolites post-ingestion of cranberry juice are 3-(4-hydroxyphenyl) propionic acid, hippuric acid, and catechol-O-sulfate; this was regardless of the amount of TP in the drink. Despite quantifying a comparatively large number of metabolites in this investigation, it should be noted that this is by no means the entirety of the cranberry (poly)phenol metabolome. Further understanding of the metabolic pathway and synthesis of further metabolites as standards is essential to fully elucidate this. This study investigated the relationship between the amount of (poly)phenols in cranberry juice and the levels of the corresponding metabolites in plasma. These data show that selected plasma (poly)phenol metabolites correlate with the amount of (poly)phenols ingested with cranberry juice, showing a linear dose response. However interestingly, this does not apply to all (poly)phenol metabolites. Although the correlation between the intake amount and AUC of the metabolite concentration is a parameter which is seldom assessed, of the 14 (poly)phenols identified as showing a dose response in this study, only three (2,4-dihydroxybenzoic acid, syringic acid, and ferulic acid) have previously been shown to correlate with the amount of (poly)phenols ingested [17]. However, this was after blueberry intake, which has a different native TP profile, and further, the investigators used an enzymatic treatment prior to quantification. Therefore, all glucuronidated, sulfated, and unconjugated metabolites would have been quantified together. Unlike the previous work after blueberry ingestion, no metabolites exhibited a significant negative correlation. Other investigations into the (poly)phenol dose relationship with metabolites do not report regression analysis in this way [15,16]; such an investigation in cranberry (poly)phenols has not previously been published. Despite the fact that less than a quarter of the 60 metabolites measured showed linear dose dependence, when assessing the sum of the plasma metabolites, these were positively correlated with the amount of (poly)phenols ingested in the drink. This suggests that those 14 metabolites are key in driving the overall correlation. Many of the metabolites assessed exhibited a very large inter-individual variability (CV up to 216%). However, each metabolite did not exhibit the same level of variability as has been discussed previously [26]. Plus, when looking at the total metabolites (sum of 60 quantified), the variability was much lower (53%), suggesting that it is not a matter of individuals poorly/effectively metabolizing poly(phenols) as a whole, but it is actually down to an individual's ability to generate specific metabolites. There are a number of factors that will influence the metabolism and absorption. These factors may include sex, genetic polymorphisms of transporters or metabolizing enzymes, environmental influences, and likely the composition of the gut microbiome. This inter-individual variability in relation to (poly)phenols has been suggested previously [27] and may be down to the variation in the make-up of the volunteer's gut microbiota. Recent work has shown that (poly)phenols are able to modulate the levels of gut bacteria, but it is also becoming more evident that the gut microbiota plays a very important role in (poly)phenol metabolism [28]. Thus, characterizing the native gut bacteria and investigating relationships between species of bacteria and specific metabolites will be necessary to understand this complex relationship between (poly)phenols and the gut microbiota. The urinary recovery of the (poly)phenols was low (≤10%), although in line with urinary recoveries after other (poly)phenol-rich foods. This could be due to not capturing the entire profile of (poly)phenol metabolites and hence underestimating urinary excretion, which is feasible. Further, fecal metabolites were not considered and it is possible that a big proportion of metabolites are lost via this route, in particular the high-molecular-weight proanthocyanidins, which are not absorbed to a big extent. The method of quantification of proanthocyanidins in cranberry that we used can also explain in part the low recovery, as previously discussed [22]. Here we used the OS4-dimethylaminocinnamaldehyde (DMAC) method rather than the often used BL DMAC method. The latter overestimates (poly)phenol levels due to the use of procyanidin A2 as a standard instead of a better representation of cranberry proanthocyanidin complexity; OS DMAC includes a standardized extract comprehending larger polymers [29]. Therefore, using what we believe is a more appropriate method of quantification of (poly)phenols in cranberry juice may explain the low urinary recovery. This is specifically important in regards to this study as proanthocyanidins contribute to ~30% of the total TP amount in the cranberry beverages tested. Although the excretion of 12 of the 60 metabolites exhibited a linear dose response, the sum of the 60 metabolites did not. Unlike the plasma metabolites, the response of the sum of the urinary metabolites seemed to plateau beyond 787 mg TP cranberry juice. Although excretion dose response is seldom investigated, similar plateaus in response to physical parameters (e.g., flow-mediated dilation) have been observed by us, in response to cranberry juice [13] and blueberry [30]. We acknowledge the limitations within this study, for example there may be metabolites that we have not measured which may impact the recovery. There are a number of compounds which escape phase I and II metabolism and undergo microbial catabolism. These compounds are transformed into small-molecular-weight compounds that are no longer polyphenol intake–specific (e.g., catechols, pyrogallols, etc.), hence making it impossible to know which are derived from the ingested (poly)phenols and which from the background diet. In addition, although the plasma was taken under the control of the analyst, most of the urine was collected under free-living conditions, and as our method of quantification was based solely on urine volume, this could have caused some error. Further, although participants were instructed regarding lifestyle and dietary adjustment prior to the study days, we had little control over this aspect. Therefore, this could have been an important factor increasing the inter-individual variation and also the differing Tmax between cranberry juices. Although in the study we intentionally investigated the effect of cranberry juice on healthy, young, male subjects, broadening the inclusion criteria (for example, including women) or modifying the inclusion criteria (deviating from healthy participants) could have impacted our findings and could be an interesting avenue of investigation. Taken together, we show that after consuming cranberry juice containing 409, 787, 1238, 1534, and 1910 mg total (poly)phenols, there is a linear dose-dependent increase in circulating plasma (poly)phenol metabolites, but not in urinary excretion. We note that not all individual metabolites exhibit the same effect with regard to linear regression, and we identify specific plasma metabolites that may be driving this overall effect. Further, herein we note the large inter-individual variation in the metabolic profile in response to (poly)phenol consumption and suggest that this may be in part due to inter-individual variation in the gut microbiome. | 5,372,931 | {
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TITLE: Adjuvant radiation for salivary gland malignancies is associated with improved survival: A National Cancer Database analysis
ABSTRACT.OBJECTIVE:
There are no randomized data to support the use of postoperative radiation for salivary gland malignancies. This study uses the National Cancer Database (NCDB) to describe the epidemiology of salivary gland cancer patients and to investigate whether treatment with adjuvant radiation improves overall survival.
ABSTRACT.METHODS AND MATERIALS:
A total of 8243 patients diagnosed with a major salivary gland cancer were identified from the NCDB. All patients received primary surgical resection of their malignancy. Patients were risk-stratified by adverse features, and overall survival rates were determined. Patients were considered high risk if they had extracapsular extension and/or positive margin after resection. Patients were considered intermediate risk if they did not meet the criteria for high risk but had pT3-T4 disease, pN+ disease, lymphovascular space invasion, adenoid cystic histology, or grade 2-3 disease. Patients who did not meet criteria for high or intermediate risk were considered low risk. Overall patient demographics, disease characteristics, treatment factors, and outcomes were summarized with descriptive statistics and analyzed with STATA.
ABSTRACT.RESULTS:
Median follow-up in this cohort was 42.4 months, with the median age of 58 years. Patients in the high-risk group had greater survival (hazard ratio [HR], 0.76; P = .002; 95% confidence interval [CI], 0.64-0.91) if they received adjuvant radiation therapy. In contrast, patients in the intermediate- (HR, 1.01; P = .904; 95% CI, 0.85-1.20) and low-risk groups (HR, 0.85; P = .427; 95% CI, 0.57-1.26) did not experience a survival benefit with adjuvant radiation therapy.
ABSTRACT.CONCLUSIONS:
This large analysis compared survival outcomes between observation and adjuvant radiation alone in risk-stratified patients after resection of major salivary glands using a national database. The use of adjuvant radiation for high-risk major salivary gland cancers appears to offer a survival benefit. Although an overall survival benefit was not seen in low- and intermediate-risk salivary gland cancers, this study could not address impact on local control because of the limitations of the NCDB.
BODY:
SummaryWe aimed to investigate whether adjuvant radiation improves overall survival in major salivary gland cancers. Furthermore, we wanted to identify which subset of patients benefits the most from receiving radiation. A total of 8243 patients with salivary gland cancer were identified from the National Cancer Database. Patients in the high-risk group had greater survival (hazard ratio, 0.76; P = .002) if they received adjuvant radiation therapy.
BODY.INTRODUCTION:
Malignant tumors of the salivary gland are rare cancers that represent less than 5% of all newly diagnosed head and neck malignancies.1 These tumors arise from malignant transformation of the cellular constituents of the secretory acini, their ducts, and supporting myoepithelial cells in both major and minor salivary glands. The World Health Organization classifies 24 subtypes of salivary gland cancers (SGCs), with mucoepidermoid carcinoma, adenoid cystic carcinoma, and adenocarcinoma being the most common histologic subtypes.2 The management of SGCs remains a challenge because of their heterogeneous nature, diverse biological behaviors, and low prevalence. In patients without evidence of distant hematogenous metastases, surgery remains the definitive treatment of choice in those with salivary gland malignancies. Outcomes after surgery in early-stage disease are excellent. A retrospective series of patients treated from 1997 to 2002 for parotid gland carcinomas demonstrated 5-year disease-free survival of 86%, with inferior disease-free survival with advanced disease stage according to the 2002 American Joint Committee on Cancer classification.3 Risk factors for disease recurrence were examined in a retrospective cohort of 565 patients treated for malignant salivary gland tumors in the Netherlands.4 The risk of local recurrence was increased in patients with T3 and T4 tumors, incomplete resection, and bone invasion. Regional recurrence was predicted by facial nerve weakness and positive margins on neck dissection, and the risk of distant metastasis was higher among patients with a T3-4, N2-N3 disease, and/or perineural invasion (PNI). There is no randomized prospective data in the literature supporting the use of postoperative radiation therapy (RT) in this patient population. The largest study completed regarding adjuvant RT for SGCs investigated 2170 patients from the Surveillance, Epidemiology, and End Results (SEER) registry. They found that postoperative adjuvant RT is associated with improved overall survival for high-risk disease (defined as poorly differentiated, undifferentiated, and/or locally advanced T3/4 or N+).5 Another SEER database study, however, investigated 1241 cases of parotid acinic cell carcinoma and found that adjuvant RT did not provide a tangible overall survival benefit in this population.6 Although SEER offers many potential benefits, there are limited data regarding radiation dose and treatment details such as fraction number, target, and pathological information, which may account for conflicting results seen in SGCs. The National Cancer Database (NCDB) is a database that offers more robust information regarding pathological and treatment information for patients and thus can allow for more detailed studies of underlying patient characteristics important for prognosis. Most data regarding adjuvant radiation for SGCs are limited to retrospective series that describe improved local control rates compared with surgical resection alone.4, 7, 8 Registry data and single-institution series have consistently demonstrated improving survival among patients with this disease over time, attributed partly to improved surgical techniques and staging techniques from imaging, but largely resulting from the widespread adoption of postoperative RT.5, 9, 10, 11 Despite the absence of compelling supporting prospective data, postoperative RT is considered a standard of care for patients with high-risk features after resection. This study uses one of the largest national SGC databases to investigate whether postoperative RT is associated with an overall survival benefit.
BODY.METHODS.DATA SOURCE:
The NCDB is supported by the Commission on Cancer and contains deidentified demographic and clinical patient data on approximately 70% of the cancers diagnosed in the United States annually. We examined patients aged 18 to 90 years with salivary gland malignancy diagnosed from 2004 through 2013.
BODY.METHODS.PATIENT DEMOGRAPHICS:
Patient demographics (age, race, sex, facility type, and insurance), disease characteristics (primary site, TNM staging), histology, pathologic features, and treatment variables were investigated as predictors of overall survival. Facility type was separated into academic and nonacademic centers (combination of community cancer programs, comprehensive community cancer programs, and other programs). Insurance status was divided into private and government (Medicare and Medicaid) insurance.
BODY.METHODS.INCLUSION AND EXCLUSION CRITERIA:
We excluded patients with metastatic disease, in situ disease only, those who did not undergo surgical resection, and those who had unknown overall staging. Clinical staging was used to exclude metastatic patients (coded as cM0 in the NCDB). Furthermore, pathologic stage was required because patients with pathologic metastases would not have been surgical candidates. Patients that received neoadjuvant chemotherapy and/or RT were excluded. Among the patients receiving RT, we excluded those receiving palliative doses (<50 Gy), restricting the doses analyzed from 50 to 70 Gy. We excluded any patients undergoing RT >90 days after resection. We focused our analysis on the most frequently represented histologies only, which included adenocarcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, acinar cell carcinoma, epithelial-myoepithelial carcinoma, and carcinoma ex pleomorphic adenoma. After these exclusions, displayed in Figure 1, there were 8243 patients with surgically managed localized salivary cancer of major histologic subtype.Figure 1Consolidated Standards of Reporting Trials flow diagram. NCDB, National Cancer Database; RT, radiation therapy.
BODY.METHODS.RISK STRATIFICATION:
Patients were stratified into 3 risk groups based on clinical and pathological criteria. Patients were considered high risk if they had extracapsular extension (ECE) and/or positive margin after resection, which is the standard definition of high-risk disease in head and neck cancers. Patients were considered intermediate risk if they did not meet criteria for high risk but had pT3-T4 disease, pN+ disease, lymphovascular space invasion (LVSI), adenoid cystic histology, and/or grade 2-3 disease. Patients who did not meet criteria for high or intermediate risk were considered low risk.
BODY.METHODS.STATISTICAL ANALYSIS:
Overall patient demographics, tumor characteristics, treatment factors, and outcomes were summarized by descriptive statistics. The comparisons between the groups were performed with the use of Student t test for continuous measures and the χ2 test for categorical measures. Overall survival was determined with the use of Kaplan-Meier methods. The hazard ratios (HRs) were estimated with the use of Cox proportional-hazard models. The multivariate Cox proportional hazards model is displayed in eTable 1 (available as supplementary material online only at www.advancesradonc.org). Two-sided P values < .05 were considered to indicate statistical significance. All statistical analyses were performed using STATA software, version 14.0 (StataCorp).
BODY.RESULTS.PATIENT CHARACTERISTICS:
For the total cohort of 8243 patients, the median follow-up time was 42.4 months (range, 0-119) and median age was 58 years. After stratifying this cohort into risk groups based on disease characteristics, there were 2489 low-risk, 3305 intermediate-risk, and 2449 high-risk patients. Table 1 displays detailed cohort characteristics and demographic information, separated based on risk group. Table 2 further elaborates on the adverse features within the intermediate-risk group. Within the high-risk group (n = 2449), 2303 (94.0%) had positive margin and 243 (9.9%) had extracapsular extension.Table 1Patient demographicsTotal cohortLR (n = 2489)IR (n = 3305)HR (n = 2449)P value (LR vs IR)∗ (LR vs HR)∗ (IR vs HR)∗Age (n = 8243)<.001 <60 y4515 (54.8%)1572 (63.2%)1711 (51.8%)1232 (50.3%)<.001 ≥60 y3728 (45.2%)917 (36.8%)1594 (48.2%)1217 (49.7%).82Sex (n = 8243)<.001 Male3764 (45.7%)962 (38.7%)1628 (49.3%)1174 (47.9%)<.001 Female4479 (54.3%)1527 (61.4%)1677 (50.7%)1275 (52.1%).97Race (n = 8218) White6791 (82.6%)2016 (81.1%)2725 (82.7%)2050 (84.1%).053 Black929 (11.3%)308 (12.4%)375 (11.4%)246 (10.1%) Asian301 (3.7%)87 (3.5%)124 (3.8%)90 (3.7%) Other197 (2.4%)74 (2.4%)70 (2.1)53 (2.2%)Ethnicity (n = 8243) Non-Hispanic7268 (88.2%)2201 (88.4%)2913 (88.1%)2154 (88.0%) Hispanic429 (5.2%)132 (5.3%)179 (5.4%)118 (4.8%).55 Other546 (6.6%)156 (6.3%)213 (6.4%)177 (7.2%)Facility type (n = 8243).08 Academic4765 (57.8%)1447 (58.1%)1826 (55.3%)1492 (60.9%).14 Nonacademic3478 (42.2%)1042 (41.9%)1479 (44.8%)957 (39.1%)<.001Insurance Type (n = 8,243) Private4477 (54.3%)1544 (62.0%)1697 (51.4%)1236 (50.5%)<.001 Medicare/Medicaid3363 (40.8%)831 (33.4%)1429 (43.2%)1103 (45.0%)<.001 Uninsured403 (4.9%)114 (4.6%)179 (5.4%)110 (4.5%).40Primary site (n = 8243) Parotid7440 (90.3%)2389 (96.0%)2890 (87.4%)2161 (88.2%)<.001 Submandibular578 (7.0%)60 (2.4%)293 (8.9%)225 (9.2%)<.001 Sublingual76 (0.9%)10 (0.4%)44 (1.3%)22 (0.9%).37 Other149 (1.8%)30 (1.2%)78 (2.4%)41 (1.7%)HR, high-risk group; IR, intermediate-risk group; LR, low-risk group.∗Bonferroni adjustment for multiple comparison was applied.Table 2Adverse features within intermediate risk groupAll patients (n = 3305)RT (n = 1741)No RT (n = 1561)pT3643 (19.5%)363 (20.8%)280 (17.9%)pT4408 (12.3%)271 (15.6%)137 (8.8%)pN+814 (24.6%)498 (28.6%)316 (20.2%)Lymphovascular space invasion234 (7.1%)153 (8.8%)81 (5.2%)Intermediate grade (2)1218 (36.9%)467 (26.8%)751 (48.1%)High grade (3)780 (23.6%)531 (30.5%)249 (16.0%)Undifferentiated grade227 (6.9%)162 (9.3%)65 (4.2%)Adenoid cystic carcinoma histology664 (20.1%)412 (23.7%)252 (16.1%)
BODY.RESULTS.DISEASE CHARACTERISTICS:
The majority of patients presented with disease in the parotid gland. A total of 7440 (90.3%) of the total cohort had a primary parotid gland malignancy. The most common disease histology was mucoepidermoid carcinoma, with 3298 (40.0%) cases in the cohort. Remaining disease histology included acinar cell carcinoma (1938 patients, 23.5%), adenoid cystic carcinoma (1188 patients, 14.4%), adenocarcinoma (1044 patients, 12.7%), carcinoma ex pleomorphic adenoma (445 patients, 5.4%), and epithelial-myoepithelial carcinoma (330 patients, 4.0%). Disease primary sites are shown in Table 1. Histology distribution, further TN staging, and disease grades are shown in Table 3. Patients commonly presented with T1 (3182 patients, 39.3%) and N0 disease (6691 patients, 83.5%).Table 3Disease characteristicsTotal cohortLR (n = 2489)IR (n = 3305)HR (n = 2449)P value (LR vs IR)∗ (LR vs HR)∗ (IR vs HR)∗Primary site (n = 8243) Parotid7440 (90.3%)2389 (96.0%)2890 (87.4%)2161 (88.2%)<.001 Submandibular578 (7.0%)60 (2.4%)293 (8.9%)225 (9.2%)<.001 Sublingual76 (0.9%)10 (0.4%)44 (1.3%)22 (0.9%).37 Other149 (1.8%)30 (1.2%)78 (2.4%)41 (1.7%)Histology (n = 8243) Adenocarcinoma1044 (12.7%)115 (4.6%)521 (15.8%)408 (16.7%)<.001 Adenoid cystic1188 (14.4%)0 (0%)664 (20.1%)524 (21.4%)<.001 Mucoepidermoid3298 (40.0%)1043 (41.9%)1412 (42.7%)843 (34.4%)<.001 Acinar cell1938 (23.5%)1058 (42.5%)410 (12.4%)470 (19.2%) Epithelial-myoepithelial carcinoma330 (4.0%)147 (5.9%)105 (3.2%)78 (3.2%) Carcinoma ex pleomorphic adenoma445 (5.4%)126 (5.1%)193 (5.8%)126 (5.1%)Grade (n = 8243) 12117 (25.7%)1382 (55.5%)329 (10.0%)406 (16.6%)NA 21682 (20.4%)0 (0%)1218 (36.9%)464 (19.0%) 31394 (16.9%)0 (0%)780 (23.6%)614 (25.1%) Undifferentiated408 (5.0%)0 (0%)227 (6.9%)181 (7.4%) Unknown2642 (32.1%)1107 (44.5%)751 (22.7%)784 (32.1%)T stage (n = 8009) 13182 (39.3%)1511 (60.7%)1119 (35.0%)552 (22.9%)NA 22227 (27.5%)759 (30.5%)823 (25.7%)645 (26.7%) 31231 (15.2%)0 (0%)643 (20.1%)588 (24.4%) 4872 (10.8%)0 (0%)408 (12.8%)464 (19.2%) X587 (7.3%)219 (8.8%)205 (6.4%)163 (6.8%)N stage (n = 8009) 06691 (83.5%)2489 (100%)2491 (79.5%)1711 (71.7%)NA 1541 (6.8%)0 (0%)305 (9.7%)236 (9.9%) 2435 (18.2%)0 (0%)333 (10.6%)435 (18.2%) 35 (0.21%)0 (0%)4 (0.1%)5 (0.2%)LVSI (n = 3066) Absent2044 (66.7%)698 (80.5%)810 (62.1%)536 (60.0%)NA Present425 (13.9%)0 (0%)234 (17.9%)191 (21.4%) Unknown/indeterminate167 (18.7%)169 (19.5%)167 (18.7%)167 (18.7%)LVSI, lymphovascular space invasion (LVSI coded after 2009 only); NA, not applicable to compare statistically. Other abbreviations as in Table 1.∗Bonferroni adjustment for multiple comparison was applied.
BODY.RESULTS.TREATMENT INFORMATION:
After identifying the initial SGC cohort, patients were separated based on treatment received. In the high-risk group, a higher proportion of patients (71.1%, 1739 patients) received RT after surgical resection compared with the lower risk groups. The intermediate-risk group had 52.7% (1741 patients) receive RT. The low-risk group had 21.5% (534 patients) receive RT. A small proportion of patients received chemotherapy after surgical resection, with an increasing proportion of patients receiving chemotherapy as their disease risk factors increased. A total of 409 (5.0%) in the entire cohort received chemotherapy. The low-risk group had 5 patients (0.2%) receive chemotherapy after surgical resection; in the intermediate-risk group, 160 patients (4.8%) received chemotherapy. Finally, the high-risk group had 244 patients (10.0%) receive chemotherapy after resection. Comorbidity distributions were also determined from the Charlson-Deyo score. The majority of patients had no comorbidities and had a score of 0 (84.3%, 6951 patients). More detailed information regarding treatment characteristics based on risk group are shown in Table 4.Table 4Treatment characteristicsTotal cohortLR (n = 2489)IR (n = 3305)HR (n = 2449)P value (LR vs IR)∗ (LR vs HR)∗ (IR vs HR)∗Chemotherapy use (n = 8243)<.001 Yes409 (5.0%)5 (0.2%)160 (4.8%)244 (10.0%)<.001 No7834 (95.0%)2484 (99.8%)3145 (95.2%)2205 (90.0%)<.001RT use (n = 8236)<.001 Yes4014 (48.7%)534 (21.5%)1741 (52.7%)1739 (71.1%)<.001 No4222 (51.3%)1954 (78.5%)1561 (47.3%)707 (28.9%)<.001Charlson-Deyo score (n = 8243) 06951 (84.3%)2118 (85.1%)2788 (84.4%)2045 (83.5%).279 11069 (13.0%)317 (12.7%)424 (12.8%)328 (13.4%) ≥2223 (2.7%)54 (2.2%)93 (2.8%)76 (3.1%)RT, radiation therapy. Other abbreviations as in Table 1.∗Bonferroni adjustment for multiple comparison was applied.
BODY.RESULTS.OUTCOMES:
In the high-risk group, after adjusting for sex, race, ethnicity, insurance type, chemotherapy, and Charlson-Deyo score, receipt of postoperative RT was associated with a reduced risk of death (HR, 0.76; 95% confidence interval [CI], 0.64-0.91) compared with not receiving RT (P = .002). In the intermediate-risk group, after adjusting for sex, race, ethnicity, insurance type, chemotherapy, and Charlson-Deyo score, postoperative RT was not found to be associated with a significantly reduced risk of death (HR, 1.01; 95% CI, 0.85-1.20) compared with not receiving RT (P = .904). In the low-risk group, adjusting for sex, race, ethnicity, insurance type, chemotherapy, and Charlson-Deyo score, differences between patients who received postoperative RT and those who did not were not significant (P = .427); (HR, 0.85; 95% CI, 0.57-1.26). The Kaplan-Meier survival curve is shown in Figure 2. Five-year overall survivals were 93% (95% CI, 91-94) for the low-risk group, no RT; 93% (95% CI, 90-95) for the low-risk group with RT; 77% (95% CI, 74-80) for the intermediate-risk group, no RT; 75% (95% CI, 72-77) for the intermediate-risk group with RT; 64% (95% CI, 59-68) for the high-risk group, no RT; 67% (95% CI, 65-70) for the high-risk group with RT.Figure 2Kaplan-Meier survival curves. Five-year overall survivals: low risk, no RT (LR), 93% (95% CI, 91-94); low-risk RT (LR-RT), 93% (95% CI, 90-95); intermediate risk, no RT (IR), 77% (95% CI, 74-80); intermediate-risk RT IR-RT, 75% (95% CI, 72-77); high risk, no RT (HR), 64% (95% CI, 59-68); high-risk RT (HR-RT), 67% (95% CI, 65-70). Dx, diagnosis.
BODY.DISCUSSION:
RT is a local treatment, and thus its benefit is often thought to be an improvement in local control rather than an overall survival benefit. To our knowledge, this analysis is the largest study reported to date that compares survival outcomes evaluating the role of adjuvant RT in salivary gland cancers based on adverse prognostic features. A recent study investigated 2210 SGC patients from the NCDB and found that postoperative chemoradiation therapy did not confer a survival benefit over RT alone.12 Our study uses the NCDB to ask more fundamental clinical questions, specifically whether adjuvant RT improves overall survival irrespective of chemotherapy, and to identify the specific subset of patients who stand to benefit from it. Our data suggest that only high-risk patients had a statistically significant improvement in overall survival when they received postoperative RT. For the high-risk group, the HR was 0.76 when patients received RT after surgical resection of their primary malignancy compared with patients who did not receive postoperative adjuvant RT. The intermediate-risk group had a HR of 1.01. In the low-risk group, the HR was 0.85, but this was not statistically significant. Here, we define our high-risk group based on generally accepted standards used in other head and neck cancers, which includes positive surgical margin and ECE. Individual randomized studies established that these consensus markers of high-risk disease included a variety of risk factors, although positive margin and ECE emerged as the most important indicators.13, 14 Our intermediate-risk group is an amalgam of the lesser but still important risk factors from those trials, including LVSI and pT3-pT4 staging as well as higher-risk features of SGCs in general, including adenoid cystic histology. There is, however, a gray area when it comes to grouping these malignancies, and we acknowledge that factors such as number of positive nodes may affect the perception of high risk or intermediate risk in some clinicians' view. Patients within the intermediate-risk group with more advanced features, such as pT4, pN+, LVSI, high or undifferentiated grade, and adenoid cystic histology, more frequently received RT (Table 2). This may confound the survival data for the intermediate group. Furthermore, it is possible for patients to present with multiple intermediate-risk factors that may increase their overall disease risk. These patients may have been more likely to receive adjuvant radiation, further confounding the survival data for the intermediate-risk group. Conversely, patients in our study who were considered low risk simply based on the absence of these features may have been in a higher risk group in reality given the presence of features, such as PNI or close margins, that are not captured in the NCDB. Finally, RT is used for local control, which is not captured in this study. Despite the lack of overall survival benefit for lower risk groups, low- and intermediate-risk patients may potentially benefit from RT because of improved local disease control. The NCDB confers several benefits over other population databases, including a larger sample size, broader inclusion of ages, detailed pathologic assessment, and the availability of in-depth RT details including dose and fractionation. The NCDB has several limitations, however. Although it provides extensive information regarding patient demographics, extent of disease, treatment regimens, and long-term overall survival, there is no central review of the data. All centers participating in the NCDB are Commission on Cancer–designated centers, which lends credibility to its overall fidelity. The database also does not include local recurrence data; therefore, we are unable to assess local control after treatment. Furthermore, PNI was not reported on the NCDB, which may have allowed for a clearer investigation to the importance of PNI in terms of prognosis. In our study, we adjusted for all known significant variables; however, it is possible that imbalances exist in unknown or uncaptured variables that may alternatively explain the improved survival associated with postoperative RT in the high- and intermediate-risk groups. Finally, the NCDB does not capture data regarding treatment toxicity, which makes it difficult to assess the true cost-benefit ratio of adding RT to patients' treatment regimens. Our study demonstrates an overall survival benefit in SGC patients undergoing adjuvant radiation with high-risk adverse features. In the low- and intermediate-risk groups, although a survival benefit was not seen, a benefit in terms of locoregional control could not be assessed. In particular, the intermediate-risk group warrants further study to better understand how various risk factors interact with each other to determine which patients benefit the most from adjuvant radiation. Regarding adjuvant chemoradiation in this setting, the benefit of concurrent cisplatin along with RT is being prospectively studied with Radiation Therapy Oncology Group 1008. As results from this trial are awaited, this study provides further rationale for the consideration of adjuvant RT in patients with SGC and adverse features. | 5,514,258 | {
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TITLE: Randomized Trial Comparing Esomeprazole and Rabeprazole in First-line Eradication Therapy for
ABSTRACT.OBJECTIVE :
CYP2C19 metabolic activity influences the efficacy of Helicobacter pylori eradication therapies comprising PPIs. Rabeprazole (RPZ) and esomeprazole (EPZ) are PPIs not extensively metabolized by CYP2C19. The aim of this study was to elucidate whether or not first-line triple therapies using RPZ or EPZ are equally effective in Japanese patients with different CYP2C19 genotypes.
ABSTRACT.METHODS :
Two-hundred patients infected with H. pylori were randomized to receive one of the following regimens: amoxicillin (750 mg), clarithromycin (200 mg), and either esomeprazole (20 mg) (EAC group) or rabeprazole (10 mg) (RAC group), twice a day for one week. The CYP2C19 polymorphisms were determined by polymerase chain reaction and the serum level of pepsinogens was measured.
ABSTRACT.RESULTS :
The eradication rates of the EAC and RAC regimens were 79.8% (95% confidential interval: 71.7-89.0%) and 74.7% (66.0-83.4%), respectively, in a per protocol (PP) analysis (p=0.488). The eradication rates of the EAC and RAC regimens were not significantly different between patients with the homo EM genotype (p=0.999) or hetero IM or PM genotypes (p=0.286). A lower PG I/II ratio was associated with lower eradication rates (p=0.025).
ABSTRACT.CONCLUSION :
Although the eradication rate was less than 80%, the EAC and RAC regimens were equally effective in each CYP2C19 genotype group. The PG I/II ratio was associated with the results of EAC and RAC therapy in this series of patients.
BODY.INTRODUCTION:
Helicobacter pylori infection has been associated with gastro-duodenal and systematic diseases, and the eradication of H. pylori infection has been shown to reduce the risk of gastric cancer (1, 2). In 2014, the International Agency for Research on Cancer suggested that the eradication of H. pylori should be considered as a strategy for preventing gastric cancer (3). The Japanese health insurance system approved efforts to eradicate H. pylori for all infected patients to eliminate gastric cancer in 2013 (4), and the number of patients receiving eradication therapy is on the rise. Since the approval of H. pylori eradication in November 2000, first-line eradication therapy has consisted of one week of triple therapy with a proton pump inhibitor (PPI), amoxicillin (AMOX) and clarithromycin (CLA) (5). In this therapy, the role of the PPI is to achieve a high intragastric pH for acid-labile antibiotics. PPIs are known to stabilize AMOX in the gastric mucus and the eradication rates of regimens containing AMOX are affected by the dose of PPI (6). The effect of PPIs such as omeprazole (OPZ) or lansoprazole (LPZ) are affected by the metabolic activity of the hepatic enzyme, cytochrome P450 (CYP) 2C19 (7). Indeed, some previous reports have shown lower eradication rates of triple therapy with OPZ or LPZ in patients with wild-type CYP2C19 compared to that in patients with a mutated genotype (8, 9). In contrast, later PPIs such as rabeprazole (RPZ) and esomeprazole (EPZ) have less CYP2C19-mediated metabolism than OPZ or LPZ (10, 11), and a meta-analysis showed that EPZ and RPZ had higher eradication rates than LPZ or OPZ in the treatment of H. pylori infection (12). However, in Japan, the efficacy of triple therapy with RPZ or EPZ in association with CYP2C19 genetic polymorphism has never been compared in a prospective, randomized trial. In the present study, we conducted a prospective, open, randomized multi-center trial to elucidate whether or not triple therapies using RPZ or EPZ are equally effective in patients with different CYP2C19 genotypes. We also examined the association between several factors, including serum level of pepsinogens, and the results of triple therapy using EPZ or RPZ.
BODY.MATERIALS AND METHODS.PATIENTS:
Patients who received upper GI endoscopy at any of eight institutes in Aomori Prefecture were enrolled in the study from May through September 2014. The presence of H. pylori was confirmed with a rapid urease test, 13C-urea breath test (UBT), stool antigen test or serum or urine antibody. Patients who met any of the following criteria were excluded from the study: [1] age under 16 years or over 70 years; [2] received antibiotic and/or PPI treatment(s) within 2 weeks of study commencement; [3] active peptic ulcer(s); [4] a history of gastric surgery; [5] a history of H. pylori eradication therapy; or [6] suspected of having malignant disease(s). A total of 200 patients were registered and 1 patient in the RPZ group was excluded due to severe heart disease (Fig. 1). The characteristics of the patients who completed the study are shown in Table 1. All patients gave their written informed consent before receiving eradication therapy. Peripheral blood was obtained and leukocytes were used for the CYP2C19 genotype analysis. Genotyping procedures for identifying the CYP2C19 wild-type gene and two mutated alleles, CYP2C19m1 and CYP2C19m2, were performed by a PCR-restriction fragment length polymorphism (PCR-RFLP) method with allele-specific primers (13). Serum samples were stored at -20°C and the titer of IgG antibody to H. pylori was determined by an enzyme immunoassay (E-plate; Eiken, Tokyo, Japan) and the levels of pepsinogen (PG) I and PG II by a radioimmunoassay. Figure 1.Assignment of patients and subsequent study flow. The study enrolled 200 patients at 8 medical institutes in Aomori Prefecture. The patients were randomly assigned to either the EAC group (n=99) or the RAC group (n=100). Table 1. Characteristics of the Patients who Completed the Regimen. EAC RAC Total p value Number 94 95 189 Sex Men 43 (45.7) 47 (49.5) 90 (47.6) 0.663 Women 51 (54.3) 48 (50.5) 99 (52.4) Age (years) <40 8 ( 8.5) 7 ( 7.4) 15 ( 7.9) 0.800 ≥40 86 (91.5) 88 (92.6) 174 (92.1) Smoking Non 73 (77.7) 75 (78.9) 148 (78.3) 0.861 Current 21 (22.3) 20 (21.1) 41 (21.7) Drinking Non 43 (45.7) 46 (48.4) 89 (47.1) 0.771 Current 51 (54.3) 49 (51.6) 100 (52.9) PG I (ng/mL) <49.0 23 (24.2) 26 (27.7) 49 (25.9) 0.753 49.0≤<69.0 24 (25.3) 25 (26.6) 49 (25.9) 69.0≤<89.0 17 (17.9) 19 (20.2) 36 (19) 89.0< 31 (32.6) 24 (25.5) 55 (29.2) PG II (ng/mL) <15.0 17 (17.9) 26 (27.7) 43 (22.8) 0.270 15.0≤<23.0 29 (30.5) 30 (31.9) 59 (31.2) 23.0≤<31.0 19 (20.0) 18 (19.1) 37 (19.6) 31.0< 30 (31.6) 20 (21.3) 50 (26.4) PG I/II ratio <2.2 25 (26.3) 19 (20.2) 44 (23.3) 0.370 2.2≤<2.9 25 (26.3) 19 (20.2) 44 (23.3) 2.9≤<3.6 16 (16.8) 23 (24.5) 39 (20.6) 3.6< 29 (30.6) 33 (35.1) 62 (32.8) CYP2C19 homo EM 30 (31.9) 30 (31.6) 60 (31.7) hetero IM/PM 64 (68.1) 65 (68.4) 129 (68.3) 0.999 anti-Hp antibody <24 34 (36.2) 28 (29.5) 62 (32.8) 0.514 (U/mL) 24≤<46 29 (30.9) 36 (37.9) 65 (34.4) ≥46 31 (33.0) 31 (32.6) 62 (32.8) N, (%)
BODY.MATERIALS AND METHODS.ERADICATION THERAPY:
Patients were randomly assigned to one of the following eradication therapy groups: [1] EAC group: EPZ (20 mg) twice a day (bid), AMPC (750 mg) bid, and CLA (200 mg) bid for one week; or [2] RAC group: RPZ (10 mg) bid, AMPC (750 mg) bid, and CLA (200 mg) bid for one week. After completing the treatment, any PPIs and other anti-ulcer agents that might affect the viability of H. pylori or urease activity were not used. Eradication assessment using a UBT (14) or stool antigen test (15) was performed 6 (±2) weeks after the completion of eradication therapy. One patient in the RAC group could not complete the regimen due to severe itching. During the treatment, eruption was observed in three patients, loose stool was recorded in two patients, and one patient complained of a metallic taste. However, these patients completed their regimens. Five patients in the EAC group and four patients in the RAC group did not visit the hospital and dropped out.
BODY.MATERIALS AND METHODS.ETHICS ASSIGNMENT:
The unit of randomization was the individual, and the allocation sequence was generated by an unaffiliated person at the Hirosaki University Hospital who was blinded to the details of the study. This study was approved by Hirosaki University Medical Ethics Committee and registered to UMIN Clinical Trials Registry (UMIN000014366).
BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Differences between the groups were compared using the χ2 test. A p value of <0.05 was considered significant.
BODY.RESULTS:
The eradication rates of the EAC and RAC regimen groups were 79.8% [95% confidential interval (CI): 71.7-89.0%] and 74.7% (66.0-83.4%) for the per protocol (PP) analysis and 75.8% (67.4-84.2%) and 71.0% (62.1-79.9%) for the intention-to-treat (ITT) analysis, respectively (Fig. 2A). No significant differences were observed between the two regimens. Regarding the CYP2C19 genetic polymorphism status, 62 patients were assigned to the homozygous extensive metabolizer (homo EM) group, 102 patients with 1 mutation were assigned to the heterozygous intermediate metabolizer group (hetero IM), and 35 patients with 2 mutations were assigned to the poor metabolizer (PM) group. Fig. 2B shows the PP-based eradication rates in relation to the CYP2C19 polymorphism. The eradication rate of the EAC and RAC regimens in the homo EM patients was 73.3% (CI: 57.5-89.1%) and 76.7% (CI: 61.6-91.8%), respectively. In the hetero IM and PM patients, the eradication rate of the EAC regimen was 82.8% (73.6-92.0%), and that of the RAC regimen was 73.8% (63.1-84.5%). The eradication rates of the EAC and RAC regimen groups were not significantly different between the patients with homo EM genotype and those with hetero IM or PM genotype. The eradication rates of homo EM patients were not markedly different from those of the hetero IM or PM patients in the EAC (p=0.287) or RAC (p=0.999) regimen groups. Figure 2.(A) The eradication rates of EAC and RAC therapy by a per-protocol (PP) analysis or intention-to-treat analysis. (B) The eradication rates of EAC and RAC therapy by a PP analysis in patients with homo EM versus those with hetero IM or PM. Table 2 shows the association between the patients' characteristics and the results of eradication therapy in 189 patients who completed the protocol. No factors were associated with the results of eradication therapy. Table 3 shows the association between the serum pepsinogen levels and the results of eradication therapy. Although the levels of PG I and II were not significantly associated with the treatment results, the eradication rates tended to increase with an increasing PG I/II ratio (p=0.025). The eradication rate was 68.2% in the 44 patients with a PG I/II ratio lower than 2.2 and 84.2% in those with a PG I/II ratio higher than 2.9. Table 2. Patients’ Characteristics and the Results of Eradication Therapy. Eradication p value failure success Sex Men 19 (21.1) 71 (78.9) 0.729 Women 24 (24.2) 75 (75.8) Age (years) <40 4 (26.7) 11 (73.3) 0.749 ≥40 39 (22.4) 135 (77.6) Smoking Non 34 (23) 114 (77) 0.999 Current 9 (22) 32 (78) Drinking Non 17 (19.1) 72 (80.9) 0.299 Current 26 (26) 74 (74) CYP2C19 homo EM 15 (25) 45 (75) 0.710 Hetero IM+PM 28 (21.7) 101 (78.3) anti-Hp antibody <24 14 (22.6) 48 (77.4) 0.997 (U/mL) 24≤<46 15 (23.1) 50 (76.9) ≥46 14 (22.6) 48 (77.4) N, (%) Table 3. Level of Pepsinogens and the Results of Eradication Therapy. eradication p value success (N) failure (N) rate (%) PG I (ng/mL) <49.0 35 14 71.4 0.177 49.0≤<69.0 37 12 75.5 69.0≤<89.0 29 7 80.6 89.0< 45 10 81.8 PG II (ng/mL) <15.0 35 8 81.4 0.573 15.0≤<23.0 46 13 78.0 23.0≤<31.0 26 11 70.3 31.0< 39 11 78.0 PG I/II ratio <2.2 30 14 68.2 0.025 2.2≤<2.9 31 13 70.5 2.9≤<3.6 33 6 84.6 3.6< 52 10 83.9
BODY.DISCUSSION:
EPZ has been the most popular PPI worldwide for more than 10 years. However, in Japan, the use of EPZ was only just approved in September 2011, and thus relatively few studies have examined the efficacy of EPZ in H. pylori eradication therapy compared with other PPIs in a Japanese population. The present study is the first prospective randomized study to compare the efficacy of EPZ and RPZ in first-line eradication therapy for H. pylori infection among Japanese patients with different CYP2C19 genotypes. Suppression of gastric acid is important for the eradication therapy of H. pylori infection (6, 16). Better eradication rates have been observed in PM patients undergoing PPI-based triple therapies using OPZ or LPZ than in EM patients (7, 8). Similarly, a recent meta-analysis showed that CYP2C19 loss-of-function variants are associated with increased H. pylori eradication rates in patients receiving these therapies (17). In this study, the eradication rates in EM patients were not significantly different from those in IM and PM patients receiving the EAC and RAC regimens. Therefore, the genotyping of CYP2C19 is not necessary for first-line eradication therapy when EPZ or RPZ are used with AMOX and CLA. However, even the highest eradication rate, which was observed in the IM and PM patients treated with EAC regimen, remained 82.8%. Generally, regimens with >90% eradication rate are recognized as effective (18). The results of this study indicate that 7-days of EAC and RAC regimens both had an insufficient effect without testing susceptibility to antibiotics. Indeed, the European guideline suggests that EAC and RAC regimens should last 10-14 days and PPIs should be administered at high dose (19). Furthermore, EAC and RAC regimens containing higher doses of EPZ or RPZ had higher eradication rates (20). To use EAC and RAC regimens as the first-line therapy, a longer duration and higher dose of EPZ or RPZ as well as testing for CLA resistance should be approved by the Japanese health insurance system. The most common cause of failure of first-line therapy is bacterial resistance to CLA (3). Determining CLA resistance is important for predicting the results of triple therapy. However, bacterial culture is not always available. Therefore, it would be useful to determine other factors associated with the results of first-line therapy using RPZ or EPZ. Recently, ABC classification for the risk of gastric cancer has been introduced by many health surveys (21). In this classification, patients are tested serum antibody to H. pylori with the serum levels of PGs. Therefore, information about the serum level of PGs is available for these patients before starting eradication therapy. The results of the present study showed that a lower PG I/II ratio was associated with failure of EAC or RAC therapy. Generally, low levels of PG I reflect mucosal atrophy of the gastric corpus, while higher levels of PG II reflect more severe gastric mucosal inflammation. The PG I/II ratio increases after successful eradication (22) and is usually high in patients not infected by H. pylori (23). Therefore, the present results suggest that failure of H. pylori eradication by EAC or RAC therapy might be more frequent in stomachs with advanced mucosal atrophy and persistent inflammation. However, a previous study showed that a low pepsinogen I/II ratio was associated with successful eradication in a different eradication regimen (24). Further studies are required to determine whether or not the serum level of PGs is associated with the results of eradication therapy and to elucidate whether or not alternative therapy is required for patients who have a lower level of PG I/II. The limitation of this study is the lack of information about bacterial susceptibility to antibiotics. As already mentioned, resistance to CLA is the most common cause for the failure of first-line therapy (5). However, bacterial culture is not always successful, and it takes more than 10 days to obtain the results of susceptibility to antibiotics in most medical institutions. Furthermore, at present, the tests for neither the susceptibility of H. pylori to antibiotics nor the detection of the point mutation of bacterial 23S rRNA gene are covered by the Japanese health insurance system. For many patients, the extra cost and longer duration before starting treatment are not acceptable. In addition, AMOX-resistant H. pylori is very rare in Japan (5). We therefore did not examine bacterial susceptibility to antibiotics in this study. Since this study is a prospective randomized trial, the influence of bacterial susceptibility on the differential eradication rates between EAC and RAC therapies would be minimal. However, we cannot exclude the possibility that a higher CLA resistance rate caused the lower eradication rate in patients with a lower PG I/II ratio. In conclusion, both the EAC and RAC regimens were safe and similarly effective as first-line eradication therapies for H. pylori infection, regardless of CYP2C19 genotype. However, the eradication rates of both therapies were insufficient under the current approval of the Japanese health insurance system. The PG I/II ratio seems to be associated with the results of EAC or RAC therapy.
BODY:
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TITLE: A randomised controlled trial to prevent smoking relapse among recently quit smokers enrolled in employer and health plan sponsored quitlines
ABSTRACT.OBJECTIVE:
To test adding an interactive voice response (IVR)-supported protocol to standard quitline treatment to prevent relapse among recently quit smokers.
ABSTRACT.DESIGN:
Parallel randomised controlled trial with three arms: standard quitline, standard plus technology enhanced quitline with 10 risk assessments (TEQ-10), standard plus 20 TEQ assessments (TEQ-20).
ABSTRACT.SETTING:
Quit For Life (QFL) programme.
ABSTRACT.PARTICIPANTS:
1785 QFL enrolees through 19 employers or health plans who were 24+ h quit.
ABSTRACT.INTERVENTIONS:
QFL is a 5-call telephone-based cessation programme including medications and web-based support. TEQ interventions included 10 or 20 IVR-delivered relapse risk assessments over 8 weeks with automated transfer to counselling for those at risk.
ABSTRACT.MAIN OUTCOME MEASURES:
Self-reported 7-day and 30-day abstinence assessed at 6-month and 12-month post-enrolment (response rates: 61% and 59%, respectively). Missing data were imputed.
ABSTRACT.RESULTS:
1785 were randomised (standard n=592, TEQ-10 n=602, TEQ-20 n=591). Multiple imputation-derived, intent-to-treat 30-day quit rates (95% CI) at 6 months were 59.4% (53.7% to 63.8%) for standard, 62.3% (57.7% to 66.9%) for TEQ-10, 59.4% (53.7% to 65.1%) for TEQ-20 and 30-day quit rates at 12 months were 61.2% (55.6% to 66.8%) for standard, 60.6% (56.0% to 65.2%) for TEQ-10, 54.9% (49.0% to 60.9%) for TEQ-20. There were no significant differences in quit rates. 73.3% of TEQ participants were identified as at-risk by IVR assessments; on average, participants completed 0.41 IVR-transferred counselling calls. Positive risk assessments identified participants less likely (OR=0.56, 95% CI 0.42 to 0.76) to be abstinent at 6 months.
ABSTRACT.CONCLUSIONS:
Standard treatment was highly effective, with 61% remaining abstinent at 12 months using multiple imputation intent-to-treat (intent-to-treat missing=smoking quit rate: 38%). TEQ assessments identified quitters at risk for relapse. However, adding IVR-transferred counselling did not yield higher quit rates. Research is needed to determine if alternative designs can improve outcomes.
ABSTRACT.TRIAL REGISTRATION NUMBER:
NCT00888992.
BODY:
Strengths and limitations of this studyFirst large randomised controlled trial to examine the use of interactive voice response (IVR) technology for prevention of smoking relapse.Large sample of participants recruited from employer and health plan quitline programmes serving tobacco users across the USA.Protocol used an innovative and potentially cost-effective technology to connect those at risk for relapse to immediate counselling.We compared two risk assessment intensities over the first 8 weeks following successful abstinence.Although participants rated the IVR system positively, fewer accepted immediate risk-focused counselling than anticipated; thus, the increase in treatment exposure was small. Smoking continues to be the leading preventable cause of premature death and disease in the USA and worldwide.1
2 Quitting tobacco is one of the most important steps a tobacco user can take to improve their health.3 Free publicly (state and government) and privately (eg, employer and health plan) funded telephone-based tobacco cessation quitlines are available throughout the USA and increasingly around the world to help tobacco users quit. With the advent of the Affordable Care Act in the USA, telephone-based tobacco cessation services offer an important resource to ensure that tobacco users have access to the empirically supported tobacco treatments that are required components of coverage. Although extensive evidence exists regarding the efficacy and cost-effectiveness of tobacco cessation quitlines,4–6 as with other behavioural and pharmacological tobacco treatment options, little is known about how best to intervene with callers at the time of greatest risk for relapse. A recent Cochrane Review concluded that previously tested behavioural relapse prevention interventions, which primarily included skills training or extended therapeutic contact, did not provide additional benefit over no treatment or intervention without a relapse prevention component.7 Survival studies have identified that the highest relapse risk, on average, is in the first 2 weeks after a quit attempt; however, there is considerable between-individual and within-individual variability in risk-related symptom patterns.8 Relapse prevention interventions may be most effective if provided at the time of relapse risk given the multifaceted and individualised nature of withdrawal and environmentally induced relapse risks over time.8 Interactive voice response (IVR) technology offers a resource-efficient solution for connecting tobacco users with relapse prevention interventions at the time of need, especially those already enrolled in phone-based tobacco cessation treatment. IVR is increasingly incorporated into some tobacco treatment protocols,9
10 and has been used in chronic disease management, posthospital discharge management, medication compliance monitoring, and in a small number of addiction and depression self-help interventions.11 IVR has been piloted as a smoking relapse prevention tool following a single group counselling call and 12 weeks of varenicline,12 but was insufficiently powered to draw meaningful conclusions about the effectiveness of the nine-call and nurse call-back intervention. The purpose of this present study is to examine the effectiveness of augmenting standard multisession tobacco quitline treatment with repeated IVR assessments to monitor recent quitters' relapse risk, and transfer those at risk to a Quit Coach for a brief, focused, intervention targeting the identified relapse trigger. We hypothesised that smokers receiving IVR risk assessments during the first 2 months after quitting would be more likely to stay quit than those receiving standard quitline treatment, and that more frequent assessments (20 vs 10) would be more beneficial.
BODY.METHODS.STUDY DESIGN:
In this parallel randomised controlled trial, tobacco users enrolled in the Quit For Life (QFL) programme who achieved abstinence for at least 24 h after their quit date were randomised into one of three study groups: (1) standard treatment, (2) Technology Enhanced Quitline-10 (TEQ-10): standard treatment plus 10 IVR-delivered relapse risk assessments which triggered a transfer to a Quit Coach for participants exceeding risk thresholds and (3) Technology Enhanced Quitline-20 (TEQ-20): same as the TEQ-10 condition except with 20 relapse risk assessments rather than 10. Participants were randomised using blocked randomisation to ensure similar group sizes throughout the study; every nine participants within each employer or health plan contract were randomly assigned with an allocation ratio for the three groups of 3:3:3. These random allocation tables were generated by the study management team and integrated into the QFL computer system where they were not accessible to coaches or participants. Once study eligibility was confirmed, the Quit Coach clicked a 'Randomise' button and the system automatically assigned the participant to the group listed in the next available cell of the allocation table. The planned and final sample size was 1785 and was determined a priori to achieve at least 80% power to detect 30-day point prevalence quit rate differences of 8% between any pair of three arms for intent-to-treat (ITT) analyses, including the traditional penalised imputation approach in which non-responders to data collection are considered relapsed13 and the state-of-the-art multiple imputation method14 (assuming quit rates of 29.6%, 37.6% and 45.6% at 6 months and 26.6%, 34.6% and 42.6% at 12 months for standard care, TEQ-10 and TEQ-20, respectively; n=595) and of 10% for a responder analysis between standard care and either intervention at 6 or 12 months (assuming quit rates of 52.1% standard care, 62.1% TEQ-10, 62.1% TEQ-20; assuming 25% attrition, with 446 responders per arm). The primary analysis using ITT multiple imputation has slightly greater than 80% power because, like ITT using penalised imputation (missing=smoking), it uses all persons with baseline data. However, compared with penalised imputation, or responder-only analysis, multiple imputation ITT uses more information and produces results with greater power, less bias, and greater accuracy.13
14 Participants gave informed consent prior to study enrolment and received a US$25 gift card for completed 6-month and 12-month follow-up surveys (potential for US$50 total).
BODY.METHODS.PARTICIPANTS:
Tobacco users were eligible for the study if they had enrolled in the QFL programme between April 2010 and October 2012 through 1 of 19 employers or health plans who offered QFL as part of their benefits package. Because the purpose of this study was to examine the potential benefit of IVR assessments, and their triggering of counselling at the point of need to reduce relapse, tobacco users were screened for study criteria and invited to participate after reporting they had been quit for 24 h or more after their quit date. This typically occurred during their second or third call (their quit date call or the call after) of the five-call programme. Additional eligibility criteria included being English-speaking, 18 years of age or older, and having access to a touch-tone phone. Tobacco users were excluded if they exclusively used smokeless tobacco, were actively participating in another tobacco cessation programme, had previously enrolled in the QFL programme during the past 6 months, or had limited phone access (eg, incarceration). Of the 3723 tobacco users who received the study offer, 1840 (49.4%) agreed to participate and 1785 completed the baseline survey and were randomised to one of the three study groups (figure 1). Figure 1CONSORT Diagram. *36 participants did not receive all of their relapse risk assessments due to a programming error in the interactive voice response (IVR) code.
BODY.METHODS.THE QFL PROGRAMME:
QFL, operated by Alere Wellbeing (formerly Free & Clear), has been commercially available for nearly 30 years, and its effectiveness and cost-effectiveness has been demonstrated in various studies.5
15–19 The QFL programme includes five counselling calls (an initial assessment and planning call plus four additional proactive outbound calls from an expert Quit Coach). Quit Coaches are required to have a bachelor's degree in a related field, complete more than 200 h of training, and receive ongoing supervision and feedback. The call schedule and content is tailored to each participant's needs. The default call schedule includes the initial planning and assessment call, a quit date call (QDC), a quit date follow-up call 7 days after the QDC, and two additional follow-up calls that take place approximately every 3 weeks after the previous call. Participants are also encouraged to call in for support as needed (ie, participant-initiated inbound calls). Calls vary in length: the planning and assessment call is 25–30 min, while other calls are 15–20 min. Calls focus on creating a quit plan, developing problem-solving and coping skills, identifying social support, and using cessation medications to achieve and maintain abstinence. Participants may receive over-the-counter nicotine replacement products directly via mail (or other prescription cessation medications depending upon their cessation benefit with their employer or health plan). They also receive a printed quit guide, and access to Web Coach, an online interactive web-based programme designed to complement the phone programme.
BODY.METHODS.IVR INTERVENTION:
In the two TEQ groups, participants were contacted for relapse risk assessments through automated IVR calls over their first 8 weeks postquit. Two intensities of IVR monitoring were examined. TEQ-10 participants were contacted twice weekly for the first 2 weeks, then weekly for 6 weeks. TEQ-20 participants were contacted daily for the first 2 weeks, then weekly for 6 weeks. An IVR service contractor programmed and delivered the risk assessments (approximately 5 min), which included questions to identify relapse risk on five factors: lapses, cravings, negative affect, self-efficacy and motivation to remain quit. An algorithm was used to flag participants as 'at risk' if they answered any of the screening questions over an established threshold, based on previous research.20–22 Participants who exceeded the threshold were then transferred directly to a Quit Coach for a brief intervention (approximately 15 min) specifically addressing the risk factor(s) that triggered their transfer. Intervention fidelity was monitored by study staff and investigators. Randomly sampled recordings of IVR-triggered telephone counselling sessions were rated for compliance with the study protocol (the primary criterion being whether the counsellor focused the call on identified relapse risk(s)) by two independent reviewers (a study staff member and a Quit Coach supervisor). Reviews revealed some Quit Coaches did not receive information about the risk factor that triggered a participant's transfer due to technological issues. These programming errors were corrected by the IVR vendor. In these circumstances, participants still received empirically based tobacco cessation support at the time of need. As part of quality monitoring, any protocol deviations were addressed with individual feedback from Quit Coach supervisors and ongoing training for all Quit Coaches.
BODY.MEASURES.BASELINE MEASURES:
During registration and the first Quit Coach call, participants completed standard assessment questions regarding demographic characteristics (age, gender, health comorbidities) and tobacco use (tobacco type, time to first use, cigarettes per day, number of previous quit attempts, social contact with smokers). After study recruitment, participants completed an additional baseline measure assessing age, race, ethnicity, education, depressive symptoms (PHQ-2; 2-item measure21), and stress (Perceived Stress Scale; 4-item measure23).
BODY.MEASURES.IVR-POSITIVE SCREENS AND PROGRAM CALL COMPLETION:
The IVR system stored the number of relapse risk assessments participants answered, participants' responses to the relapse risk questions, and the number of IVR assessments on which a participant had a positive risk screen. Counselling calls completed as a result of a positive IVR screen and successful transfer to a Quit Coach (ie, IVR-transferred counselling calls) were tracked in addition to standard programme calls (5 planned calls plus participant-initiated inbound calls).
BODY.MEASURES.OUTCOMES MEASURED AT 6 AND 12 MONTHS:
At 6 and 12 months after randomisation, participants completed telephone interviewsi administered by outcomes evaluators from the Indiana University Center for Survey Research who were blind to study condition to measure abstinence. All participants rated their satisfaction with the QFL service, and those in the TEQ groups were asked their opinions of the IVR system during the 6-month survey. When participants could not be reached after repeated phone attempts, we also mailed a brief paper survey with only the smoking abstinence questions. Survey response rates were 61% and 59% at 6 and 12 months, respectively. The primary study outcomes were quit rates at 6 and 12 months, defined as 7-day and 30-day self-reported point prevalence abstinence measured by the question, 'In the last [7/30] days, have you smoked a cigarette, even a puff?'. Time to relapse was examined as a secondary outcome and was identified using three questions: 'Since [end of two-week grace period], have you ever smoked at least a part of a cigarette on 7 days in a row?'; 'Since [end of two-week grace period], have you ever smoked any in each of two consecutive weeks (at least 1 day for 2 weeks in a row)?', and [if yes to either of the 2 previous questions] 'What was the first day of that 7-day or two-week period that you smoked?'.16
BODY.MEASURES.STATISTICAL ANALYSES:
Missing values on all 6-month and 12-month outcomes were imputed using the state-of-the-art imputation method called 'multiple imputation'24 with sequential regression.25 Multiple imputation allows all cases (N=1785) to be included in the analysis. Two imputation models were performed: one for 7-day and one for 30-day point prevalence abstinence. With this approach, variables with no missing values served as independent variables. The variable with the least amount of missing data was imputed first, and used as the dependent variable. Once imputation was carried out, the next variable with the least amount of missing data was imputed using all variables with non-missing values as independent variables including the variable imputed on the previous step. This cycle continued until all missing values were imputed resulting in a series of regressions, hence the name sequential regression. Variables used to provide information for imputation (and to be imputed themselves if missing) included intervention group (no data missing), baseline characteristics listed in table 1 (with the exception of years of tobacco use and stress, due to high correlations with age and depression, respectively), and number of planned calls plus participant-initiated inbound counselling calls completed. These variables had a minimal amount of missing data with, at most, 3.5% missing for the motivation variable. Abstinence outcomes measured at both 6 and 12 months were included in each imputation model and had the greatest amount of missing data. Ten multiple-imputed data sets were generated and analysed. Table 1 Baseline characteristics (N=1785) Variable Overall (N=1785) Standard (N=592) Standard plus TEQ-10 (N=602) Standard plus TEQ-20 (N=591) Demographics Age, mean (SD) 43.4 (11.9) 43.3 (12.2) 44.0 (11.5) 43.0 (12.0) Gender, N (%) Female 967 (54.2) 321 (54.2) 326 (54.1) 320 (54.2) Male 818 (45.8) 271 (45.8) 276 (45.9) 271 (45.8) Race, N (%) Caucasian 1489 (83.4) 497 (84.0) 501 (83.2) 491 (83.1) African-American 204 (11.4) 63 (10.6) 71 (11.8) 70 (11.8) Other 51 (2.9) 16 (2.7) 19 (3.2) 16 (2.7) Missing 43 (2.3) 16 (2.7) 11 (1.8) 14 (2.4) Education, N (%) High school or less 667 (37.4) 229 (38.7) 225 (37.4) 213 (36.0) More than high school 1117 (62.6) 363 (61.3) 376 (62.6) 378 (64.0) Comorbidities, N (%) Asthma 176 (9.9) 62 (10.5) 61 (10.1) 53 (9.0) COPD 108 (6.0) 39 (6.6) 32 (5.3) 37 (6.3) CAD 75 (4.2) 27 (4.6) 25 (4.2) 23 (3.9) Diabetes 138 (7.7) 53 (8.9) 46 (7.6) 39 (6.6) Any chronic comorbidity* 395 (22.1) 136 (23.0) 136 (22.6) 123 (20.8) Tobacco use Time to first cigarette, N (%), min 5 539 (30.2) 165 (27.9) 197 (32.7) 177 (30.0) 6–30 618 (34.6) 213 (36.0) 201 (33.4) 204 (34.5) 31–60 285 (16.0) 89 (15.0) 101 (16.8) 95 (16.1) >60 289 (16.2) 105 (17.7) 88 (14.6) 96 (16.2) Missing 54 (3.0) 20 (3.4) 15 (2.5) 19 (3.2) Cigarettes per day, mean (SD) 16.8 (9.0) 16.8 (9.1) 17.2 (8.9) 16.4 (9.1) Number of quit attempts, N (%) 0–1 377 (21.1) 116 (19.6) 127 (21.1) 134 (22.7) 2–5 1033 (57.9) 371 (62.7) 335 (55.7) 327 (55.3) 6+ 347 (19.4) 97 (16.4) 127 (21.3) 122 (20.6) Missing 28 (1.6) 8 (1.4) 12 (2.0) 8 (1.4) Tobacco use ≥20 years, N (%) Yes 1098 (61.5) 361 (61.0) 383 (63.6) 354 (59.9) No 671 (37.6) 227 (38.3) 211 (35.1) 233 (39.4) Missing 16 (0.9) 4 (0.7) 8 (1.3) 4 (0.7) Social contact with smokers, N (%) No 470 (26.3) 146 (24.7) 179 (29.7) 145 (24.5) Work 572 (32.0) 192 (32.4) 188 (31.2) 192 (32.5) Home 342 (19.2) 122 (20.6) 104 (17.3) 116 (19.6) Both work and home 344 (19.3) 112 (18.9) 111 (18.4) 121 (20.5) Missing 57 (3.2) 20 (3.4) 20 (3.3) 17 (2.9) Scale scores Motivation to quit, mean (SD) 9.1 (1.3) 9.0 (1.3) 9.0 (1.2) 9.1 (1.2) Depression, mean (SD) 1.0 (1.3) 1.0 (1.3) 1.0 (1.3) 1.0 (1.3) Perceived stress, mean (SD) 4.3 (2.8) 4.3 (2.9) 4.2 (2.8) 4.5 (2.8) *Defined as having asthma or COPD or CAD or diabetes. CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; TEQ-10, Technology Enhanced Quitline-10; TEQ-20, Technology Enhanced Quitline-20. Logistic regression models were used to model intervention efficacy on the 6-month and 12-month outcomes of abstinence, while adjusting for theoretically important potentially confounding baseline covariates.26 There were four main outcomes (7-day and 30-day point prevalence quit rates assessed at 6 and 12 months) and each was analysed with a separate logistic regression model. The multiple imputation quit rate results were our primary outcome metric. However, outcomes were reported using three methods: (1) for all survey respondents (responder analysis), (2) using penalised imputation reporting (assumes non-respondents are treatment failures) which is the traditional ITT analysis used in the smoking literature and (3) with results imputed for participants with missing data using the state-of-the-art multiple imputation method. Although ITT outcomes using penalised imputation are commonly reported in cessation trials, methodological research, including simulation studies, have shown that multiple imputation ITT uses more information and produces greater power, less bias, and more accuracy compared with simpler ad hoc methods for handling missing data such as traditional penalised imputation ITT, or responder-only analysis.13
14 Missing values for relapse date were imputed using the procedures described above. Using this relapse date and the baseline date, proportional hazards regression was used to examine factors associated with time to relapse. The variables representing number of calls (table 2) were generally skewed to the right with a large number of zeroes. These data were complete and did not require imputation. To compare study groups on these count variables, a generalised linear model with log link function and negative binomial distribution was used. Six-month satisfaction data were also analysed (without imputation) to determine levels of satisfaction with the QFL programme and IVR protocol. The satisfaction variable was not imputed since it was not a primary outcome. Satisfaction comparisons between intervention groups were made using a χ2 test. Mplus software for Windows (V.7.2) was used to generate imputed data and PROC MIANALYZE from SAS/STAT software (V.9.3) was used to pool results and analyse the imputed data sets. All other statistical comparisons were performed using SAS/BASE and SAS/STAT software for Windows (V.9.3). Table 2 Descriptives for number of phone calls (N=1785) Variable Overall (N=1785) Standard (N=592) Standard plus TEQ-10 (N=602) Standard plus TEQ-20 (N=591) p Value* (1) Planned programme counselling calls (1–5), mean (SD); range 3.29 (1.09); 1–5 3.29 (1.09); 1–5 3.32 (1.09); 1–5 3.25 (1.08); 1–5 0.8085 (2) Participant-initiated inbound calls, mean (SD); range 0.38 (1.05); 0–14 0.37 (0.92); 0–8 0.40 (1.13); 0–14 0.37 (1.08); 0–12 0.9082 ≥1 vs 0, N (%) 284 (15.9) 99 (16.7) 96 (16.0) 89 (15.1) 0.7361† (1+2) Sum of planned and participant-initiated inbound calls, mean (SD); range 3.67 (1.53); 2–17 3.66 (1.48); 2–13 3.72 (1.62); 2–17 3.62 (1.48); 2–13 0.6851 (3) IVR-transferred counselling calls, mean (SD); range 0.41 (0.75); 0–6 N/A 0.39 (0.72); 0–6 0.43 (0.79); 0–6 0.2791‡ ≥1 vs 0, N (%) 361 (30.3) N/A 175 (29.1) 186 (31.5) 0.3665†‡ (1+2+3) Sum of all calls, mean (SD); range 3.94 (1.71); 2–19 3.66 (1.48); 2–13 4.11 (1.82); 2–19 4.06 (1.77); 2–17 <0.0001 *p Value obtained from generalised linear model for a count outcome except where indicated. †p Value obtained from χ 2 test. ‡p Value is for comparison between TEQ-10 and TEQ-20 groups. IVR, interactive voice response; TEQ-10, Technology Enhanced Quitline-10.
BODY.RESULTS.PARTICIPANTS:
Baseline characteristics across the three intervention groups are shown in table 1. Overall, the average age of study participants was 43 years (range 18–85). A little over half (54%) were women. A majority of the sample was Caucasian (83%) and reported having a high school education or more (62%). Just under a quarter of the sample reported having ≥1 chronic comorbidity (22%). The average number of reported cigarettes used per day was 17 (range 0–60) with about two-thirds of the sample reporting having had a cigarette within 30 min from the time they wake in the morning. About 20% of the sample reported 0 or one quit attempts, with a similar percentage reporting six or more quit attempts. A little over 60% reported using tobacco for 20 or more years, and about three-quarters reported having contact with smokers at work, home, or both. Overall, participants reported feeling motivated to quit smoking, with an average rating of 9 on a 1–10 scale (1=low, 10=high). The average PHQ-2 depression score was 1.0 (possible range 0–6, with high scores indicating higher levels of depression,21 and the average perceived stress score was 4.3 (possible range 0–16, with higher scores indicating higher perceived stress.23 At the time of study offer, 56.5% of participants had been quit for 1–6 days, 40% had been quit for 7–29 days, and 3.5% had been quit for 30 days or more.
BODY.RESULTS.PROGRAMME ENGAGEMENT AND POSITIVE RISK SCREENS:
Programme engagement was measured as the number of counselling calls completed by participants:1 planned programme counselling calls,2 participant-initiated inbound calls, or3 IVR-transferred counselling calls (table 2). Overall, the average number of total calls completed was 3.9 (SD=1.7; range 2–19). There was a statistical difference between groups; the TEQ-10 and TEQ-20 groups completed slightly more calls than the standard study group due to the additional IVR-transferred counselling calls they received after a positive screen (p<0.001). There were no statistical differences between participant-initiated (p=0.91) or planned programme calls completed (p=0.81). Also, there was no statistical difference in IVR-transferred counselling calls between the TEQ-10 and TEQ-20 groups (p=0.28). There was a statistical difference in the number of positive screens between the two intervention groups, with TEQ-20 having slightly more positive screens than TEQ-10 (on average, 1.52 (SD=1.66) for TEQ-10 and 1.82 (SD=1.99) for TEQ-20, p=0.003). The percentage of one or more positive screens was also larger in the TEQ-20 group (76% vs 70%; p=0.03).
BODY.RESULTS.SIX-MONTH AND 12-MONTH OUTCOMES:
Seven-day and 30-day point prevalence abstinence rates at 6-month and 12-month follow-up are shown in table 3. As aforementioned, outcomes are reported using three methods: (1) for all survey respondents (responder analysis), (2) using a crude ITT analysis based on penalised imputation reporting (assumes non-respondents are treatment failures) and (3) using state-of-the-art ITT based on multiple imputation for participants with missing data. Since we had missing data, we used the multiple imputation quit rate as our primary outcome. Table 3 Estimates of abstinence at 6 and 12 months, N=1785 Intervention group 6-Month survey outcomes 12-Month survey outcomes N Did not smoke in last 7 days N Did not smoke in the last 30 days N Did not smoke in last 7 days N Did not smoke in the last 30 days Responders* Standard 368 66.0 (61.2 to 70.9) 368 60.6 (55.6 to 65.6) 363 65.3 (60.4 to 70.2) 362 61.6 (56.6 to 66.6) Standard plus TEQ-10 368 69.6 (64.9 to 74.3) 368 65.2 (60.4 to 70.1) 370 67.0 (62.2 to 71.8) 371 63.1 (58.2 to 68.0) Difference compared to standard 3.5 (−3.2 to 10.3) p=0.3051 4.6 (−2.4 to 11.6) p=0.1946 1.7 (−5.1 to 8.6) p=0.6191 1.5 (−5.5 to 8.5) p=0.6812 Standard plus TEQ-20 352 67.3 (62.4 to 72.2) 352 61.1 (56.0 to 66.2) 310 62.6 (57.2 to 68.0) 311 56.6 (51.1 to 62.1) Difference compared to standard 1.3 (−5.6 to 8.2) p=0.7121 0.5 (−6.6 to 7.6) p=0.8947 −2.7 (−10.0 to 4.6) p=0.4655 −5.0 (−12.5 to 2.4) p=0.1871 Intent-to-treat penalised imputation (missing=smoking)† Standard 592 41.1 (37.1 to 45.0) 592 37.6 (33.8 to 41.6) 592 40.0 (36.1 to 44.0) 592 37.7 (33.8 to 41.6) Standard plus TEQ-10 602 42.5 (38.6 to 46.5) 602 39.9 (36.0 to 43.8) 602 41.2 (37.3 to 45.1) 602 38.9 (35.0 to 42.8) Difference compared to standard 1.5 (−4.1 to 7.1) p=0.6047 2.2 (−3.3 to 7.7) p=0.4357 1.2 (−4.4 to 6.7) p=0.6827 1.2 (−4.3 to 6.7) p=0.6693 Standard plus TEQ-20 591 40.1 (36.2 to 44.1) 591 36.4 (32.5 to 40.3) 591 32.8 (29.0 to 36.6) 591 29.8 (26.1 to 33.5) Difference compared to standard −1.0 (−6.5 to 4.7) p=0.7405 −1.3 (−6.8 to 4.2) p=0.6459 −7.2 (−12.7 to −1.7) p=0.0100 −7.9 (−13.3 to −2.5) p=0.0041 Multiple imputation‡ Standard 592 64.2 (59.5 to 68.9) 592 59.4 (53.7 to 63.8) 592 63.3 (58.4 to 68.4) 592 61.2 (55.6 to 66.8) Standard plus TEQ-10 602 67.8 (63.0 to 72.7) 602 62.3 (57.7 to 66.9) 602 65.1 (60.3 to 69.9) 602 60.6 (56.0 to 65.2) Difference compared to standard 3.6 (−3.3 to 10.5) p=0.2980 3.6 (−3.2 to 10.4) p=0.2969 1.7 (−4.4 to 7.7) p=0.5831 −0.6 (−7.6 to 6.4) p=0.8647 Standard plus TEQ-20 591 64.7 (59.2 to 70.2) 591 59.4 (53.7 to 65.1) 591 60.9 (56.4 to 65.5) 591 54.9 (49.0 to 60.9) Difference compared to standard 0.5 (−7.0 to 8.0) p=0.8982 0.7 (−6.4 to 7.8) p=0.8468 −2.5 (−9.4 to 4.5) p=0.4808 −6.3 (−14.9 to 2.3) p=0.1471 Percentage of participants reporting abstinence is shown in table above with 95% CIs in parentheses. p Values obtained from χ 2 test for difference between proportions. *Estimates were obtained among participants having completed a 6-month or 12-month survey. †Estimates were obtained assuming participants missing a 6-month or 12-month survey were not abstinent. ‡Estimates were obtained by pooling results across 10 multiply imputed data sets. TEQ-10, Technology Enhanced Quitline-10. ITT-penalised imputation quit rates at 12 months were significantly lower for the TEQ-20 group compared with the standard and TEQ-10 groups. However, there were no significant differences in responder or imputed quit rates at 6 or 12 months, or rates of relapse. The quit rates based on multiple imputation at 6 and 12 months ranged from 55% to 68% depending on intervention group, follow-up time point, and outcome measure. Controlling for baseline characteristics, logistic regression models further illustrated no statistical difference between intervention groups for either primary outcome and either time point (table 4). A few baseline characteristics were statistically associated with the outcomes. Across the four models shown in table 4, a higher number of counselling calls, and being motivated to quit, were consistently associated with higher odds of being abstinent (all p<0.05). Depression also played a role in three of the models, with higher depression scores being associated with lower odds of being abstinent (all p<0.05). Older age resulted in higher odds of abstinence for 6-month outcomes only (both p<0.01). Having at least one comorbid chronic condition was associated with lower odds of abstinence in three of the models (all p<0.05). Table 4 ORs from adjusted logistic models of multiple imputation quit rates at 6 and 12 months, N=1785 6-Month survey outcomes 12-Month survey outcomes Variable Did not smoke in the last 7 days Did not smoke in the last 30 days Did not smoke in the last 7 days Did not smoke in the last 30 days Randomisation groups Standard plus TEQ-10 vs standard 1.15 (0.83 to 1.59) 1.14 (0.85 to 1.54) 1.07 (0.82 to 1.41) 0.96 (0.71 to 1.30) Standard plus TEQ-20 vs standard 1.00 (0.71 to 1.42) 1.01 (0.74 to 1.37) 0.87 (0.64 to 1.19) 0.75 (0.52 to 1.09) Number of programme counselling calls Planned+participant−initiated 1.10 (1.02 to 1.18)* 1.10 (1.02 to 1.19)* 1.12 (1.02 to 1.22)* 1.10 (1.02 to 1.19)* Demographics Gender Female vs male 0.92 (0.70 to 1.21) 1.00 (0.80 to 1.25) 1.17 (0.91 to 1.49) 1.16 (0.92 to 1.46) Age 1.02 (1.01 to 1.03)*** 1.02 (1.00 to 1.03)** 1.01 (0.99 to 1.02) 1.01 (0.99 to 1.02) Race African–American vs Caucasian 1.32 (0.89 to 1.96) 1.41 (0.91 to 2.21) 1.16 (0.75 to 1.80) 1.12 (0.72 to 1.76) Other vs Caucasian 0.73 (0.34 to 1.56) 0.72 (0.32 to 1.66) 1.09 (0.55 to 2.16) 0.98 (0.53 to 1.81) Education High school or less vs more than high school 1.12 (0.84 to 1.50) 1.05 (0.77 to 1.43) 0.86 (0.65 to 1.13) 1.01 (0.76 to 1.33) Comorbidities Any chronic comorbidity 0.69 (0.51 to 0.94)* 0.65 (0.46 to 0.92)* 0.72 (0.53 to 0.98)* 0.76 (0.56 to 1.03) Tobacco use Cigarettes per day 0.98 (0.97 to 0.99)* 0.99 (0.97 to 1.00) 0.98 (0.97 to 1.00) 0.99 (0.98 to 1.00) Time to first cigarette 5 min vs all others 0.92 (0.68 to 1.24) 1.10 (0.82 to 1.48) 0.88 (0.64 to 1.20) 0.85 (0.65 to 1.12) Number of quit attempts 2–5 vs 0–1 0.96 (0.69 to 1.34) 0.98 (0.75 to 1.29) 0.80 (0.58 to 1.10) 0.93 (0.69 to 1.24) 6+ vs 0–1 0.88 (0.57 to 1.35) 0.85 (0.56 to 1.28) 0.68 (0.47 to 0.99)* 0.79 (0.55 to 1.13) Social contact with smokers Work or home vs all others 0.74 (0.56 to 0.97)* 0.95 (0.73 to 1.24) 0.98 (0.74 to 1.30) 0.89 (0.68 to 1.17) Scale scores Motivation to quit 1.24 (1.12 to 1.36)*** 1.24 (1.11 to 1.39)*** 1.22 (1.11 to 1.34)*** 1.23 (1.12 to 1.35)*** Depression 0.87 (0.78 to 0.96)** 0.88 (0.80 to 0.97)** 0.94 (0.83 to 1.06) 0.89 (0.80 to 0.99)* All variables shown were included in each model. Estimates for each model were obtained by combining results across 10 multiply imputed data sets; 95% CIs are shown in parentheses. *p<0.05; **p<0.01; ***p<0.001. TEQ-10, Technology Enhanced Quitline-10.
BODY.RESULTS.TIME TO RELAPSE:
There was no significant association between time to relapse and randomisation group (table 5). Other factors related to time to relapse included number of counselling calls, having comorbid health condition, number of quit attempts, motivation to quit and depression. Higher number of counselling calls and higher levels of motivation to quit were associated with being less likely to relapse sooner (HR=0.87, p<0.001; HR=0.84, p<0.001, respectively). By contrast, participants reporting higher levels of depression were more likely to relapse sooner (HR=1.07, p=0.02). Compared to those with no chronic comorbidities, participants reporting one or more chronic comorbidities were more likely to relapse sooner (HR=1.29, p=0.04). Those reporting six or more quit attempts were also more likely to relapse sooner compared to those with 0–1 attempts (HR=1.32, p=0.04). Table 5 HRs from adjusted proportional hazard models of time to relapse, N=1785 Variable HR (95% CI) p Value Randomisation groups Standard plus TEQ-10 vs standard 0.85 (0.69 to 1.04) 0.1171 Standard plus TEQ-20 vs standard 1.05 (0.85 to 1.31) 0.6282 Number of programme counselling calls Planned+participant−initiated 0.87 (0.82 to 0.92)*** <0.0001 Demographics Gender Female vs male 0.90 (0.75 to 1.09) 0.2838 Age 1.00 (0.99 to 1.01) 0.5278 Race African–American vs Caucasian 0.97 (0.75 to 1.26) 0.8400 Other vs White 1.11 (0.67 to 1.84) 0.6762 Education High school or less vs more than high school 1.06 (0.87 to 1.30) 0.5368 Comorbidities Any chronic comorbidity 1.29 (1.01 to 1.64)* 0.0430 Tobacco use Cigarettes per day 1.01 (0.99 to 1.02) 0.0639 Time to first cigarette 5 min vs all others 1.08 (0.88 to 1.34) 0.4430 Number of quit attempts 2–5 vs 0–1 1.14 (0.90 to 1.43) 0.2657 6+ vs 0–1 1.32 (1.02 to 1.72)* 0.0345 Social contact with smokers Work or home vs all others 0.99 (0.80 to 1.24) 0.9713 Scale scores Motivation to quit 0.84 (0.79 to 0.90)*** <0.0001 Depression 1.07 (1.01 to 1.13)* 0.0198 All variables shown were included in each model. Estimates for each model were obtained by combining results across 10 multiply imputed data sets; 95% CIs are shown in parentheses. *p<0.05; **p<0.01; ***p<0.001. TEQ-10, Technology Enhanced Quitline-10.
BODY.RESULTS.USING IVR TO IDENTIFY RISK:
Figure 2 presents quit outcomes for TEQ-10 and TEQ-20 groups (separately in panel A and combined in panel B) according to their positive screen status (≥1 positive screen vs no positive screen); 70.4% in TEQ-10 and 76.1% in TEQ-20 had ≥1 positive screen during the study. Compared with participants who screened positive in either TEQ group, participants who did not screen positive were more likely to be abstinent at 6 (OR=1.69, p=0.01 for 7-day point prevalence; OR=1.77, p≤0.001 for 30-day point prevalence) and 12 months (OR=1.47, p=0.03 for 7-day point prevalence; OR=1.50, p=0.01 for 30-day point prevalence). Figure 2Abstinence rates for intervention and positive screen groups, N=1785. Estimates for each model were obtained by combining results across 10 multiple-imputed data sets. Error bars indicate 95% CIs. (A) Displays results for the TEQ-10 and TEQ-20 groups separately. (B) Displays data for the two TEQ-groups combined. '1+ positive screen' is defined as exceeding the predetermined risk threshold on any of the IVR assessment questions (topics: lapses, cravings, negative effect, self-efficacy, and motivation to remain quit) on any IVR assessment call. IVR, interactive voice response; TEQ-10, Technology Enhanced Quitline-10; TEQ-20, Technology Enhanced Quitline-20.
BODY.RESULTS.SATISFACTION WITH QFL AND THE IVR PROTOCOL:
Satisfaction was measured at 6 months after enrolment. Participants completing the 6-month survey (n=1091, 61.1%) were generally satisfied with the overall QFL programme and the counselling they received (96% and 98%, respectively, were somewhat satisfied, satisfied, or very satisfied at 6 months). A similar percentage (98%) would recommend the programme to others. There were no differences in QFL programme satisfaction between the three study groups. Compared to TEQ-10 participants, those receiving TEQ-20 were more likely to report the number of relapse risk assessments were too many (36% vs 23%, p≤0.001) and also were marginally more likely to agree that the risk assessments took too much time (28% vs 23%, p=0.09). The majority of participants reported it was easy to answer questions through the IVR system (95%), that the system was helpful (87%), and that they would recommend the IVR system to others trying to stay quit (86%), with no significant differences between the TEQ-10 and TEQ-20 groups.
BODY.DISCUSSION:
In this randomised controlled trial investigating the use of an automated, IVR-supported protocol to identify risk and prevent smoking relapse among recently quit tobacco users enrolled in the QFL programme, there were no differences in tobacco abstinence rates between the control (standard QFL) and technology-enhanced (IVR-delivered risk assessments and transfer for counselling) groups at 6-month and 12-month follow-up. Although the risk assessment and transfer protocols did not yield better abstinence rates, the IVR-delivered screenings did successfully identify participants who were less likely to be quit at follow-up. Participants who did not screen positive during the relapse risk assessments were 77% more likely to be abstinent at 6-month follow-up. We tested two risk screening and transfer protocols of varying intensities. The more intensive screening protocol with 20 IVR-delivered assessments did not demonstrate any benefit over the 10-assessment group, and the TEQ-20 respondents were more likely to indicate there were too many IVR assessments. In addition, we explored whether the TEQ intervention was more effective for certain populations in this study with regard to quit outcomes, by testing interaction effects, but did not identify any significant moderating relationships. There are several possible explanations for why the intervention did not reduce relapse rates. The TEQ interventions were designed to immediately transfer participants who met risk thresholds for tobacco counselling to target the identified relapse risk. About three-quarters (73.3%) of the TEQ participants were identified as being at risk at least one time over the 8-week intervention period. Having a positive screen was predictive of relapse; however, it is possible that other risk factors are more predictive of risk than those included in the assessment. Also, participants identified as at risk by the IVR assessments and automatically transferred to a coach failed to remain on the line to receive cessation counselling at the anticipated rate. That is, less than one third of those in the TEQ arms completed an IVR-transferred counselling call and 41.3% of those with a positive risk screen completed one or more IVR-transferred counselling calls, resulting in participants in the TEQ conditions completing only 0.41 calls, on average, more than the planned programme calls from the standard programme. Thus, it is possible that we failed to observe an effect because we did not increase the actual treatment exposure much above the base rate of calls. It remains unclear why some callers did not accept these additional calls when the satisfaction data showed positive perceptions of the IVR automated assessment system (87% felt it was helpful when they need to talk to a Quit Coach; 86% would recommend). Most callers were still receiving planned standard programme calls at the time of their risk assessments; perhaps callers who had recently spoken to a coach did not feel they needed another call at that time. Future studies should assess reasons for lack of counselling uptake and consider an automated system that would allow participants to schedule a call in the near future or would initiate outbound calls to participants identified as at risk who do not immediately transfer to a counsellor. The study had high quit outcomes, in spite of the fact that the TEQ intervention did not significantly improve outcomes. The 61% respondent and 38% ITT penalised imputation (missing=smoking) 30-day point prevalence quit rates at 6 months in the standard treatment group indicated that tobacco users who receive a multiple-call phone counselling programme, have access to cessation medication benefits, and successfully achieve at least a 24 h abstinence period early in treatment do quite well. These quit rates are high compared to studies focusing on all commercial quitline enrolees (eg, 34.3–41.1% responder quit rate at 6 months27
28). The relatively strong performance and engagement in standard treatment for this study may have made achieving improvements with a low intensity relapse prevention intervention even more challenging. This finding also aligns with previous recommendations that increasing quit attempts may be one of the most important factors for increasing cessation at the population level,29 and demonstrates the importance of achieving at least 24 h of abstinence. More counselling calls completed, higher motivation to quit, lower depression scores, and not having chronic health condition were consistently related to greater likelihood of being abstinent at follow-up. These variables were also associated with time to relapse; additionally, callers with a greater number of previous quit attempts (6+) were more likely to relapse sooner. These findings are consistent with previous quitline studies which have demonstrated the importance of programme engagement (ie, number of calls completed15
30
31). Callers in this study had a high motivation to quit (9 out of 10, on average); a previous study has linked high motivation to quit with making a quit attempt but not with likelihood of remaining quit.32 Moreover, previous work has identified that callers with depressive symptoms33 and chronic health conditions31 may have more difficulty quitting. Dependence level (time to first use and cigarettes per day) was not consistently related to outcomes in this study, which differs from previous literature that has often linked baseline dependence and outcomes.31
32 Compared with other behavioural relapse prevention research, strengths of this study included a relatively large sample size, use of an innovative and potentially cost-effective technology that could be disseminated to large populations if shown to be effective, and attempting to connect those at risk to immediate counselling. Most previous behavioural relapse prevention studies have focused on skills training and have not yielded significant effects.7 As noted by Hajek et al,7 future relapse prevention research efforts may be best applied in examining new and alternative approaches to those previously studied. One recent small pilot study examined extended IVR assessments following varenicline treatment, and also did not find significant effects for the extended IVR group.12 That article did not report on whether those who screened positive during IVR assessments were more likely to have returned to smoking at follow-up, and likely had too small of sample size to meaningfully do so. Additionally, the McNaughton et al's12 study included an intensive IVR contact schedule with 80 contacts over 40 weeks; low IVR assessment completion rates (37% of IVR calls and 16% of assessments were completed) in that study align with our findings that more contact is not necessarily better. Identifying the most effective and cost-effective number of contacts should continue to be a focus in future studies using IVR technology. The response rates to our 6-month and 12-month outcome surveys were 61% and 59%, respectively, which may limit the validity of our findings. Multiple imputation, a preferred method for ITT analysis, was used to reduce potential non-response bias, and the findings from these analyses agreed closely with results from a sensitivity analysis using respondent-only data. Another potential limitation to our study design is the lack of biochemical verification of abstinence, particularly in light of the high reported abstinence rates. However, our study procedures were consistent with recommendations of the SRNT Subcommittee on Biochemical Verification,34 and the results should be considered with respect to this. Additionally, we have no reason to believe there was a systematic bias in reporting abstinence across groups. Third, the protocol aimed for IVR-triggered counselling calls to focus on the specific risk factor(s) identified by the IVR assessment; all participants received empirically based support at the time of need, but not all calls were focused on the identified risk factor(s). Finally, as with other research on prevention of smoking relapse, the time frame for intervention and data collection poses limitations. The IVR-delivered risk assessments in this study were limited to the first 8 weeks following successful abstinence. Although previous research has identified the first weeks as being the greatest risk for relapse, callers also relapse at later dates. Ongoing plans for prevention of relapse, or risk intervention, may be needed; future research may be able to identify those in need of ongoing relapse risk monitoring and intervention. Augmenting tobacco quitline treatment with IVR-delivered relapse risk screening assessments was acceptable to participants, and successfully identified recently quit tobacco users who may be in need of more intensive or different intervention. More research is needed to identify how to engage at-risk participants in additional treatment. Using a technology-based screening for relapse risk to connect recent tobacco users to cessation counselling at the time of risk could offer a scalable, cost-effective approach for delivering tailored services to those in need, if future research can identify the appropriate services to deliver at that time of need. | 4,486,943 | {
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TITLE: Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial
ABSTRACT.BACKGROUND:
Traumatic brain injury (TBI) is commonly accompanied by intracranial bleeding which can worsen after hospital admission. Tranexamic acid (TXA) has been shown to reduce bleeding in elective surgery and there is evidence that short courses of TXA can reduce rebleeding in spontaneous intracranial haemorrhage. We aimed to determine the effectiveness and safety of TXA in preventing progressive intracranial haemorrhage in TBI.
ABSTRACT.METHODS:
This is a double blinded, placebo controlled randomized trial. We enrolled 238 patients older than 16 years with moderate to severe TBI (post-resuscitation Glasgow Coma Scale (GCS) 4 to 12) who had a computerized tomography (CT) brain scan within eight hours of injury and in whom there was no immediate indication for surgery. We excluded patients if they had a coagulopathy or a serum creatinine over than 2.0 milligrams%. The treatment was a single dose of 2 grams of TXA in addition to other standard treatments. The primary outcome was progressive intracranial haemorrhage (PIH) which was defined as an intracranial haemorrhage seen on the second CT scan that was not seen on the first CT scan, or an intracranial haemorrhage seen on the first scan that had expanded by 25% or more on any dimension (height, length, or width) on the second scan.
ABSTRACT.RESULTS:
Progressive intracranial haemorrhage was present in 21 (18%) of 120 patients allocated to TXA and in 32 (27%) of 118 patients allocated to placebo. The difference was not statistically significant [RR = 0.65 (95% CI 0.40 to 1.05)]. There were no significant difference in the risk of death from all causes in patients allocated to TXA compared with placebo [RR = 0.69 (95% CI 0.35 to 1.39)] and the risk of unfavourable outcome on the Glasgow Outcome Scale [RR = 0.76 (95% CI 0.46 to 1.27)]. There was no evidence of increased risk of thromboembolic events in those patients allocated to TXA.
ABSTRACT.CONCLUSIONS:
TXA may reduce PIH in patients with TBI; however, the difference was not statistically significant in this trial. Large clinical trials are needed to confirm and to assess the effect of TXA on death or disability after TBI.
BODY.BACKGROUND:
Each year, world-wide more than 1.5 million people die and about 10 million people are hospitalized following traumatic brain injury (TBI) [1]. Many survivors experienced long term disability [2]. In Thailand, each year around 8,000 people died following acute TBI and tens of thousands were hospitalized. A follow up study of 418 patients who were admitted to Khon Kaen regional hospital following TBI found that 29% of patients were either dead or severely disabled six months following the injury [3]. TBI is commonly accompanied by intracranial bleeding which occurs in 25% to 45%, 3% to 12% and 0.2% of severe, moderate and mild TBI cases respectively [4]. There were evidences indicating that this bleeding can develop or continue after hospital admission and that larger bleeds have a worse prognosis [5]–[12]. Delayed enlargement of traumatic intraparenchymal contusions and hematomas is the most common cause of clinical deterioration and death in patients who had a lucid interval after TBI [8,13]. A systematic review of randomized controlled trials (RCT) shows that antifibrinolytic agents are effective in reducing bleeding in elective surgery. The review summarized data from 211 RCTs involving 20,781 participants showed that both Aprotinin and Tranexamic acid (TXA) reduced the need for blood transfusion in elective surgery by about one third [RR = 0.61 (95% CI 0.54 to 0.69)] with no evidences of increased adverse effects [14]. If antifibrinolytics reduced intracranial bleeding in patients with TBI, this would have important clinical implications. However, a systematic review of haemostatic drugs in patients with TBI found no RCTs [15]. There were some evidences on the use of TXA in patients with spontaneous aneurysmal intracranial bleeding. A systematic review of RCTs of TXA in aneurysmal haemorrhage found that although rebleeding was reduced by 45% [odds ratio = 0.55 (95% CI 0.42 to 0.71)], this benefit was offset by cerebral ischaemia such that there was no overall patients benefit [16]. However, these trials used high doses TXA for about six weeks and it has been suggested that a shorter and lower dose might prevent rebleeding whilst avoiding the risk of ischaemia. Indeed, since the review was published a trial of early short course (3 days) TXA showed that it reduced rebleeding from 10.8% to 2.4% without ischaemic adverse effects [17]. We conducted a double blind randomized controlled trials to evaluate the effect of early short course TXA on the occurrence of progressive intracranial haemorrhage (PIH) in patients with TBI treated at a large regional trauma centre in rural Thailand.
BODY.METHODS:
A randomized, double-blind, placebo-controlled, parallel group trial was conducted. The trial protocol was approved by the Khon Kaen hospital's ethics committee and the Khon Kaen University's ethics committee. The trial protocol was registered with http://www.clinicaltrials.gov with the trial identifier NCT00755209. All written informed consent forms were obtained from legally acceptable representative of comatose participants.
BODY.METHODS.PARTICIPANTS:
All patients, older than 16 years, with moderate to severe TBI (post-resuscitation Glasgow Coma Scale (GCS) 4 to 12) who had a computerized tomography (CT) brain scan performed within eight hours of injury, and whom there was no immediate indication for surgery, were eligible for inclusion. There were both of isolated TBI and polytrauma patients whom there were critical concern for TBI management during the admission period. Patients were excluded if they were pregnant, had evidences of coagulopathy, known to be receiving a medication which affects haemostasis, or had a serum creatinine over than 2 mg/decilitre. Coagulopathy was considered present if any of the following hematological parameters were observed: (1) platelet count less than 100,000 cells/mm3; (2) Prothrombin time (PT) or international normalized ratio (INR) prolonged more than 1.5 times normal value; (3) activated partial thromboplastin time (aPTT) more than 10 seconds greater than normal value. Coagulopathy was a risk factor for developing PIH and mortality in previous studies [10,11,18]–[22] or recent reports [23,24]. Hence it was confounding factor to be controlled by exclusion.
BODY.METHODS.INTERVENTION:
Patients were randomly allocated to receive TXA (loading dose of 1.0 gram over 30 minutes followed by a maintenance dose of 1.0 gram infused over eight hours) or matching placebo. The placebo was sterile water and was purchased on the open market in Thailand.
BODY.METHODS.STUDY OUTCOMES:
The primary outcome was progressive intracranial haemorrhage. It would have more association to therapeutic effect of given tranexamic acid than other outcomes in this study [25]. Moreover it was a significant source or link to morbidity and mortality in TBI [8,10,18]–[20,26]. PIH was defined as an intracranial haemorrhage seen on the second CT scan that was not seen on the first CT scan, or an intracranial haemorrhage seen on the first scan that had expanded by 25% or more on any dimension (height, length, or width) on the second scan. Progressive pressure effect was defined as either an increase in midline shift of greater than 1 mm or an increase in basal cistern between the first and second CT scan. The second CT scan was to be taken 24 hours ± 8 hours after the first CT scan. Improved Glasgow Coma Scale (GCS) motor score was also recorded to see if there is compatible change between clinical and radiological progression at 24 hours. The presence or absence of PIH was assessed by two independent readers. Both were neurosurgeons at KKH with experiences in reading posttraumatic CT scans. When there was disagreement about the presence or absence of PIH this was resolved by a third neurosurgeon reader. Inter-rater reliability was assessed by kappa statistic. Secondary outcomes were death, functional status assessed using the Glasgow Outcome Scale (GOS) at hospital discharge, blood transfusion, neurosurgical operation and any in-hospital thromboembolic events (myocardial infarction, pulmonary embolism, deep vein thrombosis, and stroke).
BODY.METHODS.SAMPLE SIZE:
We planned to randomize approximately 240 patients, 120 to each group. We estimated that the proportion of patients with PIH would be 30% in the placebo group and that TXA would reduce to be 15%. A trial with 240 patients would have about 80% power at the 0.05 level of significance (two-sided test) to detect a treatment effect of this magnitude.
BODY.METHODS.RANDOMISATION AND BLINDING:
The randomisation sequence (with a randomly varied block size) was generated from a computer by a person who was not involved with the trial and this sequence was used to prepare the sequentially numbered treatment packs. Whenever an eligible patient was recruited, the recruiting clinician asked that the next sequentially numbered sealed opaque treatment pack be opened and that the trial loading dose and maintenance infusion be prepared and sent to the relevant ward. This preparation was done out of sight of the recruiting clinician and research participants by nurses who were not involved in the trial. Each treatment pack contained unlabelled vials of either drug or placebo. Although drug and placebo vials contained an identical amount of colorless solution, there was a small size discrepancy between the drug and placebo vials. It was for this reason that the vials were enclosed within sequentially numbered sealed opaque envelopes that were opened by nurses who were not involved in the trial. This approach ensured good allocation concealment and also ensured that those caring for the patient and those conducting the trial did not know the assigned treatment. The allocation scheme was kept confidential from all research participants until the end of the study.
BODY.METHODS.STATISTICAL METHODS:
The primary analysis was on an intention-to-treat (ITT) basis with complete case analysis for other outcomes and was done using STATA software version 10.0. The presence or absence of PIH was analyzed as a dichotomous variable. The Glasgow Outcome Scale was also dichotomized such that death, persistent vegetative state, and severe disability constituted an unfavorable outcome while favorable outcome included moderate disability and good recovery. We calculated relative risks, risk difference with their 95% confidence intervals and hypothesis testing between the two treatment groups.
BODY.RESULTS.PATIENT RECRUITMENT:
Figure 1 shows the participant flow into the trial. The first patient was recruited on the 23rd October 2008 and the last patient on 14th August 2009 by which time a total of 238 patients had been included in the trial. All patients received the allocated trial treatments (TXA or placebo) and there were no protocol violations. There were nine patients for whom a second CT scan could not be obtained: seven patients died before the second CT scan, one patient could not be scanned because of agitation, and one patient refused the second scan. There were two consents withdrawal in the placebo group after randomization because they were signed by the unauthorized relatives. The related ethic committees were informed with an agreement for this exclusion. The inter-rater reliability of the assessment of the presence or absence of PIH was high with a kappa statistic of 0.95. The patients were enrolled with comparable profile including about mean age (40 years), male gender (80%), injury onset (within 7 hours), associated organ injury with injury severity score 24 (range from 9–43) and initial haematocrit level (38 volumes%) with moderately severe GCS severity. There were similar pressures effects finding of the first CT scan in both groups. Treatment and control groups were approximately balanced with respect to baseline characteristics (Table 1). Figure 1Participant flow. Table 1 Baseline characteristics Characteristics TXA (n =120) Placebo (n = 118) Age at randomization (years) 34.8 (16.0) 34.1 (15.3) Male 103 (86%) 107 (91%) Glasgow coma scale (GCS) severity: Moderate (9 – 12) Severe (4 – 8) 52 (53%) 47 (47%) 68 (49%) 71 (51%) Baseline haematocrit (volume %) 38 (7.4) 38 (6.7) Time since injury (hours) 6.6 (1.69) 7.1 1.29) Isolated TBI injury 20 (17%) 16 (14%) Polytrauma with TBI injury 100 (83%) 102 (86%) Mean injury severity score (range) 23.3 (9–43) 24.8 (9–43) Midline shift (>3 mm) on first CT (mm) 2 (0.02%) 3 (0.03%) Basal cistern compression on first CT 54 (45%) 53 (45%) Table 2 shows the effect of TXA on the study outcomes by the intention to treat analysis with assuming poor outcome which is used to represent the effectiveness of treatment effect. Progressive intracranial haemorrhage was present in 21 (18%) of patients allocated to TXA and in 32 (27%) of patients allocated to placebo. The difference was not statistically significant [RR = 0.65 (95% CI 0.40 to 1.05)]. The relative risk of death from all causes in patients allocated to TXA compared with placebo was 0.69 (95% CI 0.35 to 1.39) and the relative risk for unfavourable outcome on the Glasgow Outcome Scale was 0.76 (95% CI 0.46 to 1.27). The relative risk of blood transfusion need in patients allocated to TXA compared with placebo was 0.92 (95% CI 0.61 to 1.40). Although we had informed the clinical condition and proposed for emergency neurosurgical operation in all patients with PIH to their relatives. The neurosurgical interventions were not done in placebo group because the patients' relatives did not allow us to perform the operation hence the relative risk for neurosurgical interventions could not be calculated. There were very few adverse effects in both groups. There was no patient in TXA group who developed vascular occlusion event in this study. Table 2 Study outcomes Outcomes TXA Placebo RD RR (n = 120) (n = 118) [95% CI] [95% CI] Progressive intracranial haemorrhage (PIH) 21 (18%) 32 (27%) −0.10 0.65 moderate TBI (n = 24) 7 (6%) 17 (14%) [(−0.20)- [0.40-1.05] severe TBI (n = 20) 9 (8%) 11 (9%) (−0.01)] indicated neurosurgery 6 (5%) 6 (5%) Increase in pressure effect* *11 (10%) 12 (11%) −0.01 0.91 [(−0.09) – 0.07] [0.42-1.97] Improved GCS motor score at 24 hours 37 (31%) 37 (31%) −0.01 0.98 [(−0.12) – 0.11] [0.67-1.44] Neurosurgical intervention 3 (3%) 0 0.03 --- [(−0.00) – 0.05] --- Blood products transfusion 31 (26%) 33 (28%) −0.02 0.92 [(−0.13) – 0.09] [0.61-1.40] Death 12 (10%) 17 (14%) −0.04 0.69 [(−0.13) – 0.04] [0.35-1.39] Unfavorable (GOS) outcome 21 (18%) 27 (23%) −0.05 0.76 [(−0.16) – 0.05] [0.46-1.27] Adverse events Stroke 0 3 --- --- Pulmonary embolus 0 0 --- --- Deep vein thrombosis 0 0 --- --- Gastrointestinal bleeding 0 1 --- --- *Denominator for outcomes is 114 for TXA group and 115 for placebo group. This is an analysis based on complete case analysis that is not assumed the missing outcome. Table 3 shows the effect of various methods of handling missing response in the primary outcome. The different analyses have different assumptions on existing PIH. A complete case analysis may be undertaken for primary outcome to avoid the assumption about PIH without imputation for the unavailable outcome. However different analyses give similar trend of potential benefit for treatment with tranexamic acid. Table 3 Effect of various methods of handling missing response in trial Methods of analysis PIH in TXA and placebo group Group n/N Rate RD RR (person) (%) [95% CI] [95% CI] 1. Complete case analysis TXA 16/115 14% −0.11 0.57 Placebo 28/114 25% [(−0.21)-(−0.01)] [0.32-0.99] 2. Assuming poor outcome TXA 21/120 18% −0.10 0.65 Placebo 32/118 27% [(−0.20)-(−0.01)] [0.40-1.05] 3. Assuming good outcome TXA 16/120 13% −0.10 0.56 Placebo 28/118 24% [(−0.20)-(−0.01)] [0.32-0.98] 4. Extreme case favoring placebo TXA 21/120 18% −0.06 0.74 Placebo 28/118 24% [(−0.16)-0.04] [0.44-1.22] 5. Extreme case favoring TXA TXA 16/120 13% −0.14 0.49 Placebo 32/118 27% [(−0.24)-(−0.04)] [0.29-0.85]
BODY.DISCUSSION.PRINCIPAL FINDINGS:
We found a statistically insignificant difference but with a trend towards significant reduction in the risk of PIH in patients allocated to TXA without evidence of increased risk of thrombotic adverse events. The risks of death and of unfavorable outcome on the Glasgow Outcome Score were lower for patients allocated to TXA. The safety of early short course treatment of TXA in our TBI patients was compatible to no increasing risk of non-fatal vascular occlusive events with early short course treatment of TXA in traumatic bleeding patients in CRASH2 trial [27].
BODY.DISCUSSION.STRENGTHS AND WEAKNESSES:
This is the leading randomized trial to examine the effectiveness of the early administration of a short course of TXA in patients with acute TBI. We are aware of a recent study publication of CRASH2 trial and we anticipate that the results of all relevant trials will ultimately be combined in the Cochrane systematic review of haemostatic drugs for TBI [15]. Our trial was properly randomized with good allocation concealment. The timing of the second CT scan was pre-specified in the protocol and all outcome measurements were made without knowledge of treatment allocation. The main weakness of our study is the low power to estimate the effect of TXA on clinical outcomes. In particular, although our study has shown statistically insignificant difference that TXA may reduce PIH, because of the low powers to examine the effect of TXA on death and on disability, the clinical implications of our findings are still limited. Another limitation is lacking to explore an effect of associated injury or injury severity score in multiple trauma patients which was concerned in some studies [19,21]. We precluded exploring this association to the treatment by our limited sample size. Polytrauma subjects were almost patients whom there was agreement from trauma care team to concern treatment for TBI as same as isolated TBI subjects at first moment. Therefore we assigned serious, critical and serious injury degree for moderate TBI, severe TBI and other anatomical organ injuries in the category of injury severity score assessment respectively. The common associated injuries were extremity fracture, facial fracture, rib or clavicular fracture and a few cases of other chest injury or minor abdominal trauma. Finally the exclusion of coagulopathy is also a limitation of our study and this subject could be a point to explore in further research.
BODY.DISCUSSION.PIH IN TBI:
Various terms have been used to describe the development or enlargement of intracranial bleeding after TBI. Terms include delayed traumatic intracranial haemorrhage (DTICH) [7], expanding hematoma [19] and progressive hemorrhagic injury [10]. In this paper we combined these concepts such that we included both new haemorrhage and expanding haemorrhage (progressive intracranial haemorrhage). Our rationale was that both lesions may exacerbate intracranial hypertension and the occurrence of both may be affected by the administration of TXA. Although patients were excluded if they had evidence of coagulopathy at baseline the proportion of patients with PIH among the patients was surprisingly high. Had we not excluded coagulopathic patients it is likely that the proportion of patients with PIH would have been even higher. Previous estimates of the occurrence of PIH vary widely from 7% to 60% [20]. These differences are likely to reflect difference in timing of the CT scan, clinical setting and diagnostic criteria. Nevertheless, given the relatively high prevalence of PIH in patients with TBI observed in this study the potential for TXA to improve clinical outcomes could be high.
BODY.DISCUSSION.METHODS OF HANDLING MISSING RESPONSE IN TRIAL:
We summarize the result of handling missing outcome for the primary outcome in Table 3.
BODY.CONCLUSIONS:
We have not shown that TXA improves clinical outcomes and this information would be required in order to make any recommendation about the use of TXA in clinical practice. Our results have important implications for research. If an early short course of TXA could be demonstrated to improve clinical outcomes after TBI without any important adverse effects, then this treatment, because it is cheap and widely practicable, could contribute importantly to reducing mortality and disability after TBI.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS’ CONTRIBUTIONS:
SY, BT, NP and PL designed, analysed and wrote the paper. WK and PP suggested the design, collected the data and conducted analyses. SY wrote the paper with input from all other authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscript.
BODY.PRE-PUBLICATION HISTORY:
The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-227X/13/20/prepub | 4,221,638 | {
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TITLE: Pioglitazone Decreases Hepatitis C Viral Load in Overweight, Treatment Naïve, Genotype 4 Infected-Patients: A Pilot Study
ABSTRACT.BACKGROUND:
Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population.
ABSTRACT.METHODOLOGY/PRINCIPAL FINDINGS:
We designed a two-arm, parallel Pilot Study of overweight, treatment naïve genotype 4 HCV-infected patients at a public referral Liver Clinic in Giza, Egypt. The subjects received Pioglitazone (30 mg/day for 14 days) or Prednisone (40 mg/day for 4 days) in a randomized fashion, but the two arms can be considered independent pilot studies. Only changes from baseline within each arm were assessed and no contrasts of the interventions were made, as this was not an aim of the study. Among 105 consecutive HCV genotype 4 patients, 39 were enrolled based on the optimal sample size and power analysis according to the CONSORT statement; 20 to the Pioglitazone group and 19 to the Prednisone group. Pioglitazone was effective in decreasing serum HCV RNA at day-14 (n = 10; difference of means = 205,618 IU/ml; 95% CI 26,600 to 384,600; P<0.001). Although Prednisone did increase serum HCV RNA at day-4 (n = 10; change from baseline = −42,786 IU/ml; 95% CI −85,500 to −15,700; P = 0.049), the log10 HCV RNA titers were statistically not different from baseline day-0.
ABSTRACT.CONCLUSION/SIGNIFICANCE:
This is the first documentation that Pioglitazone decreases the serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The novel findings of our Study provide the foundation for basic and clinical investigations on the molecular mechanisms responsible for the Pioglitazone-induced decrease in HCV genotype 4 RNA titers.
ABSTRACT.TRIAL REGISTRATION:
ClinicalTrials.gov NCT01157975
BODY.INTRODUCTION:
Chronic hepatitis C viral (HCV) infection markedly increased the risk for type 2 diabetes in cohorts with recognized diabetes risk factors [1]. A meta-analysis also found that HCV infection is associated with excess type 2 diabetes risk [2]. Moreover, IR is a specific feature of chronic HCV genotypes 1 and 4 infections since its prevalence is ∼7-fold higher among these patients compared to chronic Hepatitis B-infected patients [3], and changes in IR occur among patients with chronic HCV infection during and after treatment of HCV with PEG-interferon-α and ribavirin [4]. In patients with genotypes 1, 2 and 3 increased IR was associated with decreased sustained virological response (SVR) [5]. Among patients infected with genotype 1, decreases in Homeostasis Model Assessment (HOMA)-IR correlated with obtaining an SVR and increases in HOMA-IR were observed in patients who relapsed [6]. Similarly, IR may correlate with the virological response to standard of care treatment of HCV genotype 4 patients in Egypt [7]. Because Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, improves insulin sensitivity [8] and it is also effective in controlling liver inflammation in subjects with non-alcoholic steatohepatitis (NASH) [9], it has been used as triple therapy in addition to PEG-interferon-α and ribavirin to treat HCV-infected patients. The study in HCV genotype 1 non-responders was terminated when none of the five patients responded to the triple therapy at week 12 [10]. In contrast, Pioglitazone improved virological response to PEG-interferon α-2b/ribavirin combination therapy in hepatitis C genotype 4 treatment naïve patients with insulin resistance [11]. However, the mechanisms by which Pioglitazone influenced SVR in treatment naïve patients with HCV genotype 4 infection remain unknown. It is unknown whether Pioglitazone modifies the bioavailability of PEG-interferon α-2b/ribavirin or directly or indirectly affects HCV infection and replication. Therefore, we designed a Pilot Study to assess whether Pioglitazone decreases HCV viral load in overweight HCV genotype 4, treatment naïve patients independently of standard of care PEG-interferon α-2b/ribavirin treatment. A secondary end-point was to analyze whether Prednisone, a drug that induces insulin resistance in susceptible patients [12] and stimulates HCV viral entry and replication in replicon culture systems [13], increases HCV viral load in this population. There were no data available on the effect of Pioglitazone or Prednisone on HCV RNA viral load in patients. Here, we provide the first documentation that Pioglitazone decreases the serum HCV genotype 4 RNA titers independently of treatment with PEG-Interferon-α2/ribavirin. Prednisone did increase serum HCV RNA viral load at day-4 in this cohort.
BODY.METHODS:
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.
BODY.METHODS.PARTICIPANTS:
Eligible participants were all overweight (BMI>25 kg/m2), given their susceptibility for IR, adults age 25 to 65 years, with active HCV genotype 4 chronic infection (>10,000 IU/ml viral load) who had a liver biopsy within two years of recruitment (added to the protocol), were treatment naïve (never treated for HCV infection) and met the eligibility criteria for the Study. Exclusion criteria included cirrhosis, the presence of other liver diseases, diabetes, pregnancy, significant clinical co-morbidities, and the inability to provide informed consent. Participants were recruited from July 2010 to February 2011 at the primary care referral of subjects of a disadvantaged social-economical group at the Agouza Hospital in Giza, Egypt. The estimated prevalence of Hepatitis C in Egypt is 12% in adults.
BODY.METHODS.ETHICS:
Written informed consent was obtained by the medical staff before entry into the Study. The study was registered at the clinicaltrials.gov website (NCT-01157975) and received Human Subjects' Research approval at the University of California, San Diego (UCSD Human Research protections Program) and at the Agouza Hospital, Giza, Egypt (Director's Research Board) before starting the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
BODY.METHODS.OBJECTIVES:
Because the objective of the Study was to determine whether Pioglitazone and Prednisone treatment would affect the HCV RNA viral load (decrease and increase it, respectively), and these were not a treatment of the HCV infection in this situation, we decided not to use a placebo since we utilized de-identified samples to blinding the investigators analyzing the outcomes.
BODY.METHODS.INTERVENTIONS:
Eligible subjects were randomly assigned to receive orally Pioglitazone 30 mg/day for 14 days or Prednisone 40 mg/day for 4 days. These medications were taken in the morning. Visits were at screening (up to 30 days before randomization); randomization (day -2); baseline visit (day 0); and follow-up visits for the Pioglitazone group (on days 2, 4, 7 and 14) and the Prednisone group (on days 2 and 4). For safety issues subjects were continued to be seen off protocol at day-7 post-treatment. Blood samples were obtained at each visit for HCV RNA viral load and for inflammatory, adipogenic, and insulin resistance markers. In addition, a 2-hr oral 75 g glucose tolerance test (OGTT) was performed after a 10-hr fast at day-0 before administration of the medication and at the last day of treatment (day-14 for Pioglitazone and day-4 for Prednisone). On all other visits, patients were also fasting. Patients received the first dose of the study drug (oral Pioglitazone 30 mg or Prednisone 40 mg) after blood samples were obtained on day 0. Compliance with the medication was >90% as assessed at each visit.
BODY.METHODS.OUTCOMES:
The primary outcome with respect to the effect of Pioglitazone in HCV genotype 4 infections was the decrease in HCV RNA viral load at day 14. The secondary outcome with respect to the effect of Prednisone in HCV genotype 4 infections was the increase in HCV RNA viral load at day 4 instead of at day 14 for safety reasons given the potential adverse events associated with longer corticosteroid treatment. Additional secondary outcome measures were insulin resistance (oral glucose tolerance test; serum insulin, C-peptide; HOMA-IR; insulin sensitivity check index (QUICKI); HOMA-B; sex hormone BG (SHBG); resistin; adiponectin) and liver injury (alanine aminotransferase (ALT); aspartate aminotransferase (AST)) and inflammation (serum interleukin (IL)-8, IL-28B, tumor necrosis factor (TNF), IL-1α, IL-1β, IL-6, IL-8, IL-10, IFN-γ, monocyte chemokine protein (MCP) and hepatocyte growth factor (HGF)). De-identified blood samples from all the enrolled subjects that received the treatments were analyzed for the standard clinical laboratory tests and for HCV RNA viral load using PCR amplification (COBAS, TACKMAN) (lowest detectable limit: 50 IU/ml). A multiplex peptide detection system (Quansys Biosciences, Logan, UT) was utilized according to the manufacturer's protocol to determine inflammatory, adipogenic, and insulin resistance markers. Values calculated from individual pixels using the Q-View Imager system. An enzyme-linked immunosorbent assay kit was used to determine human adiponectin according to the manufacturer's protocol (BioVision, Mountain View, CA). Surrogate indicators of insulin resistance and β-cell function were analyzed as described previously [14]. The indicators of insulin resistance HOMA1-IR and QUICKI were determined. HOMA1-IR = (FSI×FSG)/22.5 where FSI is fasting serum insulin concentration (μU/l) and FSG is fasting serum glucose (mmol/l). QUICKI = 1/[log (fasting insulin-μU/ml)+log (fasting glucose- mg/dl)]. β-Cell function was assessed by the HOMA –B 20.I0/(G0 -3.5); I0 = fasting insulin in μU/ml and G0 = fasting glucose in mmol/l [14].
BODY.METHODS.SAMPLE SIZE:
There were no data available on the effect of Pioglitazone or Prednisone on HCV RNA viral load. However, we considered a reduction of 25% in HCV RNA viral load in 14 days to be relevant as proof of principle of the effects of Pioglitazone on HCV RNA titers. To detect a reduction of 25% in HCV RNA in the Pioglitazone group at day-14 assuming a standard deviation of 20% with a two-sided 5% significance level and a power of 90%, a sample size of 9 patients per group completing the study was necessary, and it was decided to enroll at least 19 subjects per group given an anticipated dropout rate of 50% mainly prior to dosing. Because the cultural environment (unwillingness to tell the research staff that they cannot participate in the study) and the social conditions (such as severe problems with transportation and employer's authorization) were expected to prevent a significant proportion of patients to attend the Clinic for follow-up visits after randomization, a larger number of eligible subjects were randomized to achieve the desirable number of subjects completing the Study. To recruit this number of patients a 12-month inclusion period was anticipated. No interim analysis was performed during the trial. An intention-to-treat analysis was conducted in patients who had received ≥1 dose of study medication (10 patients in each group was optimal based on sample size and power analysis).
BODY.METHODS.RANDOMIZATION—SEQUENCE GENERATION:
Participants were randomly assigned following simple randomization procedures (computerized random numbers) to one of two treatment groups. Independent pharmacists dispensed either Pioglitazone or Prednisone according to a computer generated randomization list.
BODY.METHODS.RANDOMIZATION—ALLOCATION CONCEALMENT:
The decision to accept or reject a participant was made, and informed consent was obtained from the participant, in ignorance of the next assignment in the sequence.
BODY.METHODS.RANDOMIZATION—IMPLEMENTATION:
Block randomization was by a computer generated random number list prepared by a pharmacist with no clinical involvement in the trial. After the research nurse had obtained the subject's consent, she contacted the pharmacist who was independent of the recruitment process for allocation consignment.
BODY.METHODS.BLINDING:
Whereas patients and physicians allocated to the intervention groups were aware of the allocated arm, outcome assessors and data analysts of primary and secondary end-points were kept blinded to the allocation.
BODY.METHODS.STATISTICAL METHODS:
An intention-to-treat analysis was conducted in patients who had received ≥1 dose of study medication. The primary and secondary endpoints were assessed with a paired-sample t-test. We also explored correlations between IL8 and TNFα using Pearson's correlation coefficient with 95% confidence intervals. The significance level was fixed at α = 5% for all tests. All analyses were carried using R version 2.12.2 (2011 Vienna, Austria; http://www.R-project.org).
BODY.RESULTS.PARTICIPANT FLOW:
The optimal subjects' recruitment number was pre-determined by sample size and power analysis as described above. One hundredth and five consecutive patients with chronic Hepatitis C genotype 4 referred to the Hepatology Clinic were assessed for eligibility (
Fig. 1
). Among these 105 patients, 66 were excluded because they did not meet the eligibility criteria (42 subjects), they refused to participate (8 subjects), or for other reasons (16 subjects). Therefore, 39 patients were randomized; 20 to the Pioglitazone group and 19 to the Prednisone group. Ten patients in each group received the allocated intervention, while 10 patients in the Pioglitazone group and 9 patients in the Prednisone group were unable to participate because of their inability to attend the Clinic visits. These patients did not receive the allocated intervention (
Fig. 1
). The randomized groups that received the allocated intervention were balanced in regards to age, gender, HCV genotype and titers and the severity of their liver disease (
Table 1
). 10.1371/journal.pone.0031516.g001Figure 1Participant Flow.Patients with chronic Hepatitis C genotype 4 referred to the Hepatology Clinic were assessed for eligibility as described in Methods. 10.1371/journal.pone.0031516.t001 Table 1 Baseline demographic and clinical characteristics of treated subjects. Pioglitazone (N = 10) Prednisone (N = 10)
P value
Age (years) 44 (9.3) 42(10.4) 0.592
Sex (male) 7 (70%) 8 (80%) 0.429
Ethnic origin: Arab
10 (100%) 10 (100%) 1.000
Height (cm) 173 (5.8) 175(8.7) 0.458
Weight (kg) 88.3 (9.2) 85.7(9.9) 0.550
BMI (kg/m 2 ) 29.5(1.5) 27.9(1.6) 0.027
HCV Genotype 4
10 (100%) 10 (100%) 1.000
HCV RNA (log 10 ) 5.41(0.80) 5.10(0.92) 0.432
Albumin (g/dl) 3.8(0.3) 3.8(0.3) 0.939
Total bilirubin (mg/dl) 0.97(0.15) 0.90 (0.16) 0.319
ALT (IU/ml) 63 (23) 53 (14) 0.283
AST (IU/ml) 54 (17) 52 (11) 0.795
Metavir score:
A (inflammation) A1(n:5) A2(n:5) A1(n:5) A2(n:5) 1.000
F (fibrosis) F1(n:7); F2(n:3) F1(n:6); F2(n:4) 0.639 Data are means (SD) or numbers (%). The patients that did receive the allocated intervention were similar in demographics, ethnicity and degree of liver disease to those that did not receive the allocated intervention (
Table 2
). By chance allocation, the serum ALT was lower in the group that received Prednisone than in the group that did not received the allocated Prednisone (53 vs 69 IU/ml; P = 0.012) (
Tables 1
and
2
). 10.1371/journal.pone.0031516.t002 Table 2 Baseline demographic and clinical characteristics of non-treated subjects. Pioglitazone (N = 10)
P value
Prednisone (N = 9)
P value
Age (years) 39 (4.2) 0.139 43(11.2) 0.842
Sex (male) 6 (60%) 0.660 5 (55%) 0.277
Ethnic origin: Arab
10 (100%) 1.000 9 (100%) 1.000
Height (cm) 172 (5.9) 0.706 177(8.1) 0.612
Weight (kg) 85.7 (7.6) 0.499 84.8(8.8) 0.837
BMI (kg/m 2 ) 28.8(2.1) 0.402 28.2(3.7) 0.818
HCV Genotype 4
10 (100%) 1.000 9 (100%) 1.000
ALT (IU/ml) 68 (10) 0.536 69 (10) 0.012
AST (IU/ml) 63 (12) 0.188 57 (8) 0.278
Metavir score:
A (inflammation) A1(n:4); A2(n:6) 0.673 A1(n:4); A2(n:5) 0.821
F (fibrosis) F1(n:5); F2(n:5) 0.388 F1(n:5); F2(n:4) 0.855 Data are means (SD) or numbers (%). P values are for comparisons between treated and untreated subjects within the same arm. No participant was excluded after randomization because they were found not to meet eligibility criteria. All the patients allocated to the interventions (10 in each arm) completed the study (
Fig. 1
).
BODY.RESULTS.BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS:
An intention-to-treat analysis was conducted in patients who had received ≥1 dose of study medication; all of these patients had a subsequent efficacy observation (10 patients in each group). As outlined in
Table 1
, all patients were middle age Egyptian Arabs, predominantly males that had HCV genotype 4 with mild or moderate inflammation (A1 and A2, respectively) and mild or moderate fibrosis (F1 and F2, respectively) on their liver biopsy. They had normal albumin and total bilirubin and mild increase in ALT/AST. All subjects were overweight and five were obese (body mass index, BMI; the weight in kg divided by the square of the height in meters was >29 kg/m2: 3 in the Pioglitazone group and 2 in the Prednisone group). By chance allocation, the BMI was higher in the group receiving Pioglitazone than in the group receiving Prednisone (29.5 vs 27.9 kg/m2; P = 0.027) (
Table 1
). There was no indication that significant chance imbalances had occurred between the two groups. Further, no direct analysis between the two groups was intended for the primary or secondary end points. Rather, a comparison between baseline and post-treatment results within each group was the Pilot Study's intent.
BODY.RESULTS.EFFECT OF PIOGLITAZONE ON SERUM HCV RNA TITERS:
Pioglitazone decreased serum HCV RNA titers in overweight HCV genotype 4, treatment naïve patients. In the Pioglitazone-treated group, the log10 transformed HCV RNA titers were statistically different from baseline day-0 (5.41+/−0.80) on day-14 (5.24+/−0.79; P<0.001) and day-7 (5.30+/−0.78; P = 0.009) (
Table 3
), providing evidence that Pioglitazone was effective in decreasing HCV RNA in this cohort of patients. Pioglitazone treatment decreased the HCV RNA from baseline in 9 out of 10 subjects at day-7. The log10 HCV RNA values were also decreased by day-4 but they were statistically not different from baseline (5.38+/−0.78; P = 0.059). The log10 HCV RNA values were not affected at day-2 by Pioglitazone treatment. Further, the decrease in the log10 HCV RNA between day-7 and day-14 was highly significant (mean change = 0.063; 95% CI, 0.045; P<0.001) (
Table 3
). 10.1371/journal.pone.0031516.t003 Table 3 Effects of Pioglitazone on serum HCV RNA titers. Day HCV (IU/ml ×10 −3 )
P value
95% CI
HCV log 10
P value
95% CI
0
608.2(696.4) 5.41(0.80)
2
586.9(663.9) 0.178 −11.5, 53.9 5.41(0.78) 0.854 −0.029
4
531.5(553.6) 0.151 −33.6, 186.9 5.38(0.78) 0.077 −0.002
7
455.3(504.4) 0.044 4.8, 300.7 5.30(0.78) 0.001 −0.156
14
402.5(452.4) 0.029 26.6, 384.6 5.24(0.79) <0.001 −0.215 Values are mean (SD) of HCV RNA titers determined as described in Methods . In spite of the variable baseline HCV RNA viral load, Pioglitazone also decreased significantly the absolute HCV RNA levels at day-14 (mean change = 205,618 IU/ml; P = 0.028) and at day-7 (mean change = 152,772 IU/ml; P = 0.044) (
Table 3
).
BODY.RESULTS.EFFECT OF PIOGLITAZONE ON INDICES OF INSULIN RESISTANCE:
Pioglitazone treatment decreased by day-14 fasting serum glucose (Glucose-0) (mean change = 8.2 mg/dL; P = 0.024) as well as the 2-hr glucose (Glucose-120 min) after an OGTT (mean change = 18.8 mg/dL; P = 0.001) (
Table 4
). 10.1371/journal.pone.0031516.t004 Table 4 Effects of Pioglitazone on glucose homeostasis, insulin resistance and secretion. Test Day-0 Day-14
P value
95% CI
Glucose-0 (mg/dL) 105 (11.4) 96.8 (6.8) 0.024 1.3, 15.1
Glucose-120 (mg/dL) 120.6 (11.9) 101.8 (7.4) 0.0004 10.9, 26.7
HOMA-IR
2.71 (1.61) 2.38 (1.60) 0.326 −0.95
QUICK-I
0.339 (0.031) 0.348 (0.036) 0.587
……
HOMA-B
92.65 (57.5) 115.26 (90.85) 0.52 −99.6, 54.4
Insulin (µIU/ml) 10.4 (6.2) 10.1 (7.0) 0.914 −6.2, 6.8
C-peptide (nmol/L) 6.4 (9.4) 9.6 (8.5) 0.278
− 9.5, 3.1
SHBG (µg/ml) 3.8 (2.4) 1.7 (2.1) 0.062 −140
Adiponectin (µg/ml) 3.19 (1.32) 3.64 (1.71) 0.512
……‥
Resistin (ng/ml) 2,0 (0.2) 1,7 (0.6) 0.116 −2.0 Values are mean (+/− SD). Tests were performed as described in Methods . However, Pioglitazone treatment did not affect by day-14 the following surrogate indicators of insulin resistance and secretion: HOMA-IR; QUICK-I; and HOMA-B. In addition, other surrogate indicators of insulin resistance were not affected by Pioglitazone treatment on day-14, including fasting serum insulin; C-peptide; SHBG; resistin; and adiponectin (
Table 4
).
BODY.RESULTS.EFFECT OF PIOGLITAZONE ON INDICATORS OF LIVER INJURY AND INFLAMMATION:
Elevated serum ALT and AST values are surrogate indicators of liver injury used in patient care and clinical research [9]. Pioglitazone treatment decreased at day-14 serum ALT levels (mean change = 7.5 IU/ml; 95% CI: 2.1 to 12.9; P = 0.012) and to a smaller degree serum AST levels (mean change = 2.6 IU/ml; 95% CI: −0.6 to 5.8; P = 0.096) (
Table 5
). 10.1371/journal.pone.0031516.t005 Table 5 Effects of Pioglitazone on liver injury indicators. Day ALT (IU/L)
P value
95% CI
AST (IU/L)
P value
95% CI
0
62.7 (23.1) 53.6 (15.6)
14
55.2(18.7) 0.0118 2.1, 12.9 51.0 (14.0) 0.0963 −0.6, 5.8 Values are mean (+/− SD). ALT and AST were determined as described in Methods . It has been suggested that serum IL-8 values are elevated in HCV infection and that these values may reflect the effects of the HCV on il-8 gene transcription [15]. Pioglitazone increased serum IL-8 levels at day-14 when compared to baseline day-0 values (mean change = −166.8 IU/ml; 95% CI: −300.1 to −33.5; P = 0.019) (
Table 6
). Given the possible induction of IL-8 expression by TNF-α [15], we analyzed post-hoc their correlation by a Pearson's correlation coefficient. We found that there was a relatively strong correlation between serum IL-8 and serum TNF-α levels for day-0 and day-14 (n = 20; r = 0.64; 95% CI = 0.28 to 0.85; P = 0.002). 10.1371/journal.pone.0031516.t006 Table 6 Effects of Pioglitazine on serum cytokines. Serum Cytokine Day-0 Day-14
P value
95% CI
IL-8 (pg/ml) 181.0 (182.8) 347.8 (123.9) 0.020 −300, −33.5
IL-28B (pg/ml) 837.2 (1,068) 1,597 (955.5) 0.060 −1,564, 47
TNF-α (pg/ml) 92.9 (139.6) 275.5 (268.5) 0.056 −371.7, 6.6
IL-1α (pg/ml) 136.6 (324.4) 223.6 (452.1) 0.415 −317, 143
IL-1β (pg/ml) 627.4 (1,046) 724.0 (1,098) 0.748 −760, 566
IL-2 (pg/ml) 13.9 (11.1) 16.1 (10.1) 0.632 −12.3, 7.9
IL-4 (pg/ml) 10.9 (4.9) 10.4 (4.3) 0.817 −4.8, 5.9
IL-6 (pg/ml) 337.9 (454.8) 560.5 (482.1) 0.280 −661, 216
IL-10 (pg/ml) 32.4 (58.2) 27.6 (44.6) 0.831 −44.7, 54.3
IFN-γ (pg/ml) 5.7(4.2) 7.4 (4.6) 0.403 −5.9, 2.6
MCP-1 (pg/ml) 338.4(151.4) 330.6(157.9) 0.915 155, 170
HGF (pg/ml) 1008 (736) 975 (603) 0.914 −665, 732 Values are mean (+/− SD). Serum cytokines were determined as described in Methods . We found no statistically significant differences between day-0 and day-14 in serum IL-28B, TNF-α, IL-1α, IL-1β, IL-6, IL-8, IL-10, IFN-γ, MCP-1 and HGF (
Table 6
).
BODY.RESULTS.EFFECT OF PREDNISONE ON SERUM HCV RNA:
Prednisone increased the absolute HCV RNA level at day-2 (mean change = −35,636 IU/ml; 95% CI −64,665 to −6,607; P = 0.021) and at day-4 (mean change = −42,786 IU/ml; 95% CI −85,556 to −15.7; P = 0.049) (
Table 7
), providing some evidence that Prednisone may be effective in increasing HCV RNA in this cohort of patients for that short period of time. When compared to their baseline day-0 values, eight of 10 subjects had an increase in HCV RNA at day-4. Prednisone treatment also increased HCV RNA from baseline day-0 in 9 of 10 subjects at day-2 (
Table 7
). However, in the Prednisone-treated group, the HCV RNA titers expressed as log10 values on day-2 and day-4 were not statistically different from baseline day-0 (
Table 7
). 10.1371/journal.pone.0031516.t007 Table 7 Effects of Prednisone on serum HCV RNA titers. Day HCV (IU/ml ×10 −3 )
P value
95% CI
HCV log 10
P value
95% CI
0
498.0(805.3) 5.10(0.92)
2
533.7(834.4) 0.0215 −64.6,−6.6 5.14(0.94) 0.059 0.08
4
540.8(855.2) 0.0499 −85.5,−15.7 5.13(0.92) 0.18 0.03 Values are mean (SD). HCV RNA titers were determined as described in Methods .
BODY.RESULTS.EFFECT OF PREDNISONE ON INDICES OF INSULIN RESISTANCE:
Prednisone treatment increased by day-4, when compared to baseline day-0 values, fasting serum glucose (Glucose-0) (mean change = 9.0 mg/dL; 95% CI: 20.4 to −2.4; P = 0.108) as well as the 2-hr (Glucose-120 min) after an OGTT (mean change = 11.0 mg/dL; 95% CI: 17.9 to 4.1; P = 0.006). Collectively, the CI and t-tests suggest that Prednisone increased serum glucose levels at day-4 (
Table 8
). However, Prednisone treatment did not affect by day-4 other surrogate indicators of insulin resistance and secretion (
Table 8
). 10.1371/journal.pone.0031516.t008 Table 8 Effects of Prednisone on glucose homeostasis, insulin resistance and secretion. Test Day-0 Day-4
P value
95% CI
Glucose-0 (mg/dL) 88.0 (14.7) 97.0 (12.9) 0.107 −20.4, 2.4
Glucose-120 (mg/dL) 96.4 (10.5) 107.4 (12.3) 0.0055 −17.9, −4.1
HOMA-IR
1.73 (1.06) 2.55(1.96) 0.162 −1.06
QUICK-I
0.358(0.022) 0.345 (0.032) 0.275
HOMA-B
95.48 (49.35) 115.86 (95.96) 0.623 −20.38
Insulin (µIU/ml) 7.5(3.9) 10.5 (8.2) 0.374 −10.2, 4.4
C-peptide (nmol/L) 11.3 (8.9) 4.1 (1.3) 0.061 −0.5, 14.9
SHBG (µg/ml) 3.4(2.5) 2.7 (2.2) 0.591 −2.4
Adiponectin (µg/ml) 5.9 (8.2) 2.6 (2.1) 0.306 −4.5
Resistin (ng/ml) 3.4 (2.5) 2.7 (2.2) 0.591 −2.4 Values are mean (+/− SD). Tests were performed as described in Methods .
BODY.RESULTS.EFFECT OF PREDNISONE ON INDICATORS OF LIVER INJURY AND INFLAMMATION:
Prednisone treatment did not affect at day-4 either serum ALT, AST, IL-8 or other inflammatory mediators (
Tables 9
and
10
). 10.1371/journal.pone.0031516.t009 Table 9 Effects of Prednisone on liver injury indicators. Day ALT (IU/L)
P value
95% CI
AST (IU/L)
P value
95% CI
0
53.2 (14.4) 52.0(11.3)
4
55.7 (15.7) 0.080 5.4, −0.4 52.2 (12.8) 0.896 3.6, −3.2 Values are mean (+/− SD). ALT and AST were determined as described in Methods . 10.1371/journal.pone.0031516.t010 Table 10 Effects of Prednisone on serum cytokines. Serum Cytokine Day-0 Day-4
P value
95% CI
IL-8 (pg/ml) 123.1 (163.5) 159.5 (185.1) 0.353 −123, 50
IL-28B (pg/ml) 485.9(876.4) 610.8 (857.7) 0.120 −292, 42
TNF-α (pg/ml) 146.6 (268.8) 146.1 (284.4) 0.996 −275, 276
IL-1α (pg/ml) 80.1 (208.3) 19.2(38.3) 0.450 −119, 240
IL-1β (pg/ml) 92.7 (120.3) 144.8 (293.0) 0.682 −348, 244
IL-2 (pg/ml) 11.8 (9.8) 11.3 (9.6) 0.742 −3.1, 4.2
IL-4 (pg/ml) 19.3 (19.1) 10.9 (7.2) 0.329 −10.5, 27.3
IL-6 (pg/ml) 292.8 (445.7) 359.9 (501.4) 0.492 −282, 149
IL-10 (pg/ml) 67.4 (106.8) 30.8 (51.2) 0.144 −16.1, 89.4
IFNγ (pg/ml) 13.9 (24.9) 4.9 (4.3) 0.342 −11.9, 29.9
MCP-1 (pg/ml) 232.7 (126.1) 266.8 (112.8) 0.469 −139, 71
HGF (pg/ml) 1345 (800) 1022 (681) 0.483 −711, 1357 Values are mean (+/− SD). Serum cytokines were determined as described in Methods .
BODY.RESULTS.ADVERSE EVENTS:
There were no serious adverse events in either treatment group. Mild or moderate adverse events unrelated to the allocated treatment occurred in 20% of subjects in the Prednisone group and in 30% of the subjects in the Pioglitazone group. There were no significant changes from baseline during treatment in safety laboratory tests in either treatment group.
BODY.DISCUSSION:
It was not known whether Pioglitazone and Prednisone affect serum HCV genotype 4 RNA titers independently of PEG-Interferon-α2/ribavirin treatment. This Study documented for the first time that Pioglitazone (30 mg daily) decreases the serum HCV RNA titers after a 14-day treatment in overweight subjects with treatment naïve, chronic HCV genotype 4 infections. The statistical differences between the mean at day-0 (baseline) and day-14 were highly significant whether the serum HCV RNA was analyzed as IU/ml or log10 values (
Table 3
). Pioglitazone treatment also decreased the HCV genotype 4 titers on day-4 and day-7, suggesting a rapid effect on HCV RNA titers. The comparable mean decrease in HCV RNA for the first week and for the second week indicates a continuing effect during the 14-day treatment. It remains to be studied whether the rate of decrease of serum HCV RNA titers continues after day-14 in the Pioglitazone group. If the effects of Pioglitazone on in HCV genotype 4 RNA titers would continue at the same rate as for the first 2 weeks, it would achieve a clinically significant decrease of ∼1 log10 in HCV RNA titers by week-12, an important predictive timeline for a sustained virological response in HCV treatments [16]. Given the relative safety of Pioglitazone administration [9],[17], it could be, as a co-adjuvant, a valuable therapeutic effect for difficult to treat HCV genotype 4-infected patients. This Study also documented for the first time that Prednisone (40 mg daily) increases the serum HCV RNA titers after a 4-day treatment of HCV genotype 4 overweighed patients (
Table 7
). Our results with Prednisone treatment are congruent with the recently reported increased HCV replication by corticosteroids in the Huh-7 replicon system [13], but whether in HCV genotype 4-infected patients, this reflects a direct corticosteroid effect on HCV replication, an indirect effect mediated by insulin resistance, or another mechanism is unknown. Because the Huh-7 replicon system uses de-differentiated, tumoral liver cells that have higher expression of glucose metabolism enzymes (glucose-6-phosphate 1-dehydrogenase and isocitrate dehydrogenase) and of the mitochondrial dicarboxylate carrier [18], it may not be suitable for the evaluation of interaction between glucose homeostasis and HCV replication. To minimize potential adverse events associated with the administration of Prednisone, its use was limited to 40 mg/day for a 4-day treatment, a relatively safe and frequent standard of care practice for some clinical conditions [19]. It remains to be determined whether a more prolonged corticosteroid treatment in HCV-infected patients has detrimental effects on RNA titers of different HCV genotypes. The subjects' recruitment number was pre-determined by the sample size and power analysis. An appropriate sample size was utilized in this study, which achieved the primary and secondary end-points with a relatively small cohort of patients. If the sample size of the study were unnecessarily large, then the risks to the subjects would have been excessive according to the CONSORT statement [20]. An intention-to-treat analysis was conducted in patients who had received ≥1 dose of study medication; all of these subjects completed the study and had a subsequent efficacy observation. Because these randomized arms were not treatments of the HCV infection in this Study, and because during chronic infection, the level of serum HCV RNA is in a steady state with only minor fluctuations in untreated patients [21], instead of using demanding placebo arms, we utilized randomization as well as de-identified samples to blinding the investigators analyzing the outcomes. These approaches minimize biases in executing the study and in analyzing the outcomes according to the CONSORT statement [20]. Triple combination therapy of Pioglitazone/PEG-Interferon-α2/ribavirin has been used for previously treated HCV genotype 1 infection unsuccessfully in Switzerland [10] and in the USA [22], [23] or for treatment naive HCV genotype 4 infection successfully in Egypt [11]. It is unknown whether the beneficial effects of Pioglitazone together with PEG-Interferon-α2/ribavirin are circumscribed to HCV genotype 4 or to treatment naïve HCV of various genotypes. Although, the relatively low 15 mg Pioglitazone dose used in the INSPIRED-HCV trial in Switzerland [10] could have been insufficient to achieve efficacy, higher Pioglitazone doses (30 mg or 45 mg per day) have been utilized in HCV genotype 1 infection trials together with PEG-Interferon-α2/ribavirin without improving the sustained virological response [22], [23]. These higher Pioglitazone doses (30 mg or 45 mg per day) have been successfully utilized to prevent the development of type 2 diabetes in patients with impaired glucose tolerance in the USA [8], in the treatment of HCV genotype 4 treatment naive patients together with PEG-Interferon-α2/ribavirin in Egypt [11] and in our Study. Further, the known effects of Pioglitazone and related PPARγ agonists on glucose homeostasis [8],[12] and as documented in our Study, and their effects on serum HCV RNA titers (
Table 3
) suggest, but does not prove, that improving insulin sensitivity lowers HCV RNA titers. This has been proposed by Harrison on the basis that patients with QUICK-I values <0.35 (equivalent to HOMA-IR>1.8) have significantly higher HCV titers than patients with QUICK-I values >0.35 [24]. Further, treating patients with hepatitis C genotype 1 and insulin resistance using metformin improves insulin sensitivity and increases SVR rate in patients who reached HOMA lower than 2 at week 24 of therapy and in women, in whom the therapy doubled the SVR rate [25]. The findings of our Study support the notion that sequential treatment with Pioglitazone and PEG-Interferon-α2/ribavirin rather than concomitant administration should be considered in the treatment of chronic HCV genotype 4 infections, as suggested by Serfaty and coworkers [26]. The beneficial effects of Pioglitazone treatment on glucose homeostasis have been well documented in patients with impaired glucose tolerance [8], and it was also reported in triple combination therapy of Pioglitazone/PEG-Interferon-α2/ribavirin in patients with HCV genotype 1 or 4 [10],[11]. In our Study, Pioglitazone treatment decreased by day-14 and Prednisone increased by day-4 fasting serum glucose as well as the 2-hr glucose after an OGTT (
Table 4
and
8
). However, when compared to baseline day-0 values, neither Pioglitazone treatment at day-14 nor Prednisone treatment at day-4 affected HOMA-IR; QUICK-I; and HOMA-B, surrogate indicators of insulin resistance and secretion (
Tables 4
and
8
). It would probably require a more prolonged treatment with Pioglitazone and Prednisone to induce changes in these surrogate indicators of insulin resistance and secretion [26]. Elevated serum ALT and AST values are surrogate indicators of liver injury used in patient care and clinical research [9]. Pioglitazone treatment decreased at day-14 serum ALT levels and to a smaller degree serum AST levels (
Table 5
). Additional insights into the mechanisms of Pioglitazone on liver injury in chronic HCV infection would require assessment of liver biopsies before and after prolonged treatment since the effects on serum ALT were clinically modest at day-14. Prednisone treatment did not affect at day-4 serum ALT or AST levels (
Table 9
). Many experimental and clinical studies have shown that PPARγ signaling has anti-inflammatory properties in the liver [27]. Interestingly, HCV infection in Huh-7 cells and in humans inhibits PPARγ expression and function [27]. Two studies suggested therapeutic effects of bezafibrate, a non-selective agonist of PPAR α/δ/γ, during chronic HCV infection. Patients with HCV genotype 1 and 2 unresponsive to interferon therapy were treated for 8 weeks or 6 months with bezafibrate [28], [29]. At endpoint, HCV viral load (−0.5 log10) and ALT were statistically significantly decreased, suggesting anti-inflammatory and antiviral activities of the PPAR α/δ/γ signaling pathways in patients with chronic HCV infection. Given the non-selective nature of the PPAR α/δ/γ agonist, it is difficult to determine whether induction of PPARγ pathways occurred and played a role in the decreased HCV RNA. Pioglitazone also has shown improvement in liver injury and inflammation in patients with non-alcoholic steatohepatitis [9] and this has been attributed to the beneficial effects of Pioglitazone on insulin signaling [8]. An alternative explanation is a possible direct effect of Pioglitazone either as a PPARγ agonist or through other mechanisms on liver injury, independently of its insulin sensitizing actions [8]. Indeed, PPARγ agonists induce alternative, anti-inflammatory M2 macrophage activation [30], possibly linking insulin sensitivity with decreased liver injury in patients with HCV infection. At the molecular level, insulin resistance is promoted by a transition from an anti-inflammatory macrophage M2 state maintained by STAT6 and PPARγ to a pro-inflammatory macrophage M1 state driven by C/EBPβ and NF-κB activation and other transcription factors that play important roles in innate immunity [30]. Relevant to the management of HCV infected patients, liver fibrogenesis is expected to be ameliorated by PPARγ signaling [31] as well as by decreased inflammatory pathways arising from M2 macrophages [32] and resulting in decreased activation of hepatic stellate cells [33]. Pioglitazone increased serum IL-8 levels at day-14 when compared to baseline day-0 values (
Table 6
). Serum IL-8 values are elevated in HCV infection [34] and these values may reflect the effects of the HCV on il-8 gene transcription as well as its induction by TNFα [15]. We found that there was a relatively strong correlation between serum IL-8 and serum TNF-α levels for day-0 and day-14. Although it has been suggested that elevated levels of serum IL-8 may be associated with HCV resistance to Interferon-α2 therapy, the clinical or biological significance of the elevated serum IL-8 in HCV genotype 4 patients treated with Pioglitazone remains to be determined. Prednisone did not affect serum IL-8 levels at day-4 when compared to baseline day-0 values (
Table 10
). We found no differences between day-0 and day-14 in the Pioglitazone group and day-4 in the Prednisone group in other inflammatory markers such as serum IL-28B, TNF-α, IL-1α, IL-1β, IL-6, IL-8, IL-10, IFN-γ, MCP-1 and HGF (
Tables 6
and
10
). The lack of changes in IL-28B (IFN-γ3) is relevant since genetic variation in IL-28B affects the spontaneous clearance of HCV in patients [35]. Our study has some limitations: i] there were, as expected, clinically modest decreases in HCV RNA at day-14 in the Pioglitazone group; ii] the relatively small cohort could introduce potential biases; and iii] the findings may not be applicable for patients with HCV genotype 4 in other ethnic groups It remains to be elucidated whether the effects of Pioglitazone also occur in HCV genotype 4 infections in previously treated patients. The novel findings of our Study provide the foundation for basic and clinical investigations on the molecular mechanisms responsible for the Pioglitazone-induced decrease in HCV genotype 4 RNA titers. Future research should characterize whether the effects of Pioglitazone on HCV genotype 4 RNA titers are mediated indirectly by insulin signaling pathways or directly by affecting HCV genotype 4 hepatocyte entry and/or replication.
BODY.SUPPORTING INFORMATION:
Checklist S1
CONSORT Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial.(DOC)Click here for additional data file. Protocol S1
Trial Protocol.
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TITLE: How do patients with severe mental diagnosis cope in everyday life - a qualitative study comparing patients’ experiences of self-referral inpatient treatment with treatment as usual?
ABSTRACT.BACKGROUND:
Several hospitals in Norway provide short self-referral inpatient treatment to patients with severe mental diagnosis. No studies have compared the experiences of patients who have had the opportunity to self-refer to inpatient treatment with patients who have received treatment as usual. This qualitative study was nested within a randomised controlled trial investigating the effect of self-referral to inpatient treatment. The aim was to explore how patients with severe mental diagnosis coped four months after signing a contract for self-referral, as compared to patients receiving treatment as usual.
ABSTRACT.METHODS:
Data was collected using qualitative individual interviews with patients with severe mental diagnosis, conducted four months after being randomised either to a contract for self-referral (intervention group) or to treatment as usual (control group).
ABSTRACT.RESULTS:
Twenty-five patients participated in interviews - 11 from the intervention group and 14 from the control group. Results four months after randomisation showed that patients with a contract for self-referral appeared to have more confidence in strategies to cope with mental illness and to apply more active cognitive strategies. Patients with a contract also expressed less resignation, hopelessness and powerlessness than patients without a contract. In addition, patients with a contract seemed to be closer to the ideal of living a "normal" life and being a "normal" person.
ABSTRACT.CONCLUSION:
The results indicate that the patients who had a contract for self-referral had come further in the recovery process and should possibly be better off during treatment.
ABSTRACT.ELECTRONIC SUPPLEMENTARY MATERIAL:
The online version of this article (doi:10.1186/1472-6963-14-347) contains supplementary material, which is available to authorized users.
BODY.BACKGROUND:
Mental health services have changed considerably during the last decades. In Norway, an increasing number of mental health service users live outside institutions and receive health care from community health services, ambulatory service teams or outpatient treatment in community mental health centers
[1]. The focus has also shifted from perceiving severe mental illness as a permanent diagnosis towards focusing on what facilitates full or partial recovery
[2]. Recovery is described as a process where the illness's negative impact is minimized by focusing on the patient's strengths and interests
[3]. This shift has also moved the delivery of mental health services towards less institutional treatment and more integration in the patient's community
[4]. Ambulatory health services and outpatient treatment are considered to be important and cost-efficient means of strengthening the service user's independence and responsibility for the treatment
[4]. Outreach mental health services via community teams are widespread in the US and in Europe, especially for severe and chronic mental problems such as psychosis and schizophrenia
[5], and are also provided in crisis
[6]. It has been argued that institutional hospitalization should be reduced, and that when inpatient treatment is necessary, restraints should be minimized and patient control and self-determination strengthened
[4]. Health service users have described that services at home, for instance from ambulatory acute treatment teams, have increased feelings of being in control and being seen and heard, making the users feel more responsible for the treatment
[7]. Several qualitative studies have shown that the experience of control, autonomy and power to make choices is connected to improved quality of life
[8], thereby underlining the importance of such experiences. Although crisis resolution is increasingly provided in the service user's home
[6], periodically inpatient treatment is still necessary for patients with severe mental illness
[9]. Mental health service users have emphasized that services should be flexible and provide safe and predictable care in phases with strong symptoms, as well as facilitating the user's responsibility and ability to cope in phases with fewer symptoms
[10]. This emphasis suggests a combination of services such as home-based care to strengthen coping in good phases, and, periodically, inpatient care in phases with more symptoms. Even when inpatient treatment is necessary, it is essential to encourage and maintain the patient's control and responsibility. One way to achieve this is to give patients the opportunity to self-refer to inpatient treatment. The intention behind self-referral inpatient treatment is, in addition to reduce health service costs, to empower the service user and thereby improve symptoms as well as increase responsibility, coping, and quality of life. Giving service users the opportunity to self-refer provides the users with decision-making power during severe mental illness, and should therefore transfer responsibility and power to the service users. Several mental health hospitals in Norway provide self-referral to short inpatient treatment for some service users
[11–14]. Patients can refer themselves to short inpatient treatment when they feel that this is necessary. Such hospitalization is meant to be in line with the service user's wishes and needs, and the service user is considered the best judge of when inpatient treatment is necessary. The proposed effects of self-referral inpatient treatment include reduced numbers of inpatient hospitalizations, fewer acute hospitalizations in crisis, more appropriate use of inpatient treatment, improved quality of life, and improved coping
[11–14]. So far, there is no robust evidence for these effects. Internal evaluations have shown that the total amount of inpatient treatment can be reduced when service users have the opportunity to self-refer. One of these evaluations (published in Norway) indicated that the opportunity to self-refer for up to five days of inpatient treatment increased the total frequency of hospitalizations but decreased the number of hospitalization days by over 30%. In addition, the total amount of coerced hospitalizations was reduced by 50% six months after signing the contract
[13]. Service users have also reported satisfaction with the opportunity to self-refer and have emphasized that services became more predictable, increased the feeling of safety and reduced symptoms
[11]. Moreover, patients have reported that self-referral gave them more choices and a stronger feeling of control and autonomy
[11, 12] A randomised controlled study is currently investigating the effect of self-referral inpatient treatment in a community health center in Mid-Norway. This paper describes a qualitative study nested into this randomised controlled trial. The aim was to explore the patients' experiences with the intervention. It is reasonable to believe that self-referral to inpatient treatment will influence the patients' experience of control and autonomy. Exploring the patients' experiences would provide valuable knowledge about a new and growing treatment approach in mental health services. No studies thus far have compared the experiences of patients who have the opportunity to self-refer with patients who receive treatment as usual.
BODY.BACKGROUND.AIM:
The aim of the study was to compare the experiences of service users who had signed a contract for self-referral to inpatient treatment with the experiences of users who received treatment as usual, four months after randomization.
BODY.METHODS.DESIGN AND SETTING:
This was a qualitative interview study involving patients at a community mental health center in Mid-Norway. The study was nested into a randomised controlled trial (RCT) investigating the effect of a contract for self-referral inpatient treatment on the numbers of hospitalizations and hospitalization days, mental health symptoms and functioning, quality of life and coping (trial registration no. NCT01133587). Patients randomised to the intervention group in the RCT signed a contract with the hospital. This contract gave the patients authority to refer themselves to up to five days of inpatient hospitalization when they felt that such treatment was necessary. In addition to any hospitalizations initiated by health personnel, patients with a contract could thus admit themselves without contacting their doctor, duty doctor or emergency department. The contract was an internal written agreement between the patient and the mental health center and had legal status as such. The contract was an addition to the regular treatment offered and did not replace the patients' regular treatment plan. Patients randomised to the control group received treatment as usual and were offered a contract for self-referral after taking part in the RCT.
BODY.METHODS.PARTICIPANTS AND RECRUITMENT:
Inclusion criteria for the RCT were a diagnosis of psychosis or bipolar disorders with or without abuse problems. All participants were in need of long-term treatment in the hospital unit and the psychiatric community service. Health professionals with treatment responsibilities suggested participants for the randomized trial. All participants in the RCT were asked to participate in individual qualitative interviews.
BODY.METHODS.DATA COLLECTION:
Twenty-five patients were interviewed four months after randomisation - 11 in the intervention group and 14 in the control group. The interviews were conducted between November 2010 and December 2012, either in the hospital or in the patient's home. Three of the authors (MR, IEOM and GHE) conducted the interviews. All are psychiatric nurses and have extensive clinical experience. A research associate with extensive user experience participated in some of the interviews as well. The interviews lasted between 20 and 60 minutes. Themes in the interviews were taken from a pre-defined, semi-structured interview guide with open-ended questions (Additional file
1). The main questions in the interviews related to how the patients experienced their current mental health problems and everyday life. Typical questions were: "How is your life at present?" and "How is it for you when you are feeling ill?" All participants were invited to elaborate on what they did to prevent symptoms and maintain stability, on their experiences of previous and current symptoms and on current or previous experiences with mental health services. To avoid influencing the participants during the RCT and to ask the same questions of patients in both groups, no participants were asked directly about their experiences with the interventions. The interview questions were therefore general and focused on the participants' overall situation at the time. The interventions thus became topics in the interviews only if the participants brought it up themselves. All interviews were transcribed verbatim, although redundant words and pauses were deleted and local dialect was translated to written language. The quotes used in the result section were translated into English by the first author (MBR) and verified by the rest of the author group.
BODY.METHODS.ANALYSIS:
The analysis was conducted by a group consisting of a clinical psychologist, a researcher with extensive user experience, three psychiatric nurses, and an academic researcher on public health. The aim of this study emerged during an initial reading of the transcripts with a different research question in mind and with the intention to analyze the interviews across group allocation. Since there seemed to be several differences between the descriptions of the participants in the two groups, we chose to pursue these differences further. The authors were at that point already aware of the participants' group allocation, and we did not add new or "blinded" authors to the group. The interviews with patients from the control group (treatment as usual) were read and coded first, from which a list of codes (meaning units) and main themes were made. The coding process was conducted during several meetings in the author group. Then, the interviews with the patients from the intervention group (contract for self-referral) were coded. The code list and main themes from these interviews were compared with the codes and themes from the control patients. The main themes common for both groups were: Main themes from interviews: Experiences of disease and symptoms Strategies of copingShieldingStructure (food, sleep, medication)DistractionsSocial lifeThinking strategies Identity as a person with an illness Feeling safe Relationships (family, friends) Work and studies Dignity and power Values in life A normal life Four differences between the intervention group and the control group were found, which were then outlined and discussed in the author group. After the group analysis and discussion the first author (MBR) recoded all interviews and cross-checked the results with the transcripts to challenge the findings and look for different interpretations. The process confirmed the findings from the group's analysis. Quotes from the interviews were chosen to illustrate and substantiate the results. Quotes used in the result presentation are marked with the speaker's gender and study group (intervention or control). The final results were discussed and approved by the author group during the writing process.
BODY.METHODS.ETHICS:
The regional committee for medical ethics in Central Norway approved of the study, which was registered with the Norwegian Data Inspectorate. All participants were given verbal and written information about the study, and signed a consent form before taking part in interviews. All participants were given the opportunity to make contact with the staff at the department after the interview.
BODY.RESULTS:
Twenty-five patients participated in this study, 11 had a contract for self-referral to treatment (intervention group) and 14 received treatment as usual (control group). Nine of the participants were female. The mean age was 41 years (range 21-60 years). The participants had one or several diagnoses, including psychosis, bipolar disorders and substance use. Eight of the participants had a job or were studying. The sample is described in Table
1.Table 1
Characteristics of participants
VariablesTotal sampleIntervention (contract for self-referral)Control (treatment as usual)No. of participants251114GenderFemales963Age (mean (range))41 (21-60)44 (31- 58)33 (21-60)Diagnosis (some have more than one)Psychosis (ICD-10; F 20-29)19712Bipolar disorders (ICD-10; F 30-39)642Substance use (ICD-10; F 10-19)633Others (ICD-10; F 60-61)211No. of years since receiving diagnosis (mean (range))9 (2-23)10 (4-19)8 (2-23)EmploymentPaid work321Disability benefits1477Sick leave3-3StudiesStudies or serious plans to study523 The results present four aspects where the experiences of patients with a contract for self-referral appeared different than the experiences of patients who received treatment as usual. Patients with a contract expressed stronger confidence in strategies to cope with mental illness and seemed to apply more active cognitive strategies. Patients with a contract also had fewer expressions of resignation, hopelessness and powerlessness than patients who received treatment as usual. In addition, patients with a contract appeared to be closer to the ideal of living a "normal" life and being a "normal" person. The differences between the groups are described in light of what were common for all participants.
BODY.RESULTS.STRONGER CONFIDENCE IN COPING STRATEGIES:
All participants described several strategies to prevent and cope with symptom aggravation. They emphasized the importance of living a structured life with regular meals, sleep and medication, as well as avoiding smoking, excessive alcohol and drugs. Participants also talked about strategies to shield and distract themselves. Common shielding strategies were to be quiet, to be alone, to relax, and to avoid an excess of impressions, such as too many people or TV programs. Common distraction strategies were to watch TV, play computer games, read books, exercise and work, all of which could help curb anxiety, voices and visions. The participants also described that being with people or animals could both act as distraction, and provide meaningful relationships and experiences. These interactions could help to prevent and diminish symptoms. Overall, the participants described that a balance between activity and rest was necessary to cope with the mental illness. P: I have discovered that the more I talk to other people... the more stable I am. It is a sort of self-treatment or self-medication. To actively seek contact with other people every day. Some days, when I can't get in touch with anybody I walk down to the city and look at people. I do that because I don't want to be alone. That's a bad idea. Other days I have a strong need to be alone. Then I withdraw, turn off the phone and don't meet a single person during the whole day. I sit all day and watch TV-series or DVDs or play Playstation games or read a book. And these days come and go. There is no pattern – some days are like this and some days are like that.[...] I: So books help you?P: Yes, it is good to have something where things happen. [...] When I read I disappear a little. I disappear a little from this world. I just dream myself into the book. It is very relaxing. And it is a good way to ignore the things I don't want to think about... things that are stressful to think about.(Male, Control group) Although all participants identified coping strategies, there were some differences between the ways patients with and without a contract for self-referral described them. Patients with a contract voiced stronger self-confidence in applying coping strategies, both to prevent symptoms and to handle symptom aggravation. These patients also expressed greater confidence in keeping a good balance between activity and rest. Their descriptions appeared to include more experiences in applying and mastering various coping strategies. While patients without a contract described fairly common strategies to cope and prevent symptoms, patients with a contract appeared to have stronger and more independent creativity when describing how they prevented and coped with poorer phases. Some of the patients with a contract also described new and different ways to cope with their illness. Some of these strategies contradicted the advice usually given by professionals, such as preferring to be alone instead of having an extended social life. One patient, for example, expressed a deep satisfaction with having a certain distance from other people: P: I like to eat alone. I do. I have discovered that I like to do some things on my own. [...]I have two friends at present and we have a good distance... a good distance. We text each other and meet maybe once a week, and I really appreciate that.I: The friendship?P: Yes, the distance when we meet so rarely. We are in touch on the phone... to state that we are fine. [...] I read somewhere that friendship is what you think about the other person [...] having a presence even though they are not present.(Male, Intervention group)
BODY.RESULTS.COGNITIVE STRATEGIES TO INFLUENCE THINKING PATTERNS:
All participants reported that they experienced anxiety, mood swings and negative thoughts. Almost all participants also talked about disturbing voices and visions, describing cognitive techniques to cope with these symptoms. In addition, all patients relayed that their thinking was associated with control over their situation. Despite these commonalities, comparison showed that the participants used these techniques differently. Patients without a contract talked mostly about cognitive strategies as a means of adapting to the illness and helping them to do their best. They used words such as "observing", "understanding", and "recognizing" symptoms and emphasized accepting the illness. Their main focus centered on being conscious about their thoughts and views and on achieving more knowledge about the nature of the symptoms in order to decrease anxiety when those symptoms rose. One participant described cognitive strategies such as observing and recording the physical surroundings during strong anxiety and claustrophobia: P: I am supposed to observe and notice details in rooms and such... when these things happen. I don't know if it has helped so much. It has become worse and worse. And the feeling is very strong when I am in the midst of it. I almost have to vomit. It affects me physically.(Female, Control group) Meanwhile, patients with a contract talked less about recognizing, understanding and accepting. Instead, they used words such as "power", "control" and "strength". They also displayed stronger ability to influence their thinking patterns through the use of cognitive strategies. Furthermore, these patients talked more about being active and working with themselves in order to grow, to break barriers and to take opportunities. Some of them questioned if the voices and views were true, or whether there were other ways to interpret and understand them: P: [...] I used to think that everybody knew more than me about certain things. I don't anymore. [...] It's just confusing... and that's a difficult state. You become unsure of yourself and that's heavy. It's not that I know so much, but what do other people know? [...] I read for instance in a book about what happens after death. And I said to myself: How can he [the author] know more about that than me? Has he been there - or is he sitting on this side and imagining what happens afterwards? These simple things... I use tactics like these. Then it is not so bad. [...]It still annoys me when someone comes and tells me I can never get rid of it [the illness]. It will probably never be completely over, but... [...] There are limits to what I don't know [laughs]. It is important to believe in the experiences you have. Others might have similar or opposite experiences, but they are not necessarily stronger or more correct.(Male, Intervention group) The results also indicated that patients with a contract had more experience and more control over the cognitive techniques, as well as a deeper understanding of the relationship between thoughts and feelings. They seemed to be more focused on the possibility of choosing cognitive strategies to influence their thinking. While patients without a contract described some efforts to manage being in a painful situation, patients with a contract presented a wider variety of techniques to influence their mental state. This enabled them to change their ways of thinking and thus influenced their overall situation. P: Nowadays, I read a lot of self-help books. I used to be very skeptical... they had very simple solutions, but now I find them developing.I: What do you get from them?P: I guess they speak to my own problems. You work with yourself while you read. For example to shut out the past... that is described in all self-help books. To have bulkheads forwards and backwards... To think less about worries for the future and self-reproach about the past. That resonates with me... and then the brain works with it while I read.(Male, Intervention group)
BODY.RESULTS.RESIGNATION AND POWERLESSNESS:
All participants talked about the experience of being ill. Most of them described experiences of psychosis, explaining how emotions were experienced as bodily phenomena and how the symptoms were placed in their lives. Most of the participants also talked about negative and painful experiences, both with previous and current illness and with previous and current treatment. There seemed, however, to be a difference in the way that participants in the two groups talked about these experiences. Patients in the control group expressed more resignation and passivity, giving the impression that they were stuck in these experiences. They used phrases such as "yielding", "enduring", "resigning", "giving in" and "getting used to". Their descriptions included being powerless when facing their lives and problems, a stronger need for care and being more dependent on health services. These patients gave several examples of experiencing hopelessness and powerlessness. Although there were examples of interviews where feelings of helplessness and resignation were less prominent, the following examples represent very common descriptions for the control group participants: P: I have accepted the situation I am in. I think I have resigned a little. I have withdrawn from the things that I will never experience.I: Like what?P: Well... [sighs]... my life situation, for instance. I have for instance not had a partner in years... and it is quite stressful because you get very lonely. And after some time you come to a place where you realize that the hopelessness has come to stay.(Male, Control group) Patients who had a contract for self-referral, on the other hand, discussed courage and strength and talked about conscious choices and opinions. Their descriptions reflected being in a better place in their lives, and they seemed more active and less dependent on others. These patients expressed that they had influence over their overall situation. P: Well... how do you move on? It is to work... work with yourself. To locate the problems. Some would say to accept the problems, but that sounds a bit defensive to me. Maybe you get there... when you work with your problems they become more distant. You have to learn to like yourself until you get so sure that you are not put off by any little comment... like I used to be. It was... I had a word that emerged in my head during the last hospitalization: "Show off". That I was a show off. Like I knew it all, and wanted to have a piece of everyone else. But then I asked a friend of mine who was admitted during the same period: Do you think I am a show off? And she laughed a little. That is a way to get your problems more distant. Is it really like this? Is it possible? To be confident... to be sure... that you throw it around instead.(Male, Intervention group) There were also a few examples of patients with a contract who seemed to have achieved some distance from their previous bad experiences, as if they had success in moving on with their lives. P: And time heals all wounds. That's how it is. That's hard to say when you are ill, but when you are recovering you see that it is a one way street. Even though you might be temporarily dumped or feel bad and upset.I: Like a crisis?P: Yes, the crisis lasts around two hours. It's like that. I don't know how other people feel, but when I am ill I feel it could last forever. I am scared that it will be a permanent death row, but it doesn't. It takes shorter and shorter time before I am well again. And that is reassuring.[...] The problems I have aren't smaller or steeper, only shorter. It feels like I can put them behind me. Previously I could have days and weeks with the same problems and feel thrown around like a ball. Now it takes three or four hours.(Male, Intervention group)
BODY.RESULTS.BEING NORMAL AND LIVING A NORMAL LIFE:
Participants in both groups talked about the importance of having a normal life, doing normal things, and feeling like everyone else. A common theme was being identified with the illness, and many emphasized that being ill was not their sole identity. The patients reflected on their own status as persons with mental illness, expressing a desire for an identity beyond the role of a patient. P: I have a diagnosis, and that makes me ill – in medical terms. But it is a difference between that and perceiving yourself as an ill person. Cause I am only a guy. I'm just me.[...] I would like to build a different fundament to base the rest of my life on. To build my whole life on the foundation that I am an ill person in a treatment process... that I have an illness that defines me... I feel that it will be a very unstable life. It will fall apart. So I have decided to find the most stable foundation possible... that's what I'm trying to do.(Male, Control group) An important difference between the patient groups was that patients with a contract for self-referral had several descriptions which seemed much closer to the ideal of living a normal life and being a normal person. They used active phrases when describing their everyday life, such as "I know", "I will", and "I can". They also acknowledged "the good life" and seemed to experience more closeness to a normal everyday life. Patients who had a contract talked about the normal life with more confidence and seemed more independent of social expectations and acceptable values. I: What is the point with having an ambulatory supervisor?P: You press an extra button and get feedback on things that might... that you do well or that people notice... that there are some positive things too. They emphasize it to strengthen your self-confidence. The self-confidence isn't very strong. You get set back from being admitted. I was away for nine months. I was admitted for nine months. Afterwards you are handicapped. While I was admitted I received my meals every day... some places they helped me get up in the morning. I was helped and supported all the time. And that was difficult to give up. But it is very good to have control over your own life. Cooking and having a nice time... to light candles and... to enjoy living.(Female, Intervention group) As part of a normal life, most participants wanted to study or work, and work was associated with identity and a good life. Many of the patients who received treatment as usual highlighted studies and education as a goal which might be difficult to reach, and some of them expressed a great deal of uncertainty regarding the possibility of coping with work on an everyday basis. P: I had my job until I realized that it was enough and then I quit.I: You quit?P: Yes. My contract expired... and at the same time I told them I had to quit.I: How was that for you?P: I stayed on the sofa for a week doing nothing. And then I woke up again. It felt like... like I recharged my strength.(Female, Control group) In contrast, many of the patients who had a contract for self-referral seemed to have progressed beyond having education or work as a distant goal. Several had taken the initiative to commence studies and had concrete plans for completion, and they did not mention having to interrupt the progress of their studies due to illness as a problem. They focused instead on the courage and strength necessary to continue and complete. P: I found out that the deadline for applications was expired, but I called today and they told me it was fine after all. I have a week to make an application for a [...] degree to finish the last two years... [...] If I can manage to work with art in some way, or with doing odd jobs. It is very exciting and I look forward to writing things this week and to look through my previous work.(Female, Intervention group)
BODY.RESULTS.EXPERIENCES WITH A CONTRACT FOR SELF-REFERRAL OR TREATMENT AS USUAL:
Although the patients were not asked directly about their experiences with the intervention (contract for self-referral or treatment as usual) some of the patients raised the subject on their own accord. Patients who had a contract for self-referral expressed a great deal of authority and strength when talking about the contract, their contact with the health services and what they needed in the future. Some said that the contract gave them more influence and that this gave them a sense of control. Some also described that they felt safe since they had the option to self-refer at any time: P: I believe in the project with self-referral. It is a pillar... where you know that if something happens which is really bad... You know that you can come here and get a break. It feels safe.(Female, Intervention group) Meanwhile, a few of the patients who did not have a contract for self-referral were very dissatisfied: P: I am very disappointed to be in the control-group [receiving treatment as usual]. I am done with the ordinary mental health services. I just want the self-referral inpatient contract.(Male, Control group)
BODY.DISCUSSION.STRENGTHS AND LIMITATIONS:
Two researchers with extensive user experience in mental health services participated in different parts of this study. One participated in the data collection and took part in the initial analysis, while the other (DB) participated in the analysis process and in writing the manuscript. User participation during the research process strengthens the authenticity of the results and helps ensure that the users' voices are heard. Since this study was nested within a randomised controlled trial the interviews had to avoid direct questions about the intervention and focus instead on the participants' general perceptions of their current situation. This made the data material rich and focused on everyday life, which strengthens the quality of the findings. Although the interviewers were advised to avoid direct questions about the intervention, several of the participants talked about having or not having a contract. Some participants who had been randomised to treatment as usual were disappointed, and the interviewers had to respond to this. This feeling of disappointment may have led to negative expressions from those participants. Effort was made to not lead the participants to overstate the positive experiences with the intervention so as to please the interviewers, but the effectiveness of this effort is unclear. Although the sample is fair-sized for a qualitative interview study, the results might not be valid for other samples in other areas of health services. The interviews were mostly conducted by researchers who have worked as psychiatric nurses at the hospital. The nurses were chosen as interviewers because they were very competent health professionals and familiar to the patients. They were thus able to ensure that patients were taken good care of if they had adverse reactions during or after the interview. In addition, some participants stated that they would not have participated in interviews with unfamiliar interviewers. However, this familiarity might also have led to more favourable evaluations of the hospital's services and the intervention than if the interviews had been conducted by independent researchers. Moreover, since the participants in the two different groups were treated in the same health service organisation, they had the possibility to interact and discuss their experiences. Making comparisons based on qualitative interview data is a challenging undertaking. Since the aim of the study emerged during an initial reading of the transcripts, across group allocation, the authors were not "blind" before the more "comparative" analysis. We consider it a strength to pursue the initial surprising findings in the data material. However, at that point we should have included new and "blind" authors in the following analysis, as that would have strengthened the analysis process and the results. We analysed the interviews with patients in the control group before comparing the main themes from the control patients with the interviews with those of the intervention group. The differences between the groups were cross-checked with the data material and discussed in the analysis group to reduce the risk of overstating the differences. The differences presented in the results section are based on general impressions when reading and analysing the interview transcripts and must be interpreted with caution. Considering that several specific words and phrases were more present in either of the two groups, we could have used a computer-based system to compare the occurrences, which could have in turn supported the findings. Not all participants in the RCT participated in interviews after four months. Despite the initial randomisation, those agreeing to participate in interviews were self-selected. Direct comparison is therefore difficult. In addition, it is not clear whether the differences were due to the intervention (self-referral to treatment) or to other factors. A comparison of the groups on demographic variables (Table
1) also shows that there are some differences between the groups: the participants in the control group were younger, had a higher rate of psychosis diagnosis, and had a higher proportion of males. The differences between the groups in terms of age, diagnosis and gender may have influenced the results of this study.
BODY.DISCUSSION.DISCUSSION:
The results showed that many of the patients with a contract for self-referral expressed more confidence in strategies to cope with mental illness, and they seemed to apply more active cognitive strategies. Patients with a contract also expressed less resignation, hopelessness and powerlessness than patients without a contract, appearing to be closer to the ideal of living a "normal" life and being a "normal" person. Coping strategies are important in the management of mental illnesses
[15, 16]. Such strategies are used to cope with life stressors, to ameliorate symptoms and to prevent periods of symptom aggravation. Most persons who suffer from psychosis apply one or several strategies to cope with mental symptoms
[17]. Although there is little knowledge about the usefulness of specific coping strategies, research shows that having several strategies at hand is more effective than relying on just one, although there is not one specific coping strategy which is more effective than the others
[17]. In the present study, the patients who had a contract for self-referral described coping strategies which appeared more advanced, especially the cognitive strategies they used to influence their thinking patterns. Strategies to manage mental health symptoms are often taught by professionals during treatment
[18]. In addition to these, most persons suffering from mental health illnesses develop personal coping strategies
[18]. In the present study, all patients described coping strategies that they had learned, and some of the patients described self-developed strategies. Compared to patients who received treatment as usual, patients with a contract for self-referral described new and different coping mechanisms. Previous evaluations of self-referral have shown that although the total frequency of hospitalizations increased, the number of hospitalization days in fact decreased by more than 30%. Furthermore, the patients reported that a contract for self-referral lessened the burden of having to "convince" professionals that hospitalization was necessary and to be "sick enough" to need inpatient treatment
[11, 13]. In other evaluations, patients have also expressed that the opportunity to self-refer gave them safety and confidence to make new efforts and to challenge old behavioral patterns
[12]. This might help account for the differences in coping strategies we found in the present study. Using coping strategies is in line with the recovery model. According to this model, a person with long-term mental illness takes an increasingly active role in managing the impact of the mental illness as they move towards recovery
[19]. Coping strategies can be divided into reactive, anticipatory, preventive and proactive strategies
[16], and can be placed on a recovery continuum, where proactive strategies are used by persons who have come farthest in the recovery process. One of the findings in the present study was that patients with a contract for self-referral described more confidence in applying coping strategies than patients without a contract. This indicates that the patients with a contract had more experience in successfully using coping strategies and thus had come further in the recovery process. They talked more about being active, growing, breaking barriers and taking advantage of opportunities. This finding is in line with previous research, where empowerment has been described as the most important factor for recovery
[18]. The patients who had a contract for self-referral also described some coping strategies which sometimes ran counter to the advice typically given by professionals. This indicates that patients who have had the opportunity to self-refer to treatment felt more in control and more able to contradict or neglect advice from the mental health services. This might be due to the opportunity to be in charge of decisions regarding treatment which could increase autonomy and the feeling of being in control. In the present study, the participants contrasted the identity of being an ill person with that of being a normal person. The term "illness identity" has been described as a set of roles and attitudes that persons with a mental illness have developed
[2]. The participants in the present study related the perception of being a person with an illness to the possibility of being a normal person capable of leading a normal life. Perceiving oneself as an ill person is closely linked to feelings of stigmatization, which is connected to low self-esteem and low self-efficacy
[20, 21]. The perception of an illness identity has been described as an important part of the recovery process
[2]. Some have linked illness identity to hope and self-esteem, which is in turn linked to coping, engagement, and social interaction
[2]. Coping, engagement and social interaction subsequently have an impact on vocational outcomes and symptom severity. Authors have argued that changing illness identity is an important step in improving mental health illness and functioning
[2]. The results from the present study indicate that patients with a contract for self-referral might have a more clarified relationship towards their illness identity than patients without a contract, therefore suggesting that the former group may have come further in the recovery process. That said, it is not self-evident that having a contract for self-referral to treatment necessarily impacts illness identity, especially since the present study is based on interviews only four months after signing a contract for self-referral. It would be important to further investigate whether an opportunity to self-refer leads to increased autonomy, sense of control and decision-making power, all of which might subsequently impact the perception of illness identity. Another important finding in the present study was that the patients who had a contract for self-referral tended to express less powerlessness, resignation and hopelessness than those who received treatment as usual. The patients who received treatment as usual referred to their problems as something that they were stuck with, and they described themselves as being dependent on care from the health services. This difference in focus might be related to the finding that patients in the intervention group had stronger confidence in using coping strategies. Some have argued that stronger hope and self-esteem might lead to less avoidance, more problem-oriented strategies and more social interaction
[2]. Previous research has shown that persons with more hope and insight in their illness use more problem-oriented and less avoidant coping strategies
[22] and that poor confidence is connected to using avoidant strategies
[23]. These findings are in line with the present study, which also illustrates Bandura's idea of self-efficacy
[24]. Self-efficacy is explained as a personal capability and distinguishes one's belief in capability from self-esteem and whether you like yourself
[25]. In the present study, we found that patients with a contract for self-referral talked more about living a normal life with work and studies. They seemed to have a closer relationship to what they called a "normal life" and a somewhat more active attitude towards coping, thereby possibly exhibiting a greater sense of control. Davidson and Roe argue that recovery has to be pursued actively by the patient, and that not everybody does this
[3]. The findings in the present study indicate that patients who have had the opportunity to decide whether and when they needed referral to inpatient treatment are more actively pursuing recovery, both from and in mental illness. In this context signing a contract for self-referral seems to be a rehabilitation approach that encourages and supports activity, self-determination, control, and participation.
BODY.CONCLUSION:
Patients with a contract for self-referral to treatment appeared to have a wider range of coping mechanisms, more self-developed and advanced strategies, and stronger confidence in applying the strategies. The findings indicate that having the opportunity to self-refer might help strengthen autonomy, sense of control, and self-determination. According to research on coping strategies, these patients could be better off both during treatment and in the recovery process. In a similar vein, patients with a contract voiced less resignation, hopelessness and powerlessness and appeared to be closer to experiencing a "normal" life.
BODY.ELECTRONIC SUPPLEMENTARY MATERIAL:
Additional file 1:
Interview guide - Self-referral inpatient treatment.
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TITLE: Nicotine delivery, tolerability and reduction of smoking urge in smokers following short-term use of one brand of electronic cigarettes
ABSTRACT.BACKGROUND:
This randomized, partially single-blinded, 6-period crossover clinical study of adult smokers compared the nicotine pharmacokinetics, impacts on smoking urge and tolerability of various formulations of one brand of e-cigarettes with that of a tobacco cigarette.
ABSTRACT.METHODS:
Five e-cigarettes with different e-liquid formulations containing 1.6 % and 2.4 % nicotine and a conventional tobacco cigarette were randomized among 24 subjects under two exposure sessions consisting of a 30-min controlled and a one-hour ad lib use period to assess plasma nicotine levels, impacts on smoking urge and adverse events. The 30-min controlled use session comprised an intensive use of the e-cigarettes with a total of 50 puffs taken every 30 s for comparison to a single conventional cigarette having a typical machine-measured nicotine yield (~0.8 mg). Ad lib product use conditions provided insight into more naturalistic product use behaviors and their accompanying smoking urge reductions. Adverse events (AEs) were assessed by the Principal Investigator.
ABSTRACT.RESULTS:
Significant (p < 0.05) increases in plasma nicotine concentrations occurred within 10 min of controlled e-cigarette use and significant (p < 0.001) reductions from baseline smoking urge were observed within 5 min. E-cigarette and cigarette nicotine plasma levels were comparable for up to one hour of use. After both sessions (90 min), nicotine exposure was the highest for the cigarette, with all e-cigarettes showing 23 % to 53 % lower plasma concentrations. During controlled use, peak reduction in smoking urge for e-cigs occurred later than for the cigarette. After completion of both sessions, significant smoking urge reduction persisted for most of the tested e-cigarettes, albeit at levels lower than that provided by the tobacco cigarette. Nicotine content, vehicle differences, and the presence of menthol did not significantly affect smoking urge reduction by the e-cigarettes. No subjects were discontinued due to AEs. The most frequently reported AEs events included cough, throat irritation, headache, and dizziness.
ABSTRACT.CONCLUSIONS:
Blood plasma nicotine levels obtained from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine were significant, but lower than those of conventional tobacco cigarettes, yet the reduction in craving symptoms were broadly comparable. The types of AEs were consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated.
ABSTRACT.TRIAL REGISTRATION:
http://ClinicalTrials.gov identifier: NCT02210754. Registered 8 August 2014.
BODY.BACKGROUND:
Smoking remains the leading preventable cause of premature death in the United States [1]. Electronic cigarettes (e-cigarettes) are rapidly becoming a popular alternative to cigarette smoking worldwide and are garnering significant attention as potentially reduced-exposure replacements for conventional cigarettes (cigarettes) [2–6]. E-cigarettes consist of a battery, heating component, and a cartridge containing tobacco-derived nicotine in a solution composed of glycerin and/or propylene glycol (PG), and flavorings. Upon activation, the heating element heats the solution to generate an aerosol that is inhaled by the consumer in a manner that mimics smoking. Pharmacokinetic studies with early-generation e-cigarettes found that they delivered markedly lower levels of plasma nicotine than conventional cigarettes [7, 8]. More recent studies have reported that experienced subjects using later-generation e-cigarettes containing 9 to 24 mg/mL of nicotine attain significant increases in plasma nicotine concentrations over baseline values that can be similar to those obtained from conventional cigarette smoking [9–11]. These results suggest that an acclimation to the product may be necessary for naïve smokers to become familiar with the characteristics of the specific e-cigarettes in order to effectively use them in a subjectively enjoyable manner. Moreover, these studies also demonstrated a reduction in smoking urge or abstinence symptoms following e-cigarette use, even for products that deliver less nicotine than conventional tobacco cigarettes. This is quite consistent with a perspective that the substantial sensory and behavioral aspects of cigarette smoking that are mimicked by e-cigarettes may provide meaningful relief of the cigarette cravings commonly reported by abstinent smokers. Surveys and clinical studies evaluating the impacts, tolerability and adverse events (AEs) associated with e-cigarette use suggest that they are generally well-tolerated following short-term use [1, 9, 12–16]. Commonly reported AEs include symptoms such as mouth and throat irritation, light-headedness, dizziness and dry cough. The primary objective of this study was to examine the nicotine blood plasma levels and smoking urge impacts of various formulations of one brand of e-cigarette with that of a tobacco cigarette. The tested products contained different flavorings, aerosol forming excipients (i.e., propylene glycol, glycerin) and nicotine levels. The secondary objectives were to assess the tolerability and any adverse events associated with the study products following short-term use under intensive controlled use conditions, as well as under more natural ad-lib use conditions.
BODY.METHODS.PARTICIPANTS:
The study protocol and the informed consent forms were approved by Chesapeake IRB, Columbia, MD. A total of 107 potential subjects were recruited from the Lincoln, NE area using standard advertising methods (i.e., print and radio advertisements) and from a database of subjects who had previously participated a clinical research study or who had expressed interest in participating in a study. All potential subjects were provided details regarding the study and written informed consent was obtained prior to completion of any study procedures. Sixty-one subjects were excluded for not meeting the predefined inclusion/exclusion criteria, while five subjects declined to participate prior to enrollment and three subjects were excluded because the study had reached the recruitment target of 38 eligible subjects. The 38 subjects meeting the eligibility criteria participated in a 7-day at-home lead-in period during which they used and became familiar with two of e-cigarette study products (non-menthol and menthol, 2.4 % nicotine with glycerin). All subjects who participated in the at-home lead-in period were allowed to check in at the start of clinical conduct. Two subjects chose not to participate further after the lead-in period and one subject failed further screening requirements at check-in. A final study population of 24 subjects were enrolled into the study and randomized into one of six product usage sequences with four subjects per sequence. One subject withdrew consent after completion of the first product use on Day 1 of the trial due to a personal reason (family emergency). All subjects participating in the study from the time of the lead-in period were paid for their participation. The main criteria for inclusion were as follows: healthy adult male and female smokers, 21 to 65 years of age, inclusive; smoker for at least 12 months and currently smoked an average of 10 or more manufactured cigarettes per day (no restriction on brand-style); positive urine cotinine at screening (≥ 500 ng/mL); and exhaled carbon monoxide CO > 10 ppm at screening. Exclusion criteria included: history or presence of clinically significant mental or physical health conditions; females who were pregnant or breastfeeding; high blood pressure; body mass index < 18 kg/m2 or > 40 kg/m2; acute illnesses (e.g., upper respiratory infection, viral infection) requiring treatment within 2 weeks prior to check-in; use of prescription smoking cessation treatments, anti-diabetic or insulin drugs or medications known to interact with cytochrome P450 2A6; positive urine screen for alcohol or drugs of abuse; and self-reported puffers (i.e., smokers who draw smoke from the cigarette into the mouth and throat but do not inhale). Subjects who had used any tobacco- or nicotine-containing products other than manufactured cigarettes or e-cigarettes within 28 days of in-clinic product use were also excluded.
BODY.METHODS.PRODUCTS TESTED:
A rechargeable version of an e-cigarette that is currently sold in retail outlets throughout the United States was used in this study. The rechargeable e-cigarette consists of a battery segment and a cartomizer segment comprising the heating unit and a liquid reservoir which can be separated from the battery for recharging or replacement when the e-liquid is depleted. The battery operates at a voltage of 3.7 volts (nominal) and the resistance of the heating element is approximately 3 ohms. The maximum operating temperature is dependent on both the state of reservoir fluid fill and on the manner of use and was not recorded in this study. Two commercial e-cigarette products that contained 16 mg/mL (1.6 %) USP grade nicotine were used in this study. As well, three non-commercial products that contained 24 mg/mL (2.4 %) USP grade nicotine were used in this study to evaluate various product characteristics considered important to further product development. In addition to nicotine, the e-cigarettes used in this study contained USP grade glycerin and/or propylene glycol (as described below), distilled water (<20 %), citric acid (<1.0 %) and natural or artificial flavors (<10 %). The nicotine yield of the conventional cigarette used in the study was approximately 0.8 mg per cigarette [17]. The study products included:Product A: Classic Tobacco flavored e-cigarette (2.4 % nicotine, ~75 % glycerin)Product B: Classic Tobacco flavored e-cigarette (2.4 % nicotine, ~50 % glycerin/~20 % propylene glycol)Product C: Menthol flavored e-cigarette (2.4 % nicotine, ~75 % glycerin)Product D: Classic Tobacco flavored e-cigarette (1.6 % nicotine, ~75 % glycerin)Product E: Classic Tobacco flavored e-cigarette (1.6 % nicotine, ~50 % glycerin/~20 % propylene glycol)Product F: Tobacco Cigarette
BODY.METHODS.STUDY DESIGN:
This was a randomized, partially single-blinded, six-period crossover study conducted at a single independent research center (Celerion, Lincoln, NE). Twenty-four subjects were randomly selected from the pool of 38 subjects who participated in the at-home lead-in period were enrolled into the testing phase of the trial and randomized to assigned product sequences. The subjects checked into the clinic on Day −2 and abstained from using of nicotine-containing products until product use on Day 1. Days 1, 3, 5, 7, 9, and 11 were designated product use days while Days −1, 2, 4, 6, 8, and 10 were designated wash-out days. The subjects were housed at the test site from the time of check-in through completion of study events on Day 11. The clinic staff monitored the subjects during the confinement period to ensure that no illicit nicotine or tobacco products were used. Study investigators were not blinded, but the subjects were as the all the e-cigarette products appeared the same. The menthol product, however, was easily discernible due to taste. Previous studies have demonstrated that a lack of familiarity with e-cigarette products may result in low nicotine intake with their use [7, 18]. In order to allow study participants to become familiar with the e-cigarette devices, subjects were instructed on the appropriate use of the products and were required to demonstrate the appropriate use to clinic staff. Each subject was then provided with two units of the menthol and non-menthol 2.4 % nicotine products containing glycerin for at-home use prior to the start of the study and instructed to use the products each day during the 7-day lead-in period. Two types of exposures were utilized in the study on each product use day: a controlled use period followed by an ad lib use period. Similar 2-stage designs have been informative in prior studies evaluating the nicotine delivery and subjective effects of e-cigarettes [5–9, 19]. Enrolled subjects were randomized into one of six product usage sequences (Table 1) with four subjects per sequence.Table 1Summary of study demographics and FTCD scores by study product sequence and overallTrait/TestCategory/StatisticStudy product sequenceABFCED (N = 4)BCADFE (N = 4)CDBEAF (N = 4)DECFBA (N = 4)EFDACB (N = 4)FAEBDC (N = 4)Overall (N = 24)SexFemale2 (50 %)2 (50 %)2 (50 %)2 (50 %)2 (50 %)2 (50 %)12 (50 %)Male2 (50 %)2 (50 %)2 (50 %)2 (50 %)2 (50 %)2 (50 %)12 (50 %)RaceAmerican Indian/Alaska Native1 (25 %)0 (0 %)0 (0 %)0 (0 %)0 (0 %)0 (0 %)1 (4 %)Black or African American0 (0 %)1 (25 %)0 (0 %)2 (50 %)0 (0 %)0 (0 %)3 (13 %)White3 (75 %)3 (75 %)4 (100 %)2 (50 %)4 (100 %)4 (100 %)20 (83 %)EthnicityHispanic or Latino1 (25 %)0 (0 %)0 (0 %)0 (0 %)0 (0 %)0 (0 %)1 (4 %)Not Hispanic or Latino3 (75 %)4 (100 %)4 (100 %)4 (100 %)4 (100 %)4 (100 %)23 (96 %)Age (yrs)Mean38.340.538.335.334.045.838.7SD12.0415.7015.444.039.496.1310.77Height (cm)Mean167.25175.75168.75172.75167.00171.75170.54SD3.40310.2436.1313.7758.2069.8117.331Weight (kg)Mean84.179.270.874.780.083.978.8SD16.5225.896.1513.1312.9314.1414.91BMI (kg/m2)Mean30.05025.19824.79825.01528.94828.37527.064SD6.04395.76220.68543.84646.38104.32554.8512Fagerström Test for Cigarette Dependence ScoreMean4.05.35.06.04.07.85.3SD2.160.51.412.162.162.632.18Median3.55.04.55.54.58.55.0Minimum2544141Maximum767961010 Given the wide variability in smoking behaviors, the controlled use period of the study was intended to provide some degree of standardization of the nicotine "dose" associated with each of the study products to better understand potential influences of different vehicles, flavor characteristics and nicotine content on measured parameters. As such, the controlled use period of the study consisted of 50 puffs of the assigned e-cigarette product (5-s puffs at 30-s intervals, approximately 24.5 min of use) and smoking one conventional tobacco cigarette (30-s intervals with the subjects' normal puff duration, approximately 4.5 min of use). Fifty e-cigarette puffs was selected as an optimal controlled "dose" as it approximated the dose of nicotine delivered by the cigarette used in the study (~0.8 mg) based on machine yields of the e-cigarettes determined previously using a standardized Canadian Intense puffing protocol [20, 21]. Thus, this controlled "dose" period was intended to reflect intensive usage of the e-cigarettes for comparison to the tobacco cigarette used in the study. During the controlled use period, subject puff counts were monitored by the clinical staff and all e-cigarettes were weighed before and after use in order determine the amount of solution consumed. Further, evaluation under the ad lib use conditions provided plasma nicotine levels under uncontrolled, natural use conditions and insights into product use behaviors accompanied by subjective self-assessments of smoking urge. During ad lib use, subjects assigned to an e-cigarette or tobacco cigarette product were allowed to use the product as desired for the entire hour (use of the assigned e-cigarette products in an unrestricted manner or smoking as many tobacco cigarettes as they chose) and subjects were responsible for maintaining their own puff counts. All e-cigarette products were weighed before and after use. The ad lib use period was conducted immediately following the end of the controlled product use session. Blood samples for plasma nicotine determinations, smoking urge assessments, blood pressure, pulse rate, and exhaled CO measurements were also obtained at scheduled time points on each product use day.
BODY.METHODS.PHARMACOKINETICS (PK) - PLASMA NICOTINE:
Blood samples for the measurement of plasma nicotine concentrations were taken by direct venipuncture at 10 min prior to, and at 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 min following the start of the controlled product usage on Days 1, 3, 5, 7, 9, and 11. Plasma nicotine was analyzed by LC-MS/MS using validated analytical methods with appropriate quality controls in accordance with applicable FDA Good Laboratory Practice regulations (Title 21 CFR Part 58). The limit of quantification for nicotine was 0.200 ng/mL. The following PK parameters were calculated:Cmax0–30 - maximum observed concentration from time zero to 30 min.AUC0–30 - area under the concentration-time curve from time zero to 30 min.tmax0–30 - time of the maximum concentration from time zero to 30 min.AUC30–90 - area under the concentration-time curve from 30 to 90 min.C90 - maximum observed concentration at 90 min.
BODY.METHODS.PHARMACODYNAMICS – SMOKING URGE:
Smoking urge was assessed using a simple and subjective 100 mm visual analog scale (VAS). Various forms of VAS have been used in e-cigarette studies as a tool for obtaining various subjective effects data associated with e-cigarette use and measuring nicotine and smoking abstinence symptom suppression [6–10]. Participants were asked to rate "how strong is your urge to smoke right now?" by placing a line through a 100 mm line where far left indicated: 'not at all' and far right indicated: 'extremely'. Assessments occurred within 1 min prior to the −10 (pre-product use), 5, 15, 25, 30, 60, and 90-min PK blood draws. The smoking urge change-from-baseline was calculated as the difference between the pre-use and post-use smoking urge result for each tested product. The following pharmacodynamic (PD) parameters were calculated:Emax0–30 - Maximum smoking urge change-from-baseline from time zero to 30 min.Emaxreduction0–30 - Maximum smoking urge reduction from baseline from time zero to 30 min.AUEC0–30 - Area under the effect curve (smoking urge change-from-baseline) from time zero to 30 min.tEmax0–30 - Time of the maximum smoking urge change-from-baseline from time zero to 30 min.AUEC30–90 - Area under the effect curve (smoking urge change-from-baseline) from 30 to 90 min.E90 - Observed smoking urge change-from-baseline at 90 min.
BODY.METHODS.TOLERABILITY AND ADVERSE EVENTS (AES):
Tolerability evaluations included assessments of AEs, vital signs and concomitant medications. AEs reported by the subjects or observed by the clinic staff were assessed for severity (mild, moderate, or severe), as serious or not serious, and relationship to the study products (unrelated, unlikely, possible, probable, or definite) by the Principal Investigator. A study product use-emergent AE was defined as an AE that started or intensified at the time of or after study product usage. An AE that occurred during the washout period between study products was considered study product use-emergent for the last study product given. All reported AEs were coded with Medical Dictionary for Regulatory Activities (MedDRA®), Version 17.0. AEs were recorded by frequency by study product and the number of subjects experiencing product use-emergent AEs.
BODY.METHODS.DATA ANALYSES:
Non-compartmental PK and smoking urge parameters were calculated using Phoenix® WinNonlin® Version 6.3 (Certara, Princeton, NJ) from the individual nicotine concentration and smoking urge change-from-baseline data. All statistical summarizations and comparisons were calculated using SAS® Version 9.3 (SAS, Cary, NC). Analyses of variance were performed on the plasma nicotine AUC0–30, AUC30–90, Cmax0–30, and C90 parameters, and a Wilcoxon Signed Rank Test was used for the tmax0–30 parameter to assess differences between the e-cigarettes and the tobacco cigarette. Usual brand cigarette flavor (menthol or non-menthol) was included in each of the analyses as a covariate to account for any impact that flavor preference might have had on the results. Repeated measures ANOVA with simple contrasts were used to compare the maximum observed concentrations of plasma nicotine within the first 30 min and at 90 min (Cmax0–30 and C90) to the pre-product use concentration. The smoking urge parameters AUEC0–30, AUEC30–90, Emax0–30, E90, and tmax0–30 were compared using methods similar to those used in the PK analyses. Differences were considered statistically significant at an alpha level of 5 %.
BODY.RESULTS AND DISCUSSION.PARTICIPANT CHARACTERISTICS:
Of the 24 subjects who were enrolled into the testing phase of the study and randomized to study product sequences, 23 subjects completed the study and one subject withdrew due to a family emergency. A summary of the subjects' demographics together with the results of the Fagerström Test for Cigarette Dependence (FTCD) scores [22, 23] for all study participants by study product sequence and overall is presented in Table 1.
BODY.RESULTS AND DISCUSSION.PRODUCT USE:
The mean pre-to-post use product weight differences for the e-cigarettes and the mean puffs taken from all products during each period of the study are provided in Table 2. During controlled product administration, all subjects were to take the same number of puffs (50) from the e-cigarette products with a defined inhalation pattern (5-s puffs every 30 s) while monitored by the clinical staff in an attempt to standardize nicotine intake. The resulting mean weight differences were comparable across study products (0.2238 - 0.2570 g), with the highest and lowest estimated nicotine delivery from the 1.6 % nicotine products. During the ad lib product use period, subjects were free to puff as often as they chose with no limitation on puff duration. As a result, the number of puffs from each of the e-cigarette products varied widely across subjects during the ad lib use period. However, the mean puff counts were fairly comparable across products, averaging between 49.5 and 60.3, with the highest and lowest mean puff counts again noted with the 1.6 % nicotine products. Product weight differences followed the same pattern. Hence, there was no clear indication in either period that subjects compensated during use of the lower nicotine-containing products by taking more or deeper puffs in an attempt to self-administer more nicotine.Table 2Product use summaryControlled Use Period
Ad Lib Use PeriodE-CigarettePuffsPre-to-Post Use Weight Difference (g)PuffsPre-to-Post Use Weight Difference (g)2.4 % nic + Gly50.0 (50–51)0.2251 ± 0.040852.3 (5–128)0.1467 ± 0.0843
N = 232.4 % nic + Gly/PG50.0 (50–51)0.2349 ± 0.063355.4 (4–136)0.1445 ± 0.0880
N = 232.4 % nic + Gly + menthol50.0 (50–51)0.2421 ± 0.047758.0 (8–140)0.1604 ± 0.0827
N = 231.6 % nic + Gly50.0 (50–51)0.2238 ± 0.039960.3 (8–112)0.1738 ± 0.0937
N = 231.6 % nic + Gly/PG50.0 (50–51)0.2570 ± 0.043349.5 (3–118)0.1194 ± 0.0675
N = 23PuffsCigarettes SmokedPuffsCigarettes SmokedTobacco Cigarette10.5 (9–13)1.0 (NA)38.6 (16–103)3.6 (2–7)
N = 24Values for puff count and cigarettes smoked are presented as mean (range). Values for the pre-to-post weight differences are presented as mean ± SD
nic nicotine, Gly glycerine, PG propylene glycol The mean differences in product weights were observed to be smaller for each e-cigarette (~22 % - 54 %) following ad lib product use compared to the controlled product administration despite the subjects having taken similar numbers of puffs, or more, during ad lib product use. This was likely due to shorter puff durations during ad lib product use. For the tobacco cigarettes, subjects smoked only a single cigarette during the controlled product administration, with an average of 10.5 puffs per cigarette taken. During the ad lib phase subjects smoked an average of 3.6 cigarettes, with approximately the same number of puffs taken per cigarette.
BODY.RESULTS AND DISCUSSION.NICOTINE PHARMACOKINETICS AND BLOOD PLASMA LEVELS:
The mean plasma nicotine concentration-time profiles are presented in Fig. 1. Baseline nicotine concentrations were below the limit of quantification in the majority of subjects and mean baseline nicotine concentrations were comparable across study products, all representing less than half the limit of quantification of 0.200 ng/mL. During the controlled use period, mean concentrations increased peaked immediately after use of the single tobacco cigarette (p < 0.05 compared to baseline) and then steadily decreased until reaching a minimum at the end of the period. For all e-cigarettes, nicotine plasma absorption was slower, with mean concentrations steadily increasing with continued product use and peaking at the end of the period. Usage of the study e-cigarettes resulted in statistically significant (p < 0.05) increases from baseline in nicotine concentration as soon as 5 min following the start of product use with the exception of the 1.6 % nicotine product with glycerin, which also reached statistical significance after 10 min of use. Plasma nicotine concentrations steadily increased during the one-hour ad lib use of the tobacco cigarettes, whereas ad lib use of the e-cigarettes resulted in plasma nicotine concentrations that increased during the first 45 min and then plateaued during the last 15 min.Fig. 1Mean Plasma Nicotine Concentration Versus Time The summary of nicotine plasma PK parameters is presented in Table 3. The controlled e-cigarette puffing regimen provided peak (Cmax30) and overall (AUC0-30) nicotine exposures comparable to the tobacco cigarette for the two non-menthol 2.4 % nicotine products and the 1.6 % nicotine product containing glycerin and PG (all differences within 15 % of the tobacco cigarette). However, use of 1.6 % nicotine product containing only glycerin provided significantly lower peak (35 %) and overall (39 %) exposures despite having the highest mean puff counts of any of the e-cigarette products. Use of the menthol product (2.4 % nicotine with glycerin) also yielded a significantly lower overall exposure (16 %) compared to the tobacco cigarette, but a comparable peak concentration. Not surprisingly, the use pattern of the e-cigarette during the controlled use period resulted in a significantly longer time to peak nicotine concentration (Tmax0–30) than for the single tobacco cigarette.Table 3Summary of plasma nicotine pharmacokinetic parameters and statistical comparisons to the tobacco cigaretteE-CigarettesPharmacokinetic Parameters2.4 % nic + Gly2.4 % nic + Gly/PG2.4 % nic + Gly + menthol1.6 % nic + Gly1.6 % nic + Gly/PGTobacco Cigarette
N = 23
N = 23
N = 23
N = 23
N = 23
N = 24Cmax0–30 (ng/mL)17.4 ± 5.9718.1 ± 6.4715.3 ± 5.1610.3 ± 3.70*15.1 ± 4.6115.8 ± 8.64
p-value0.12420.05080.88580.00020.7776Tmax0–30 (hr)0.50 (0.33, 0.55)0.50 (0.33, 0.52)0.50 (0.33, 0.52)0.50 (0.33, 0.61)0.50 (0.33, 0.62)0.09 (0.08, 0.42)
p-value<0.0001<0.0001<0.0001<0.0001<0.0001AUC0–30 (ng*hr/mL)4.7 ± 1.844.9 ± 1.754.1 ± 1.633.0 ± 1.184.3 ± 1.394.9 ± 1.79
p-value0.76360.84430.0406<0.00010.0928AUC30–90 (ng*hr/mL)22.4 ± 5.6124.6 ± 7.9921.6 ± 5.0814.7 ± 5.1519.8 ± 4.7222.1 ± 5.98
p-value0.84630.06020.6319<0.00010.0756C90 (ng/mL)19.7 ± 5.7222.4 ± 7.6519.4 ± 5.8013.7 ± 5.9816.8 ± 4.4429.2 ± 10.86
p-value<0.0001<0.0001<0.0001<0.0001<0.0001Tmax0–30 is presented as median (minimum, maximum), all other values are presented as arithmetic mean ± SD. Statistical significance is based on the differences in least squares means between groups. P-values represent the comparison to the tobacco cigarette
nic nicotine, Gly glycerine, PG propylene glycol During the ad lib use period, overall nicotine exposure (AUC30–90) was comparable (differences within 11 %) between the tobacco cigarette and all e-cigarette products with the exception of the 1.6 % nicotine product with only glycerin, which provided a 33 % lower overall exposure. However, the nicotine concentration at the end of the ad lib use period was significantly higher following use of the tobacco cigarette compared to the e-cigarettes, with concentrations ranging from 23 % to 53 % lower after 60 min of ad lib use. Overall, the exposure parameters among the e-cigarette products tended to be higher for the 2.4 % nicotine products, higher for the products containing both glycerin and PG, and lower for the product containing menthol compared to the other 2.4 % nicotine products.
BODY.RESULTS AND DISCUSSION.PHARMACODYNAMICS: EFFECTS ON URGE TO SMOKE:
The mean smoking urge change from baseline-time profiles are presented in Fig. 2. Mean baseline smoking urge values across all test products were comparable, with the mean visual assessment scale (VAS) responses ranging from 62 to 68 out of 100 (mm).Fig. 2Mean Smoking Urge Change from Baseline versus Time (Note: More Negative Values Indicate a Stronger Urge Reduction) An immediate statistically significant (p < 0.001) reduction in smoking urge was observed at 5 min following the start of controlled use of each study product. Following use of a single tobacco cigarette, the maximum reduction in smoking urge was observed at 5 min, approximately corresponding to the end of use of that study product, and then increased during the remainder of the controlled use period. Continuous use of the e-cigarette products throughout the controlled use period resulted in a maximal reduction in smoking urge also approximately corresponding to the end of product use. During the ad lib use period, use of the tobacco cigarette resulted in a steady decrease in smoking urge, peaking at the final time point, while the response with the e-cigarettes peaked 30 min into ad lib use and stabilized during the final 30 min. Table 4 summarizes the change in smoking urge PD parameters. No statistically significant differences were found in the maximal smoking urge reduction parameters Emax0–30 and Emaxreduction0–30 (all differences within 11 %) or the overall smoking urge reduction parameter AUEC0-30 (all differences within 21 %) between the use of a single tobacco cigarette and each of the e-cigarettes during the controlled use period. The mean time to the maximal reduction in smoking urge was shorter for the tobacco cigarette (15 min) than each of the e-cigarettes (25 – 30 min), but only significantly so for both of the 1.6 % nicotine products and the 2.4 % nicotine product with menthol.Table 4Summary of change in smoking urge parameters and statistical comparisons to the tobacco cigaretteE-CigarettesSmoking Urge Parameters2.4 % nic + Gly2.4 % nic + Gly/PG2.4 % nic + Gly + menthol1.6 % nic + Gly1.6 % nic + Gly/PGTobacco Cigarette
N = 23
N = 23
N = 23
N = 23
N = 23
N = 24Emax0–30 (mm)−41.9 ± 26.56−44.7 ± 26.98−37.0 ± 30.25−40.2 ± 32.47−40.7 ± 24.25−41.5 ± 27.43
p-value0.92850.64270.30230.69720.7450Emaxreduction0–30 (mm)−42.2 ± 26.01−44.7 ± 26.98−39.1 ± 25.86−41.4 ± 30.40−40.7 ± 24.25−41.7 ± 27.08
p-value0.94890.65050.50560.84800.7079AUEC0–30 (hr*mm)−14.1 ± 10.56−15.5 ± 10.39−12.2 ± 10.75−13.9 ± 12.09−13.3 ± 8.29−15.4 ± 12.67
p-value0.40540.89120.08820.35900.2225TEmax0–30 (hr)0.41 (0.07, 0.50)0.41 (0.07, 0.50)0.41 (0.08, 0.50)0.42 (0.08, 0.50)0.49 (0.24, 0.50)0.25 (0.07, 0.51)
p-value0.17640.09480.00140.00120.0009AUEC30–90 (hr*mm)−44.3 ± 35.39−50.9 ± 33.64−42.7 ± 38.24−46.2 ± 40.23−47.7 ± 34.16−46.9 ± 30.14
p-value0.66790.52750.50460.89190.9395E90 (mm)−37.0 ± 30.69−42.5 ± 29.85−34.3 ± 34.03−37.4 ± 35.08−38.5 ± 30.12−52.2 ± 26.33
p-value0.00600.09210.00100.00660.0122TEmax0–30 is presented as median (minimum, maximum), all other values are presented as arithmetic mean ± SD. Statistical significance is based on the differences in least squares means between groups. P-values represent the comparison to the tobacco cigarette
nic nicotine, Gly glycerine, PG propylene glycol During the ad lib use period, the overall smoking urge reduction (AUEC30-90) achieved with use of the e-cigarettes were comparable to that of the tobacco cigarette, with all differences less than 10 %. However, at the end of the ad lib period, use of the tobacco cigarette resulted in a 19 % to 34 % greater relief of smoking urge (E90) when compared to the e-cigarettes, with statistically significant differences for all except the 2.4 % nicotine product containing both glycerin and PG. The smoking urge reduction appeared comparable among the e-cigarette products with the exception of the 2.4 % nicotine product with menthol which tended to provide a somewhat lower level of relief compared to the other four products.
BODY.RESULTS AND DISCUSSION.TOLERABILITY AND REPORTED ADVERSE EVENTS:
During the course of the study, a total of 38 subjects were exposed to one or more of the study products. There were no serious adverse events reported and no subjects were discontinued due to AEs. Mild product-use-emergent AEs were reported by 18 of 38 subjects provided a study product (including the lead-in period). The number of subjects reporting AEs was similar among products, ranging from 3 to 10 subjects each, with slightly fewer subjects experiencing AEs following use of the menthol-flavored product. The most frequent AE was cough, reported 20 times by 11 subjects (more commonly with use of an e-cigarette product than the tobacco cigarette), followed by throat irritation (8 reports by 5 subjects) and headache (6 reports by 5 subjects), and dizziness (5 reports by 4 subjects). All AEs resolved without sequelae. The observed acute effects of the study products on blood pressure, heart rate and CO levels were previously reported by the authors under a separate publication [24] where it was noted that heart rate and systolic and diastolic blood pressure were significantly elevated after the use of the tobacco cigarette, but the elevation was less after use of most of the e-cigarettes. Furthermore, it was also observed that the use of the e-cigarettes produced no increase the exhaled CO levels, whereas the cigarette significantly increased the exhaled CO more than eight (8) times above the baseline.
BODY.CONCLUSIONS:
The key objectives of this study were to examine the nicotine blood plasma levels and smoking urge impacts of various formulations of one brand of e-cigarette for comparison to a conventional tobacco cigarette, and to assess the tolerability and adverse events associated with the study products following short-term use under intensive and naturalistic use conditions. The study design and results are not intended to support the potential for e-cigarettes as harm-reduction products. While not all puffing parameters can be controlled across all subjects, a product use that includes the same number of puffs, puff duration, and puff interval as utilized in this study allows for standardization of nicotine intake to the extent possible in order to accurately characterize uptake and reduction in smoking urge. The small difference in pre-to-post use weight differences across the e-cigarette products supports this. When compared to a tobacco cigarette, the nicotine PK following a controlled, 50-puff use of the e-cigarettes was characterized by slower absorption than from a single tobacco cigarette, but comparable maximal and overall nicotine exposures for all but the 1.6 % nicotine product with glycerin. Analysis of the mean maximum plasma concentrations attained during the controlled use period showed that the non-menthol e-cigarettes containing 2.4 % nicotine exceeded that of the tobacco cigarette (15.8 ng/mL at approximately 5 min) with approximately 25 min of use (17.8 to 18.1 ng/mL). This observation is most likely attributable to the rather intensive e-cigarette puffing regimen (one puff every 30 s) imposed during the controlled use interval when compared to the single tobacco cigarette regimen (average 10.5 puffs total). However, it also suggests that under an intensive puffing scenario, e-cigarettes are capable of delivering similar amounts of nicotine as a tobacco cigarette. The continuous rise in nicotine concentrations achieved with use of the e-cigarettes during the controlled use period appeared to be matched by a consistent decrease in smoking urge, though at the end of the 30-min controlled use period the urge reduction was comparable across those products. Smoking a single cigarette during the controlled use period produced a predictable nicotine concentration-time curve, with a rapid peak nicotine concentration followed by a gradual elimination. The rise and fall of nicotine concentration was matched by the smoking urge response, with a rapid decrease in urge followed by a gradual return toward baseline. While the time to maximum urge reductions was significantly shorter for the tobacco cigarette during the controlled use period compared to each of the e-cigarettes, there were no significant differences in the maximal or overall urge reduction achieved between the two types of products. Ad lib use of the study products can provide insight into use patterns and nicotine concentrations that will allow consumers to satisfy their smoking urge and provide an overall satisfying product use experience. As should be expected, individual use of the products as measured by puff counts varied widely and followed the amount of nicotine solution that was consumed during use as measured by pre-to-post use product weight difference. Use of the e-cigarettes during the ad lib use period resulted in a relatively small increase in nicotine concentration during the first 45 min, followed by a plateau during the last 15 min. In contrast, use of the cigarette during the ad lib use period resulted in a continuous increase in nicotine concentration and continued reduction in smoking urge through the final time point. Following ad lib use of all products for 60 min, the tobacco cigarette yielded a significantly higher nicotine concentration (C90) compared to each of the e-cigarettes. The higher nicotine concentration coincided with a greater reduction in smoking urge at the end of the ad lib use period (E90) for the tobacco cigarette compared to all e-cigarettes, and significantly greater than all except the 2.4 % nicotine product containing glycerin and PG. However, there was no overall impact on urge as assessed by AUEC30–90. This was likely due to the relatively short duration of the ad lib use. Indeed, as the smoking urge response appeared to have reached a plateau with the e-cigarettes and continued to increase with the cigarette following 60 min of ad lib use, a longer evaluation period may have resulted in a difference in the AUEC parameter as well. Among the e-cigarettes, use of the e-cigarettes containing 1.6 % nicotine resulted in lower nicotine exposure compared to the e-cigarettes containing 2.4 % nicotine. However, this did not translate into significant differences in the smoking urge response. Further, while the suppression of urge to smoke appeared comparable between the 1.6 % and the 2.4 % test formulations in the present study, evaluation of the mean puff counts and the amount of solution consumed did not suggest that the subjects compensated by puffing on the lower-nicotine products consciously or subconsciously more so than the higher-nicotine products to achieve a similar level of satisfaction. In addition, higher nicotine content, the presence of PG in the vehicle, and the absence of menthol in the e-cigarettes were found to increase plasma nicotine levels during both controlled and ad lib use. Such factors, however, did not appear to significantly affect smoking urge. However, consistent with prior research documenting the prominent role of conditioned behavior and nicotine addiction, in addition to the concentration of nicotine, the respiratory tract sensory cues and manipulation of smoking materials that are associated with smoking, and mimicked by e-cigarettes, may have had a role in relieving smoking urges [25]. Thus, the present findings further suggest that some of the substantial sensory and behavioral aspects of smoking that are mirrored by e-cigarettes, may be essential elements in the reduction of craving or abstinence symptoms. To the extent that e-cigarettes may provide some measure of reduction in smoking urges, they may serve as cigarette substitutes for smokers who would otherwise seek to smoke a conventional tobacco cigarette. Despite the aggressive puff regime employed in the controlled use period, there were no SAEs in this study and no subjects were discontinued due to AEs. The incidence of AEs was similar among products, with slightly fewer subjects experiencing AEs following use of the menthol-flavored product. The most frequently reported minor AEs were cough, followed by throat irritation, headache, and dizziness. These findings are consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated as compared to tobacco cigarette use [2, 26]. This study was not without limitations. It was performed at a single site with a small number of subjects, which might lead to the conclusion that the data is not generalizable to a broader population. However, many initial PK evaluations of tobacco and pharmaceutical products are performed using a similar approach. Further, the comparison to the e-cigarettes was made based on a single product use and a short-term ad lib product use to a single brand of tobacco cigarette. Indeed, the trend we noted at the end of the ad lib use period did show that nicotine concentrations appeared to be continuing to rise and smoking urge appeared to be continuing to decrease. Hence, a longer term comparison in future studies would be beneficial. Finally, while the product use data did not provide a clear indication that subjects compensated by using the products with less nicotine more intensively, use of topography measurements providing insight into puff volume and inhalation rate coupled with product evaluation questionnaires in future studies might lend additional information regarding product use behaviors leading to PK and smoking urge responses. Overall, the findings of this study indicate that nicotine uptake from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine are significant, but lower than those of tobacco cigarettes, yet the reduction in urge-to-smoke or craving symptoms are broadly comparable. Moreover, it was also found that the short-term use of e-cigarettes by adult smokers is well-tolerated as compared to tobacco cigarette use. | 4,588,874 | {
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TITLE: Efficacy of Web-Based Weight Loss Maintenance Programs: A Randomized Controlled Trial Comparing Standard Features Versus the Addition of Enhanced Personalized Feedback over 12 Months
ABSTRACT:
Few randomized controlled trials (RCT) have evaluated the efficacy of web-based programs targeting maintenance of lost weight. The aims of this study were to evaluate two versions of a commercially available web-based weight loss maintenance (WLM) program and examine whether the provision of enhanced feedback was associated with better WLM. The study was an assessor-blinded RCT of change in body mass index (BMI) over 12 months WLM. Participants were 227 adults (44% male, 42.3 ± 10.1 years, BMI 30.4 ± 4.1 kg/m2) randomized to either a basic (Basic WLM) or enhanced program with additional support (Enhanced WLM). Analysis was intention-to-treat with imputation using last observation carried forward. There was no significant weight rebound from the start of weight loss maintenance to 12 months for either group (mean: basic 1.3%, enhanced 1.5%) and limited change in secondary outcomes for either program. There were no significant between-group differences in the primary outcome of change in BMI (basic −0.5 (1.9) kg/m2, enhanced −0.5 (1.6) kg/m2, p = 0.93). In conclusion, a web-based WLM program was effective in preventing weight regain over one year following weight loss. However, the addition of personalized e-feedback provided limited additional benefits compared to a standard program. Given the potential reach of web-based approaches, further research examining which web-based program components optimize weight outcomes long-term is required.
BODY.1. INTRODUCTION:
Obesity rates are continuing to rise globally [1] in contrast to the limited access to treatment programs. While web-based approaches to treatment could potentially have broad reach, especially as households gain access to broadband internet, their evaluation in the context of longer-term follow-up has been limited. Studies have shown that passive follow-up with no active intervention after weight loss is associated with weight gain [2], with 50–80% of participants gradually regaining weight lost following treatment, with most regain occurring in the first year [3,4,5,6]. A systematic review of weight loss maintenance (WLM) trials found that active WLM interventions facilitated a 1.56 kg (95% CI −2.27 to −0.86 kg) lower weight regain compared with passive follow-up after 12 months. Most WLM studies have required attendance at group sessions and have been hampered by methodological issues, such as mainly recruiting females or mid-aged adults and including only those with a good response to an initial weight loss phase, while excluding those with low adherence. [7]. Few studies have evaluated the use of eHealth technologies (e.g., websites, smartphone applications, text messages) to deliver WLM interventions. Furthermore, most research in this area has looked at short-term interventions (<6 months) without longer-term follow-up [8,9]. The small number of longer-term studies have reported a gradual regain of weight lost following treatment, with regain occurring after the first six months [10,11]. A recent randomized controlled trial examined the effectiveness of a 12-week short message service (SMS) based WLM program following an initial 12-week commercial weight loss program. At three and nine months follow-up, there was no significant difference in weight maintenance between the usual care control group who received a brief telephone call providing lifestyle information and a mailed leaflet with advice on weight loss maintenance and the intervention group who received a weekly SMS to remind them to self-weigh in addition to the call [12]. A systematic review published in 2017, evaluated the efficacy of web-based interventions on weight loss or WLM in adults with overweight or obesity and found web-based interventions were more effective than minimal treatments but less effective than face-to-face interventions [13]. Furthermore, a recent systematic review concluded that there was insufficient evidence to recommend the use of eHealth interventions for WLM [14]. There were however promising results from the eHealth weight loss trials with the addition of newer technologies including text messages, self-monitoring devices, and mobile applications, with meta-analysis demonstrating significantly greater weight loss (1.46 kg [0.80, 2.13], p < 0.001) in interventions with enhanced behavioral features (e.g., individualized counselling, feedback on dietary intake or weight change) or technologies (e.g., addition of text messaging) than standard eHealth interventions. There is some evidence to suggest that these 'enhanced' interventions positively impact participant engagement, retention, and behavior change. We have previously published results of an online commercially available weight loss maintenance (WLM) program which demonstrated limited between-group differences for the basic and enhanced versions of the program after six months [15]. While the enhanced version resulted in greater retention (81.0% vs. 68.5%) and usage of the web-program, it did not result in a difference in weight loss [15]. A study using a 12-month intervention program (6-month weight loss plus a 6-month WLM) compared a self-directed web-based commercial program to a therapist-led behavioral web-based program and found greater weight loss in the behavioral web-based program than the therapist-led program at 12 months [16]. We have previously reported that adults randomized to this therapist-led web-based weight loss program initially lost more weight compared to wait list controls [17], and that there was no difference in weight loss between basic or enhanced versions of the weight loss program after either 12 weeks [17] or after 24 weeks [15] of participation. To date, no WLM trials have specifically evaluated the inclusion of enhanced behavioral features in an eHealth WLM program, including those outlined in Table S1, such as automatically-generated personalized reports; personalized feedback on diet, physical activity, and weight loss, as well as reminders to use the online diary, visit the website, and weigh-in. Therefore, the aim of the current study was to evaluate the impact of two versions of a WLM program on BMI in adults with overweight or obesity who had previously completed a weight loss program. The secondary aim was to compare differences in waist circumference and clinical measures including cholesterol, triglycerides, glucose and insulin between a standard version of a web-based WLM program (basic) and an enhanced version that provided additional personalized e-support.
BODY.2. MATERIALS AND METHODS.2.1. PARTICIPANTS:
Adults (BMI 25–40 kg/m2), aged 18–60 years were initially recruited into a weight loss trial in 2009 from the Hunter community in NSW, Australia [18]. Written informed consent was obtained from all participants for the weight loss maintenance trial. The study was approved by the University of Newcastle Human Ethics Research Committee (H-2009-0245) on 10 September 2009. The trial was registered with the Australian New Zealand Clinical Trials Registry, anzctr.org.au ACTRN12610000197033.
BODY.2. MATERIALS AND METHODS.2.2. STUDY DESIGN:
Participants who completed an initial 24-week web-based weight loss intervention (The Biggest Loser Club, SP Health Co Pty Ltd., North Sydney, Australia) were randomly assigned into one of two weight loss maintenance groups for 12 months using a stratified randomized block design. Participants were allocated to either a basic weight loss maintenance program (Basic WLM) or an enhanced version of the weight loss maintenance program (Enhanced WLM) (see Figure 1). Both participants and the outcome assessors were blinded to group allocation. Detailed methods of the RCT have been published elsewhere [18]. The WLM programs were developed to follow on directly after completion of 24 weeks of a web-based weight loss program [15]. Program features and differences between groups are summarized in Table S1 and also described in detail elsewhere [18]. The Basic WLM group received free access to the weight loss program, but the weekly meal plans were based on an energy intake target equivalent to weight maintenance. The Enhanced WLM group received access to these same meal plans and dietary information, but they also received personalized system-generated feedback on their progress. The feedback on progress was provided using system-generated personalized reports that were populated with the data entered into the platform by the participant. Feedback included progress in relation to weight maintenance goals; usage of the online diet and physical activity diary (which was recommended but not mandated); usage patterns for website features; and level of success with weight loss. Those allocated to the enhanced group also received an escalating scale of email reminders followed by SMS text message reminders (if no response) to use the diary, visit the website, to 'weigh-in' by recording their weekly weight in the online program, and a relapse phone call if their recorded weight rebounded by ≥3% to remind them to return to weight loss mode (Table S1).
BODY.2. MATERIALS AND METHODS.2.3. MEASURES:
Participants were assessed at baseline and 12 months [18] by blinded research assistants. Height, weight, waist circumference, and blood pressure were measured using standardized procedures [18] and BMI calculated. Following an overnight fast, blood samples were collected and analyzed for total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) cholesterol, triglycerides, glucose, and insulin by a single National Association of Testing Authorities accredited pathology service using standard automated techniques.
BODY.2. MATERIALS AND METHODS.2.4. DATA ANALYSIS:
Baseline variables were compared between treatment groups using analysis of variance (ANOVA) for continuous variables and chi-square tests for categorical variables. Analysis of covariance (ANCOVA) was used to test for group differences in outcomes at 12 months after adjusting for the baseline values of the outcome and sex. Analyses were performed in Stata v11 or SAS v9.2 (StataCorp, College Station, TX, USA). Intention-to-treat (ITT) analyses included all participants randomized at the weight loss management phase baseline, with missing follow-up data imputed using the last observation carried forward (LOCF).
BODY.3. RESULTS:
At entry into WLM 227 participants were randomized to Basic WLM (n = 114) or Enhanced WLM (n = 113) program versions, with demographic data summarized in Table 1. Mean age was 43.3 (±9.7) years, with a mean BMI of 30.6 (±4.1) kg/m2, 42% were male and 95% were Australian-born (Table 1). There was no significant between-group difference in attrition after 12 months, basic 18.4% and enhanced 23.9%, p = 0.31. Both the Basic and Enhanced WLM groups successfully achieved WLM after 12 months with no significant rebound in weight. There were no significant between-group differences (p > 0.05) for the primary outcome of BMI with mean weight change (12 months—baseline) similar between the basic (−0.5 (1.9) kg/m2) and enhanced groups (−0.5 (1.6) kg/m2), p > 0.05 (Table 2). Table 2 shows that there were no significant differences in secondary outcomes between groups up to 12 months (p > 0.05).
BODY.4. DISCUSSION:
Whilst participants in both intervention arms of the current trial successfully maintained weight over one year of participating in a web-based program design to support maintenance of lost weight, those with access to the additional features designed to provide support and personalized feedback on diet, physical activity, and weight loss did not achieve better outcomes compared to those receiving access to the online program with minimal support. Both groups regained approximately one-and-a-half kilograms over the 12-month maintenance period, which was not significantly different between groups. This is comparable to results of the active intervention arms from a recent systematic review of all WLM intervention modes that included both food intake and physical activity advice, including group programs, face-to-face, and internet interventions [7]. The review included almost 3000 participants across 25 comparisons and found that the active intervention arms were associated with less weight regain of approximately 1.56 kg, up to 12 months [7]. This suggests that both active intervention arms in the current study were successful in achieving WLM. In our study, it appears that doing 'anything' was enough to support WLM, compared to the no-intervention arms in the systematic review, which also found no evidence that specific modes of intervention delivery were more effective than others. This suggests that having access to the level support provided in both the basic and enhanced versions of the current web-based WLM intervention, following a weight loss intervention did facilitate maintenance of lost weight. Given that it is well established that weight regain is common following initial weight loss [19], the results of the current study are important. Our systematic review evaluating effectiveness of 56 interventions that included a specific dietary component within the WLM intervention found that 14 achieved significant between-group differences at follow-up [2]. Furthermore, our recent systematic review and meta-analysis which evaluated the effectiveness of 84 e-Health interventions, found that e-Health weight loss interventions that include extra support strategies including counselling, personalized feedback, motivational interviewing and/or personal contact, appear to achieve significantly greater weight loss compared with standard eHealth interventions [13]. However, five studies which focused specifically on WLM interventions found no significant difference in weight change between eHealth WLM programs vs. control [14]. The authors concluded that there is currently insufficient evidence to recommended eHealth interventions for WLM and that further high-quality research is required to determine their effectiveness [14]. Although the included studies were heterogeneous the typical intervention characteristics were WLM interventions that lasted 39 weeks on average, had approximately 180 participants and attrition of 26% compared to the current WLM study which lasted 52 weeks had 227 participants and an attrition rate of 21%. The current study is important because individual studies to date suggest that face-to-face contact involving either weekly or monthly individual or group counseling sessions are more likely to achieve WLM than internet support in studies lasting 18 to 30 months. Recent systematic reviews on WLM interventions [7,14] suggest that there is a need for extended support for weight management following participation in weight loss programs internationally, as in-person attendance is not likely to be viable long-term. Hence, prolonged WLM support using eHealth technologies need to be evaluated for both feasibility, engagement, and cost-effectiveness in the long-term. Limitations include the lack of a wait list control group, which is similar to the majority of WLM maintenance studies to date [2]. Although the small sample size and attrition likely reduced the power to detect significant differences between groups for the secondary outcomes, it is similar to other WLM trials lasting 12 or more months which had an average drop-out of 20% [7]. Furthermore. results from the current study need to be interpreted with caution given the meta-analysis within the systematic review [14] indicates that there is no significant difference between the support methods during WLM. This is also supported by our review of web-based interventions which also reported no difference between these two methods of delivery [20]. Strengths include the RCT design, use of blinded assessors, and the comparison of two versions of the WLM program for 12 months, following an initial period of weight loss. Future studies should consider evaluating cost-effectiveness and efficacy in specific population groups for whom access services may be a challenge, based on a range of issues related to time, cost, convenience, rurality, health conditions, or other socio-economic factors. In conclusion, a commercial web-based weight loss maintenance program, with a specific intervention component targeting maintenance of lost weight can be effective at preventing weight re-gain up to one year following 24 weeks of weight loss. While the addition of enhanced features that provide additional feedback and social support did not provide additional benefits during maintenance, health professionals should advise clients that a specific WLM strategy does facilitate WLM up to one year following weight loss. Further research addressing level of feedback and support required to optimize weight status long-term in an online environment is required. | 5,746,685 | {
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TITLE: Randomised controlled trial to evaluate the efficacy and usability of a computerised phone-based lifestyle coaching system for primary and secondary prevention of stroke
ABSTRACT.BACKGROUND:
One of the most effective current approaches to preventing stroke events is the reduction of lifestyle risk factors, such as unhealthy diet, physical inactivity and smoking. In this study, we assessed the efficacy and usability of the phone-based Computer-aided Prevention System (CAPSYS) in supporting the reduction of lifestyle-related risk factors.
ABSTRACT.METHODS:
A single-centre two-arm clinical trial was performed between January 2013 and February 2014, based on individual follow-up periods of six months with 94 patients at high risk of stroke, randomly assigned to an intervention group (IC: 48; advised to use the CAPSYS system) or a standard care group (SC: 46). Study parameters, such as blood pressure, blood values (HDL, LDL, HbA1c, glycaemia and triglycerides), weight, height, physical activity as well as nutrition and smoking habits were captured through questionnaires and medical records at baseline and post-intervention and analysed to detect significant changes. The usability of the intervention was assessed based on the standardised System Usability Scale (SUS) complemented by a more system-specific user satisfaction and feedback questionnaire.
ABSTRACT.RESULTS:
The statistical evaluation of primary measures revealed significant decreases of systolic blood pressure (mean of the differences = –9 mmHg; p = 0.03; 95 % CI = [–17.29, –0.71]), LDL (pseudo-median of the differences = –7.9 mg/dl; p = 0.04; 95 % CI = [–18.5, –0.5]) and triglyceride values (pseudo-median of the differences = –12.5 mg/dl; p = 0.04; 95 % CI = [–26, –0.5]) in the intervention group, while no such changes could be observed in the control group. Furthermore, we detected a statistically significant increase in self-reported fruit and vegetable consumption (pseudo-median of the differences = 5.4 servings/week; p = 0.04; 95 % CI = [0.5, 10.5]) and a decrease in sweets consumption (pseudo-median of the differences = –2 servings/week; p = 0.04; 95 % CI = [–4, –0.00001]) in the intervention group. The usability assessment showed that the CAPSYS system was, in general, highly accepted by the users (average SUS score: 80.1).
ABSTRACT.CONCLUSIONS:
The study provided encouraging results indicating that a computerised phone-based lifestyle coaching system, such as CAPSYS, can support the usual treatment in reducing cerebro-cardiovascular risk factors and that such an approach is well applicable in practice.
ABSTRACT.TRIAL REGISTRATION:
ClinicalTrials.gov Identifier: NCT02444715
BODY.BACKGROUND:
Lifestyle risk factors, such as unhealthy diet, physical inactivity and smoking, have a strong influence on the personal risk of stroke. Reducing such risk factors is currently one of the most effective approaches to preventing stroke events. According to the World Health Organization (WHO), "most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood pressure, diabetes and raised lipids" [1–3]. However, many individuals have difficulties adhering to recommendations concerning a healthy lifestyle, and long-term compliance with such lifestyle changes is usually low. Early findings in behavioural research support the assumption that the mere task of self-monitoring increases habit awareness, induces reflection on habits, and thus can provoke a positive change of the monitored behaviour [4]. Furthermore, experience has shown that sustained contact is necessary in order to support people in establishing and maintaining lifestyle changes [5]. In this context, the recently developed Computer-aided Prevention System (CAPSYS) offers a cost-effective automated solution combining remote surveillance of individual cerebro-cardiovascular risk factors with tailored advice [6]. Registered patients can access CAPSYS through a phone interface, simply by dialling a landline number. In an automated dialog, patients are asked to provide information about a predefined number of risk factors (current nutrition, physical activity, smoking, weight and blood pressure) by typing in the corresponding answers using the phone keypad. Based on the patient's answers, CAPSYS issues tailored feedback aiming at motivating a positive change towards or maintenance of healthy, risk-reducing habits. The system has been designed as a multi-language tool, in which the languages German and French have already been implemented and used within the trial. Clearly, a telephone as a user interface requires sufficient hearing abilities by the patients as well as the ability to understand and follow the instructions and advice issued by the virtual lifestyle coach. Consequently, this system is not appropriate for use by persons with severe hearing impairments or cognitive limitations. In cases of doubt, a patient's cognitive abilities can be evaluated by means of the Folstein mini-mental state test [7]. On the other hand, there is no problem for patients with difficulties in articulation or speech impediments to use CAPSYS, due to the fact that patient interaction does not involve any speech input but is purely limited to pressing buttons on the telephone keypad. In order to assess the efficacy of the CAPSYS approach concerning the reduction of stroke-related risk factors as well as the usability of the system, a dedicated study was designed and carried out, the results of which are presented in this article.
BODY.METHODS:
In 2013 and 2014, a single-centre randomised controlled trial was carried out at the Department of Neurology of the Centre Hospitalier de Luxembourg. The study was designed as a six-month, parallel-group two-arm trial involving an intervention and a control group. Within this six-month study with a relatively limited number of participants, it was not possible to focus on the registration of severe events, such as stroke or death. Instead, the study concentrates on changes in different surrogate parameters for stroke (systolic blood pressure, BMI, HDL, LDL, HbA1c, glycaemia and triglycerides). A draft of the study design has already been presented in [8].
BODY.METHODS.PARTICIPANTS:
Patients aged 20 and over were eligible for the study if they had already suffered from a stroke or were at high risk of stroke (at least two risk factors according to the criteria described in [2, 9, 10]). The eligibility criteria are summarised in Table 1. Patients' stroke risk and thus their suitability to participate in the CAPSYS study were evaluated by the treating neurologist based on the patients' individual risk factor profiles.
Table 1Eligibility criteria for the CAPSYS studyInclusion criteriaExclusion criteriaAge: 20 and over; At high risk of stroke:Inability to fill out or to understand the informed consent;∙ Already suffered a stroke or Transient Ischemic Attack (TIA) orNo signed informed consent;∙ At least two risk factors for stroke:– High blood pressure (systolic blood pressure ≥ 140 mmHg)Dementia– Overweight (BMI ≥ 25 kg/m2)– Low physical activity (less than 30 min. of moderate-intensity physical exercise per week)– Smoking– Unhealthy diet
BODY.METHODS.RECRUITMENT AND RANDOMISATION:
Potential study participants were approached in the course of their regular consultations with their neurologist, where they were screened for eligibility. Prior to their enrolment in the study, all participants signed a written informed consent; 94 participants were randomised by lot to one of two groups: Interventional Care (IC: 48, 34 [71 %] male) or Standard Care (SC: 46, 29 [63 %] male). Participants were aged between 32 and 86 (SC: mean = 59.6; SD = 12.1; median = 59) (IC: mean = 60.7; SD = 11.3; median = 61). The major characteristics of the study cohort are summarised in Table 2. Due to the specific design of the intervention, the study had to be carried out in an only partially blinded manner. It is inherent to the CAPSYS approach that the treating neurologist performs regular reviews of the data collected in the intervention group. The need to have access to patient histories and the possibility to contact patients at any time in case of emerging situations has limited the use of blinding methods within the trial. However, in order to ensure the validity of the study, the CAPSYS study team was separated into three different groups: a) principal investigator and treating neurologist responsible for the initial eligibility check of potential study participants, b) hospital research nurse responsible for patient recruitment and randomisation, and c) healthcare researchers who performed the statistical evaluation of the collected data by using pseudonymised data sets. During the recruitment meeting, patients were informed about the purpose of the study and about the study approach. The CAPSYS study design was approved by the Luxembourg National Research Ethics Committee (CNER) (N° 201205/08) and the National Commission for Data Protection (CNPD) (T007990).
Table 2Descriptive statistics of the study cohortSC (n = 46)IC (n = 48)Mean age [years] (±SD)59.6 (±12.1)60.7 (±11.3)Men29 (63 %)34 (71 %)Mean BMI [ kg/m2] (±SD)27 (±4.3)28 (±4.3)Smokers2 (4 %)6 (13 %)Hypertension36 (78 %)43 (90 %)Hyper-/Dyslipidemia39 (85 %)44 (92 %)Diabetes mellitus5 (11 %)8 (17 %)Previous stroke/TIA37 (80 %)31 (65 %)
BODY.METHODS.INTERVENTION:
In addition to the usual care, participants in the IC group were advised to regularly call the phone-based prevention system CAPSYS (preferably twice a week). In the course of the recruitment process, they were carefully instructed in the proper use of the system, and they were provided a corresponding user manual in form of a leaflet. The participants could access the CAPSYS system by calling a specific land line number with their stationary or mobile phones. After choosing their preferred language (French or German) and authenticating themselves with their individual patient number and PIN code, the participants were posed the following questions:
How many servings of fruits and vegetables have you consumed yesterday?How many servings of whole-grain food have you consumed yesterday?How many servings of sweets have you consumed yesterday?Please enter your current weight.How many cigarettes have you smoked yesterday? [removed for non-smokers]How many minutes have you been physically active yesterday? [moderate or high intensity]Please enter your current systolic blood pressure. The participants could answer to these questions by typing in the numerical values (number of servings, weight, minutes etc.) using the phone key pad. During the recruitment meeting at the beginning of the study, participants were instructed on how to estimate the size of one portion for the relevant food groups, and they were advised to measure their current blood pressure and weight, and to write down all necessary values prior to calling the CAPSYS system. Depending on the data provided by the patient, he or she received immediate customized feedback after each answer concerning his or her progress and advice on how to proceed reducing the corresponding risk factor or motivation on maintaining some observed healthy behaviour respectively. The phone call was closed with a concluding statement summing up the feedback issued before by the system. The questions and feedback were automatically generated by CAPSYS and were issued to the patients in spoken natural language by means of a text-to-speech software (TTS). The system was implemented to run fully automatically and could be accessed at any time of day. In case of systolic blood pressure higher than 140 mmHg, the patient was advised to rest for a while and then repeat the measurement. The system also advised the patients to contact a doctor in case of constantly high blood pressure. Patients with values above 140 mmHg were also particularly marked in the web interface when the treating physician accessed the system. Apart from that, all participants have been informed that there were no direct alerts in cases of high blood pressure provided within the study. The treating neurologist could access the data provided by his patients through a web interface, offering both a numerical as well as an adaptable graphical representation of the patient data for a certain period of time. The use of CAPSYS within the study has not replaced or reduced the existing information exchange between the neurologist and the corresponding referring physicians, which was proceeded according to the practices of the Luxembourgish healthcare system. Technically, CAPSYS offers the possibility for further physicians, e.g. the treating general practitioner, to access and monitor the data gathered from their patients. However, in the scope of this study, this option was deliberately discarded in order to avoid potential bias caused by the general practitioner accessing and interpreting the CAPSYS data. In contrast to the IC group, SC participants received only the usual care including blood analyses, blood pressure controls and individual advice on healthy lifestyle during the outpatient treatment given by the neurologist, by the general practitioner and by other physicians. Information material concerning a healthy lifestyle was provided to both groups.
BODY.METHODS.DATA COLLECTION:
Demographic and medical information of each participant was recorded by the study personnel in a predefined form, including body weight and height, medical history, current medication, smoking habits, blood pressure and heart rate as well as recent blood test results (HDL, LDL, HbA1c, glycaemia and triglycerides). Furthermore, participants were asked to fill in three questionnaires exploring their nutritional habits, physical activity and quality of life. The latter was measured using the standardised EQ-5D-5L instrument provided by the EuroQol Group [11]. Six months after enrolment, participants were asked to fill in the same questionnaires again, and current medical data (weight, blood pressure, heart rate, blood test results, smoking habits and medication) were again recorded by the study personnel. In addition, IC participants were asked to share their experiences with using CAPSYS and to provide their opinions about the system in a predefined questionnaire, which encompasses the well-established System Usability Scale (SUS) [12] and some further more specific questions concerning the usage of CAPSYS and its particular features. There was also space left for open-ended comments and suggestions at the end of the questionnaire.
BODY.METHODS.DEPENDENT MEASURES:
The impact of the intervention was assessed based on the changes of cerebro-cardiovascular risk parameters during the six-month trial period, whereby changes in the IC group were compared to those in the control group (SC). Changes in systolic blood pressure, HDL, LDL, HbA1c, glycaemia, triglycerides and BMI were considered as primary dependent measures (see Table 3). Changes in self-reported weekly consumption of fruits and vegetables, whole grain food and sweets as well as changes in self-reported weekly duration of physical activity and quality of life were analysed as secondary measures. Due to the low number of smokers among the study participants (SC: 2, IC: 6), smoking habits were not evaluated.
Table 3Overview of baseline values and evaluation of primary dependent measures in SC and IC groupsSCICBaselineEvaluationBaselineEvaluation
Parametric data
Mean (±SD)
T-test
Mean (±SD)
T-test
Systolic BP [mmHg]139.6 (±21)mean of diff. =0.19145 (±19.4)mean of diff. =−9p =0.96
p
= 0.03*
95 % CI = [–7.5, 7.88]95 % CI = [–17.29, –0.71]Cohen's d =0.42BMI [ kg/m2]27 (±4.3)mean of diff. =0.0328 (±4.3)mean of diff. =−0.18p =0.9p =0.4395 % CI = [–0.49, 0.55]95 % CI = [–0.65, 0.28]
Non-parametric data
Median [IQR]
Wilcoxon
Median [IQR]
Wilcoxon
HDL [ mg/dl]57 [45, 51]pseudo-median of diff =1.553 [47, 74]pseudo-median of diff =−1.5p =0.53p =0.4495 % CI = [–2.5, 4.5]95 % CI = [–4.5, 2]LDL [ mg/dl]96 [71, 114]pseudo-median of diff =−195 [76, 117]pseudo-median of diff =−7.9p =0.76
p
= 0.04*
95 % CI = [–10.5, 6]95 % CI = [–18.5, –0.5]r =0.24HbA1c [ %]5.8 [5.6, 5.9]pseudo-median of diff =05.9 [5.5, 6.25]pseudo-median of diff =0.1p =0.92p =0.3795 % CI = [–0.25, 0.2]95 % CI = [–0.1, 0.25]Glycaemia [ mg/dl]98 [89, 106.75]pseudo-median of diff =0.5102 [92.5, 114.5]pseudo-median of diff =2.5p =0.78p =0.1995 % CI = [–5.5, 5]95 % CI = [–2, 6]Triglycerides [ mg/dl]95 [73, 134.25]pseudo-median of diff =−6105 [78, 132.5]pseudo-median of diff =−12.5p =0.39
p
= 0.04*
95 % CI = [–21, 10]95 % CI = [–26, –0.5]r =0.25(statistically significant values are marked in bold) Statistical analyses were carried out on an intention-to-treat basis using RStudio (Version 0.98.978) with a significance level of 0.05. Parametric data (paired and unpaired samples) were evaluated with the Student's t-test approach, and the corresponding effect size was calculated with Cohen's d. Non-parametric data were evaluated using the Wilcoxon signed-rank test (for paired samples) or the Mann-Whitney U test (for unpaired samples) respectively, and effect size was calculated as \documentclass[12pt]{minimal}
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\begin{document}$r = \frac {Z}{\sqrt {N}}$\end{document}r=ZN. For non-parametric paired samples, the pseudo-median is computed as the Hodges-Lehmann estimate.
BODY.RESULTS.EFFICACY OF THE INTERVENTION:
Final questionnaires on nutritional habits, physical activity and quality of life could be collected from 68 participants (SC: 36; IC: 32) at the end of the study. This results in an overall dropout rate of 28 % (SC: 22 %; IC: 33 %). Further participant data, such as blood test values, could be retrieved from medical records. Out of the 48 recruited IC participants, 11 (23 %) did not use CAPSYS at all. The remaining 37 IC subjects (77 %) called the system up to 55 times during the study period (mean = 23.32; SD = 14.1; median = 24). Within-subjects analyses of primary dependent measures showed the following statistically significant changes between baseline and post-intervention:
Decrease of systolic blood pressure in IC group (two-sided paired-samples t-test: mean of the differences = –9 mmHg; p = 0.03; 95 % CI = [–17.29, –0.71]; Cohen's d = 0.42: large effect size) (see Fig. 1), with no corresponding significant difference in SC group (p = 0.96);
Fig. 1Systolic blood pressure. Significant decrease of systolic blood pressure in IC groupDecrease of low-density lipoprotein (LDL) levels in IC group (Wilcoxon signed-rank test: pseudo-median of the differences = –7.9 mg/dl; p = 0.04; 95 % CI = [–18.5, –0.5]; r = 0.24: medium effect size), with no corresponding significant difference in SC group (p = 0.76) (see Fig. 2);
Fig. 2LDL. Significant decrease of LDL levels in IC groupDecrease of triglyceride levels in IC group (Wilcoxon signed-rank test: pseudo-median of the differences = –12.5 mg/dl; p = 0.04; 95 % CI = [–26, –0.5]; r = 0.25: medium effect size), with no corresponding significant difference in SC group (p = 0.39) (see Fig. 3);
Fig. 3Triglycerides. Significant decrease of triglyceride levels in IC groupNo statistically significant changes could be found for any of the other primary measures (BMI, HDL, HbA1c and glycaemia). In this context, it needs to be stated that, at baseline, there were no statistical differences between both groups concerning the proportions of patients taking antihypertensives (SC: 36 [78 %]; IC: 43 [90 %]; p = 0.22), antidiabetic drugs (SC: 5 [11 %]; IC: 8 [17 %]; p = 0.61) or cholesterol-lowering medication (SC: 39 [85 %]; IC: 44 [92 %]; p = 0.47). Concerning the secondary dependent measures, we could observe the following statistically significant results:
Increase of self-reported fruit and vegetable consumption in IC group (Wilcoxon signed-rank test: pseudo-median of the differences = 5.4 servings/week; p = 0.04; 95 % CI = [0.5, 10.5]; r = 0.26: medium effect size), with no corresponding significant difference in SC group (p = 0.67);Decrease of self-reported sweets consumption in IC group (Wilcoxon signed-rank test: pseudo-median of the differences = –2 servings/week; p = 0.04; 95 % CI = [–4, –0.00001]; r = 0.26: medium effect size), with no corresponding significant difference in SC group (p = 0.06);Difference between SC and IC groups concerning the change of self-reported whole-grain food consumption (Mann-Whitney U test: difference in location = 3.26 servings/week; p = 0.04; 95 % CI = [0.00006, 7]; r = 0.24: medium effect size);No statistically significant changes for self-reported physical activity and quality of life.
BODY.RESULTS.USABILITY AND USER ACCEPTANCE OF THE INTERVENTION:
Assessments of the intervention based on the System Usability Scale (SUS) were provided by 28 participants of the IC group, 2 of which were declared invalid, as these participants have demonstrably never used CAPSYS during the trial period, and consequently, they were considered unable to assess the intervention. The average SUS score for CAPSYS was 80.1 (SD = 16.22; median = 78.75; min = 37.5; max = 100; 95 % CI = [73.54, 86.65]). According to Sauro and Lewis, this average score corresponds to an "A–" school grade and a percentile of 85–89, meaning that CAPSYS scored better than 85 to 89 % of all systems considered in the Sauro and Lewis study (see [13], chapter 8, page 204, table 8.6). Using the simplified regression equation proposed by Lewis [14], the Likelihood to Recommend for each CAPSYS user was derived from the corresponding SUS scores as LTR = SUS/10. With these values, we could identify 10 promoters (38 %; LTR ≥ 9) and 4 detractors (23 %; LTR ≤ 6) among the 26 participants who provided valid SUS scores, which results in a positive Net Promoter Score (NPS) of 23 [15], meaning that there are 23 % more users who would recommend CAPSYS (promoters) than users who would argue against using the system (detractors). Beside the standardised SUS questionnaire, IC participants were also asked to asses the voice of the text-to-speech module applied in CAPSYS and the automatically generated utterances issued by the system. The results concerning these questions are presented in Table 4.
Table 4Evaluation of CAPSYS's voice and utterancesScaleResultsVoice1: pleasant – 5: unpleasantmean =1.77;median =1.5;SD =0.991: difficult to understand – 5: easy to understandmean =4.28;median =5;SD =1.141: natural – 5: unnaturalmean =2.15;median =2;SD =1.121: too fast – 5: too slowmean =3.2;median =3;SD =0.5Utterances1: diversified – 5: unvariedmean =3.28;median =4;SD =1.241: inappropriate – 5: appropriatemean =3.46;median =3;SD =1.071: too short – 5: too longmean =3.2;median =3;SD =0.5 Concerning the frequency of use, the majority of the 26 IC participants who answered to the usability questionnaire indicated that they would prefer using CAPSYS once (11; 42 %) or twice (9; 35 %) per week. None of the respondents was willing to use the system more than twice a week, 2 (8 %) preferred to use it less than once a week and 4 (15 %) expressed that they would not use it at all. The approach of connecting to CAPSYS by calling the system whenever they wish was favoured by most of the respondents (18; 69 %) over the potential alternatives of being called by the system (3; 12 %) or receiving reminders to call the system (2; 8 %). Although CAPSYS does not offer speech recognition, we asked users if they prefer to have such an input option instead or in combination with the implemented keypad input. In this context, using the phone keypad was identified as the most preferred way of communication with such a system (20; 77 %) as compared to speech input (1; 4 %) or a combination of both (4; 15 %). The majority of the respondents were interested in having insight into the data history gathered by CAPSYS, either online (9; 35 %) or in a printed version (11; 42 %). Concerning a potential alternative interface for CAPSYS beside the phone interface, 10 (38 %) participants were interested in a corresponding website and 4 (15 %) fancied the idea of having a CAPSYS smartphone app. Regarding the question if the use of CAPSYS has motivated them to a healthier lifestyle, 5 (19 %) of the respondents stated that through the intervention they started eating healthier, 3 (12 %) reported to have become physically more active and 12 (46 %) claimed to have achieved both healthier eating and increased physical activity. This means that, in total, 20 (77 %; 95 % CI = [59 %, 95 %]) of the respondents expressed an improvement of their health-related lifestyle (improved nutrition or increased physical activity or both) through the use of CAPSYS.
BODY.DISCUSSION:
The positive effects that could be observed in the IC group concerning systolic blood pressure, LDL and triglyceride levels as well as the self-reported improvements of nutritional habits can be regarded as an indicator that a computerised phone-based intervention, such as CAPSYS, can support the reduction of cerebro-cardiovascular risk when offered in addition to usual care. An average decrease in systolic blood pressure of 9 mmHg among CI participants can be regarded as clinically significant [16]. The same also holds for the observed average decreases of 7.9 mg/dl for LDL [17] and 12.5 mg/dl for triglycerides [18]. Though, the relatively wide 95 % confidence intervals retrieved in the statistical analysis indicate that the cohort size was probably too small to be able to demonstrate strong clinical effects. The evaluation of BMI, HDL, HbA1c and glycaemia values showed no significant changes in the two groups. Our results are to some extent supported by the recently published Australian CLIP study, which found that telephone coaching performed by human health care professionals can result in a significant reduction of LDL and total cholesterol values in the intervention group [19]. A systematic review by Goode et al. also underlines the efficacy of telephone-based lifestyle coaching. In 20 out of 26 studies, telephone support by health professionals have led to significant improvements concerning physical exercises and healthy nutrition [20]. However, personal telephone coaching by health experts requires intensive use of human resources and is associated with enormous costs, which limits its widespread distribution to larger patient groups. CAPSYS is a system that supports prevention initiatives by supporting individuals in daily life settings. It can be assumed that a large percentage of the total target group is not willing to perform any lifestyle changes at all, no matter which kind of support they will receive. So, it has to be taken into account that our study participants are a selected subgroup of the target population with a potentially higher motivation to change risk factors and lifestyle. However, this selection bias in general concerns all prevention initiatives, and the randomisation process should ensure that the general motivation is balanced across both study arms. Compared to therapy studies, participants in prevention studies mostly do not see any direct measurable advantages in their actual health status. Missing short-term improvements are therefore often a reason for higher dropout rates. However, compared to other studies in secondary prevention, the moderate and balanced dropout rates of both CAPSYS arms should not have significantly affected the study results. On the other hand, self-reported consumptions of fruits, vegetables or sweets have a high potential for reporting bias. Therefore, in our study, this kind of information is only considered as secondary depended measures. The improvements of nutritional habits in the IC group (5 servings of fruits and vegetables more per week; 2 servings of sweets less per week) are significant, but have to be treated with caution as they are based on self-reported values and thus less reliable. As the dropout rates were not significantly different for both groups (SC: 22 %; IC: 33 %; p = 0.31), it can be supposed that the withdrawal of IC patients from the clinical trial was not substantially influenced by the intervention itself, but it was due to common reasons, like lack of time, forgetting appointments or just lack of motivation. Furthermore, it remains open how the observed positive effects will evolve after the study period and if they actually are of a long-term nature. The usability evaluation revealed that the CAPSYS approach was well accepted by the study participants. In particular, the large proportion of respondents (77 %) expressing a positive change of health-related behaviour due to the use of CAPSYS is remarkable. One might argue that this result is strongly biased due to the fact that users who have a positive experience with a system are more likely to finish a study and provide corresponding feedback than users with negative experiences. However, even if we consider all dropout IC participants as non-beneficiaries, the success rate concerning a positive health behaviour change would still be 42 % (95 % CI = [27 %, 57 %]). Unfortunately, our cohort was not large enough to perform subgroup analyses in order to evaluate the characteristics of beneficiaries and non-beneficiaries. A follow-up study focussing on such aspects might help to identify appropriate target groups for which a system like CAPSYS might be most beneficial and most accepted. During informal interviews at the end of the study, many of the IC participants explained that they often could not find the time or simply forgot to call CAPSYS. Taking this into account, the implementation of a call reminder functionality seems beneficial, even though in the feedback questionnaire, the majority of the respondents did not favour the concepts of being called or reminded by the system. Another important issue concerning risk factor reduction in the stroke prevention context is the topic of medication adherence. In order to support users in regularly taking their antihypertensive or cholesterol-lowering medication, CAPSYS could be extended to incorporate prompts in its automatically generated feedback messages asking the users if they have taken their prescribed medication according to their individual medication plan. Concerning the technical implementation of CAPSYS, it could be observed that, on average, the artificial voice applied in CAPSYS was perceived as rather pleasant, easy to understand and natural, and the speech rate was perceived as appropriate. The length of the utterances was, on average, perceived as adequate, but the feedback text might also be shortened to some extent. The results also show that there is some space for improvement concerning the diversity and adequacy of the automatically generated feedback. The offered keypad interface for data input was highly accepted by the users, and the need for an alternative input method, such as speech, was detected to be low. Unsurprisingly, only few users were currently interested in a mobile app version of CAPSYS. However, with increasing spread of smartphones, a mobile solution will certainly gain in importance in the future. What is already important for most users is to have access to their own self-monitored data, even if due to technical reasons they might only be able to access them in a printed form.
BODY.CONCLUSION:
In summary, the present study provided encouraging results indicating that a computerised phone-based lifestyle coaching system, such as CAPSYS, can support the usual treatment in reducing cerebro-cardiovascular risk factors and that such an approach is in general well accepted by the affected patients. In a next step, CAPSYS could be extended to a disease management tool, involving health professionals from different disciplines, such as neurologists, cardiologists, dieticians, physiotherapists etc., in the treatment of patients. One aspect that could be explored in future research is if the motivational effect of CAPSYS could be strengthened through an increased involvement of the treating physician and through incorporation of social interaction. | 4,748,685 | {
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TITLE: Sleep quality in mechanically ventilated patients: comparison between NAVA and PSV modes
ABSTRACT.BACKGROUND:
Mechanical ventilation seems to occupy a major source in alteration in the quality and quantity of sleep among patients in intensive care. Quality of sleep is negatively affected with frequent patient-ventilator asynchronies and more specifically with modes of ventilation. The quality of sleep among ventilated patients seems to be related in part to the alteration between the capacities of the ventilator to meet patient demand. The objective of this study was to compare the impact of two modes of ventilation and patient-ventilator interaction on sleep architecture.
ABSTRACT.METHODS:
Prospective, comparative crossover study in 14 conscious, nonsedated, mechanically ventilated adults, during weaning in a university hospital medical intensive care unit. Patients were successively ventilated in a random ordered cross-over sequence with neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV). Sleep polysomnography was performed during four 4-hour periods, two with each mode in random order.
ABSTRACT.RESULTS:
The tracings of the flow, airway pressure, and electrical activity of the diaphragm were used to diagnose central apneas and ineffective efforts. The main abnormalities were a low percentage of rapid eye movement (REM) sleep, for a median (25th-75th percentiles) of 11.5% (range, 8-20%) of total sleep, and a highly fragmented sleep with 25 arousals and awakenings per hour of sleep. Proportions of REM sleep duration were different in the two ventilatory modes (4.5% (range, 3-11%) in PSV and 16.5% (range, 13-29%) during NAVA (p = 0.001)), as well as the fragmentation index, with 40 ± 20 arousals and awakenings per hour in PSV and 16 ± 9 during NAVA (p = 0.001). There were large differences in ineffective efforts (24 ± 23 per hour of sleep in PSV, and 0 during NAVA) and episodes of central apnea (10.5 ± 11 in PSV vs. 0 during NAVA). Minute ventilation was similar in both modes.
ABSTRACT.CONCLUSIONS:
NAVA improves the quality of sleep over PSV in terms of REM sleep, fragmentation index, and ineffective efforts in a nonsedated adult population.
BODY.BACKGROUND:
Sleep is severely disturbed in mechanically ventilated ICU patients [1-3]. Sleep alterations are known to have deleterious consequences in healthy subjects, but the paucity of data in the literature [4-7] makes it difficult to determine the impact of sleep abnormalities in ICU patients. Intensive care unit (ICU) patients present disrupted sleep with reduced sleep efficiency and a decrease in slow wave sleep and rapid eye movement (REM) sleep [8-10]. Furthermore, polysomnographic studies performed on mechanically ventilated ICU patients have demonstrated an increase in sleep fragmentation, a reduction in slow-wave and REM sleep, and an abnormal distribution of sleep, because almost half of the total sleep time occurred during the daytime [11-13]. In the Freedman et al. study [14], noise was considered a nuisance for the patients questioned; the most annoying noises were alarms and caregivers' conversations. When the same authors simultaneously recorded noise and microarousal, they identified an association between arousal and noise in only 11-17% of the cases [11]. This percentage is confirmed by Gabor et al. [3] where 21% of the arousal interruptions were explained by loud noises and 7% to patients' care. Seventy-eight percent of the microarousals were not associated with environment noises, suggesting other causes, such as patient/ventilator asynchrony [3,14]. The effects of assist control ventilation (ACV) and pressure support ventilation (PSV) on sleep fragmentation have been examined in critically ill patients receiving mechanical ventilation [15], where PSV mode was associated with increases in the number of central apneas and subsequent sleep fragmentation compared with AVC. Furthermore, the study suggested that PSV by itself or an excess of ventilator assistance with PSV could have caused such sleep alterations. Indeed, ventilatory settings adjusted during wakefulness may become excessive during sleep, as the patients' ventilatory demand is reduced while asleep [16]. Whether these results can be explained by the ventilatory mode itself or how it was adjusted is an important issue, because hyperventilation and patient ventilator asynchrony may result from PSV as well as ACV in mechanically ventilated ICU patients [17]. Fanfulla et al. [18] compared two ventilatory settings in nine patients under long-term PSV for neuromuscular disease. The initial setting was set according to clinical parameters, and the second setting was adjusted with measurement of esophageal pressure (physiological setting) to optimize patient effort. The physiological setting improved the duration and quality of sleep, decreased episodes of apnea, and the amount of inefficient efforts for ventilator triggering [18]. The level of pressure support and PEEP tended to decrease, with a lowering of intrinsic PEEP and patient-ventilator asynchronies. A recent study by Cabello et al. [19] compared the impact of three modes of ventilation (AVC, PSV, and SmartCareTM) on the quality of sleep in alert and nonsedated patients, and no difference for the architecture, fragmentation, and duration of sleep was found among the three modes. Our hypothesis is that NAVA ventilation is superior to PSV by allowing optimal patient-ventilator synchrony and thereby decreasing sleep fragmentation.
BODY.METHODS:
This study was approved by the Ethics Committee of the Hôpital du Sacré-Coeur de Montréal, and patients or their surrogates gave written informed consent.
BODY.METHODS.PATIENTS:
This physiologic study was conducted in a 22-bed medical ICU during a 12-month period. The weaning phase of mechanical ventilation was chosen because patient-ventilator asynchrony is common when patients are spontaneously triggering breaths. The inclusion criteria required that the patient was conscious, free from sedation and opiate analgesia for ≥ 24 hours, and ventilated in PSV mode with an FIO2 < 60%, PEEP = 5 cmH2O, and SpO2 ≥ 90%. Exclusion criteria consisted of the presence of a central nervous system disorder, Glasgow Coma Scale score < 11, hemodynamic instability, renal and/or hepatic insufficiency, and ongoing sepsis.
BODY.METHODS.METHODS:
All patients were ventilated through an endotracheal tube or a tracheostomy; once they met the inclusion criteria, they were connected to a Servo i ventilator (Maquet critical Care, Sölna, Sweden), equipped with a neurally adjusted ventilator assist system (NAVA). The electrical activity of the diaphragm (EAdi) is captured with the EAdi catheter (Maquet Critical Care, Sölna, Sweden) consisting of a 16-Fr gastric tube equipped with electrodes. End-tidal CO2 was monitored with the Servo-i Volumetric CO2 module. The two different ventilatory modes were delivered in a randomized order using a closed-envelope technique during four periods of 4 hours: a daytime period from 7 to 11 a.m. and 12 to 4 p.m., and a nocturnal period from 10 p.m. to 2 a.m. and 3 to 7 a.m. To prevent possible data contamination from the previous mode of ventilation, a 1-hour washout period after a ventilator change was introduced before data acquisition (Figure 1; Study Protocol). Figure 1Patients were studied for a period of 4 hours for each recording sequences and for more than 19 consecutive hours. During periods of wakefulness, PSV and NAVA were clinically adjusted by the attending physician to obtain a tidal volume of 8 mL/kg of predicted body weight and a respiratory rate ≤ 35 breaths/min. For both modes of ventilation, inspiratory triggering sensitivity was set at thresholds that would not allow auto-triggering for both modes of ventilation: 0.5 mV in NAVA and 5 in PSV. EEG was recorded from standard locations: left frontal/right mastoïd reference (F3/M2 or F3/A2), right frontal/left mastoid reference (F4/M1or F4/A1), left central/right mastoïd reference (C3/M2 or C3/A2), right central/left mastoïd reference (C4/M1 or C4/A1), left occipital/right mastoïd reference (O1/M2 or O1/A2), and right occipital/left mastoïd reference (O2/M1or O2/A1), according to the International 10-20 System for electrode placement [20]. The standard reference used was the left mastoid lead [20]. Two electro-oculogram and three chin electromyogram leads were used to score REM and non-REM sleep. The electroencephalogram, the right and left electro-oculogram, and the submental electromyogram signals were amplified and recorded in the data acquisition system (Alice 5 polysomnography system using Alice® SleepwareTM 2.5 software, Respironics, Nantes, France). Sleep recordings were manually read and scored by an independent pulmonologist blinded to the study, using the criteria of Rechtschaffen and Kales [21,22] and the criteria of the American Sleep Disorder Association for arousals and awakenings [23,24]. Diagnosis of central apnea was based on international recommendations [24]. The diagnosis of central apnea is characterized by absent breathing and respiratory effort for a period of at least 10 seconds. Arousals and awakenings were considered secondary to apnea when occurring within three cycles and/or 15 sec after a respiratory event [25,26]. Ineffective efforts were defined as an inspiratory effort observed by a peak electrical activity of the diaphragm (EAdi peak) without a simultaneously triggered ventilator cycle. Airflow, Paw, and EAdi were acquired from the ventilator through a RS232 interface at a sampling rate of 100 Hz, recorded by a dedicated software (Nava Tracker V. 2.0, Maquet Critical Care, Sölna, Sweden), and an analyzer using software Analysis V 1.0 (Maquet Critical Care) and a customized software based for Microsoft Excel. An arousal or awakening event was considered secondary to ineffective triggering when it occurred within 15 seconds after the asynchrony [19]. Noise was measured with a portable noise meter at the level of patient's head (Quest Technologies, Oconomowoc, WI). Arousals and awakenings were associated with the noise when they occurred 3 seconds after or within noise increase ≥10 dB [3,11]. Inspiratory trigger delay was calculated as the time difference between the onset of EAdi peak and Paw inspiratory swings. Cycling-off delay was calculated as the time difference between the end of the inspiratory EAdi peak deflection and the onset of expiratory flow.
BODY.METHODS.STATISTICS ANALYSIS:
Statistical analysis was performed using SPSS statistical software (SPSS 17.0). Continuous variables were expressed as median (25th-75th percentile) or mean ± SD. Data were compared using the general linear model for repeated measures (GLM). The small sample of patients led us to use Wilcoxon's t test for paired samples, and the p values for multiple comparisons were corrected for the Bonferroni inequality. A two-tailed p value < 0.05, corrected as needed, was retained to indicate statistical significance.
BODY.RESULTS.PATIENTS:
Fourteen patients were selected and none were excluded during the study. Their main characteristics are shown in Table 1. Acute respiratory failure was the most frequent reason to initiate mechanical ventilation in ten patients, postoperative complications in three patients, and septic shock in one patient. Table 1 Characteristics of patients Characteristics of patients Sex (M/F) (8/6) Age (yr ± SD) 64 ± 11 SAPS II ± SD 46 ± 12 Duration of MV (days ± SD) 17 ± 9 Tracheotomy (%) 2 (14) Cause for initial MV (%) Acute respiratory failure 10 (71.5%) Postoperative complication 3 (21.5%) Septic shock 1 (7%) M = male; F = female; SAPS = Simplified Acute Physiology score; MV = mechanical ventilation.
BODY.RESULTS.SLEEP RECORDINGS:
All patients completed the study, and recordings were well tolerated. Individual sleep data are shown in Table 2. The median total sleep time was 564 (range, 391-722) minutes. The median sleep efficiency (i.e., the percentage of sleep during the study) was 59% (range, 41-75%). The main abnormalities observed on each patient were a diminished percentage of REM sleep, counting for only 11.5% (range, 8-20%) of total sleep time, and a high fragmentation index with 25 arousals and awakenings per hour (range, 18-51). Although interindividual variability was large, the median quantity of slow-wave sleep (stages 3 and 4 or NREM3 stage) was normal, with a median of 18.5 (range, 11.5-22; Table 2). Table 2 Sleep architecture and fragmentation during the study (16 hours) Patient Stage 1 (%) Stage 2 (%) Stages 3 and 4 (%) Rapid eye movement (%) Fragmentation index 1 5 72.5 19.5 2.5 23.5 2 2.5 67 22.5 7 35.5 3 4 61 24.5 9 30.5 4 10 57 11 20 68 5 9 61 24 5.5 16.5 6 6 57 24 12.5 15 7 5 63 22 7.5 13.5 8 11 66.5 9 10.5 64.5 9 5.5 58 17.5 19 15.5 10 11 60.5 9.5 17 56.5 11 3 66 21 9 26 12 3.5 61.5 13 22 23 13 5.5 60 13 21.5 22 14 10 59 10.5 20.5 67.5 Median [25-75 th percentiles] 5.5 [4-10] 61 [59-65] 18.5 [11.5-22] 11.5 [8-20] 25 [18-51]
BODY.RESULTS.VENTILATORY MODES AND SLEEP DISTRIBUTION:
Sleep efficiency and architecture appeared very different for both modes of ventilation (NAVA and PSV). Stage 1 (NREM1 stage) lasted longer during PSV compared with NAVA 7.5% (range, 4-15%) vs. 4% (range, 3-5%; p = 0.006). Stage 2 (NREM2 stage) also lasted longer in PSV than NAVA 68% (range, 66-75%) vs. 55% (range, 52-58%; p = 0.001). Stage 3-4 (NREM3 stage) was shorter in PSV as opposed to NAVA 16.5% (range, 17-20%) vs. 20.5% (range, 16-25%; p = 0.001). REM stage (R stage) was much shorter in PSV than in NAVA 4.5% (range, 3-11%) vs. 16.5% (range, 13-29%; p = 0.001). The fragmentation index was different between the two ventilation modes, with 40 ± 20 arousals and awakenings per hour in PSV and 16 ± 9 during NAVA (p = 0.001; Figure 2 Sleep stage (percent of total sleep) during two ventilatory modes; Table 3). Figure 2Sleep stages (percent of total sleep) during the two ventilator modes: pressure support ventilation (PSV), and neurally adjusted ventilatory assist (NAVA). REM = rapid eye movement. Table 3 Comparison of sleep quality between the ventilatory modes PSV NAVA
p
Stage 1, % 7.5 [4-15] 4 [3-5] 0.006* Stage 2, % 68 [66-75] 55 [52-58] 0.001* Stage 3 and 4, % 16.5 [17-20] 20.5 [16-25] 0.001* REM, % 4.5 [3-11] 16.5 [13-29] 0.001* Fragmentation index, (n/h) 33.5 [25-54] 17.5 [8-21.5] 0.001* Sleep efficacy, % 44 [29-73.5] 73.5 [52.5-77] 0.001* PSV = pressure support ventilation; NAVA = neurally adjusted ventilatory assist; REM = rapid eye movement; Fragmentation Index = number of arousals and awakenings per hour of sleep; Sleep efficiency = duration of sleep/total duration of recording. Values are expressed as median [interquartile range]. * p < 0.05. Minute ventilation did not significantly differ between PSV and NAVA with median values of 9.8 L/min (range, 8.0-10.9), and 9.6 L/min (range, 7.5-11.0) respectively (p = 0.51). The median respiratory rates were 17 breaths/min (range, 14-21), and 20 breaths/min (range, 15-23) during PSV and NAVA (p = 0.14). Median tidal volume was 420 mL (8.1 mL/Kg of predicted body weight; range, 375-479 mL), and 378 mL (7.3 mL/Kg of predicted body weight; range, 370-448 mL) during PSV and NAVA, respectively (p = 0.36). The mean PSV level was 15 ± 5 cmH2O, and the mean NAVA level was 1.6 ± 1.4 cmH2O/μV. Positive end-expiratory pressure was kept at 5 cmH2O for all patients.
BODY.RESULTS.APNEAS AND INEFFECTIVE EFFORTS:
Ten of the 14 patients presented sleep apnea, and 11 exhibited ineffective efforts. The mean index of sleep apneas (number of apneas per hour of sleep) was 10.5 ± 11 apneas during PSV and 0 during NAVA (p = 0.005) and ineffective efforts (number of ineffective efforts per hour of sleep) was 24 ± 23 ineffective efforts during PSV and 0 during NAVA (p = 0.001). Over-assistance during sleep is sensed on the previous three cycles preceding central apnea. Tidal volume and minute ventilation increased, whereas ETCO2 and EAdi decreased over the three cycles preceding central apnea Table 4. Table 4 Oscillatory behaviour of various ventilator parameters for stages 3-4 with PSV mode of ventilation Respiratory variables Baseline Pre-apneas PSV V T (mL) 425 ± 67 585 ± 70 RR (breath/min) 13 ± 2 12 ± 1 VE (L/min) 5.2 ± 0.5 6.8 ± 0.8 ETCO 2 (mmHg) 46 ± 1.4 42 ± 1.0 EAdi (mVolt) 15 ± 4 10 ± 2 V T = tidal volume; RR = respiratory rate; VE = minute ventilation; ETCO 2 = end-tidal carbon dioxyde; PSV = pressure support ventilation.
BODY.RESULTS.TRIGGER DELAY AND CYCLING-OFF DELAY:
During N-REM sleep in PSV, the trigger delay increased on average by 80 ± 26 (msec) during stage 1 versus 158 ± 42 (msec) during stage 3 and 4. The expiratory trigger (cycling-off) increased in PSV by 158 ± 103 (msec) and 258 ± 87 (msec) during stage 1 and stages 3 and 4, respectively. In NAVA, the trigger delay remained stable during sleep, 68 ± 24 (msec) during stage 1 and 72 ± 32 (msec) during stages 3 and 4. The expiratory trigger also remained stable in NAVA: 39 ± 28 (msec) during stage 1 and 41 ± 34 (msec) during stages 3 and 4.
BODY.RESULTS.NOISE:
In ICU, we recorded the average baseline ambient noise level and evaluated arousals from this baseline to a peak noise level ≥ 10 dB above ambient noise level. The mean noise level was recorded at 64 ± 8 dB, with the peak level recorded at 111 dB and the minimal level at 52 dB. No differences were observed between the two different ventilatory modes concerning the index of fragmentation associated with noise: 7.5 ± 3 during PSV and 6 ± 3.5 during NAVA (p = 0.19). These data indicate that 18% during PSV and 21% during NAVA of the fragmentation was associated with sudden increases in noise.
BODY.RESULTS.SLEEP DISTRIBUTION AMONG STUDY PERIODS:
The cross-over pattern was balanced with an equal number of patients from each sequence initiating the rotation. Independent of the ventilatory mode, sleep efficiency and sleep architecture had a significantly different distribution based on the study period considered (Figure 3--sleep stage (percent of total sleep) during the four daily time periods). Sleep efficiency was the same in the two daytime periods (2 periods during the day): 52% (range, 26-67%) during the first day period (7 h-11 h a.m.) and 51.5% (range, 27-67%) during the second day period (12 h-4 h p.m.; p = 0.18). Sleep efficiency also did not differ between the two night periods: 65.5% (range, 37-82%) during the first night period (10 h p.m.-2 h a.m.) and 65% (range, 45-82.5%) during the second nighttime period (3 h-7 h a.m.; p = 0.11). Figure 3First daytime period (7 h-11 h a.m.), second daytime period (12 h-4 h p.m.), first nighttime period (10 h p.m. to 2 h a.m.) and second nighttime period (3 h-7 h a.m.). There was no statistical difference between stage 1 and 2 recording periods. A greater duration of slow-wave sleep (stage 3-4) was found during the first nocturnal period with a median percentage 22.5% (range, 20-33.5%) vs. 15.5% (range, 7-19.5%) during first day period (p = 0.03), vs. 15% (range, 7-18%) during second day period (p = 0.01) and vs. 18% (range, 13-21%) during second nighttime period (p = 0.001). The proportion of REM sleep was longer during the second nocturnal period, with a median percentage of 16.5% (range, 15-25%) vs. 11.5% (range, 5-15%) during first day period (p = 0.001) vs. 9% (range, 5-15%) during second day period (p = 0.001) and vs. 10.5% (range, 7-21%) during first nighttime period (p = 0.02). The fragmentation index did not differ with 26 (range, 20-65) arousals and awakenings/hour during first daytime vs. 24 (range, 19-55), 23 (range, 18-57), and 19 (range, 15-53) during the second day period and first and second night period, respectively (p = 0.08). Ineffective effort indexes per hour also were similar across the four periods.
BODY.DISCUSSION:
In a study where spontaneously breathing patients were conscious and under mechanical ventilation, proportions of sleep fragmentation sleep architecture and sleep quality were positively influenced by NAVA. In the PSV mode, a low percentage of REM sleep and a high degree of fragmentation were present. NAVA showed a normal percentage of REM sleep with an important decrease in fragmentation. Less than 15% of the sleep fragmentations in the PSV mode were attributed to apneas and ineffective efforts, whereas in NAVA, no asynchrony (no apnea and no ineffective patient efforts) were recorded. Environmental noise is responsible for 18% of the arousals and awakenings in PSV compared with 21% in NAVA, respectively. We observed results similar to the Cabello et al. [19] study concerning the rate of fragmentation, the number of central apneas, and the number of ineffective patient efforts during PSV. Another similar finding concerned the increased percentage of REM sleep during the second nighttime period recordings. However, one major difference between our study and the Cabello study is that they did not allocate an even distribution for each of the study periods and ventilatory strategies. Also, they did not allow washout periods between the ventilatory modes, which could possibly contaminate the recordings at the beginning of the next study period. Detecting asynchronies also was different; they used the airway pressure-flow signal and the thoracoabdominal plethysmography, whereas we observed the EAdi signal. Parthasarathy and Tobin [15] found a lower rate of sleep fragmentation during ACV compared with PSV. This was explained by the central apneas induced by over-assistance during PSV. In fact, tidal volume was much greater during PSV compared with ACV. This was validated by the addition of a dead space to the 11 patients showing central apneas, which significantly decreased the number of apneas. In the Toublanc et al. study [27], no difference was found in terms of quantity, quality of sleep, and in terms of arousal index between the AC and a low level of PSV assistance for the whole night. Toublanc et al. found that ACV was superior in terms of percentage of slow-wave sleep but not during REM sleep [27]. It is very difficult to compare the results for PSV because of a lack of information on expiratory triggering with Evita 4, number of asynchronies (tidal volume, respiratory rate, and minute ventilation). In the Toublanc study, the majority of patients were affected with COPD and pressure support was adjusted to 6 cmH2O. According to Brochard et al., it is suggested that for COPD patients, the pressure support needed to overcome resistance imposed by the endotracheal tube is higher than non-COPD patients: 12 ± 1.9 vs 5.7 ± 1.5 cmH2O respectively [28]. In the Leleu et al. study, pressure support must be superior to 6 cmH2O, particularly in COPD if the intention is to compensate work of breathing imposed by the endotracheal tube, ventilator circuit, and patient effort to trigger the demand valve during pressure support [29]. A low-pressure support only allows for partial relieve of imposed work of breathing without modifying the work necessary to trigger the demand valve. In the Toublanc study, pressure support set too low in COPD patients resulted in an increase in imposed work of breathing, which can be accounted for in the decrease in SWS and REM. The Toublanc study offers no information on expiratory triggering, which is somewhat important in COPD patients. Tassaux et al. recently have evaluated the positive impact of shortening inspiratory time in PSV on patient-ventilator asynchronies and the work of breathing in COPD patients. This study also demonstrated that the increase in expiratory trigger up to 70% of peak flow improved synchrony and decreased ineffective efforts without modifying work of breathing or minute ventilation [30]. Bosma et al. evaluated the impact on sleep with other modes of ventilation, such as the proportional assist ventilation (PAV). The objective of PAV, such as NAVA, is to improve patient ventilator synchrony by delivering ventilator assist proportional to patient effort. The study by Bosma et al. shows an improvement in the quality of sleep using PAV compared with PSV during one night sleep [31]. There are similarities between the Bosma study and ours. More specifically, PAV appeared superior to PSV in terms of decrease in arousals, improvement in sleep quality, decrease in amounts of arousals, awakenings per hour, and improved SWS and REM. With NAVA, we observed a decrease in tidal volume by up to 15% during REM sleep, which increased end-tidal CO2 by approximately 4 mmHg. Bosma et al. observed a tidal volume slightly more elevated in PSV compared with PAV (despite similar offloading of the work of breathing), resulting in a higher morning PaCO2 with PAV attributed to lower tidal volume and minute ventilation [31], thus offering perhaps a protection against central apneas. Finally, fewer patient-ventilator asynchronies were observed with PAV with fewer awakenings per hour [31]. Contrary to NAVA, PAV cannot eliminate wasted or ineffective efforts. There was a nonstatistically significant difference in ineffective triggering during inspiration; 19.6 n/hr for PSV vs. 11.6 n/hr for PAV [31]. According to Thille et al. ineffective efforts and double triggering are among the most frequent asynchronies: 85 and 13% respectively [32], which is somewhat contradictory to Bosma et al. who identify auto triggering as the most frequent asynchrony in PSV. We observed that the absence of central apnea and ineffective efforts in NAVA do not totally explain the great improvement in the SWS and REM sleep. This improvement may be explained in part by a microanalysis of the sleep architecture. The microanalysis suggests an over-assistance with PSV during the N-REM stages, because 100% of the fragmentations in PSV occurred during this stage. The tidal volume decrease in NAVA follows the respiratory physiologic changes during sleep, whereas in PSV we find a tidal volume oscillatory behavior due to constant inspiratory efforts, independent of the sleep stage and produces sequential over-assistance during N-REM sleep leading to a decrease in end-tidal CO2. It is our assumption that improvement of the slow-wave sleep and REM is most probably explained by better patient comfort through better neuromechanical coupling. During sleep, the respiratory accessory muscles (intercostals, scalene, and abdominals) decrease their muscle tone and the mechanical response of the diaphragm is, in part, spent in the production of a mechanical distortion of the chest wall, secondary to a lack of synchronization between diaphragmatic contraction and the accessory muscles. NAVA improves this mechanical distortion, whereas PSV worsens this distortion by a tidal volume oscillation (overshoot) during sleep, with a constant patient effort. Patient comfort is not only directly related to inefficient efforts and central apneas; the microanalysis showed that during N-REM sleep in PSV, the trigger delay increased during stage 1 versus during stage 3 and 4. The expiratory trigger increased in PSV during stage 1 and stages 3 and 4, respectively. In NAVA, the trigger delay remained stable during stage 1 and during stages 3 and 4. The expiratory trigger also remained stable in NAVA, during stage 1 and during stages 3 and 4. NAVA allows optimizing the neuromechanical coupling and therefore patient-ventilator synchrony [33] and allows for optimized adequacy between ventilatory load and patient breathing ability, thereby providing beneficial effects on sleep in ICU patients. It appeared to us that the EAdi tracing is much more efficient than flow and pressure tracings to detect asynchronies. Our study has some limitations; one is the open space between patients. This study included only 14 patients, which could favor the possibility of a type II error. Patients' heterogeneity implies that patients required bedside care, such as suctioning or other care, which could perhaps influence sleep fragmentation. The study by Cabello found that suctioning was associated with < 1% arousals and awakenings [19]. The choice for a 15-second interval between asynchrony and the occurrence of arousal was chosen based on one previous study on the same topic [19]. Literature on this specific time interval to choose is very scarce. In one study, it was shown that the breathing response to a complete airway occlusion was 20.4 ± 2.3 sec during NREM and 6.2 ± 1.2 sec during REM [34]. The choice of a 15-second interval seems very reasonable but may need further investigation. In a sleep laboratory, it is a lot easier to control the baseline ambient noise level. In a clinical environment, such as an ICU, we recorded the average baseline ambient noise level and evaluated arousals from this baseline to a peak noise level ≥10 dB above ambient noise level. There is therefore a potential for statistical inaccuracies. The fact that we stopped sedation 24 hours before beginning the study does not imply an absence of cumulative sedation. However, every patient had a Ramsay Score of 2 or less and a Glasgow Score of 11 (the maximum score for an intubated patient).
BODY.CONCLUSIONS:
The ventilatory mode NAVA improves the quality of sleep by increasing the slow-wave sleep and REM and by decreasing fragmentation. NAVA improves patient comfort through better neuromechanical coupling during N-REM sleep, by a shorter trigger delay, and more efficient expiratory triggering. To minimize sleep fragmentation, optimal setting of pressure support level and expiratory trigger are paramount in PSV. However, proportional assistance modes of ventilation according to patient inspiratory effort, such as NAVA, appear to be a better choice to minimize sleep fragmentation.
BODY.COMPETING INTERESTS:
The authors declare that they have no competing interests.
BODY.AUTHORS' CONTRIBUTIONS:
SD and PO drafted the manuscript, and PB, JPT, and PA revised the manuscript. | 3,224,529 | {
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TITLE: Efficacy and Safety of Subcutaneous Golimumab in Methotrexate‐Naive Patients With Rheumatoid Arthritis: Five‐Year Results of a Randomized Clinical Trial
ABSTRACT.OBJECTIVE:
To evaluate the safety and efficacy of golimumab through 5 years in adults with active rheumatoid arthritis (RA) who had not previously received methotrexate (MTX).
ABSTRACT.METHODS:
In the GO‐BEFORE study, 637 MTX‐naive adult patients with active RA were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4). Inadequate responders in groups 1, 2, and 3 entered early escape at week 28 to golimumab 50 mg + MTX, golimumab 100 mg + MTX, or golimumab 100 mg + MTX, respectively; remaining patients in group 1 could cross over to golimumab 50 mg + MTX at week 52. Assessments included the American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response, the Disease Activity Score in 28 joints (DAS28) using C‐reactive protein (CRP) level, and the modified Sharp/van der Heijde score (SHS). Efficacy was analyzed using an intent‐to‐treat (ITT) analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits.
ABSTRACT.RESULTS:
A total of 422 patients completed golimumab treatment through week 256. At week 256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n = 637) had an ACR20/50/70 response, respectively; 84.1% had a good or moderate DAS28‐CRP response; and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week 256, and the overall mean change from baseline in SHS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week 256. Antibodies to golimumab occurred in 9.6% of patients through week 256. Infections were the most common type of adverse event (AE); 204 of 616 patients (33.1%) had ≥1 serious AE.
ABSTRACT.CONCLUSION:
Clinical efficacy with golimumab treatment was maintained through week 256 of the GO‐BEFORE trial of MTX‐naive RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports.
BODY.INTRODUCTION:
Golimumab, a fully human anti–tumor necrosis factor (TNF) antibody, has been shown to improve the signs and symptoms of rheumatoid arthritis (RA) in adults in large, randomized, placebo‐controlled phase 3 trials 1, 2, 3. The GO‐BEFORE trial evaluated the safety and efficacy of subcutaneous (SC) golimumab in adult patients with RA who had not previously received methotrexate (MTX) therapy, and results through 2 years have been reported 1, 4. In the GO‐BEFORE trial, patients treated with golimumab (50 mg or 100 mg) + MTX had significantly greater improvements in the signs and symptoms of RA than those treated with MTX monotherapy. These improvements were observed at week 24 1 and were maintained through 2 years 4. In addition, golimumab + MTX‐treated patients had significantly less radiographic progression through 1 year when compared with those who received MTX monotherapy 5. Here we report the final efficacy and safety results of the GO‐BEFORE trial through 5 years. Box 1Significance & Innovations
Clinical response to golimumab (50 mg and 100 mg) + methotrexate (MTX) was maintained through 5 years in adult patients with moderate to severe rheumatoid arthritis who had not previously received MTX.Safety findings were consistent with previous golimumab studies and other anti–tumor necrosis factor agents; no unexpected adverse events occurred.The incidence of antibodies to golimumab was low, and the presence of antibodies to golimumab was not associated with adverse events.
BODY.PATIENTS AND METHODS.PATIENTS AND STUDY DESIGN:
The detailed eligibility criteria and study design of the GO‐BEFORE trial have been previously described 1. Briefly, adult patients with active RA who had not been previously treated with MTX were randomly assigned to receive SC injections of placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4); injections were administered at baseline and every 4 weeks. Active RA was defined as ≥4 swollen joints, ≥4 tender joints, and at least 2 of the following criteria: C‐reactive protein (CRP) level of ≥1.5 mg/dl or erythrocyte sedimentation rate ≥28 mm/hour using the Westergren method; morning stiffness lasting ≥30 minutes; or evidence of bone erosion radiographs or magnetic resonance imaging 1. Eligible patients also could not have a history of latent tuberculosis (TB) prior to screening and could not have any signs or symptoms of active TB. Patients were screened for TB by chest radiographs (both posteroanterior and lateral views) within 3 months before the first study drug administration and diagnostic testing (tuberculin and QuantiFERON‐TB Gold tests) within 6 weeks before the first study drug administration. Patients with a newly identified positive result (tuberculin or QuantiFERON‐TB Gold testing) could participate in the trial if they initiated appropriate treatment for latent TB. Patients were stratified by investigational site and baseline CRP level (<1.5 mg/dl or ≥1.5 mg/dl). Placebo and golimumab injections were administered at baseline and every 4 weeks. At week 28, patients in groups 1–3 with an inadequate response to treatment entered blinded early escape such that patients in group 1 switched from placebo to golimumab 50‐mg injections, patients in group 2 initiated concomitant MTX therapy while continuing golimumab 100‐mg injections, and patients in group 3 increased their golimumab dose to 100 mg; patients in groups 1 and 3 continued concomitant MTX. Patients in group 4 did not have any changes in treatment regimen, regardless of their early escape status. The active‐control period continued through week 52. The long‐term extension began with the week‐52 visit and continued through week 268 (5 years). At week 52, patients in group 1 who did not have any swollen or tender joints continued MTX monotherapy; patients with at least 1 swollen or tender joint were switched from placebo injections to golimumab 50 mg. Patients in groups 2, 3, and 4 continued the treatment they were receiving at week 52. The blind was maintained until the week‐52 database was locked, after which treatment adjustments could be made at the investigator's discretion. Patients in group 1 who were receiving MTX monotherapy could initiate treatment with golimumab 50 mg, and a 1‐time golimumab dose increase to 100 mg or decrease to 50 mg was permitted (including patients who had dose‐escalated to 100 mg). Additionally, MTX therapy could be initiated or adjusted during the long‐term extension period. Concomitant therapy with nonsteroidal antirheumatic drugs (NSAIDs), corticosteroids, or other analgesics for RA could also be adjusted at the investigator's discretion. The final study golimumab injection was at week 252. After week 256, patients transitioned to standard‐of‐care treatment for RA, including commercially available biologic agents. The GO‐BEFORE trial was conducted according to the Declaration of Helsinki. The protocol was approved by the institutional review board or ethics committee at each site, and all patients gave written informed consent before any study‐related procedures were performed.
BODY.PATIENTS AND METHODS.EVALUATIONS:
During the long‐term extension, clinical response was assessed every 12 weeks through week 256, with an additional assessment at week 104. Disease activity was assessed using the American College of Rheumatology (ACR) criteria 6 and the European League Against Rheumatism Disease Activity Score in 28 joints (DAS28) using CRP level 7. Post hoc efficacy assessments included the Simplified Disease Activity Index (SDAI) 8 and the Clinical Disease Activity Index (CDAI) 9. Physical function was evaluated using the Health Assessment Questionnaire (HAQ) disability index (DI) 10. Normal physical function was defined as a HAQ DI score ≤0.5, and a minimal clinically important difference (MCID) was defined as an improvement ≥0.25 11. Health‐related quality of life was evaluated using the physical component summary (PCS) and mental component summary (MCS) scores of the Short Form 36‐item (SF‐36) health survey 12. The impact of disease on productivity was assessed using a visual analog scale (0–10 cm) at baseline and at week 256. Radiographs of the hands and feet were obtained at weeks 52, 104, 208, and 256 during the long‐term extension; results through week 104 have been previously reported 1, 4. Data from patients with radiographs at baseline, week 104, and at least 1 radiograph after week 104 were included in the current analysis. As previously detailed 5, radiographs were scored by 2 independent readers and an adjudicator using the modified Sharp/van der Heijde score (SHS) 13. Patients were monitored through week 268 for adverse events (AEs). Routine laboratory analyses were performed through week 256. The incidence of each AE was summarized according to actual treatment received at the time of the event. Blood samples were collected (prior to administration of study agents) at selected visits for the analysis of pharmacokinetics and evaluation for the presence of antibodies to golimumab using validated immunoassays 14.
BODY.PATIENTS AND METHODS.STATISTICAL ANALYSIS:
Descriptive statistics (e.g., counts and percentages and means/medians) were used to summarize the efficacy results of the long‐term extension by randomized treatment group. In the a priori analysis of clinical efficacy end points (ACR components and DAS28‐CRP), observed data were used through week 256 with no imputation for missing values. A more stringent post hoc intent‐to‐treat (ITT) analysis including all randomized patients was performed on the clinical efficacy measures, and these results are reported herein. This ITT analysis used the following data imputation and treatment failure rules: 1) missing baseline values for continuous variables were replaced with the median value of the corresponding baseline CRP level stratum (<1.5 mg/dl or ≥1.5 mg/dl), and the last observation carried forward (LOCF) methodology was applied to missing postbaseline values, and 2) patients who discontinued the study agent due to unsatisfactory therapeutic effect were imputed as nonresponders. The proportions of patients achieving at least a 20%, 50%, or 70% improvement in the ACR criteria (ACR20/50/70 response) 6, a moderate or good DAS28‐CRP response 7, 15, a DAS28‐CRP <2.6, a DAS28‐CRP ≤3.2, an MCID in HAQ DI score, and a HAQ DI score ≤0.5 were determined. SF‐36 and productivity outcomes were analyzed using observed data, with no missing data imputation, and included improvements from baseline in SF‐36 PCS and MCS scores and the impact of disease on productivity at week 256, as well as the proportions of patients with normal SF‐36 PCS or MCS scores (score ≥50). In the post hoc analysis, the proportions of patients who achieved remission, as defined by an SDAI score ≤3.3 16, a CDAI score ≤2.8 16, or Boolean definition 17 were also determined. Radiographic data through week 256 were summarized by randomized treatment group and included all patients who had radiographs at weeks 0, 104, and at least 1 radiograph after week 104. Changes from baseline to week 208 and week 256 in the SHS are reported; missing postbaseline values were replaced using the LOCF methodology. Among patients with an SHS score at baseline and week 256, annual rates of progression at baseline and 5 years were determined using the SHS score divided by RA duration for each patient at baseline and the change in SHS over 5 years. Cumulative safety data are reported for all patients who received at least 1 administration of golimumab through week 268. AEs and serious AEs were summarized according to the treatment received at the time of the event. As a result of early escape, placebo crossover, and golimumab dose adjustments allowed during the long‐term extension, patients could be included in more than 1 treatment group. AEs were summarized through week 268, with the exception of those that occurred after receipt of any commercial biologic agent (including commercial golimumab). Patients who received commercially available biologic treatment after discontinuing study golimumab, yet who remained in the study, had AEs reported through week 268, but these AEs were excluded from the safety summaries. The rates per 100 patient‐years and 95% confidence intervals (95% CIs) for the total numbers of serious infections, malignancies (including nonmelanoma skin cancers), and death are also reported. In addition, standardized incidence ratios (SIRs) for malignancies were determined using the Surveillance, Epidemiology and End Results (SEER) database; nonmelanoma skin cancers were excluded from this comparison because they are not reported in the SEER database.
BODY.RESULTS:
Data for this report were collected from December 2005 to June 2012. As previously reported, patient demographics and disease characteristics at baseline were well‐balanced among the treatment groups 1. A total of 637 patients were randomly assigned to group 1 (n = 160), group 2 (n = 159), group 3 (n = 159), and group 4 (n = 159; see Supplementary Table 1, available on the Arthritis Care & Research web siteat http://onlinelibrary.wiley.com/doi/10.1002/acr.22759/abstract). Eighty‐nine patients (group 1, n = 28; group 2, n = 22; group 3, n = 20; and group 4, n = 19) met the early escape criteria at week 28 4. Through week 104, 140 patients discontinued the SC study agent, with AEs being the most common reason 4. A total of 215 patients (33.9%) discontinued the study agent through week 252; 111 (17.5%) discontinued due to an AE, including worsening of RA (n = 4, 0.6%), and 23 patients (3.6%) discontinued due to unsatisfactory therapeutic effect (Table 1). A total of 402 patients (63.4%) completed the safety followup through week 268. Table 1 Patients who discontinued study agent through week 252 a
Golimumab + MTX Placebo + MTX Golimumab 100 mg + placebo 50 mg 100 mg Combined Total Patients randomized, no. 160 159 159 159 318 637 Patients treated, no. 160 157 158 159 317 634 Patients who discontinued study agent 50 (31.3) 56 (35.7) 49 (31.0) 60 (37.7) 109 (34.4) 215 (33.9) Reason for discontinuation Initiated protocol‐prohibited medication(s) 0 0 0 0 0 0 Adverse event 21 (13.1) 32 (20.4) 24 (15.2) 34 (21.4) 58 (18.3) 111 (17.5) Worsening of RA 0 3 (1.9) 0 1 (0.6) 1 (0.3) 4 (0.6) Unsatisfactory therapeutic effect 5 (3.1) 6 (3.8) 5 (3.2) 7 (4.4) 12 (3.8) 23 (3.6) Lost to followup 3 (1.9) 4 (2.5) 7 (4.4) 6 (3.8) 13 (4.1) 20 (3.2) Death 0 3 (1.9) 3 (1.9) 2 (1.3) 5 (1.6) 8 (1.3) Other 21 (13.1) 11 (7.0) 10 (6.3) 11 (6.9) 21 (6.6) 53 (8.4) a Values are the number (percentage) unless indicated otherwise. MTX = methotrexate; RA = rheumatoid arthritis. Through week 256, a total of 616 patients received at least 1 administration of golimumab. Of these, 172 received only the 50‐mg dose, 243 received only the 100‐mg dose, and 201 received at least 1 administration of each dose during the trial.
BODY.RESULTS.CLINICAL EFFICACY AND PATIENT‐REPORTED OUTCOMES:
Clinical efficacy results from the ITT analysis that included all randomized patients are shown in Table 2. At week 256, 72.8% of all patients had an ACR20 response, 54.6% had an ACR50 response, and 38.0% had an ACR70 response. After the placebo crossover at week 52, ACR20 and ACR50 response rates were maintained for all treatment groups through week 256 (Figure 1). Additionally, 84.1% of all patients had either a good or moderate DAS28‐CRP response at week 256, and 43.3% of patients had a DAS28‐CRP <2.6. Approximately 28% of all patients were in remission at week 256 according to the SDAI and CDAI remission criteria, and 21.2% met the Boolean remission criteria (Table 2). Meaningful improvements in physical function were observed, with an overall mean improvement in HAQ DI score of 0.57 at week 256. Additionally, at week 256, 72.7% of all patients had an improvement from baseline ≥0.25, and 43.0% achieved normal physical function (HAQ DI ≤0.5) (Table 2) compared with 9.1% (58 of 637) who had a normal HAQ DI score at baseline. The results of the protocol‐specified efficacy analysis were consistent with this modified ITT analysis (see Supplementary Table 2, available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22759/abstract). Figure 1The proportions of patients with A) American College of Rheumatology 20% improvement criteria (ACR20) response or B) ACR50 response through week 256. MTX = methotrexate. Table 2 Clinical efficacy, patient‐reported outcomes, and radiographic results at week 256 using the ITT analysis a
Golimumab + MTX Placebo + MTX Golimumab 100 mg + placebo 50 mg 100 mg Combined Total Clinical efficacy b
Patients randomized, no. 160 159 159 159 318 637 ACR20 109 (68.1) 117 (73.6) 114 (71.7) 124 (78.0) 238 (74.8) 464 (72.8) ACR50 80 (50.0) 83 (52.2) 88 (55.3) 97 (61.0) 185 (58.2) 348 (54.6) ACR70 61 (38.1) 59 (37.1) 57 (35.8) 65 (40.9) 122 (38.4) 242 (38.0) DAS28‐CRP response c
128 (80.0) 138 (86.8) 131 (82.4) 139 (87.4) 270 (84.9) 536 (84.1) DAS28‐CRP <2.6 67 (41.9) 65 (40.9) 70 (44.0) 74 (46.5) 144 (45.3) 276 (43.3) DAS28‐CRP ≤3.2 86 (53.8) 90 (56.6) 91 (57.2) 94 (59.1) 185 (58.2) 361 (56.7) SDAI ≤3.3 47 (29.4) 40 (25.2) 42 (26.4) 46 (28.9) 88 (27.7) 175 (27.5) CDAI ≤2.8 51 (31.9) 40 (25.2) 44 (27.7) 49 (30.8) 93 (29.2) 184 (28.9) Boolean remission 30 (18.8) 32 (20.1) 38 (23.9) 35 (22.0) 73 (23.0) 135 (21.2) Improvement from baseline in HAQ DI, mean ± SD 0.68 ± 0.69 0.70 ± 0.74 0.65 ± 0.70 0.80 ± 0.72 0.72 ± 0.71 0.70 ± 0.71 Patients with improvement in HAQ DI ≥0.25 120 (75.0) 111 (69.8) 110 (69.2) 122 (76.7) 232 (73.0) 463 (72.7) Patients with HAQ DI ≤0.5 61 (38.1) 62 (39.0) 72 (45.3) 79 (49.7) 151 (47.5) 274 (43.0) Radiographic results SHS change from baseline, mean ± SD d
At week 208 2.18 ± 6.53 1.74 ± 6.71 0.68 ± 3.59 0.54 ± 2.72 0.61 ± 3.19 1.29 ± 5.23 At week 256 2.28 ± 6.65 1.81 ± 6.82 0.72 ± 3.67 0.60 ± 2.86 0.66 ± 3.30 1.36 ± 5.34 SHS change from week 104, mean ± SD d
At week 208 0.68 ± 3.19 0.79 ± 4.39 0.43 ± 1.82 0.57 ± 2.36 0.50 ± 2.10 0.62 ± 3.08 At week 256 0.78 ± 3.40 0.87 ± 4.64 0.47 ± 2.05 0.64 ± 2.64 0.55 ± 2.35 0.69 ± 3.31 Patients with change in total SHS ≤0 at week 256 65 (54.2) 64 (56.6) 75 (62.5) 73 (65.2) 148 (63.8) 277 (59.6) Patients with change in total SHS ≤0.5 at week 256 78 (65.0) 82 (72.6) 92 (76.7) 89 (79.5) 181 (78.0) 341 (73.3) Estimated annual rate of progression at baseline, mean ± SD 8.44 ± 19.37 8.32 ± 27.49 9.75 ± 24.86 6.76 ± 14.73 8.31 ± 20.61 8.34 ± 22.14 Estimated annual rate of progression at week 256, mean ± SD 0.46 ± 1.34 0.36 ± 1.36 0.14 ± 0.74 0.12 ± 0.57 0.13 ± 0.66 0.27 ± 1.07 a Values are the number (percentage) unless indicated otherwise. ITT = intent‐to‐treat; MTX = methotrexate; ACR20/50/70 = American College of Rheumatology criteria for 20%/50%/70% improvement; DAS28‐CRP = Disease Activity Score in 28 joints using the C‐reactive protein level; SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; HAQ = Health Assessment Questionnaire; DI = disability index; SHS = modified Sharp/van der Heijde score. b Modified ITT analysis in which the following rules were applied: 1) missing baseline values for continuous variables were replaced with the median value, and last observation carried forward methodology was applied to missing postbaseline values, and 2) patients who discontinued study agent due to unsatisfactory therapeutic effect were considered to be nonresponders. c Good or moderate response as defined by the European League Against Rheumatism 14 . d Includes patients who had an SHS at weeks 0 and 104 and at least 1 score after week 104. A total of 101 patients had an increase in golimumab dose from 50 mg to 100 mg during the long‐term extension (after week 52), and of these, 100 patients had ≥12 weeks of followup available. Among these patients, 84 did not have a DAS28‐CRP <2.6 immediately prior to dose escalation, and 68 did not have a score ≤3.2 prior to dose escalation. Both of these subgroups had a mean ± SD improvement in DAS28‐CRP of 1.0 ± 1.1 at 12 weeks after dose escalation. Improvements from baseline to week 256 in patient‐reported outcomes were generally similar among the treatment groups (Table 3). Mean improvements in SF‐36 PCS and MCS scores ranged from 11.3–11.9 and 4.5–7.6, respectively. Among patients with evaluable SF‐36 data at baseline and week 256, 27.9% had a normal (score ≥50) SF‐36 PCS score, and 46.9% had a normal SF‐36 MCS score at week 256 (Table 3) compared with 1.4% and 28.8% who had normal baseline SF‐36 PCS and MCS scores, respectively. Mean improvements from baseline to week 256 in the impact of disease on productivity ranged from 3.2–4.3 among the treatment groups. Table 3 Improvements in health‐related quality of life and productivity at week 256 a
Golimumab + MTX
Placebo + MTX
Golimumab 100 mg + placebo
50 mg
100 mg
Combined
Total
SF‐36 PCS score Improvement from baseline, mean ± SD 11.3 ± 10.5 11.6 ± 11.0 11.9 ± 11.1 11.9 ± 10.0 11.9 ± 10.6 11.7 ± 10.7 Patients with score ≥50, no. (%) 28 (25.7) 28 (26.9) 33 (30.6) 28 (28.3) 61 (29.5) 117 (27.9) SF‐36 MCS score Improvement from baseline, mean ± SD 4.5 ± 12.6 7.6 ± 12.0 5.7 ± 12.1 6.4 ± 11.9 6.1 ± 12.0 6.0 ± 12.2 Patients with score ≥50, no. (%) 47 (43.1) 51 (49.0) 55 (50.9) 44 (44.4) 99 (47.8) 197 (46.9) Improvement in the impact of disease on productivity, mean ± SD 3.2 ± 3.1 4.3 ± 4.3 3.9 ± 2.7 4.2 ± 2.8 4.0 ± 2.8 3.9 ± 3.3 a MTX = methotrexate; SF‐36 = Short Form 36 health survey; PCS = physical component summary; MCS = mental component summary. At week 256, 41.0% (n = 261 of 637) of all patients were receiving concomitant oral corticosteroids (mean dosage: 6.1 mg/day prednisone or equivalent) compared with 52.0% (n = 331 of 637) at baseline (mean dose: 7.4 mg/day). Likewise, 67.8% (n = 432) used concomitant NSAIDs at week 256 in comparison with 82.9% (n = 528) of patients at baseline.
BODY.RESULTS.RADIOGRAPHIC PROGRESSION:
A total of 465 patients (group 1, n = 120; group 2, n = 113; group 3, n = 120; and group 4, n = 112) had radiographic data available at baseline, week 104, and at least 1 radiograph after the week‐104 time point and were therefore included in the analysis for reading session 3. At week 256, radiographic progression was low, with a mean change from baseline in SHS for all patients of 1.36; mean changes among the treatment groups ranged from 0.60 to 2.28 (Table 2). Furthermore, approximately 60% of all patients had a change in SHS ≤0 at week 256, and 73% of patients had a change from baseline ≤0.5. At baseline, the mean estimated annual rates of radiographic progression for groups 1, 2, 3, and 4 were 8.44, 8.32, 9.75, and 6.76, respectively (mean duration of RA: group 1, 2.9 years; group 2, 4.1 years; group 3, 3.5 years, and group 4, 3.6 years). Over the 5‐year study, the mean annual rate of progression was 0.27 for all patients, and 0.46, 0.36, 0.14, and 0.12 for groups 1, 2, 3, and 4, respectively.
BODY.RESULTS.AES:
A total of 616 patients received at least 1 dose of golimumab 50 mg or 100 mg and were included in the safety analysis, and 402 patients completed the safety followup through week 268. The mean duration of followup for all golimumab‐treated patients was 205 weeks, and the mean number of golimumab administrations was 46.9 (Table 4). The most common types of AEs by the Medical Dictionary for Regulatory Activities classification were infections and infestations (n = 463, 75.2%), gastrointestinal disorders (n = 323, 52.4%), and musculoskeletal and connective tissue disorders (n = 258, 41.9%). Commonly reported AEs are listed in Table 4 and include upper respiratory tract infection (n = 181, 29.4%), nausea (n = 121, 19.6%), bronchitis (n = 102, 16.6%), and increased alanine aminotransferase (n = 99, 16.1%). Among all golimumab‐treated patients, 73 (11.9%) had at least 1 injection site reaction through week 268; none of these reactions were considered to be severe. Of the 28,866 golimumab injections administered, 258 (0.9%) were associated with an injection‐site reaction. Table 4 Adverse events through week 268 a
50 mg + MTX only 50 mg and 100 mg + placebo or MTX Golimumab 100 mg + placebo or MTX Total golimumab Treated patients, no. 172 201 243 616 Mean duration of followup, weeks 182.9 238.7 192.7 205.0 Mean number of administrations 41.5 54.9 44.0 46.9 Patients with ≥1 AE 161 (93.6) 187 (93.0) 234 (96.3) 582 (94.5) Patients who discontinued due to AEs 30 (17.4) 14 (7.0) 67 (27.6) 111 (18.0) Common AEs (≥10%) Upper respiratory tract infection 46 (26.7) 72 (35.8) 63 (25.9) 181 (29.4) Nausea 22 (12.8) 44 (21.9) 55 (22.6) 121 (19.6) Bronchitis 27 (15.7) 34 (16.9) 41 (16.9) 102 (16.6) Alanine aminotransferase increased 31 (18.0) 32 (15.9) 36 (14.8) 99 (16.1) Cough 19 (11.0) 29 (14.4) 37 (15.2) 85 (13.8) Patients with ≥1 injection site reaction 15 (8.7) 19 (9.5) 39 (16.0) 73 (11.9) Patients with ≥1 SAE 55 (32.0) 55 (27.4) 94 (38.7) 204 (33.1) Pneumonia 5 (2.9) 5 (2.5) 4 (1.6) 14 (2.3) Pulmonary tuberculosis 1 (0.6) 1 (0.5) 4 (1.6) 6 (1.0) Breast cancer 1 (0.6) 0 3 (1.2) 4 (0.6) Uterine leiomyoma 1 (0.6) 2 (1.0) 1 (0.4) 4 (0.6) Basal cell carcinoma 0 2 (1.0) 1 (0.4) 3 (0.5) Hodgkin's disease 0 0 2 (0.8) 2 (0.3) Non–small cell lung cancer 2 (1.2) 0 0 2 (0.3) Patients with ≥1 serious infection 17 (9.9) 25 (12.4) 33 (13.6) 75 (12.2) Incidence per 100 patient‐years (95% CI) 3.97 (2.54–5.90) 3.68 (2.55–5.15) 6.00 (4.50–7.82) 4.61 (3.80–5.55) Pneumonia 5 (2.9) 5 (2.5) 4 (1.6) 14 (2.3) Herpes zoster 0 3 (1.5) 2 (0.8) 5 (0.8) Pulmonary tuberculosis 1 (0.6) 1 (0.5) 3 (1.2) 5 (0.8) Sepsis 0 1 (0.5) 3 (1.2) 4 (0.6) Urinary tract infection 1 (0.6) 2 (1.0) 1 (0.4) 4 (0.6) Appendicitis 0 2 (1.0) 1 (0.4) 3 (0.5) Upper respiratory tract infection 1 (0.6) 0 2 (0.8) 3 (0.5) Malignancies Lymphoma 0 0 2 (0.8) 2 (0.3) Incidence per 100 patient‐years (95% CI) 0.00 (0.00–0.50) 0.00 (0.00–0.32) 0.22 (0.03–0.80) 0.08 (0.01–0.30) SIR (95% CI) b
0.00 (0.00–18.91) 0.00 (0.00–12.15) 9.54 (1.16–34.48) 3.26 (0.39–11.76) Nonmelanoma skin cancers 0 3 (1.5) 2 (0.8) 5 (0.8) Incidence per 100 patient‐years (95% CI) 0.00 (0.00–0.50) 0.33 (0.07–0.95) 0.22 (0.03–0.80) 0.21 (0.07–0.48) Other malignancies 8 (4.7) 2 (1.0) 4 (1.6) 14 (2.3) Incidence per 100 patient‐years (95% CI) 1.33 (0.57–2.62) 0.22 (0.03–0.78) 0.44 (0.12–1.14) 0.58 (0.32–0.97) SIR (95% CI) b
2.21 (0.95–4.35) 0.36 (0.04–1.28) 0.85 (0.23–2.18) 1.00 (0.55–1.68) Total malignancies 8 (4.7) 5 (2.5) 8 (3.3) 21 (3.4) Incidence per 100 patient‐years (95% CI) 1.33 (0.57–2.62) 0.54 (0.18–1.27) 0.89 (0.38–1.75) 0.87 (0.54–1.33) SIR (95% CI) b
2.12 (0.91–4.18) 0.34 (0.04–1.23) 1.23 (0.45–2.67) 1.10 (0.63–1.79) Deaths 6 (3.5) 0 6 (2.5) 12 (1.9) Incidence per 100 patient‐years (95% CI) 0.99 (0.36–2.16) 0.00 (0.00–0.32) 0.67 (0.24–1.45) 0.49 (0.26–0.86) a Data presented as number (percentage) unless indicated otherwise. MTX = methotrexate; AE = adverse event; SAE = serious AE; 95% CI = 95% confidence interval; SIR = standardized incidence ratio. b The SIR is in comparison with the expected number of events in the Surveillance, Epidemiology, and End Results database (2004), which does not include nonmelanoma skin cancers. Through week 268, 204 patients (33.1%) had at least 1 serious AE. Seventy‐five patients (12.2%) had a serious infection, the most common being pneumonia (n = 14; 2.3%) (Table 4). Among all golimumab‐treated patients, the incidence (95% CI) of serious infections per 100 patient‐years was 4.61 (3.80–5.55). At baseline, 106 patients (16.6%) required treatment for latent TB. Through week 268, 13 patients were diagnosed with active TB (golimumab 50 mg: n = 2; 100 mg: n = 11). The majority of these cases were in endemic countries (e.g., Philippines, Chile, and Thailand). Ten of these patients had negative tuberculin and QuantiFERON testing at screening; the remaining patients were identified as having latent TB, completed the required treatment as specified in the protocol, and developed active TB several months after completing the treatment for latent TB. Eleven TB cases occurred before week 104 and have been previously described 4. The 2 cases that occurred after week 104 were TB pleurisy and intestinal TB. There were no cases of disseminated TB or deaths resulting from TB in this study. Five opportunistic infections were reported through week 268. Two were classified as serious infections (pneumonia legionella, n = 1; Pneumocystitis jiroveci pneumonia, n = 1), and 3 were classified as nonserious infections (esophageal candidiasis, n = 2; aspergillosis, n = 1). Two patients experienced demyelination AEs (demyelination of the central nervous system and autoimmune demyelination); both patients were receiving golimumab 100 mg + MTX. Both AEs were considered to be serious, and the patients discontinued study treatment. No cases of systemic lupus erythematosus were reported. Among all patients who received golimumab, 21 reported a malignancy through week 268. The incidence (95% CI) of all malignancies per 100 patient‐years was 0.87 (0.54–1.33) (Table 4). Two cases of lymphoma were reported among golimumab‐treated patients (both patients received the 100‐mg dose); the incidence (95% CI) per 100 patient‐years for lymphoma was 0.08 (0.01–0.30). Eight deaths occurred prior to week 104 and have been previously described 1, 4. An additional 4 deaths occurred after week 104: two patients receiving golimumab 50 mg + MTX (a 71‐year‐old woman, with a history of cigarette smoking, died from myocardial infarction, and a 50‐year‐old woman, with a history of chronic lung disease, hypertension, and cigarette smoking, died from unknown causes), 1 patient receiving golimumab 100 mg + placebo (a 68‐year‐old woman died from hematemesis), and 1 patient receiving golimumab 100 mg + MTX (a 61‐year‐old woman, with a history of hyperlipidemia, hypertension, and cigarette smoking, died of sepsis). Through week 268, the incidence (95% CI) of death per 100 patient‐years for all golimumab‐treated patients was 0.49 (0.26–0.86). After discontinuing the study golimumab injections, a total of 47 patients received a commercial biologic agent (including commercial golimumab) after week 256. Six of these patients had an AE after receiving commercial golimumab; most AEs were similar to those reported during receipt of study drug during the trial. One of these 6 patients had a serious AE (cellulitis).
BODY.RESULTS.GOLIMUMAB PHARMACOKINETICS AND IMMUNOGENICITY:
Serum trough golimumab concentrations were approximately dose proportional and were generally maintained through week 256 for patients who did not have any changes in golimumab dose. Through week 256, a total of 57 golimumab‐treated patients (9.6%) tested positive for antibodies to golimumab, and of these, 46 patients (92.0%) were positive for neutralizing antibodies. Eight patients (14.0%) who were positive for antibodies to golimumab also had an injection site reaction; 1 reaction of moderate injection site erythema was classified as serious and led to discontinuation of the study agent. Among the 538 patients who tested negative for antibodies to golimumab, 78 (14.5%) had an injection site reaction; none were serious or led to study discontinuation.
BODY.DISCUSSION:
The GO‐BEFORE trial evaluated the safety and efficacy of golimumab with and without MTX in MTX‐naive patients with active RA. Through 24 weeks, patients treated with golimumab 50 mg or 100 mg + MTX had substantial improvements in disease activity 1, and these improvements were sustained through weeks 52 and 104 4. Through 1 year, patients treated with golimumab + MTX had significantly less radiographic progression than did patients who received MTX monotherapy 5, and progression was minimal in all treatment groups at week 104, when all patients had been receiving golimumab 4. Here we report the final clinical efficacy, radiographic, and safety findings through 5 years of the GO‐BEFORE trial. Approximately 66% of patients who were randomized at baseline continued study treatment through week 252. Long‐term completion rates through 5 years were approximately 46–49% in previous trials of other SC anti‐TNF therapies in patients with RA who were MTX naive 18, 19. Among all randomized patients in the GO‐BEFORE trial, 72.8% of patients had an ACR20 response, 54.6% had an ACR50 response, and 38.0% had an ACR70 response at week 256 (when all patients were receiving golimumab), with no appreciable differences among the treatment groups. Additionally, more than 80% of golimumab‐treated patients had either a good or moderate DAS28‐CRP response at week 256. Golimumab‐treated patients also had clinically meaningful improvements in physical function as demonstrated by an overall mean improvement from baseline in HAQ DI score of 0.57, and by 72.7% of patients having an improvement ≥0.25. Radiographic progression was low through 5 years; the mean change in SHS was 0.72 and 0.60 over 5 years in patients randomized to golimumab 50 mg + MTX and 100 mg + MTX, respectively, with nearly three‐quarters of all patients having no progression (change in SHS of ≤0.5). The proportion of patients using oral corticosteroids and the median dose received decreased from baseline to week 256. The proportion of patients using NSAIDs also decreased during the trial. These observations may suggest that reduced use of these concomitant medications could be achieved with golimumab treatment. However, it should be noted that the use of these medications was solely at the discretion of the investigator. Safety findings through week 268 were generally consistent with those reported through week 104 1, 4. The majority of cases of active TB occurred in patients receiving the 100‐mg dose; however, it is difficult to compare the 2 doses (50 and 100 mg) due to the treatment changes allowed through early escape and adjustments to golimumab and concomitant medications during the long‐term extension. The incidences of serious infections, lymphoma, and deaths adjusted for patient‐years of exposure for both golimumab doses were generally consistent with long‐term data reported for other biologic anti‐TNF agents from both randomized clinical trials 18, 19, 20 and observational studies 21, 22. Throughout the trial, infections were the most common type of AE and serious AE; pneumonia was the most common type of serious infection (n = 14, 2.3%). There were a total of 13 cases of active TB. All patients were screened for TB prior to study entry and had to either have negative TB test results or initiate treatment for latent TB. The 13 cases of TB in the GO‐BEFORE trial were considered to be new, active infections and most were in areas with a high background rate of TB (e.g., Philippines, Chile, and Thailand). Given the substantial number of patients who were enrolled from regions with a high TB incidence rate, the comprehensive screening procedures utilized in this trial may have contributed to a lower than expected rate of TB 23. However, physicians should remain vigilant regarding the development of new TB infections. Five opportunistic infections were reported, including pneumonia legionella, P jiroveci pneumonia, and esophageal candidiasis. A total of 12 deaths occurred through week 268; no predominant cause of death was identified. Among golimumab‐treated patients, 21 malignancies were reported. Two cases of lymphoma occurred through week 268, both in patients receiving golimumab 100 mg, which corresponded to an SIR (95% CI) of 9.54 (1.16–34.48). A previous registry analysis of more than 6,000 patients with RA did not show an increase in lymphoma risk with increasing duration of anti‐TNF therapy 24. Throughout the trial, less than 1% of all golimumab injections were associated with an injection site reaction. The incidence of injection site reactions through week 256 was similar between patients who tested positive for antibodies to golimumab (14.0%) and those who tested negative for antibodies to golimumab (14.5%). A substantial portion of the patients (66%) who were enrolled and treated in the GO‐BEFORE trial completed treatment with golimumab through week 252. Interpretation of the long‐term efficacy and safety results is limited by selection bias over time, although our use of an ITT analysis including all randomized patients may have mitigated this effect. The results through 5 years of this study are also limited by the lack of a control group after week 52, as well as possible confounding effects of concomitant medications and golimumab dose changes that were permitted during the long‐term extension. The overall findings of the GO‐BEFORE trial indicate that the majority of patients remained in the trial through 5 years and had sustained improvements in clinical and radiographic outcomes with long‐term safety results consistent with other anti‐TNF therapies.
BODY.AUTHOR CONTRIBUTIONS:
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Emery had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
BODY.AUTHOR CONTRIBUTIONS.STUDY CONCEPTION AND DESIGN:
Emery, Fleischmann, Park, Han, Leu, Hsia.
BODY.AUTHOR CONTRIBUTIONS.ACQUISITION OF DATA:
Emery, Fleischmann, Strusberg, Durez, Nash, Amante, Churchill, Park, Pons‐Estel, Han, Zhou, Hsia.
BODY.AUTHOR CONTRIBUTIONS.ANALYSIS AND INTERPRETATION OF DATA:
Emery, Fleischmann, Durez, Churchill, Park, Han, Gathany, Xu, Zhou, Leu, Hsia.
BODY.ROLE OF THE STUDY SPONSOR:
Authors who are or were employees of Janssen Research & Development, LLC were involved in the study design and in the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. All authors approved the manuscript for submission. Rebecca Clemente, PhD, and Mary Whitman, PhD, of Janssen Scientific Affairs provided writing support.
BODY.SUPPORTING INFORMATION:
Supplementary Table 1. Actual treatment received through week 256Click here for additional data file. Supplementary Table 2. Clinical efficacy results at week 256 (observed data analysis).Click here for additional data file. | 5,089,605 | {
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TITLE: Evaluation of different sodium bicarbonate regimens for the prevention of contrast medium-induced nephropathy
ABSTRACT.INTRODUCTION:
The rapid decline in renal function caused by radiographic contrast agents usually is transient, but it can result in chronic kidney disease. The pathophysiology of contrast-induced nephropathy (CIN) is poorly understood, but it may include acute hypoxia-induced oxidative stress and free radicals generated within the acid environment of the renal medulla. Thus, the alkalization of urine by sodium bicarbonate has been regarded as resulting in the reduction of CIN. The aim of this study was to determine whether a long-duration sodium bicarbonate regimen is more effective than a short-duration regimen in reducing CIN.
ABSTRACT.METHODS:
One hundred patients were assigned randomly to treatment with sodium bicarbonate solution using either the short regimen (intravenous bolus 3 mL/kg/h of 166 mEq/L sodium bicarbonate for 1 hour immediately before radiocontrast) or the long regimen (initial intravenous bolus of 3 mL/kg/h of 166 mEq/L sodium bicarbonate for 6 hr). Patients with renal dysfunction (estimated glomerular filtration rate [eGFR], 60 mL/min/1.73 m2 or less) who underwent elective or emergent coronary angiography (CAG) with/without percutaneous coronary intervention (PCI) at Nephrology Department (Theodor Bilharz Research Institute) were enrolled in the study. Data were analyzed by SPSS version 12, using Kruskal Wallis, ANOVA, Chi square test and Spearman rank correlation coefficient.
ABSTRACT.RESULTS:
There was a significant increase in serum creatinine and a decrease in eGFR 48 hr post-intervention in group 1 (short regimen) with no statically difference regarding those parameters group 2 (long regimen). Serum potassium clearly was decreased significantly post procedure in both groups.
ABSTRACT.CONCLUSIONS:
The results of our study indicated that the long regimen of bicarbonate supplementation was a more effective strategy to prevent CIN than the short regimen.
BODY.1. INTRODUCTION:
The rapid decline in renal function caused by radiographic contrast agents usually is transient, but it can result in chronic kidney disease (CKD) or even end-stage renal disease (ESRD). Contrast-induced nephropathy (CIN) is a leading cause of new-onset renal failure in hospitalized patients, with the highest risk observed in patients with CKD (1, 2). It is associated with significantly increased in-hospital and long-term morbidity and mortality and acceleration of chronic renal disease (3). Since there is no specific therapy for CIN and the disease is iatrogenic, prevention is of paramount importance. The pathophysiology of CIN is poorly understood, but it may include acute vasoconstriction resulting in renal hypoperfusion, hypoxia-induced oxidative stress, and free radicals generated within the acid environment of the renal medulla (4, 5). Thus, the alkalization of urine by sodium bicarbonate has been regarded as resulting in the reduction of CIN (6–11). Putting into consideration that the alkalization of urine can be used to prevent CIN, our aim was to evaluate whether a longer duration of sodium bicarbonate infusion is more beneficial than a shorter duration infusion in reducing the frequency of contrast nephropathy in patients after coronary angiography.
BODY.2. MATERIAL AND METHODS:
The protocol of this study was approved by the Ethics Committee of Theodor Bilharz Research Institute, and written informed consent was obtained from all patients. The study complies with the Declaration of Helsinki. All adult patients, i.e., those over the age of 18 who were scheduled for coronary angiography, were screened for inclusion and exclusion criteria. Between November 2013 and November 2014, 200 patients were considered eligible for the trial. After 100 exclusions, 100 patients were assigned randomly to either the short-duration or the long duration treatment with sodium bicarbonate solution. The short-duration treatment consisted of intravenous bolus 3 mL/kg/h of 166 mEq/L sodium bicarbonate for 1 hour immediately before the injection of the radiocontrast, with subsequent treatment with the same fluid at a rate of 1 mL/kg/h during the contrast exposure and for 6 h after the procedure. The long-duration treatment consisted of initial intravenous bolus of 3 mL/kg/h of 166 mEq/L sodium bicarbonate for 6 hr before the injection of the radiocontrast, after which the patients received the same fluid at a rate of 1 mL/kg/h during the contrast exposure and for 6 h after the procedure. Demographic data, current medication, and medical history were recorded at baseline. Serum creatinine (S. Cr), eGFR, and serum potassium were measured before initiating the pre-procedural hydration. Urine samples were obtained to analyze the pH of the urine one hour prior to the procedure. Two days after coronary angiography, serum creatinine, eGFR, and serum potassium were analyzed again. We calculated eGFR according to the MDRD formula (20). Change in creatinine, percent change in creatinine, percent change in eGFR, change in serum potassium, and urine pH were compared between the two groups. The side effects of the high-dose of sodium bicarbonate, such as congestive heart failure, respiratory disorder, and low potassium, were carefully evaluated during the study. CIN was defined as an increase of more than absolute 0.5 mg/dL and/or relative 25% in serum creatinine after 48 hr. Consecutive patients with renal dysfunction (estimated glomerular filtration rate [eGFR], 60 mL/min/1.73 m2 or less) who underwent elective or emergency coronary angiography (CAG) with/without percutaneous coronary intervention (PCI) at our institution were enrolled. The eGFR was calculated using the MDRD formula. Patients were excluded for any of the following reasons: end-stage renal insufficiency (eGFR <15 mL/min), acute renal insufficiency, a history of reaction to contrast media, the use of potentially nephrotoxic medicines (48 h before and 24 h after the procedure), pulmonary edema, multiple myeloma, exposure to contrast media within 7 days before the procedure, pregnancy, patient non-compliance, and the use of either N-acetylcystein, dopamine, fenoldopam, or mannitol before coronary angiography. Patients were randomized to one of the two regimens of volume supplementation described below. Randomization with stratification for intra-arterial and intravenous radiographic contrast procedures were performed by using sealed envelopes, 1:1 to each group (12). The analysis was performed according to the intent-to-treat principle. All patients were hydrated with intravenous normal saline at 1 mL/kg/h for 12 hr before exposure to the contrast and 12 h after coronary angiography. The rate of infusion was reduced in patients who developed signs of pulmonary congestion. Data were analyzed by SPSS version 12, using Kruskal Wallis, ANOVA, Chi square test and Spearman rank correlation coefficient.
BODY.3. RESULTS AND DISCUSSION:
Between November 2013 and November 2014, 200 patients were screened, and, after 100 exclusions, 100 patients were randomly assigned to treatment either with short regimen (60 minutes) bicarbonate solution prior to contrast administration (50 patients) or with long regimen (6 hr prior to the intervention) (50 patients). Thus, the final study population was 100 patients. No side effects of sodium bicarbonate infusion were observed, and discontinuation of protocol dose of infusion was not necessary in any of the patients. Our findings showed that there were no significant differences between the two groups in age, gender, smoking, body mass index, diabetes mellitus, hypertension, percutaneous coronary intervention, and volume of contrast administered (Table 1). There were no statistical differences in baseline urine pH, baseline S. Cr., baseline eGFR by MDRD, or baseline serum potassium (S. K.) between the two groups (Table 2). There was a significant increase in S. Cr., and a significant decrease in eGFR by MDRD 48 hr post-intervention in group 1 (short regimen) with no statically difference regarding those parameters in group 2 (long regimen). S. K clearly was decreased significantly post-procedure in both groups (short and long regimens). There was no correlation between S. K. and S. Cr. and eGFR by MDRD 48 hr post intervention in both groups. Also, a highly-significant negative correlation between s. Cr and eGFR by MDRD was reported in both groups (Table 3). Note that acute deterioration in renal function can be caused by radiographic contrast agents, but, generally, it is mild and transient. However, acute deterioration can result in lasting renal dysfunction and the need for renal replacement therapy (1). Contrast-induced nephropathy (CIN) is a leading cause of new onset renal failure in hospitalized patients, with the highest risk observed in patients with pre-existing impaired renal function (2). It is associated with significantly increased long-term morbidity and mortality, acceleration of chronic renal disease, and increased costs of medical care (13). The pathophysiology of CIN is poorly understood, but it may include acute vasoconstriction, resulting in renal hypoperfusion, hypoxia induced oxidative stress, and free radicals generated within the acid environment of the renal medulla (4). Thus, studies have begun to evaluate the effect of volume supplementation with sodium bicarbonate in prevention of CIN based on the hypothesis that alkalinizing renal tubular fluid with bicarbonate may reduce renal injury and increase medullary pH with subsequent slowing of the production of free radicals (14). Similarly, it was stated in (4) that the role of bicarbonate in protecting against CIN is attributed to buffering of subclinical acidosis-induced vasoconstriction, which is typical of acute settings and may amplify the vasoconstriction induced by the contrast itself. On the contrary, some studies have indicated that the effectiveness of sodium bicarbonate treatment to prevent CIN in high risk patients remains uncertain and that the magnitude of any benefit probably had ben overestimated (15, 16). However Klima et al. (16) explained these discrepant findings by the early termination of these studies, publication bias, small differences in the concentration, the overall amount of sodium bicarbonate applied, the type of the contrast procedure, and the patient selection. In our study we compared two procedures of CIN prevention in patients with renal dysfunction: group 1 (short regimen) in which the patients received sodium bicarbonate 20 minutes prior to the contrast administration and group 2 (long regimen) in which the patients received the same amount and concentration sodium bicarbonate but 7 hr prior to the intervention, taken into consideration that all patients in our study received non-ionic low osmolar contrast agents. We observed a significant increase in S. Cr. and significant decrease in eGFR calculated by MDRD formula in (group 1) when we compare their levels prior to contrast administration with their levels 48 hr after the intervention (S. Cr: 2.32 ± 0.41 vs. 2.42 ± 0.48) and (eGFR by MDRD: 30.22 ± 6.07 vs, 28.97 ± 6.57). Regarding group 2, the results of our study showed no statistical difference in S. Cr. and eGFR calculated by MDRD 48 hr post-procedure (S. Cr: 2.26 ± 0.47 vs. 2.26 ± 0.49) and (eGFR by MDRD: 30.97 ± 7.13 vs. 31.06 ± 7.41). Also, we demonstrated a significant inverse correlation between S. Cr. and eGFR calculated by MDRD for both group 1 and group 2 (group 1: r = −0.856, p < 0.001) and (group 2: r = −0.908, p < 0.001). In agreement with our study, Briguori et al. (17) found that the long-term regimen of sodium bicarbonate was superior to the short regimen. This was in agreement with with Recio-Mayoral et al. (18). On the contrary, Klima et al. (16) and Mueller (4) stated that both regimens (the long and the short regimens) have the same effectiveness with very high safety, even in patients with NYHA class I or II heart failure, and, thus, the short-term regimen may be the regimen of choice because it is very easy to apply, even to outpatient procedures (15–17). Our research also showed that S. K. has significantly decreased post procedure in both group 1 and group 2 (group1: 4.21 ± 0.43 vs. 3.88 ± 0.33) and (group 2: 4.16 ± 0.42 vs. 3.92 ± 0.34). Also, we demonstrated a non-significant negative correlation between S. Cr. and S. K. in both groups (group 1: r = −0.184) and (group 2: r = −0.235). This was in agreement with Walter et al. (19) who reported that the infusion of sodium bicarbonate can shift potassium from the extracellular to the intracellular space by increasing blood pH. However, this should be reserved for situations with severe educational environments (19). In contrast, Kim (20) stated that sodium bicarbonate is no longer recommended to lower potassium, although it may be appropriate in patients with severe metabolic acidosis (20). Regarding the pH of urine, we found that it was (5.95 ± 0.26) in group 1 and (5.97 ± 0.24) in group 2, showing no statistical difference and highlighting the fact that both regimen had almost the same alkalinizing efficacy with no proven extra benefit for patients with pH values greater than 6.
BODY.4. CONCLUSIONS:
We should stress the importance of sodium bicarbonate infusion prior to the administration of the contrast medium to guard against CIN, especially in renally-impaired patients who could easily be susceptible to CIN. In addition, the results of our study indicated that the long regimen of bicarbonate supplementation was a better and more efficient strategy to prevent CIN than the short regimen. | 4,821,313 | {
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TITLE: Self-reported immature defense style as a predictor of outcome in short-term and long-term psychotherapy
ABSTRACT.OBJECTIVE:
Identification of pretreatment patient characteristics predictive of psychotherapy outcome could help to guide treatment choices. This study evaluates patients' initial level of immature defense style as a predictor of the outcome of short-term versus long-term psychotherapy.
ABSTRACT.METHOD:
In the Helsinki Psychotherapy Study, 326 adult outpatients with mood or anxiety disorder were randomized to individual short-term (psychodynamic or solution-focused) or long-term (psychodynamic) psychotherapy. Their defense style was assessed at baseline using the 88-item Defense Style Questionnaire and classified as low or high around the median value of the respective score. Both specific (Beck Depression Inventory [BDI], Hamilton Depression Rating Scale [HDRS], Symptom Check List Anxiety Scale [SCL-90-Anx], Hamilton Anxiety Rating Scale [HARS]) and global (Symptom Check List Global Severity Index [SCL-90-GSI], Global Assessment of Functioning Scale [GAF]) psychiatric symptoms were measured at baseline and 3–7 times during a 3-year follow-up.
ABSTRACT.RESULTS:
Patients with high use of immature defense style experienced greater symptom reduction in long-term than in short-term psychotherapy by the end of the 3-year follow-up (50% vs. 34%). Patients with low use of immature defense style experienced faster symptom reduction in short-term than in long-term psychotherapy during the first year of follow-up (34% vs. 19%).
ABSTRACT.CONCLUSION:
Knowledge of patients' initial level of immature defense style may potentially be utilized in tailoring treatments. Further research on defense styles as outcome predictors in psychotherapies of different types is needed.
BODY.INTRODUCTION:
Both short-term and long-term psychotherapies are common in the treatment of mood and anxiety disorders. Evidence-based knowledge on which treatment is most effective for whom is, however, scarce. Various patient-related variables have been suggested as being essential in the evaluation of patients' suitability for psychotherapies and thus in the prediction of their psychotherapy outcome (Blenkiron 1999; Valbak 2004; Norcross and Wampold 2011). One such variable is the initial level of defense style, that is, availability and integration of individual regulating functions, defense mechanisms, aimed at alleviating anxiety-provoking stressors and maintaining mental balance (American Psychiatric Association 1994; OPD Task Force 2001). Healthy aspects of personality, such as a well-integrated, mature defense style, are considered important predictors of positive outcome of short-term psychotherapies, not aiming to achieve structural changes in personality (Van et al. 2009). On the other hand, patients with a less integrated, immature defense style may need long-term treatments to recover. The use of defense styles as outcome predictors in individual psychotherapies has been little studied to date, only in short-term psychotherapies, and with somewhat contradictory findings (Hersoug et al. 2002; Kronström et al. 2009; Van et al. 2009). No studies comparing the prediction of outcome by defense styles in short-term versus long-term psychotherapies have so far been published. More research on the use of defense styles as predictors of psychotherapy outcomes in general and on potential differential prediction of immature defense style on short-term versus long-term psychotherapy outcome in particular is thus needed.
BODY.AIMS OF THE STUDY:
This study examines the relationship between level of self-reported immature defense style and subsequent changes in psychiatric symptoms in individual short-term and long-term psychotherapy during a 3-year follow-up period. Our aim was to find out whether the level of immature defense style prior to therapy differentiates the outcome of short-term and long-term therapy.
BODY.MATERIAL AND METHODS:
This study was part of the Helsinki Psychotherapy Study (HPS). The methods used have been described in detail elsewhere (Knekt and Lindfors 2004; Knekt et al. 2008, 2012) and are summarized here. Patients gave written informed consent. The study protocol was approved by the Helsinki University Central Hospital's ethics council.
BODY.MATERIAL AND METHODS.PATIENTS:
Outpatients from the Helsinki region were referred to the study by local practitioners from June 1994 to June 2000 (Knekt and Lindfors 2004; Knekt et al. 2008). Eligible patients were 20–45 years of age and had a long-standing (>1 year) disorder causing work dysfunction. Patients were required to meet the DSM-IV criteria (American Psychiatric Association 1994) for anxiety or mood disorders evaluated based on a semi-structured diagnostic interview (Knekt and Lindfors 2004) and Kernberg's criteria (Kernberg 1996) for neurosis to high-level borderline personality organization evaluated based on a psychodynamic assessment interview (Kernberg 1996). Patients with psychotic disorder or severe personality disorder (DSM-IV cluster A personality disorder and/or lower level borderline personality organization), adjustment disorder, substance-related disorder, organic brain disease, or mental retardation were excluded from the study. Patients suffering from such disorders are generally considered to be in need of a longer treatment as they are unlikely able to tolerate considerable anxiety, which is a requirement for a shorter, more anxiety-provoking treatment; therefore their randomization to short-term therapy was not considered fair (American Psychiatric Association 1985; Blenkiron 1999). Patients treated with psychotherapy within the previous 2 years, psychiatric health employees and persons known to the research team members were also excluded. Altogether 459 patients were considered eligible, of which 133 declined to participate. The remaining 326 patients were randomized according to a central computerized randomization schedule in a 1: 1: 1.3 ratio to individual solution-focused therapy (N = 97), short-term psychodynamic psychotherapy (N = 101), or long-term psychodynamic therapy (N = 128) (Knekt et al. 2008). Of the patients randomized, 33 declined to participate, and 42 of those starting treatment discontinued prematurely. The patients were followed up for 3 years after randomization. During this 3-year follow-up, the patients were provided, in accordance with the study protocol, with either short-term therapy followed by no treatment, or long-term therapy. Follow-up measurements were carried out at eight occasions (at 0, 3, 7, 9, 12, 18, 24, and 36 months). The mean dropout rates over these eight measurement occasions in the three therapy groups were similar (15% in the solution-focused, 13% in the short-term psychodynamic, and 18% in the long-term psychodynamic therapy group) (Knekt et al. 2008).
BODY.MATERIAL AND METHODS.THERAPIES:
Solution-focused therapy is a brief resource-oriented and goal-focused therapeutic approach, helping clients change by constructing solutions (Johnson and Miller 1994; Lambert et al. 1998). The orientation was based on an approach developed by de Shazer et al. (1986), de Shazer (1991). The frequency of sessions was flexible, usually one every second or third week, with a maximum of 12 sessions (90 min each) over no more than 8 months. Short-term psychodynamic psychotherapy is a brief, focal, transference-based therapeutic approach, helping patients by exploring and working through specific intrapsychic and interpersonal conflicts. The orientation was based on approaches described by Malan (1976) and Sifneos (1978). The therapy was scheduled for 20 treatment sessions (60 min each), one session a week, over 5–6 months. Long-term psychodynamic psychotherapy is an open-ended, intensive, transference-based therapeutic approach, helping patients by exploring and working through a broad area of intrapsychic and interpersonal conflicts. Therapy includes both expressive and supportive elements, the use of which depends on patient needs. The orientation followed the clinical principles of long-term psychodynamic psychotherapy (Gabbard 2004). The session frequency was 2–3 sessions a week and the duration of therapy up to 3 years.
BODY.MATERIAL AND METHODS.THERAPISTS:
Altogether 55 therapists participated in the study; six provided solution-focused therapy, 12 short-term psychodynamic psychotherapy, and 41 long-term psychodynamic psychotherapy (Knekt et al. 2008). All the therapists had been trained in the respective therapy form. The mean number of years of experience in the therapy form provided was nine (range 3–15) in solution-focused therapy, nine (range 2–20) in short-term psychodynamic psychotherapy, and 18 (range 6–30) in long-term psychodynamic psychotherapy. Additionally, the therapists providing short-term psychodynamic psychotherapy had a mean of 16 years (range 10–21) experience of long-term psychodynamic psychotherapy. None of the therapists providing solution-focused therapy had received any training in psychodynamic psychotherapy and vice versa. Only solution-focused therapy was manualized, and clinical adherence monitoring was performed. All the solution-focused therapists carried out therapy at a center for solution-focused therapy, in which group supervision was part of the institute procedures. On the contrary, all the psychodynamic therapists were private practitioners who had a variety of different arrangements with regard to (primarily individual) supervision. Both psychodynamic psychotherapies were conducted in accordance with clinical practice, where interventions can be modified to patients' needs within the psychodynamic framework.
BODY.MATERIAL AND METHODS.ASSESSMENTS AT BASELINE:
Patient defense style was assessed using a self-report questionnaire at baseline, before randomization of patients into therapies. Other baseline factors potentially confounding the relationship between the baseline defense style and psychotherapy outcome during follow-up were assessed using questionnaires and interviews.
BODY.MATERIAL AND METHODS.ASSESSMENTS AT BASELINE.DEFENSE STYLE:
Psychological defense styles were assessed as a part of personality functions assessment using the Finnish translation (Sammallahti et al. 1994) of the revised 88-item Defense Style Questionnaire (DSQ) by Andrews et al. (1989). Each item consists of an attitudinal statement describing defenses along an ordinal continuum ranging from no agreement (score 1) to total agreement (score 9). A three-factor scale, based on factor analysis (Andrews et al. 1993), has been developed to group the individual defenses into three different types of defense styles: immature, neurotic, and mature (Andrews et al. 1989). This scale has been proven to be an internally reliable instrument, the internal consistency reliabilities (Cronbach's alpha) being 0.89, 0.72, and 0.59 for factors 1, 2, and 3, respectively (Kim and Mueller 1978). Of the 88 items, 72 items are included in the calculation of defense style scores (16 items were control questions); immature, neurotic, and mature defense style scores are based on 46, 16, and 10 items, respectively. The immature defense style covers the specific defenses of acting out, autistic fantasy, denial, devaluation, displacement, dissociation, isolation, passive aggression, projection, rationalization, splitting, and somatization. A score describing the amount of defense style at present is calculated as a mean of the corresponding items, varying thus from 1.0 to 9.0. A factor analysis was carried out to investigate the internal factor structure of the DSQ in the HPS sample. The three-factor solution resembled the original solution (Kim and Mueller 1978; Andrews et al. 1989), with Cronbach's alphas 0.81, 0.68, and 0.50 for immature, neurotic, and mature defense style factors, respectively. The level of immature defense style in this study was classified as low or high around the median value of the score (3.98); a score under the median represented low use of immature defense style and a score equal to or above the median represented high use of immature defense style.
BODY.MATERIAL AND METHODS.ASSESSMENTS AT BASELINE.POTENTIAL CONFOUNDING FACTORS:
Psychiatric diagnoses at Axes I and II were assessed based on a semi-structured interview (Knekt and Lindfors 2004) according to the DSM-IV diagnostic criteria (American Psychiatric Association 1994). Sociodemographic factors (gender, age, education), psychiatric history (previous depressive states, previous psychotherapy), personality functions, including suitability for psychotherapy (SPS; median kappa coefficient for agreement 0.69 [Laaksonen et al. 2012]), quality of object relations (QORS; Azim et al. 1991), and interpersonal problems (IIP; Horowitz et al. 2000), as well as social functioning, including life orientation (LOT; Scheier and Carver 1985), sense of coherence (SOC; Antonovsky 1993), and social adjustment (SAS-SR; Weissmann and Bothwell 1976) were assessed using questionnaires.
BODY.MATERIAL AND METHODS.ASSESSMENTS AT FOLLOW-UP:
The primary outcome measures were specific depressive and anxiety symptoms. The symptoms of depression were assessed with the 21-item self-report Beck Depression Inventory (BDI; Beck et al. 1961) and with the 17-item observer-rated Hamilton Depression Rating Scale (HDRS; Hamilton 1960). The symptoms of anxiety were assessed with the 10-item self-reported Symptom Check List Anxiety Scale (SCL-90-Anx; Derogatis et al. 1973) and with the 14-item observer-rated Hamilton Anxiety Rating Scale (HARS; Hamilton 1959). Secondary outcome measures describing general psychiatric symptoms and global functional capacity were assessed with the Symptom Check List Global Severity Index (SCL-90-GSI; Derogatis et al. 1973) and the Global Assessment of Functioning Scale (GAF; American Psychiatric Association 1994). The self-report measures (BDI, SCL-90-Anx, SCL-90-GSI) were assessed at baseline and 3, 7, 9, 12, 18, 24, and 36 months after the start of the treatment, and the observer-rated measures (HDRS, HARS, GAF) at baseline and 7, 12, and 36 months after the start of the treatment.
BODY.MATERIAL AND METHODS.STATISTICAL METHODS:
The statistical analyses were based on linear mixed models (Verbeke and Molenberghs 1997) carried out with SAS software, version 9.1. (SAS Institute Inc 2007). The main analyses were based on the "intention-to-treat" (ITT) design. Complementary "as-treated" (AT) analyses were also performed (Härkänen et al. 2005; Knekt et al. 2008). The primary analyses were based on the assumption of ignorable dropouts (Knekt et al. 2008). In the secondary analyses, missing values were replaced by multiple imputation. The imputation was based on the Markov chain Monte Carlo methods. Model adjusted outcome means and mean differences were calculated for different measurement points (Lee 1981). The delta method was used for the calculation of confidence intervals (Migon and Gamerman 1999). The statistical significance of the model used was tested with the Wald test. In the ITT analyses, two models were used: a basic model and a complete model. The dependent variable in the analyses was each of the outcome measures (BDI, HDRS, SCL-90-Anx, HARS, SCL-90-GSI, GAF) at a time. The basic ITT model included as independent variables the immature defense style measured at baseline, therapy group, and time (i.e., measurement points), their first- and second-order interactions, a correction term (i.e., the second-order interaction of the difference between theoretical and realized date of measurement, time and immature defense style), and outcome measure at baseline. The complete ITT model further included sociodemographic variables (age, gender, education), DSM-IV diagnoses (Axes I and II, major depressive disorder, and comorbidity of mood and anxiety disorder), psychiatric history data (previous depressive states, previous psychotherapy), personality functions (SPS, QORS, IIP) and social functioning (LOT, SOC, SAS-SR). These were all measured at baseline and satisfied the criteria for confounding, that is, were related with the immature defense style and preceded and were causally related to any of the six outcome measures, without being an intermediate or latent variable (Rothman and Greenland 1998). To account for the deviations from the study protocol, an AT model was created by adding variables describing noncompliance, that is, waiting time from randomization to initiation of treatment and degree of participation (i.e., withdrawal from or discontinuation of treatment) during follow-up as main effects to the complete ITT model. All three models (ITT basic, ITT complete, AT) were carried out based on both the original data and imputed data. The independent variable of main interest was the interaction term between the immature defense style score, therapy group, and time. As no notable differences in the prediction of the immature defense style on outcome of solution-focused therapy and short-term psychodynamic psychotherapy were found during the 3-year follow-up, these two short-term therapies were combined into one short-term therapy group which was compared to the long-term therapy group. A comparison between the basic and complete ITT models demonstrated that the results were slightly different depending on whether potential confounding factors were used in the statistical model, whereas no major difference between the ITT and AT models were found (data not shown). Imputation caused the confidence intervals to widen, and accordingly resulted in statistical significance of some of the comparisons to disappear (data not shown). The results presented are based on the complete ITT model as based on the original data. The significance of the immature defense style in predicting the outcome of short-term versus long-term therapy during the 3-year follow-up was evaluated by testing the statistical significance of the interaction term between the immature defense style and the therapy group throughout the follow-up. The Wald test was used. We assessed statistical significance of the change in outcome from baseline to the different measurement points for each therapy group (short-term and long-term) and category (low and high) of immature defense style. Therapy was considered beneficial for the patients who experienced and maintained a statistically significant reduction in symptoms in comparison with the baseline during the 3-year follow-up. We measured the statistical significance of the model-adjusted difference in the outcome between the therapy groups in the immature defense style categories at the different measurement points. We considered short-term therapy to be equally or more beneficial than long-term therapy when there were no statistically significant differences between the therapy groups or greater benefit from short-term therapy, whereas long-term therapy was considered to be more beneficial when comparisons favored long-term over short-term therapy.
BODY.RESULTS:
The study sample consisted of 326 patients ranging in age from 20 to 46 years (mean 32 years) (Table 1). Approximately 25% of the patients were men, about 50% lived alone, and 25% had an academic education. The majority (85%) of the patients suffered from mood disorder, 44% from anxiety disorder, and 18% from personality disorder. No notable differences between short-term and long-term therapy groups were found with respect to baseline sociodemographic or clinical characteristics, with the exception of significantly higher prevalence of anxiety disorder and personality disorder in the short-term therapy group. Table 1 Baseline characteristics of the 326 patients intended to treat by treatment group Treatment 1 Characteristic Short ( N = 198) Long ( N = 128) Sociodemographic variables Men (%) 25.8 21.1 Age (years) 2 32.8 (7.1) 31.6 (6.6) University degree (%) 24.2 28.1 Living alone (%) 52.5 49.2 Employed (%) 3 84.2 75.4 Psychiatric diagnoses 4 Mood disorder (%) 82.3 88.3 Anxiety disorder (%) 48.0 36.7 Comorbid mood and anxiety disorder (%) 30.3 25.0 Personality disorder (%) 21.7 12.5 Psychiatric symptoms Beck Depression Inventory (BDI) 2 18.0 (7.6) 18.8 (8.3) Hamilton Depression Rating Scale (HDRS) 2 15.6 (4.7) 15.8 (4.9) Symptom Check List, Anxiety scale (SCL-90-Anx) 2 1.3 (0.7) 1.2 (0.7) Hamilton Anxiety Rating Scale (HARS) 2 15.0 (5.3) 14.8 (5.2) Symptom Check List, Global Severity Index (SCL-90-GSI) 2 1.3 (0.5) 1.3 (0.6) Global Assessment of Functioning Scale (GAF) 2 55.1 (7.1) 55.5 (8.1) Psychiatric background Recurrent episodes of major depressive disorder (%) 64.1 69.1 Duration of primary disorder over 5 years (%) 34.3 29.7 Previous psychotherapy (%) 19.4 19.0 Psychological defenses (DSQ) Immature defense style 2 3.93 (0.76) 3.93 (0.69) Neurotic defense style 2 4.21 (0.96) 4.21 (0.94) Mature defense style 2 5.25 (0.92) 5.12 (1.01)) 1 Short, Short-term psychodynamic psychotherapy and solution-focused therapy combined; Long, Long-term psychodynamic psychotherapy. 2 . 3 Full-time/part-time work or full-time student/student at work. 4 Mood disorder: mood disorder only or comorbid mood and anxiety disorder. Anxiety disorder: anxiety disorder only or comorbid mood and anxiety disorder. Personality disorder: main diagnoses on Axis II. During the 3-year follow-up, a statistically significant symptom reduction was found in all six outcome measures (BDI, HDRS, SCL-90-Anx, HARS, SCL-90-GSI, GAF) in both short-term and long-term therapy groups (Table 2). There was no statistically significant interaction between immature defense style and therapy group in the 3-year follow-up. Numerous consistent statistically significant differences in symptom development between short-term and long-term therapies at different points of follow-up were, however, found in relation to the level of immature defense style. During the first year of the follow-up, a statistically larger symptom reduction in the short-term therapy group than in the long-term therapy group (18–45% vs. 9–31%, respectively) was found among patients with low immature defense style according to all six outcome measures. At the end of the 3-year follow-up, on the other hand, a statistically larger symptom reduction in the long-term therapy group than in the short-term therapy group (26–64% vs. 21–45%, respectively) was found among patients with high immature defense style according to five outcome measures. Table 2 Mean values and mean value differences (95% confidence intervals) between short-term and long-term therapy at baseline and at 7, 12, and 36 month follow-up according to the low and high values of the immature defense style score. 1961 Low 2 High 2 Outcome measure Therapy 0 7 12 36 0 7 12 36 P -value 3 BDI Short 18.0 10.7 10.1 10.0 18.0 9.91 9.55 10.1 0.50 Long 18.2 14.7 12.7 7.58 19.2 14.1 12.8 6.47 S-L 4 −3.96 * (−6.57, −1.35) −2.60 (−5.36, 0.15) 2.43 (−0.49, 5.35) − 4.23 * (−6.79, −1.67) − 3.26 * (−5.99, −0.52) 3.63 * (0.62, 6.65) HDRS Short 15.3 10.7 10.6 10.7 15.9 11.1 11.1 10.7 0.26 Long 15.5 13.3 13.8 10.3 16.2 12.4 11.7 7.87 S-L 4 − 2.57 * (−4.40, −0.75) − 3.23 * (−5.16, −1.29) 0.47 (−1.54, 2.47) −1.28 (−3.12, 0.57) −0.68 (−2.66, 1.30) 2.87 * (0.77, 4.97) SCL-90-Anx Short 1.20 0.81 0.81 0.75 1.27 0.94 0.85 0.83 0.18 Long 1.08 1.10 0.96 0.74 1.38 1.03 0.98 0.53 S-L 4 − 0.29 * (−0.51, −0.07) −0.15 (−0.36, 0.05) 0.01 (−0.12, 0.23) −0.10 (−0.31, 0.12) −0.13 (−0.33, 0.07) 0.30 * (0.09, 0.52) HARS Short 14.4 10.0 9.90 9.71 15.4 10.7 10.5 9.92 0.11 Long 14.5 13.0 12.5 9.08 15.5 10.9 10.5 7.56 S-L 4 − 2.97 * (−4.68, −1.27) − 2.55 * (−4.33, −0.77) 0.63 (−1.20, 2.46) −0.21 (−1.93, 1.52) 0.05 (−1.77, 1.87) 2.35 * (0.44, 4.26) SCL-90-GSI Short 1.18 0.88 0.82 0.84 1.34 0.92 0.82 0.83 0.54 Long 1.20 1.14 1.04 0.81 1.38 1.04 0.95 0.60 S-L 4 − 0.26 * (−0.43, −0.09) − 0.21 * (−0.37, −0.05) 0.03 (−0.15, 0.20) 0.12 (−0.29, 0.05) −0.13 (−0.29, 0.03) 0.23 * (0.04, 0.41) GAF Short 54.0 65.3 65.5 67.5 56.3 65.1 66.0 66.8 0.79 Long 54.3 61.3 60.4 68.4 55.8 63.3 62.9 69.9 S-L 4 4.03 * (0.59, 7.46) 5.19 * (1.56, 8.83) −0.88 (−4.28, 3.07) 1.77 (−1.70, 5.23) 3.09 (−0.62, 6.80) −3.05 (−7.18, 1.09) BDI, Beck Depression Inventory; HDRS, Hamilton Depression Rating Scale; SCL-90-Anx, Symptom Check List, Anxiety scale; HARS, Hamilton Anxiety Rating Scale; SCL-90-GSI, Symptom Check List, Global Severity Index; GAF, Global Assessment of Functioning Scale. Underlined symptoms have changed statistically significantly in comparison with baseline symptom level. * Bold values ( P < 0.05) are for comparison between short-term and long-term therapy. 1 Complete “intention-to-treat” (ITT) model: outcome measure = interaction of immature defense style score (low, high), therapy group (short, long) and time (in months) adjusted for time, the immature defense style according to the therapy group, the difference between planned and realized date of measurement, second-order interaction of the difference between planned and realized date of measurement, time and immature defense style according to the therapy group, age, gender, education, DSM-IV Axis I diagnosis, DSM-IV Axis II diagnosis, DSM-IV major depressive disorder diagnosis, comorbidity of mood and anxiety disorder, previous depressive states, previous psychotherapy, suitability for psychotherapy, quality of object relations, interpersonal problems, life orientation, sense of coherence, social adjustment, and the baseline level of the outcome measure. 2 The median score of the immature defense style in the Helsinki Psychotherapy Study sample was 3.98. Low immature defense style was categorized as values below the median (2.00–3.97) and high immature defense style as values equal to or above the median (3.98–6.04). 3 P -value for interaction between the immature defense style, the therapy group, and time throughout the follow-up. 4 Mean value difference of outcome measure between short-term and long-term psychotherapy. Imputation, carried out to study the reliability of the ignorable drop-out assumption, attenuated the results to some extent but the benefit of short-term therapy during the first year of follow-up still remained statistically significant for five of six outcome measures (excluding GAF) and the benefit of long-term therapy during the last year of follow-up for three of five outcome measures (excluding HDRS and HARS) (data not shown). Thus, according to our criteria, for patients with low use of immature defense style short-term therapy seemed to be more beneficial, whereas for patients with high use of immature defense style long-term therapy seemed more beneficial.
BODY.DISCUSSION:
It has been suggested that healthy aspects of personality are necessary precursors for positive outcome in short-term psychotherapies which, due to the limited amount of time, in contrast to long-term psychotherapies, do not usually aim at achieving structural changes in personality (Van et al. 2009). It follows that persons with poorly functioning personality are likely to need long-term psychotherapies to recover, as long-term therapies foster capacity for growth and aim to increase self-awareness and to improve interpersonal skills through changes in personality (American Psychiatric Association 1985). A person's characteristic defenses represent one key aspect of their personality organization, manifested in the person's interpersonal behavior and personal experiences. Accordingly, the presence of immature defense style highlights the likelihood that the person is characterized also of having contradictory personality traits, low level of object relations, and an unstable sense of self and others (Kernberg 1996). An immature defense style, defined as a type of maladaptive behavior pattern in which the very occurrence of the perceived psychic threat (affect, idea, or aspect of a relationship) is denied, split-off from consciousness, or in other ways significantly distorted, thus reflects a poorly functioning, that is, more primitive, personality organization. The few previous studies on the analysis of defense styles and overall defensive functioning as predictors of treatment outcome have focused on short-term psychodynamic psychotherapy alone or in comparison to medication and have produced contradictory findings (Hersoug et al. 2002; Kronström et al. 2009; Van et al. 2009). According to Van et al. (2009), self-reported mature, but not neurotic or immature, defense style was predictive of positive symptomatic outcome in short-term psychodynamic psychotherapy. However, according to Kronström et al. (2009) and Hersoug et al. (2002), respectively, mature defense style and overall level of defenses were not predictive of psychotherapy outcome. The role of immature defense style in the prediction of long-term psychotherapy outcome or potential differential prediction of short-term versus long-term psychotherapy outcome has not been previously studied. In this study, the use of self-reported baseline immature defense style as a predictor of outcomes of short-term and long-term psychotherapies was examined for the first time. No differences in relationship between self-reported immature defense style and outcome in short-term psychodynamic psychotherapy and solution-focused therapy were found. This is in line with our previous findings on other psychotherapy suitability variables (Laaksonen et al. 2013a). The prediction, however, appeared to vary depending on the length of the treatment and follow-up. On average, patients with low use of immature defense style recovered faster in short-term than in long-term psychotherapy, whereas patients with high use of immature defense style recovered better in long-term than in short-term psychotherapy by the end of the 3-year follow-up. Our findings thus support the hypotheses presented in the literature and are also in line with our previous findings (Laaksonen et al. 2013b). This study has several strengths. First, the relatively large sample size enabled more reliable detection of possible differences. Second, the long follow-up time and frequent outcome measurements allowed a comprehensive description and comparison of the symptom development in the treatment groups. Third, use of various well-validated, both observer-rated and self-reported, outcome measures permitted evaluation of the generalizability of the phenomenon studied. The main results were found according to all these measures, indicating that the phenomenon was independent of different assessment methods. Fourth, a widely used self-report measure of defense styles, DSQ, was used. The measure has been concluded to be the best self-reported defense style assessment method based on available information on the validity and reliability of different methods (Soultanian et al. 2005). Further use also of observer-rated methods would, however, likely give a more comprehensive picture of the predictive role of defense styles, especially as defenses are automatic psychological processes that individuals often are unaware of, and therefore the self-report methods only reflect their conscious derivates and might be sensitive to the influence of the actual psychopathology (Andrews et al. 1989; Van et al. 2009). Fifth, a factor analysis was carried out to compare the internal factor structure of the DSQ in the HPS sample to the original factor solution by Andrews et al. (1989), and the DSQ was concluded to be a valid and reliable measure of immature defense style in the HPS. Sixth, comprehensive criteria, based on statistical significance, for the evaluation of different aspects of prediction of the influence of defense styles on psychotherapy outcome were applied (Laaksonen et al. 2013a,b). This study has, however, also several limitations. The general limitations related to the design of the HPS (i.e., lack of manuals and blindness of raters making follow-up assessments) are discussed in more detail elsewhere (Knekt et al. 2008, 2012), and only the limitations specific to this study are addressed here. First, although potential confounding factors were comprehensively studied and adjusted by modeling, the possibility of residual confounding cannot be fully excluded. Second, the compliance of study treatment or auxiliary treatment may potentially cause bias (Knekt et al. 2011). Results from AT analysis, adjusted for withdrawal or discontinuation and for time-dependent variables on auxiliary treatment, did not, however, notably differ from the results from ITT analysis. Third, although analyses were carried out based on both the original and imputed data, possible nonignorable dropouts may still bias the results (Härkänen et al. 2005). Some differences between the analyses based on the original and imputed data were found which also emphasizes need for further research. Fourth, a follow-up longer than 3 years is needed to be able to verify the stability of the findings in long-term therapy.
BODY.CONCLUDING REMARK:
This study suggests that patients with low use of immature defense style may be more suitable for short-term psychotherapy, while patients with high use of immature defense style may benefit more from long-term psychotherapy. More research is, however, needed to confirm these findings and to demonstrate their usefulness in practice.
BODY.SIGNIFICANT OUTCOMES:
Symptoms of patients with high use of immature defense style prior to therapy reduced significantly more in long-term than in short-term psychotherapy.Symptoms of patients with low use of immature defense style prior to therapy reduced significantly faster in short-term than in long-term psychotherapy.Level of patient's initial immature defense style appeared to differentiate the suitability of short-term and long-term psychotherapy and may be utilized to guide treatment choices to better match patients to therapies.
BODY.LIMITATIONS:
A widely used and well-validated self-report defense style measure, DSQ, was used for the assessment of immature defense style, but use of observer-rated methods would provide a more comprehensive view of these phenomena.The possible changes in the use of immature defense style during the therapies were not analyzed and thus more research is needed to find out whether the greater benefit of long-term therapy among those with high initial use of immature defense style was due to its gradually lesser use.To be able to tailor treatments more accurately, the research on psychotherapy suitability should be expanded to include a greater variety of patient, therapist and alliance factors and their combinations as well as in the context of psychotherapies of different orientation and length. | 4,075,638 | {
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TITLE: Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies
ABSTRACT.INTRODUCTION:
To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.
ABSTRACT.METHODS:
This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate).
ABSTRACT.RESULTS:
Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine.
ABSTRACT.CONCLUSION:
The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.
BODY:
What's knownOveractive bladder (OAB) is a chronic condition that is increasingly prevalent with age and represents an increasing healthcare burden to society.Antimuscarinic drugs are the current mainstay of pharmacologic treatment for OAB, but are commonly associated with adherence-limiting adverse effects including dry mouth, constipation and blurred vision.Many patients discontinue antimuscarinic therapy or seek alternative approaches to control OAB as a result of adverse effects or suboptimal efficacy.What's newMirabegron is a β3-adrenoceptor agonist, the first in a new class of drugs with a mode of action that is different from antimuscarinic agents.Mirabegron stimulates the β3-adrenoceptors in the bladder leading to detrusor relaxation and increased bladder capacity.In three international, multicentre, phase III studies, comparing mirabegron, at doses of 25, 50 and 100 mg, with placebo, mirabegron was associated with significant improvements in incontinence episodes and micturition frequency, and was well tolerated.
BODY.INTRODUCTION:
Overactive bladder (OAB) is defined by the International Continence Society as urinary urgency, with or without urinary incontinence, usually with frequency and nocturia, with no proven infection or other obvious pathology 1,2. Lower urinary tract symptoms, including those associated with OAB, are prevalent in approximately half of the general population 3, are often debilitating and have a significant impact on patients' daily routines and quality of life 3–5. OAB affects 12–16% of the adult population across Europe, the USA and Japan 6–8, and its prevalence increases with age, affecting approximately 30% of individuals > 65 years of age 9, therefore representing a substantive health problem for the ageing population. Normal bladder function is regulated by the synergistic actions of the autonomic nervous system: parasympathetic nerves stimulate contraction of the detrusor muscle via muscarinic receptors while stimulation of the sympathetic nerves leads to detrusor relaxation via β-adrenoceptors. The central pathophysiology of OAB involves involuntary contractions of the detrusor muscle as a result of increased afferent activity, decreased inhibitory control from the central nervous system, and/or increased sensitivity of the detrusor muscle to parasympathetic stimulation 10,11. Because of the role of β-adrenoceptors in relaxation of the detrusor, research was aimed at identifying an effective and well-tolerated agent directed at the β-adrenoceptor. The β3-adrenoceptor was recognised as the predominant β-receptor subtype in the human urinary bladder, representing 97% of total β-adrenoceptor mRNA expression in the human bladder 12. The importance of its role in the relaxation of the detrusor has been confirmed by in vitro pharmacological studies using human bladder strips 13–15. In animal models, activation of the β-adrenoceptor in the bladder facilitates urine storage through flattening and lengthening of the bladder base 16. Furthermore, stimulation of the β3-adrenoceptor is associated with increased bladder capacity, without change in micturition pressure, residual volume or voiding contraction 17–19. As a consequence, targeting the β3-adrenoceptor increases the storage capacity of the bladder without affecting the amplitude of the voiding contraction. Mirabegron, a β3-adrenoceptor agonist approved in Japan, the USA, Canada and Europe, for the treatment of OAB symptoms, is the first of a new class of compounds with a mechanism of action that is different from antimuscarinic agents 20. The recommended starting dose of mirabegron is 25 mg in the USA, which can be increased to 50 mg based on individual efficacy and tolerability, and 50 mg in Japan and Europe; the 100 mg dose is not approved for use. Three large-scale, 12-week, phase III studies conducted in the USA/Canada (study 047; NCT00662909) 21; Europe and Australia (study 046; NCT00689104) 22; and Europe/USA/Canada (study 074; NCT00912964)23 have demonstrated the safety, tolerability and superior efficacy of mirabegron at doses of 25 mg (NCT00912964 only), 50 mg (all three studies) and 100 mg (NCT00662909 and NCT00689104) compared with placebo for the treatment of OAB symptoms. The pooled efficacy analysis was prespecified and excluded the 25 mg mirabegron dose because it was limited to a single study. The safety analysis was an aggregate of all data from the three phase III studies and included the 25, 50 and 100 mg mirabegron doses. Pooling these data allows for additional analyses of efficacy and safety in a large dataset representative of the general OAB population in terms of demographics, previous OAB history and prevalence of comorbidities. In particular, it is important to examine the efficacy, safety and tolerability profile demonstrated in the individual studies in the pooled population for overall effect size as well as safety data reporting across the treatment groups. These pooled mirabegron data evaluations inform benefit–risk assessments and support judicious dose selection.
BODY.METHODS.STUDY DESIGN:
This was a prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, which evaluated the efficacy of mirabegron 50 and 100 mg, and safety of mirabegron 25 mg (NCT00912964 only), 50 mg or 100 mg for the treatment of symptoms of OAB. Each study shared a similar design, although the assessed doses of mirabegron and inclusion of an active control arm with tolterodine extended release (ER) 4 mg varied across trials (Figure 1). Male and female patients aged ≥ 18 years with OAB symptoms for ≥ 3 months were enrolled. Following a 2-week, single-blind, placebo run-in period to determine baseline symptoms and patient eligibility, patients were randomised if, during a 3-day micturition diary period, they recorded ≥ 8 micturitions/24 h and ≥ 3 urgency episodes – based on urgency grade of 3 or 4 according to the Patient Perception of Intensity and Urgency Scale [PPIUS 24] – with or without urgency incontinence. Patients were excluded with stress incontinence or mixed incontinence with stress predominance at screening or had an average total daily urine volume > 3000 ml. Figure 1Overview of the individual phase III studies included in the pooled analyses. †Screening from weeks −3 to −2; *Evaluation of adverse events and concomitant medication by telephone contact or visit 30 days after Final Visit in studies 046 and 047 and 2 weeks after Final Visit in Study 074. n, number of patients randomised Patients were randomised to receive once-daily oral placebo, mirabegron 25 mg (NCT00912964 only), mirabegron 50 mg (NCT00912964/NCT00689104/NCT00662909), mirabegron 100 mg (NCT00689104/NCT00662909) or tolterodine ER 4 mg (NCT00689104 only) for 12 weeks using a computer-generated randomisation scheme; after assignment to treatment, both patient and study investigator were blinded to the identity of the study drug. Efficacy data for treatment arms that were represented in only one study (i.e. mirabegron 25 mg or tolterodine ER 4 mg) were not pooled as these data were only available from one trial. In summary, the efficacy data in these pooled analyses relate to the placebo and 50 mg mirabegron groups from all three phase III studies, and the 100 mg mirabegron group from two of the studies [NCT00662909 21/NCT00689104 22]. In contrast, the pooled 12-week phase III safety analysis includes data for the placebo, 25, 50 and 100 mg mirabegron doses and the tolterodine ER 4 mg active control arm.
BODY.METHODS.EFFICACY END-POINTS:
Efficacy measures were recorded in a patient micturition diary over a 3-day period prior to clinic visits which occurred at baseline and 4, 8 and 12 weeks/Final Visit (end of treatment, i.e. last on-treatment assessment including patients who did not complete week 12 visit) after randomisation to treatment. The co-primary end-points in all three studies were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points in all three studies were change from baseline to Final Visit in the mean volume voided/micturition, change from baseline to week 4 in the mean number of incontinence episodes/24 h, and change from baseline to week 4 in the mean number of micturitions/24 h. Study 074 (NCT00912964) had three additional key secondary end-points – mean level of urgency (based on the PPIUS), mean number of urgency episodes (PPIUS grade 3 or 4)/24 h, and the mean number of urgency incontinence episodes/24 h – which were also included as additional secondary end-points in Study 046 (NCT00689104) and Study 047 (NCT00662909) but did not undergo the hierarchical testing procedure for multiple end-points. Further secondary end-points included change from baseline to Final Visit in mean number of nocturia episodes/24 h and patients considered 'responders' to treatment, i.e. the proportion of patients with incontinence episode(s) at baseline with zero incontinence at Final Visit, the proportion of patients with a ≥ 50% decrease from baseline in mean number of incontinence episodes/24 h, and a post hoc analysis of the proportion of patients with ≤ 8 micturitions/24 h at Final Visit. Patient-reported outcomes were assessed using the Treatment Satisfaction-Visual Analogue Scale (TS-VAS), a quantitative instrument measuring subjective improvement in patients with OAB. Complete satisfaction was indicated by a score of 10, with positive change from baseline indicating improvement.
BODY.METHODS.SAFETY END-POINTS:
The analysis of the pooled safety data included adverse event (AE) reporting, laboratory parameters (haematology and serum chemistry), vital signs (pulse rate and blood pressure), ECG data and postvoid residual (PVR) volume. AEs of interest were based on potential or theoretical risk related to the pharmacology of β3-agonists, observed findings in non-clinical or clinical data, or recommended monitoring for specific events. The most common treatment-emergent AEs (TEAEs), according to the preferred term, are reported herein as TEAEs in ≥ 3% of the total mirabegron population. Hypertension was reported as an AE if average systolic blood pressure (SBP) was ≥ 140 mmHg and/or average diastolic blood pressure (DBP) ≥ 90 mmHg at two consecutive postbaseline visits for normotensive patients at baseline; average SBP increased ≥ 20 mmHg and/or average DBP increased ≥ 10 mmHg at two consecutive postbaseline visits for patients with hypertension at baseline; initiation or increase in antihypertensive medication; or according to clinical assessment by the investigator. Tachycardia was to be reported as an AE if average AM or PM resting pulse rate measured by the patient over 3 days was > 100 bpm (unless in the investigator's opinion this did not constitute an AE of tachycardia). Urinary retention was summarised as a reported TEAE based on spontaneous reporting by the investigator, without a prespecified definition per protocol, and assessed concurrently with changes in PVR volume (change from baseline of ≥ 150 ml).
BODY.METHODS.STATISTICAL ANALYSES:
The safety analysis set (SAF) comprised all randomised patients who took ≥ 1 dose of double-blind study drug; the full analysis set (FAS) comprised SAF patients who had ≥ 1 micturition measurement at baseline and ≥ 1 postbaseline micturition measurement; the FAS-incontinence (FAS-I) set comprised FAS patients who reported ≥ 1 incontinence episode at baseline. Efficacy analyses were performed using the FAS except for incontinence episode end-points which used the FAS-I. Safety analyses were performed using the SAF. Descriptive statistics were used for baseline demographic and clinical characteristics. For the efficacy analysis, data for the placebo and 50 mg mirabegron groups from all three studies were pooled, and data for the 100 mg mirabegron groups from two studies were pooled. Hypothesis testing on the change from baseline in incontinence episodes was performed using a separate stratified rank analysis of covariance (ANCOVA) for each pairwise treatment group difference (mirabegron 50 and 100 mg vs. placebo). For all other efficacy end-points, hypothesis testing comparing mirabegron 50 and 100 mg vs. placebo on the change from baseline values was performed using an ANCOVA model including treatment, gender and study as fixed factors, and baseline value as a covariate. Based on the ANCOVA, least squares mean estimates and two-sided 95% confidence intervals (CIs) for mean changes from baseline were derived within treatment groups and between each mirabegron treatment group and placebo on all efficacy end-points. Multiplicity between the two primary and six key secondary efficacy end-points was controlled at the α = 0.05 type I error rate using a stepwise parallel gatekeeping procedure in which the placebo-corrected difference in mean change from baseline for each mirabegron dose had to be statistically significant to allow hypothesis testing to proceed to the next end-point step. The Hochberg procedure was performed at the α = 0.05 significance level for comparisons of the 50 and 100 mg mirabegron treatment groups with placebo to adjust for multiplicity within each stage. If only one mirabegron dose group proceeded to the next stage for any efficacy end-point, the comparison with placebo was assessed at the α = 0.025 level. Responder end-points were analysed using a logistic regression model which included treatment, gender, study and baseline value. For the pooled safety analysis, data from all three studies were included: placebo, 25, 50 and 100 mg mirabegron groups, and tolterodine ER 4 mg arm. All AEs were coded using the Medical Dictionary for Regulatory Activities version 12.1. TEAEs were defined as any AE which started, or worsened, after the first dose of study drug through 30 days after the last dose of study drug. Drug-related TEAEs included those AEs reported as probably or possibly related to study drug as assessed by the investigator or if the AE had a missing relationship. Descriptive statistics were used for measurements of laboratory parameters, ECGs and PVR volume. Change from baseline values for vital sign variables was analysed using the ANCOVA model described above.
BODY.RESULTS.DEMOGRAPHIC AND BASELINE CLINICAL CHARACTERISTICS:
Overall, there were a total of 3542 patients (placebo, n = 1328; mirabegron 50 mg, n = 1324; mirabegron 100 mg, n = 890) and 2317 patients (placebo, n = 878; mirabegron 50 mg, n = 862; mirabegron 100 mg, n = 577), respectively, in the FAS and FAS-I population for the pooled efficacy analysis. The pooled safety analysis included the additional 25 mg mirabegron dose and tolterodine active control arm and consisted of 4611 patients (mirabegron 25 mg, n = 432; mirabegron 50 mg, n = 1375; mirabegron 100 mg, n = 929; placebo, n = 1380; tolterodine, n = 495) who took at least one dose of double-blind study medication. In the FAS and SAF analyses, the disposition and reasons for discontinuation of study drug were similar for all treatment groups (Figure 2). Figure 2Patient disposition in the pooled efficacy and safety analyses Demographic and baseline characteristics were similar between the FAS and FAS-I population with the exception of gender; approximately 72% and 82% of patients were female in the FAS and FAS-I population, respectively (Table 1). Of the patients who had received prior antimuscarinic OAB medication, approximately two-thirds discontinued prior OAB treatment because of insufficient efficacy, and approximately one-quarter because of poor tolerability. The proportion discontinuing prior OAB treatment for either reason was similar across treatment groups (Table 1). Table 1 Patient demographics and baseline clinical characteristics by treatment group (FAS) Placebo ( n = 1328) Mirabegron 50 mg ( n = 1324) Mirabegron 100 mg ( n = 890) Gender, n (%) Male 362 (27.3) 382 (28.9) 241 (27.1) Female 966 (72.7) 942 (71.1) 649 (72.9) Age (years) Mean (SD) 59.2 (13.2) 59.7 (12.6) 59.8 (12.9) Range 20–95 21–91 19–90 Race, n (%) White 1227 (92.4) 1235 (93.3) 838 (94.2) Black or African American 80 (6.0) 61 (4.6) 36 (4.0) Asian 13 (1.0) 17 (1.3) 8 (0.9) Other 8 (0.6) 11 (0.8) 8 (0.9) BMI (kg/m 2 ) * Mean 29.1 (6.3) 29.0 (6.1) 29.1 (6.1) Range 15.9–58.1 16.3–60.5 16.2–62.6 Type of OAB, n (%) Urgency incontinence 442 (33.3) 491 (37.1) 297 (33.4) Mixed 415 (31.3) 412 (31.1) 271 (30.4) Frequency 471 (35.5) 421 (31.8) 322 (36.2) Duration of OAB (months) Mean (SD) 86.3 (99.1) 85.2 (93.1) 88.3 (101.6) Previous OAB drug, n (%) Yes 704 (53.0) 688 (52.0) 460 (51.7) Reasons for previous OAB drug discontinuation, n (%) † Insufficient effect Yes 466 (66.2) 464 (67.4) 296 (64.3) No 238 (33.8) 224 (32.6) 164 (35.7) Poor tolerability Yes 185 (26.3) 173 (25.1) 113 (24.6) No 519 (73.7) 515 (74.9) 347 (75.4) Mean number of incontinence episodes/24 h Mean (SD) 1.8 (2.5) 1.8 (2.5) 1.8 (2.4) Range 0–26 0–18 0–15 Mean number of micturitions/24 h Mean (SD) 11.6 (3.1) 11.7 (3.2) 11.6 (3.0) Range 4–40 6–37 7–35 FAS, full analysis set; SD, standard deviation; BMI, body mass index; OAB, overactive bladder. * For BMI, placebo ( n = 1327) and mirabegron 100 mg ( n = 889). † Percentages are based on patients who had taken previous OAB medication. Patients could choose more than one reason for discontinuation.
BODY.RESULTS.EFFICACY OUTCOMES:
Mirabegron at doses of 50 and 100 mg once daily demonstrated statistically significant improvement from baseline to Final Visit compared with placebo in reducing the mean number of incontinence episodes/24 h and the mean number of micturitions/24 h (p < 0.05 for all comparisons; Table 2 and Figures 3 and 4, respectively). The adjusted mean (95% CI) change from baseline to Final Visit in the mean number of incontinence episodes/24 h was −1.10 (−1.23, −0.97), −1.49 (−1.63, −1.36) and −1.50 (−1.67, −1.34) in the placebo, mirabegron 50 and 100 mg groups, respectively, and −1.20 (−1.34, −1.06), −1.75 (−1.89, −1.61), −1.74 (−1.91, −1.56) for the adjusted mean change from baseline to Final Visit in the mean number of micturitions/24. Table 2 Summary of primary and secondary efficacy end-points (FAS and FAS-I) Placebo Mirabegron 50 mg Mirabegron 100 mg Co-primary end-points Change from baseline to Final Visit in the mean number of incontinence episodes/24 h (FAS-I) Baseline 2.73 (0.09) 2.71 (0.09) 2.79 (0.10) Final Visit 1.64 (0.09) 1.23 (0.08) 1.25 (0.09) Change from baseline −1.09 (0.09) −1.48 (0.08) −1.54 (0.09) Adjusted change from baseline * (95% CI) −1.10 (−1.23, −0.97) −1.49 (−1.63, −1.36) −1.50 (−1.67, −1.34) Adjusted difference vs. placebo * (95% CI) – −0.40 (−0.58, −0.21) 3 −0.41 (−0.62, −0.19) 3 Change from baseline to Final Visit in the mean number of micturitions/24 h (FAS) Baseline 11.58 (0.09) 11.70 (0.09) 11.58 (0.10) Final Visit 10.39 (0.09) 9.93 (0.09) 9.83 (0.11) Change from baseline −1.18 (0.08) −1.77 (0.08) −1.75 (0.09) Adjusted change from baseline * (95% CI) −1.20 (−1.34, −1.06) −1.75 (−1.89, −1.61) −1.74 (−1.91, −1.56) Adjusted difference vs. placebo * (95% CI) – −0.55 (−0.75, −0.36) † −0.54 (−0.77, −0.31) † Key secondary end-points Change from baseline to Final Visit in the mean volume voided/micturition (FAS) Baseline 159.2 (1.54) 159.0 (1.55) 157.9 (1.89) Final Visit 168.6 (1.90) 180.2 (2.01) 179.9 (2.39) Change from baseline 9.4 (1.31) 21.2 (1.31) 22.0 (1.52) Adjusted change from baseline * (95% CI) 9.4 (6.9, 12.0) 21.4 (18.8, 23.9) 21.7 (18.5, 24.9) Adjusted difference vs. placebo * (95% CI) – 11.9 (8.3, 15.5) † 12.3 (8.1, 16.5) † Change from baseline to week 4 in the mean number of incontinence episodes/24 h (FAS-I) Baseline 2.73 (0.09) 2.71 (0.09) 2.79 (0.10) Week 4 2.06 (0.10) 1.59 (0.08) 1.69 (0.10) Change from baseline −0.67 (0.08) −1.12 (0.08) −1.10 (0.09) Adjusted change from baseline * (95% CI) −0.67 (−0.81, −0.54) −1.12 (−1.26, −0.98) −1.09 (−1.27, −0.92) Adjusted difference vs. placebo * (95% CI) – −0.45 (−0.64, −0.26) † −0.42 (−0.65, −0.20) † Change from baseline to week 4 in the mean number of micturitions/24 h (FAS) Baseline 11.58 (0.09) 11.71 (0.09) 11.58 (0.10) Week 4 10.82 (0.09) 10.52 (0.10) 10.26 (0.11) Change from baseline −0.76 (0.07) −1.19 (0.07) −1.32 (0.09) Adjusted change from baseline * (95% CI) −0.77 (−0.90, −0.64) −1.17 (−1.30, −1.04) −1.33 (−1.50, −1.16) Adjusted difference vs. placebo * (95% CI) – −0.40 (−0.59, −0.22) † −0.56 (−0.78, −0.35) † Mean level of urgency (FAS) Baseline 2.39 (0.02) 2.42 (0.02) 2.46 (0.02) Final Visit 2.25 (0.02) 2.15 (0.02) 2.19 (0.02) Change from baseline −0.14 (0.02) −0.27 (0.02) −0.27 (0.02) Adjusted change from baseline * (95% CI) −0.15 (−0.18, −0.12) −0.26 (−0.30, −0.23) −0.26 (−0.30, −0.22) Adjusted difference vs. placebo * (95% CI) – −0.11 (−0.16, −0.07) † −0.11 (−0.16, −0.06) † Mean number of urgency incontinence episodes/24 h (FAS−I) Baseline 2.42 (0.08) 2.42 (0.08) 2.53 (0.10) Final Visit 1.46 (0.08) 1.05 (0.07) 1.11 (0.09) Change from baseline −0.96 (0.08) −1.37 (0.07) −1.42 (0.09) Adjusted change from baseline * (95% CI) −0.98 (−1.10, −0.86) −1.38 (−1.50, −1.26) −1.38 (−1.53, −1.23) Adjusted difference vs. placebo * (95% CI) – −0.40 (−0.57, −0.23) † −0.40 (−0.60, −0.20) † Mean number of urgency episodes (PPIUS grade 3 or 4)/24 h (FAS) Baseline 5.61 (0.10) 5.80 (0.10) 5.96 (0.12) Final Visit 4.38 (0.11) 3.85 (0.11) 4.02 (0.13) Change from baseline −1.23 (0.10) −1.95 (0.10) −1.94 (0.12) Adjusted change from baseline * (95% CI) −1.29 (−1.47, −1.11) −1.93 (−2.11, −1.75) −1.89 (−2.11, −1.66) Adjusted difference vs. placebo * (95% CI) – −0.64 (−0.89, −0.39) † −0.60 (−0.89, −0.31) † Additional secondary end-points Change from baseline to Final Visit in mean number of nocturia episodes/24 h (FAS) Baseline 2.18 (0.04) 2.22 (0.04) 2.25 (0.05) Final Visit 1.78 (0.04) 1.66 (0.04) 1.71 (0.05) Change from baseline −0.41 (0.04) −0.56 (0.04) −0.54 (0.04) Adjusted change from baseline * (95% CI) −0.42 (−0.48, −0.35) −0.55 (−0.62, −0.49) −0.54 (−0.62, −0.46) Adjusted difference vs. placebo * (95% CI) – −0.14 (−0.23, −0.05) ‡ −0.12 (−0.23, −0.02) ‡ Change from baseline to Final Visit in TS-VAS (FAS) Baseline 4.87 (0.11) 4.82 (0.11) 4.43 (0.13) Final Visit 6.05 (0.10) 6.79 (0.09) 6.94 (0.11) Change from baseline 1.18 (0.11) 1.96 (0.12) 2.51 (0.14) Adjusted change from baseline * (95% CI) 1.25 (1.08, 1.42) 2.01 (1.84, 2.19) 2.33 (2.11, 2.55) Adjusted difference vs. placebo * (95% CI) – 0.76 (0.52, 1.01) ‡ 1.08 (0.80, 1.37) ‡ All values mean (SE) unless otherwise stated. * Estimates are based on an analysis of covariance model, which included treatment group, gender and study as fixed factors, and baseline as a covariate. † p < 0.05 vs. placebo with multiplicity adjustment. ‡ p < 0.05 vs. placebo without multiplicity adjustment. Figure 3Adjusted mean change from baseline (±SE) by time point in the mean number of incontinence episodes/24 h for the pooled placebo, mirabegron 50 and 100 mg groups (FAS-I). #Statistically significant treatment benefit relative to placebo (p < 0.05) with multiplicity adjustment. *Statistically significant treatment benefit relative to placebo (p < 0.05) without multiplicity adjustment. SE, standard error; FAS-I, full analysis set-incontinence. Figure 4Adjusted mean change from baseline (±SE) by time point in mean number of micturitions/24 h for the pooled placebo, mirabegron 50 and 100 mg groups (FAS). #Statistically significant treatment benefit relative to placebo (p < 0.05) with multiplicity adjustment. *Statistically significant treatment benefit relative to placebo (p < 0.05) without multiplicity adjustment. SE, standard error; FAS, full analysis set. The key secondary end-points, change from baseline to week 4 (first time point assessed) in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h, were significantly improved for both mirabegron doses compared with placebo (p < 0.05, all comparisons; Table 2 and Figures 3 and 4, respectively). The adjusted mean (95% CI) change from baseline to week 4 in the mean number of incontinence episodes/24 h was −0.67 (−0.81, −0.54), −1.12 (−1.26, −0.98) and −1.09 (−1.27, −0.92) in the placebo, mirabegron 50 and 100 mg groups, respectively. The adjusted mean (95% CI) change from baseline to week 4 in the mean number of micturitions/24 h was −0.77 (−0.90, −0.64), −1.17 (−1.30, −1.04) and −1.33 (−1.50, −1.16) in the placebo, mirabegron 50 and 100 mg groups, respectively. Both 50 and 100 mg mirabegron doses were associated with statistically significant improvements from baseline to Final Visit compared with placebo for the key secondary efficacy end-points of mean volume voided/micturition (p < 0.05 for all comparisons; Table 2), mean level of urgency, mean number of urgency episodes (grade 3 or 4)/24 h and mean number of urgency incontinence episodes/24 h (p < 0.05 for all comparisons; Table 2 and Figure 5). Figure 5Adjusted mean change from baseline to Final Visit (SE) in key secondary end-points: (A) mean level of urgency (FAS) (B) number of urgency episodes/24 h (FAS) and number of urgency incontinence episodes/24 h (FAS-I). #Statistically significant treatment benefit compared with placebo (p < 0.05) with multiplicity adjustment. SE, standard error; FAS, full analysis set; FAS-I, full analysis set-incontinence. Significant improvements were also evident in the pooled efficacy analysis with respect to the change from baseline to Final Visit (95% CI) in the mean number of nocturia episodes/24 h in the mirabegron 50 mg [−0.55 (−0.62, −0.49)] and mirabegron 100 mg groups [−0.54 (−0.62, −0.46)] vs. placebo [−0.42 (−0.48, −0.35)] (p < 0.05; Table 2). For the responder analyses, the percentage of patients with zero incontinence episodes at Final Visit ('dry rate') was significantly higher in the mirabegron 50 and 100 mg groups (44.1% and 46.4%, respectively) compared with placebo (37.8%). The corresponding odds ratios (95% CI) for the mirabegron 50 and 100 mg groups were 1.32 (1.08, 1.61) and 1.58 (1.25, 2.00), respectively (p < 0.05). The percentage of patients with a ≥ 50% reduction from baseline to Final Visit in mean number of incontinence episodes/24 h was also significantly higher in the mirabegron 50 and 100 mg groups (69.5% and 70.5%, respectively) compared with placebo (59.6%). The corresponding odds ratios (95% CI) for the mirabegron 50 and 100 mg groups were 1.54 (1.26, 1.89) and 1.64 (1.29, 2.07), respectively (p < 0.05). In the post hoc responder analysis, both 50 and 100 mg mirabegron doses were also associated with a significant improvement in 'micturition normalisation' (i.e. the percentage of patients with ≤ 8 micturitions/24 h) at Final Visit (31.6% and 34.0%) compared with placebo (24.6%). The corresponding odds ratios (95% CI) for the mirabegron 50 and 100 mg groups were 1.57 (1.30, 1.89) and 1.69 (1.37, 2.09), respectively (p < 0.05). In health-related quality of life outcomes, mirabegron 50 and 100 mg was associated with a statistically significant improvement in the TS-VAS score at Final Visit compared with placebo (p < 0.05; Table 2). The adjusted mean (95% CI) changes from baseline to Final Visit were 1.25 (1.08, 1.42), 2.01 (1.84, 2.19) and 2.33 (2.11, 2.55) for the placebo, mirabegron 50 and 100 mg groups, respectively.
BODY.RESULTS.EFFICACY IN PATIENTS WITH PRIOR ANTIMUSCARINIC USE AND TREATMENT-NAÏVE PATIENTS:
Both mirabegron 50 and 100 mg doses improved the co-primary end-points in patients who had discontinued previous antimuscarinic medication and in treatment-naïve patients. The adjusted mean difference (95% CI) from baseline to Final Visit in the mean number of incontinence episodes/24 h in patients who had discontinued previous antimuscarinic medication was −0.92 (−1.09, −0.75), −1.49 (−1.66, −1.32) and −1.42 (−.64, −1.21) in the placebo, mirabegron 50 mg and mirabegron 100 mg groups, respectively, and −1.35 (−1.55, −1.14), −1.50 (−1.71, −1.29) and −1.62 (−1.87, −1.36) in treatment-naïve patients. The adjusted mean difference (95% CI) in the mean number of micturitions/24 h from baseline to Final Visit in the placebo, mirabegron 50 and 100 mg groups, respectively, was −0.93 (−1.12, −0.74), −1.67 (−1.86, −1.48) and −1.61 (−1.85, −1.37) in patients who discontinued previous antimuscarinic therapy, and −1.51 (−1.71, −1.31), −1.84 (−2.04, −1.64) and −1.87 (−2.12, −1.63) in treatment-naïve patients. The adjusted mean difference vs. placebo in patients who discontinued previous antimuscarinic therapy was of a greater magnitude than in treatment-naïve patients because of the higher placebo response in treatment-naïve patients.
BODY.RESULTS.SAFETY OUTCOMES:
The overall incidence of TEAEs was similar across treatment groups (Table 3) and there was no evidence of a dose–response relationship across the mirabegron treatment groups for overall rates of TEAEs: placebo (47.7%), mirabegron 25 mg (48.6%), mirabegron 50 mg (47.1%), mirabegron 100 mg (43.3%), total mirabegron (46.0%) and tolterodine ER 4 mg (46.7%). The most common TEAEs reported in ≥ 3% of the total mirabegron group were hypertension, nasopharyngitis and urinary tract infection (Table 3). The incidence of hypertension and urinary tract infection decreased as the dose of mirabegron increased from 25 to 100 mg. The most common drug-related TEAEs in the mirabegron groups were hypertension and headache, which were of similar incidence with placebo and tolterodine, with the exception of dry mouth, which was at placebo level for mirabegron but of a higher magnitude in the tolterodine group (Table 3). The majority of AEs were of mild or moderate severity across treatment groups. Table 3 Overview of treatment-emergent adverse events in the pooled safety analysis (SAF) Mirabegron Number of patients (%) Placebo ( n = 1380) 25 mg ( n = 432) 50 mg ( n = 1375) 100 mg ( n = 929) Total ( n = 2736) Tolterodine ER 4 mg ( n = 495) Any TEAE 658 (47.7) 210 (48.6) 647 (47.1) 402 (43.3) 1259 (46.0) 231 (46.7) Drug-related TEAE 232 (16.8) 87 (20.1) 256 (18.6) 172 (18.5) 515 (18.8) 131 (26.5) TEAE leading to discontinuation 46 (3.3) 17 (3.9) 53 (3.9) 34 (3.7) 104 (3.8) 22 (4.4) Drug-related TEAE leading to discontinuation 27 (2.0) 11 (2.5) 35 (2.5) 25 (2.7) 71 (2.6) 20 (4.0) SAE 29 (2.1) 7 (1.6) 29 (2.1) 26 (2.8) 62 (2.3) 11 (2.2) Drug-related SAE 6 (0.4) 3 (0.7) 7 (0.5) 3 (0.3) 13 (0.5) 6 (1.2) Common TEAEs by preferred term (reported by ≥ 3% in total mirabegron group) Hypertension 105 (7.6) 49 (11.3) 103 (7.5) 48 (5.2) 200 (7.3) 40 (8.1) Nasopharyngitis 35 (2.5) 15 (3.5) 54 (3.9) 25 (2.7) 94 (3.4) 14 (2.8) Urinary tract infection 25 (1.8) 18 (4.2) 40 (2.9) 25 (2.7) 83 (3.0) 10 (2.0) Antimuscarinic AEs of interest by preferred term (reported by ≥ 2% in any group) Headache 43 (3.1) 10 (2.3) 47 (3.4) 23 (2.5) 80 (2.9) 18 (3.6) Dry mouth 29 (2.1) 8 (1.9) 23 (1.7) 23 (2.5) 54 (2.0) 50 (10.1) Constipation 20 (1.4) 7 (1.6) 22 (1.6) 15 (1.6) 44 (1.6) 10 (2.0) Drug-related *
TEAEs by preferred term (reported by ≥ 2% in any group) Hypertension 63 (4.6) 30 (6.9) 65 (4.7) 32 (3.4) 127 (4.6) 30 (6.1) Headache 18 (1.3) 4 (0.9) 28 (2.0) 12 (1.3) 44 (1.6) 11 (2.2) Dry mouth 22 (1.6) 7 (1.6) 13 (0.9) 20 (2.2) 40 (1.5) 47 (9.5) SAF, safety analysis set; ER, extended release; TEAE, treatment-emergent adverse event; SAE, serious adverse event. * Possible or probable, as assessed by the investigator, or records where relationship was missing. The proportion of patients discontinuing study drug because of TEAEs was low and similar across each group: placebo (3.3%), mirabegron 25 mg (3.9%), mirabegron 50 mg (3.9%), mirabegron 100 mg (3.7%), total mirabegron (3.8%) and tolterodine ER 4 mg (4.4%). The incidence of serious AEs was also low and similar between placebo and mirabegron groups: placebo (2.1%), mirabegron 25 mg (1.6%), mirabegron 50 mg (2.1%), mirabegron 100 mg (2.8%), total mirabegron (2.3%) and tolterodine ER 4 mg (2.2%). Three deaths were reported in this pooled 12-week safety analysis: in the placebo group, a 76-year-old woman died as a result of cardiac arrest 56 days after the last dose of study drug; in the mirabegron 100 mg group, a 66-year-old woman died because of metastatic colon cancer 30 days after the last dose of study drug – neither case was considered to be related to study drug – and in the tolterodine ER 4 mg group, a 74-year-old man died because of a ruptured cerebral aneurysm on day 70 (treatment-emergent), 10 days after the last dose of study drug was administered, and was considered as possibly related to study drug. In terms of vital sign measurements for blood pressure and pulse rate, the adjusted mean difference vs. placebo for change from baseline to Final Visit in SBP and DBP (AM and PM measurements) was negligible and comparable across each mirabegron group and the tolterodine ER 4 mg group. The adjusted mean difference vs. placebo for change from baseline to Final Visit in pulse rate (AM and PM measurements) increased dose-dependently by 0.6–2.3 bpm in the mirabegron groups and by 1.0–2.1 bpm in the tolterodine ER 4 mg group (Table 4). The overall occurrence of tachycardia events, either based on TEAE and/or observations of pulse rate ≥ 100 bpm captured by patient diary, was less than 5% in each treatment group and comparable with placebo (Table 4). ECG findings revealed no overt trends in central tendency or categorical outliers for QTc interval assessment across treatment groups. Changes in haematology and serum chemistry, including renal parameters, were small and comparable across treatment groups. Table 4 Summary of changes from baseline to Final Visit in blood pressure and pulse rate Placebo ( n = 1380) Mirabegron 25 mg ( n = 432) Mirabegron 50 mg ( n = 1375) Mirabegron 100 mg ( n = 929) Tolterodine ER 4 mg ( n = 495) AM PM AM PM AM PM AM PM AM PM Blood pressure (mmHg) SBP N 1329 1326 410 410 1327 1327 891 890 476 476 Baseline, mean (SE) 125.9 (0.47) 125.0 (0.41) 129.2 (0.81) 129.0 (0.71) 126.4 (0.47) 125.6 (0.43) 125.0 (0.55) 123.7 (0.49) 128.2 (0.75) 127.4 (0.64) Final Visit, mean (SE) 126.2 (0.45) 125.7 (0.41) 128.8 (0.75) 128.3 (0.67) 127.2 (0.46) 126.6 (0.41) 125.6 (0.51) 125.2 (0.46) 128.4 (0.70) 127.9 (0.63) Adjusted change from baseline, mean (SE), (95% CI) † 0.2 (0.25), (−0.3, 0.7) 0.6 (0.25), (0.1, 1.1) −0.3 (0.52), (−1.3, 0.7) −0.5 (0.53), (−1.5, 0.6) 0.8 (0.25), (0.3, 1.3) 1.1 (0.25), (0.6, 1.6) 0.6 (0.32), (−0.0, 1.2) 1.4 (0.33), (0.8, 2.1) 0.1 (0.45), (−0.8, 1.0) 0.5 (0.46), (−0.4, 1.4) Difference vs. placebo, mean (SE), (95% CI) ‡ – – −0.5 (0.57), (−1.6, 0.6) −1.0 (0.58), (−2.2, 0.1) 0.6 (0.35), (−0.1, 1.3) 0.5 (0.36), (−0.2, 1.2) 0.4 (0.41), (−0.4, 1.2) 0.9 (0.42), (0.1, 1.7) −0.1 (0.52), (−1.1, 1.0) −0.0 (0.53), (−1.1, 1.0) DBP N 1329 1326 410 410 1327 1327 890 890 476 476 Baseline, mean (SE) 77.1 (0.26) 75.3 (0.23) 78.2 (0.48) 76.1 (0.46) 77.2 (0.25) 75.4 (0.24) 77.4 (0.30) 75.3 (0.28) 76.8 (0.40) 75.4 (0.38) Final Visit, mean (SE) 77.2 (0.25) 75.7 (0.24) 77.6 (0.43) 75.7 (0.42) 77.6 (0.24) 76.2 (0.24) 77.7 (0.28) 76.3 (0.28) 77.7 (0.39) 76.6 (0.36) Adjusted change from baseline, mean (SE), (95% CI) † 0.0 (0.16), (−0.3, 0.3) 0.4 (0.16), (0.1, 0.7) −0.1 (0.33), (−0.8, 0.5) 0.1 (0.34), (−0.6, 0.7) 0.4 (0.16), (0.1, 0.7) 0.7 (0.16), (0.4, 1.1) 0.2 (0.21), (−0.2, 0.6) 0.9 (0.21), (0.5, 1.3) 0.8 (0.29), (0.2, 1.3) 1.4 (0.30), (0.8, 2.0) Difference vs. placebo, mean (SE), (95% CI) ‡ – – −0.1 (0.37), (−0.9, 0.6) −0.3 (0.37), (−1.0, 0.4) 0.4 (0.22), (−0.1, 0.8) 0.4 (0.23), (−0.1, 0.8) 0.2 (0.26), (−0.3, 0.7) 0.5 (0.27), (−0.0, 1.0) 0.7 (0.33), (0.1, 1.4) 1.0 (0.34), (0.4, 1.7) Pulse rate (bpm) N 1329 1326 410 410 1327 1327 891 890 476 476 Baseline, mean (SE) 70.5 (0.28) 75.3 (0.29) 71.0 (0.50) 75.5 (0.51) 70.4 (0.28) 74.9 (0.28) 70.4 (0.34) 74.4 (0.34) 69.8 (0.44) 73.9 (0.45) Final Visit, mean (SE) 70.9 (0.29) 74.7 (0.29) 71.7 (0.52) 75.3 (0.53) 71.8 (0.29) 75.5 (0.28) 72.9 (0.34) 76.5 (0.34) 71.4 (0.44) 76.0 (0.45) Adjusted change from baseline, mean (SE), (95% CI) † 0.4 (0.17), (0.1, 0.8) −0.4 (0.18), (−0.8, −0.1) 1.3 (0.36), (0.6, 2.0) 0.2 (0.37), (−0.6, 0.9) 1.4 (0.17), (1.1, 1.8) 0.6 (0.18), (0.2, 0.9) 2.3 (0.22), (1.9, 2.8) 1.9 (0.23), (1.4, 2.3) 1.4 (0.31), (0.8, 2.0) 1.7 (0.32), (1.1, 2.3) Difference vs. placebo, mean (SE), (95% CI) ‡ – – 0.9 (0.40), (0.1, 1.6) 0.6 (0.41), (−0.2, 1.4) 1.0 (0.24), (0.5, 1.5) 1.0 (0.25), (0.5, 1.5) 1.9 (0.28), (1.3, 2.5) 2.3 (0.29), (1.7, 2.9) 1.0 (0.36), (0.3, 1.7) 2.1 (0.37), (1.4, 2.8) Incidence of tachycardia (%) * Tachycardia events, N (%) 43 (3.1) 21 (4.9) 52 (3.8) 43 (4.6) 16 (3.2) SBP, systolic blood pressure; DBP, diastolic blood pressure. * Based on TEAE and/or observations of pulse rate ≥ 100 bpm captured by patient diary. † Adjusted change from baseline is generated from the ANCOVA model with treatment group, gender and study as fixed factors, and baseline as a covariate. ‡ Differences in the adjusted means are calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. With respect to other events of interest, the incidence of urinary retention was infrequent in the studies and less in mirabegron-treated patients than in placebo or tolterodine-treated patients: placebo (n = 7; 0.5%), mirabegron 25 mg (n = 0), mirabegron 50 mg (n = 1; 0.1%), mirabegron 100 mg (n = 0), total mirabegron (n = 1; < 0.1%) and tolterodine (n = 3; 0.6%). The mean change from baseline to Final Visit in PVR volume was unremarkable across treatment groups: placebo (−1.6 ml), mirabegron 25 mg (−3.0 ml), mirabegron 50 mg (−0.9 ml), mirabegron 100 mg (−0.7 ml) and tolterodine ER 4 mg (+ 0.1 ml). The proportion of patients experiencing ≥ 150 ml change from baseline in PVR volume was lower in the mirabegron groups compared with placebo and tolterodine: placebo (0.7%), mirabegron 25 mg (0%), mirabegron 50 mg (0.3%), mirabegron 100 mg (0.4%) and tolterodine ER 4 mg (0.8%).
BODY.DISCUSSION:
Mirabegron, a β3-adrenoceptor agonist, is approved for the treatment of OAB symptoms in Japan, the USA, Canada and Europe, and has a different mechanism of action from the antimuscarinic agents currently available. Mirabegron facilitates detrusor relaxation during the storage phase of the micturition cycle and, in contrast with antimuscarinic agents, improves the storage capacity of the bladder without impairing the amplitude of the contraction during the voiding phase of the micturition cycle 25. In this pooled analysis of three international phase III studies 21–23, a total of 3542 OAB patients were included in the efficacy analysis, and 4611 OAB patients in the safety analysis, reflective of the general OAB population. More than half of these patients were randomised to mirabegron for 12 weeks at doses of 25, 50 and 100 mg. Furthermore, this pooled dataset included approximately 50% of OAB patients who had been previously treated with antimuscarinic agents but had discontinued either because of insufficient efficacy and/or poor tolerability. In OAB patients, mirabegron 50 and 100 mg demonstrated significant and clinically meaningful efficacy in terms of improving the symptoms of OAB, including incontinence episodes, micturition frequency and urgency, which are recognised by international guidelines as important outcome measures for OAB therapies 26. The benefit of mirabegron is evident in both treatment-naïve and previous OAB-treated patients. This is a clinically relevant observation, given the poor persistence rate associated with antimuscarinic drugs – discontinuation rates above 50% and 75% have been reported at 6 months and 1 year, respectively 27,28 – and the fact that, in addition to bothersome AEs (e.g., dry mouth), inadequate response to treatment is an underlying reason for discontinuation of antimuscarinic treatment 27,29–31. Both 50 and 100 mg doses of mirabegron demonstrated significant improvements compared with placebo for all of the key secondary end-points, including measures of urgency (the core symptom of OAB), and mean volume voided/micturition. Across primary and key secondary end-points, significant improvements with both mirabegron doses were evident at the first assessment period (week 4) and were maintained throughout the 12-week treatment period – an earlier benefit cannot be ruled out but was not assessed prior to the initial 4-week evaluation. Responder analyses showed a significant improvement with mirabegron 50 and 100 mg in terms of dry rates, ≥ 50% reduction in mean number of incontinence episodes/24 h and the proportion of patients with ≤ 8 micturitions/24 h at Final Visit. Taken together, these data demonstrate a clinically meaningful benefit with mirabegron in the objective end-points of OAB. As OAB is a symptom complex, it can be difficult to determine the efficacy of treatments using objective measures alone. Hence, patient-reported outcomes are increasingly important in the assessment of treatments for symptom-based conditions such as OAB 4. The TS-VAS scores for the 50 and 100 mg mirabegron doses were significantly better and approximately one point higher than patients receiving placebo and reflect the directional parallelism of the subjective and objective improvements in OAB symptoms. The mirabegron 100 mg dose does not appear to afford a greater efficacy benefit than the 50 mg dose for reduction in incontinence episodes or micturition frequency vs. placebo. A dose–response effect was not evident with the 50 and 100 mg doses across the co-primary and secondary end-points. Although data from the 25 mg mirabegron arm 23 were not included in the pooled efficacy analysis, 25 mg is the recommended starting dose in the USA. In the NCT00912964 phase III study, mirabegron 25 mg showed clinically significant efficacy compared with placebo for the co-primary end-points; however, for the majority of the secondary end-points it did not demonstrate significance vs. placebo 23. In terms of the safety and tolerability profile of mirabegron, the pooled analysis confirms the results of the individual phase III studies 21–23. The most common AEs (> 3% of total mirabegron group) were hypertension, nasopharyngitis and urinary tract infection. The incidence of hypertension and urinary tract infection decreased as the mirabegron dose increased and both incidences in the total mirabegron group were similar to placebo or tolterodine. The incidence of the most bothersome AE for antimuscarinic drugs, dry mouth, was at placebo level with each mirabegron dose and lower than tolterodine. This finding is consistent with previous randomised, controlled trials of other antimuscarinic therapies, which have reported even higher incidences of dry mouth (9–93%); these studies have also reported high incidences of constipation (4–21%) 32–41. Given that dry mouth is the chief cause of discontinuation because of poor tolerability with antimuscarinic drugs 27,29, the pooled safety data indicate that mirabegron may be a valuable treatment option for patients with OAB. The pooled safety analysis offers more precise estimates of certain safety parameters, such as vital signs and AEs related to cardiovascular safety, than the individual phase III studies. In this pooled analysis, mirabegron was associated with approximate increases of ≤ 1 mmHg in blood pressure and ≥ 1 bpm in pulse rate vs. placebo. The incidence of hypertension was similar among the total mirabegron group, placebo and tolterodine. The incidence of urinary retention was greater in the placebo and tolterodine groups than in mirabegron-treated patients. ECG, PVR volume and laboratory data were unremarkable across each treatment group. Overall, the data support the good safety profile of mirabegron based on this pooled phase III clinical study dataset.
BODY.CONCLUSIONS:
Mirabegron, a β3-adrenoceptor agonist, and the first in its class for the treatment of OAB symptoms, has a distinct mechanism of action from antimuscarinic agents, the current pharmacological mainstay in treating OAB. In these pooled analyses of efficacy and safety, mirabegron administered at daily doses of 50 and 100 mg for 12 weeks demonstrated significant and clinically meaningful improvement in treating the symptoms of OAB, including urinary incontinence, micturition frequency and urgency. Mirabegron was beneficial in both treatment-naïve patients and in patients who used prior antimuscarinic treatment. The improvement in OAB symptoms measured objectively was reflected in the improvement in the patient-reported outcome related to treatment satisfaction. Mirabegron was well tolerated with an incidence of dry mouth at placebo level and lower than tolterodine. Mirabegron represents a new therapeutic in a new class of medication for the treatment of OAB and has demonstrable efficacy and tolerability in a large clinical trial dataset in OAB patients. In clinical practice, mirabegron will provide a valuable treatment option for OAB syndrome. | 3,752,932 | {
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TITLE: Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide.
ABSTRACT:
Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m(-2) on days 1-5 every 3 weeks, with escalation to 175 mg m(-2) from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2. Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg l(-1) h (95% CI 0.1-32.8 mg l(-1) h; P = 0.05). However, the inter-patient variability of etoposide AUC(inf) was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.
BODY:
| 2,223,531 | {
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"he median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9).",
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TITLE: Effectiveness of a serious game for medical education on insulin therapy for diabetes: randomized controlled trial
ABSTRACT:
BODY.BACKGROUND:
Most patients with diabetes mellitus (DM) are followed by primary care physicians, who often lack knowledge about DM care, especially on insulin. Traditional continuing medical education has little effectiveness, so new educational approaches are required.
BODY.OBJECTIVES:
To assess the applicability, acceptance, and effectiveness of a serious game for medical education on insulin therapy for DM.
BODY.METHODS:
A serious game called InsuOnLine© was developed by experts in endocrinology, medical education, and games. Game design was based on modern adult learning theories, and recommendations were adapted from main DM guidelines. A randomized unblinded controlled trial (RCT) was performed to assess the effectiveness of the game, played in "real-world" conditions (in players' own computers and in their free time), compared to a traditional on-site learning activity, both with same content and duration (3-4 h). Primary care physicians from South of Brazil who were not specialists in endocrinology or diabetes were invited to participate, and randomly allocated to one of the groups. Knowledge, problem-solving skills, attitudes, and satisfaction were assessed by a questionnaire applied at baseline, immediately after interventions, and three months later.
BODY.RESULTS:
Eighty-eight physicians were allocated to game group; from those, 69 (78%) finished the game, which demonstrates good applicability. Those 69 were included in final analysis. Other 65 physicians were included in control group. Both groups were similar at baseline: 49% were female, and mean age was 38. Both interventions were very well rated, regarding methodology and satisfaction. The gain of knowledge and skills was significant in both groups, with the percentage of right answers going from 52% at baseline to 85% after traditional activity (p<0.001), and to 92% after the game (p<0.001). Three months later, that percentage decreased to 76% in control and to 80% in game group, both it remained significantly higher than at baseline. Absolute increase in performance was higher in the game group (40%) than in control (34%, p=0.01). Attitudes were more significantly improved in the game group than in control. Three months after interventions, all subjects in control and 99% in game group said that the intervention had had real impact on their practice.
BODY.CONCLUSION:
The serious game InsuOnLine© is applicable, well accepted, and very effective for medical education on insulin. | 4,653,470 | {
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