Use of β-Blockers and the Risk of Hip/Femur Fracture in the United Kingdom and The Netherlands Data from in vivo studies have indicated a role for β-blockers in the prevention of bone loss . Some epidemiological studies have found protective effects of β-blockers on fracture risk . However , there is limited information on the association with cumulative dose and type of β-blockers used . We conducted two case-control studies using data from the UK General Practice Research Database -LRB- GPRD -RRB- and the Dutch PHARMO Record Linkage System -LRB- RLS -RRB- . Cases were patients with a first hip or femur fracture ; controls were individually matched on practice/region , gender , year of birth , and calendar time . Current use of β-blockers was defined as a prescription in 90 days before the index date . We adjusted for medical conditions and drugs associated with falling or bone mineral density . Odds ratios -LRB- ORs -RRB- and 95 % confidence intervals -LRB- CIs -RRB- were calculated using conditional logistic regression analysis . The study population included 22,247 cases and controls in the GPRD and 6,763 cases and 26,341 controls in the PHARMO RLS . Current use of β-blockers was associated with a reduced risk of hip/femur fracture in both the GPRD -LRB- adjusted OR = 0.82 , 95 % CI 0.74 -- 0.91 -RRB- and PHARMO RLS -LRB- adjusted OR = 0.87 , 95 % CI 0.80 -- 0.95 -RRB- study populations . However , this reduction of risk was not associated with cumulative dose , lipophilicity , or receptor selectivity of β-blockers . The protective effect of β-blockers was only present among patients with a history of use of other antihypertensive agents -LRB- GPRD adjusted OR = 0.72 , 95 % CI 0.64 -- 0.83 ; PHARMO RLS adjusted OR = 0.76 , 95 % CI 0.67 -- 0.86 -RRB- but not in patients using β-blockers only -LRB- GPRD adjusted OR = 0.97 , 95 % CI 0.82 -- 1.14 ; PHARMO RLS adjusted OR = 1.01 , 95 % CI 0.90 -- 1.14 -RRB- . Also , in patients with a history of use of other antihypertensive agents , no dose-response relationship with β-blocker use was found . The effect was constant with cumulative dose and the OR was below 1.0 even among patients who just started treatment with β-blockers . As the mechanism by which β-blockers could influence bone mineral density is likely to need some time to exert a clinically relevant effect , all these finding suggests that the association between β-blockers and fracture risk is not causal . Bone remodeling comprises a phase of resorption by osteoclasts and a phase of formation by osteoblasts . Recent studies have shown bone metabolism to be mediated through the autonomic central nervous system . Leptin , a hormone produced in fat cells to signal energy insufficiency , regulates bone remodeling by modulating osteoblast proliferation and subsequent osteoclast activation via the osteoclast differentiation factor receptor activator of nuclear factor κB ligand -LRB- RANKL -RRB- . The antiosteogenic effect of leptin is not present in β2-adrenergic receptor-deficient mice , which had actual increases in bone mineral density -LRB- BMD -RRB- -LSB- 1 -- 5 -RSB- . Data from these in vivo studies indicate a role for β-blockers in the prevention of bone loss . In the early 1990s , propranolol was found to increase bone formation -LSB- 6 -RSB- . Some observational studies have reported that use of β-blockers was associated with a decreased risk of fractures -LSB- 7 -- 9 -RSB- , conflicting with other studies which found no association with fractures -LSB- 10 -- 12 -RSB- . Studies on the effects of β-blockers on subclinical endpoints , like BMD or biochemical markers of bone resorption , have also yielded inconsistent results -LSB- 7 , 10 , 12 -- 14 -RSB- . A possible role for β-blockers in the prevention of fractures is of major clinical interest , given that fractures are a major source of morbidity , disability , hospitalization , and mortality . One of the most serious fractures resulting from accidental falls is hip fracture -LSB- 15 -RSB- . However , there is still a lack of knowledge with respect to the effects of cumulative dose and type of β-blockers used . Thus , the objective of this study was to assess the strength of the association between use of β-blockers and risk of hip/femur fractures using data from two different large population-based databases in the United Kingdom and The Netherlands . Materials and Methods Setting Data for this study were obtained from the UK General Practice Research Database -LRB- GPRD -RRB- and the Dutch PHARMO Record Linkage System -LRB- RLS -RRB- . The GPRD contains the computerized medical records of general practices across the United Kingdom -LRB- http://www.gprd.com -RRB- . Approximately 6 % of the total registered population of England and Wales is represented in the database , and it includes a cumulative total of over 5 million adult patients . The age and sex distribution of patients enrolled is representative of the general English and Welsh populations . Patient details accrued in the GPRD include demographic information , diagnoses , prescription details , preventive care provided , referrals to specialist care , hospital admissions , and related major outcomes -LSB- 16 -RSB- . Clinical data are stored and retrieved by means of Oxford Medical Information Systems and Read codes for diseases or causes of morbidity and mortality that are cross-referenced to the International Classification of Diseases -LRB- ICD-9 -RRB- . Several independent validation studies have shown that the GPRD has a high level of completeness and validity , including for hip fractures -LSB- 17 , 18 -RSB- . The PHARMO RLS includes the demographic details and complete medication history of 950,000 community-dwelling residents of more than 25 population-defined areas in The Netherlands from 1985 onward . It is further linked to hospital admission records as well as several other health registries , including pathology , clinical laboratory findings , and general practitioner data -LRB- http://www.pharmo.nl -RRB- . Since the majority of all patients in The Netherlands are registered only with one community pharmacy , independently of prescriber , pharmacy records are virtually complete with regard to prescription drugs . For this study , drug-dispensing and hospitalization data were used . The computerized histories record information on the type of drug dispensed , dispensing date , prescriber , amount dispensed , and prescribed dosage regimen . Hospital discharge records include detailed information on the primary and secondary discharge diagnoses ; diagnostic , surgical , and treatment procedures ; type and frequency of consultations with medical specialists ; and dates of hospital admission and discharge . All diagnoses are coded according to the ICD-9-CM -LSB- 19 -RSB- . Definition of Cases and Controls GPRD A case-control study was conducted using GPRD data collected from January 1987 to July 1999 . The details of this study have been described elsewhere -LSB- 20 , 21 -RSB- . Briefly , cases were defined as patients aged 18 years and older with a first record of a hospital admission for a hip/femur fracture -LRB- ICD-9 codes 820 -- 821 -RRB- recorded in their medical records between the enrollment date of their practice in the GPRD and the end of data collection . The date of the occurrence of the hip/femur fracture was the index date . Each case was matched by year of birth , sex , medical practice , and calendar time to one control patient without a history of a fracture . If no eligible control was available , the age criterion was expanded consecutively at 1-yearly intervals to a maximum of 10 years . If no eligible control patient could be found , then an age - and sex-matched control patient from another practice was selected . PHARMO RLS Cases were patients aged 18 years and older with a first admission for a hip/femur fracture between January 1 , 1991 , and December 31 , 2002 . The date of the hospital admission was the index date . Up to four control patients , who did not have a history of any type of fracture , were matched to each case by year of birth , gender , region , and calendar time . Exposure Assessment For each patient , we identified all prescriptions for -LRB- GPRD -RRB- and dispensing of -LRB- PHARMO RLS -RRB- β-blockers prior to the index date . Current users were defined as patients who had a prescription/dispensing for β-blockers within 3 months prior to the index date . Recent users received a last prescription/dispensing 3 -- 6 months before the index date , past users 6 -- 12 months before the index date , and distant past users more than 12 months before the index date . The last prescribed daily dose prior to the index date was obtained from the written dosage instructions . For each patient , cumulative exposure to β-blockers ever before the index date was calculated . The effect of cumulative dose was assessed both regardless of the timing of use and stratified to current , recent , past , and distant past use . Thus , current users could be classified to a low previous cumulative exposure -LRB- e.g. , one or two 30-day prescriptions -RRB- or a high previous cumulative exposure -LRB- e.g. , 100 30-day prescriptions -RRB- . The estimated daily dose for each class of β-blocker was expressed as a fraction of the World Health Organization defined daily dose -LRB- DDD -RRB- . A DDD is defined as the assumed average maintenance dose per day for a drug if used for its main indication in adults -LSB- 22 -RSB- . DDD equivalents can be used to compare drugs within a certain therapeutic group . In this study , we converted the DDD equivalents to milligrams of metoprolol , similar to the approach used in previous studies -LSB- 21 -RSB- . Furthermore , β-blockers were categorized according to receptor selectivity and lipophilicity based on data in handbooks on clinical pharmacology and therapeutics . Statistical Analysis The strength of the association between use of β-blockers and risk of hip/femur fractures was estimated using conditional logistic regression analysis -LRB- SAS version 9.1.3 , PHREG procedure ; SAS Institute , Cary , NC -RRB- and expressed as odds ratios -LRB- ORs -RRB- and 95 % confidence intervals -LRB- CIs -RRB- . Final regression models were determined by stepwise backward elimination using a significance level of 0.05 . Smoothing spline regression plots were used to visualize the effect of cumulative β-blocker dose on risk of hip/femur fractures -LSB- 23 -RSB- . In our analysis , we controlled for a wide range of clinical variables that have been associated with risk of falls or fractures . In the GPRD study , we included the following variables in the final model : history of diabetes mellitus , rheumatoid arthritis , hyperthyroidism , congestive heart failure , seizures , anemia , dementia , depression , psychotic disorder , cerebrovascular accident , chronic obstructive pulmonary disease , osteoporosis , and a record of back pain or falls in the year before the index date . Furthermore , prescriptions , in the 6 months prior to the index date , for anticonvulsants , nonsteroidal anti-inflammatory drugs -LRB- NSAIDs -RRB- , methotrexate , hormone replacement therapy , other hypertensive drugs -LRB- low-ceiling diuretics , renin-angiotensin-aldosterone system -LSB- RAAS -RSB- inhibitors , calcium channel blockers -RRB- , anxiolytics/hypnotics , antipsychotics , antidepressants , anti-Parkinson drugs , oral and inhaled glucocorticoids , and bronchodilators as well as information on body mass index -LRB- BMI -RRB- were retained in the model . In the PHARMO RLS study , variables included in the final model were a dispensing of benzodiazepines in the 3 months prior to the index date , or , in the 6 months prior to the index date , a dispensing of oral glucocorticoids , inhaled glucocorticoids , bronchodilators , statins , BMD-modifying drugs , hormone replacement therapy , antipsychotics , antidepressants , opioids , antiepileptics , other hypertensive drugs -LRB- low-ceiling diuretics , RAAS inhibitors , calcium channel blockers -RRB- , antidiabetics , laxants , disease-modifying antirheumatic drugs , NSAIDs , or metoclopramide . A history of hospital admission for cerebrovascular disease , cancer , endocrine disorders , inflammatory bowel disease and other bowel diseases , obstructive airway disease , musculoskeletal and connective tissue diseases , anemia , and skin diseases prior to the index date were also included in the final model . Results The study population in the GPRD comprised 22,247 cases and 22,247 controls , whereas in the PHARMO RLS 6,763 cases and 26,341 controls were identified . The characteristics of both populations are displayed in Table 1 . The sex and age distributions of cases were similar in the two case-control sets , although more cases in the GPRD set were aged over 80 years . Table 1 . Characteristics of hip/femur fracture cases and controls in the GPRD and PHARMO RLSCharacteristicGPRDPHARMO RLSCases -LRB- n = 22,247 -RRB- Controls -LRB- n = 22,247 -RRB- Cases -LRB- n = 6,763 -RRB- Controls -LRB- n = 26,341 -RRB- Gender Women75 .8 % 75.8 % 72.9 % 72.7 % Age -LRB- years -RRB- < 6513.9 % 13.9 % 15.8 % 16.2 % 65 -- 7930.8 % 32.2 % 36.6 % 37.3 % ≥ 8055.2 % 53.9 % 47.6 % 46.5 % Smokinga22 .1 % 20.6 % No data availableBMIb 20 -- 2546.6 % 42.4 % < 2018.0 % 9.7 % No data available > 2535.4 % 47.9 % Antidepressants13 .0 % 7.2 % 9.5 % 5.1 % Oral glucocorticoids7 .2 % 4.4 % 5.4 % 3.5 % Thiazides11 .9 % 12.9 % 12.1 % 11.4 % Nitrates6 .9 % 7.4 % 9.4 % 9.1 % Hormone replacement0 .6 % 1.2 % 1.1 % 1.3 % a No data on smoking status for 45 % of GPRD study populationb No data on BMI for 58.5 % of GPRD study population Current use of β-blockers was associated with a significantly decreased risk of hip/femur fracture in both databases , whereas recent and past use was not -LRB- Table 2 -RRB- . Adjusted ORs for current β-blocker users were 0.83 -LRB- 95 % CI 0.75 -- 0.92 -RRB- in the GPRD and 0.87 -LRB- 95 % CI 0.80 -- 0.95 -RRB- in the PHARMO RLS . There was no strong effect of cumulative dose among current users of β-blockers in either data set -LRB- Fig. 1 -RRB- , while assessing the effect cumulative dose irrespective of timing of use yielded similar results . Table 2 . Use of β-blockers and risk of hip/femur fracture in the GPRD and PHARMO RLSβ-blocker exposureGPRDPHARMO RLSCases -LRB- % -RRB- Controls -LRB- % -RRB- Crude OR -LRB- 95 % CI -RRB- Adjusted OR -LRB- 95 % CI -RRB- aCases -LRB- % -RRB- Controls -LRB- % -RRB- Crude OR -LRB- 95 % CI -RRB- Adjusted OR -LRB- 95 % CI -RRB- aTiming of use Current use4 .55.90.70 -LRB- 0.64 -- 0.77 -RRB- 0.82 -LRB- 0.74 -- 0.91 -RRB- 12.413.70.91 -LRB- 0.83 -- 0.98 -RRB- 0.87 -LRB- 0.80 -- 0.95 -RRB- Recent use0 .60.60.89 -LRB- 0.70 -- 1.14 -RRB- 0.88 -LRB- 0.68 -- 1.15 -RRB- 1.71.71.01 -LRB- 0.82 -- 1.24 -RRB- 0.93 -LRB- 0.75 -- 1.15 -RRB- Past use0 .70.61.10 -LRB- 0.86 -- 1.40 -RRB- 0.99 -LRB- 0.76 -- 1.28 -RRB- 1.41.31.11 -LRB- 0.88 -- 1.40 -RRB- 0.99 -LRB- 0.78 -- 1.26 -RRB- Distant past use3 .72.81.10 -LRB- 0.98 -- 1.22 -RRB- 1.06 -LRB- 0.94 -- 1.20 -RRB- 6.86.31.07 -LRB- 0.96 -- 1.20 -RRB- 0.97 -LRB- 0.87 -- 1.09 -RRB- Among current users of β-blockersSelectivity Low1 .01.20.75 -LRB- 0.63 -- 0.90 -RRB- 0.86 -LRB- 0.71 -- 1.05 -RRB- 3.53.11.12 -LRB- 0.97 -- 1.30 -RRB- 1.04 -LRB- 0.89 -- 1.21 -RRB- Medium0 .10.20.79 -LRB- 0.48 -- 1.32 -RRB- 0.81 -LRB- 0.47 -- 1.41 -RRB- 0.30.50.40 -LRB- 0.20 -- 0.84 -RRB- 0.38 -LRB- 0.18 -- 0.79 -RRB- High3 .34.40.69 -LRB- 0.62 -- 0.76 -RRB- 0.77 -LRB- 0.69 -- 0.87 -RRB- 8.710.10.86 -LRB- 0.79 -- 0.95 -RRB- 0.84 -LRB- 0.76 -- 0.93 -RRB- Lipophilicity Hydrophile3 .24.20.69 -LRB- 0.62 -- 0.77 -RRB- 0.78 -LRB- 0.70 -- 0.88 -RRB- 5.15.20.98 -LRB- 0.86 -- 1.11 -RRB- 0.94 -LRB- 0.83 -- 1.06 -RRB- Intermediate0 .20.20.77 -LRB- 0.50 -- 1.20 -RRB- 0.88 -LRB- 0.56 -- 1.39 -RRB- 0.50.41.15 -LRB- 0.77 -- 1.73 -RRB- 1.04 -LRB- 0.69 -- 1.58 -RRB- Lipophile1 .11.40.72 -LRB- 0.60 -- 0.85 -RRB- 0.81 -LRB- 0.68 -- 0.98 -RRB- 6.98.00.85 -LRB- 0.77 -- 0.95 -RRB- 0.83 -LRB- 0.74 -- 0.92 -RRB- First prescription Yes0 .20.20.93 -LRB- 0.58 -- 1.48 -RRB- 1.18 -LRB- 0.69 -- 1.99 -RRB- 0.40.60.63 -LRB- 0.42 -- 0.95 -RRB- 0.62 -LRB- 0.41 -- 0.94 -RRB- Last prescribed daily dose -LRB- DDD -RRB- b < 0.670.91.20.72 -LRB- 0.59 -- 0.87 -RRB- 0.81 -LRB- 0.65 -- 1.00 -RRB- 8.79.80.89 -LRB- 0.81 -- 0.98 -RRB- 0.87 -LRB- 0.79 -- 0.96 -RRB- 0.67 -- 1.332.02.60.73 -LRB- 0.64 -- 0.83 -RRB- 0.85 -LRB- 0.74 -- 0.99 -RRB- 3.23.40.95 -LRB- 0.82 -- 1.11 -RRB- 0.90 -LRB- 0.77 -- 1.06 -RRB- > 1.331.42.00.64 -LRB- 0.55 -- 0.75 -RRB- 0.81 -LRB- 0.69 -- 0.97 -RRB- 0.40.40.95 -LRB- 0.61 -- 1.49 -RRB- 0.85 -LRB- 0.54 -- 1.35 -RRB- a Adjusted for use of other antihypertensive drugs and general risk factors for falls and fractures -LRB- see Materials and Methods -RRB- b One DDD is equivalent to 150 mg metoprololFig . 1 . Spline visualization of cumulative dose among current ß-blocker users and risk of hip/femur fractures -LRB- GPRD , dashed line , solid circles ; PHARMO RLS , solid line , open circles -RRB- . Cumulative dose is expressed in DDDs -LRB- 1,000 DDDs are equivalent to 150 g of metoprolol -RRB- . Odds ratios were adjusted for the same confounders as in Table 2 . The most frequently prescribed β-blocker in the GPRD was atenolol -LRB- 3.0 % among cases vs. 4.0 % among controls , adjusted OR = 0.80 , 95 % CI 0.71 -- 0.90 -RRB- . Current use of other β-blockers was infrequent -LRB- propranolol 0.4 % vs. 0.5 % , metoprolol 0.2 % vs. 0.2 % -RRB- and not associated with a decreased risk of hip/femur fracture -LRB- adjusted OR = 0.90 , 95 % CI 0.76 -- 1.06 -RRB- . In the PHARMO RLS , the most frequently used β-blockers at the index date were metoprolol -LRB- 4.6 % among cases vs. 5.6 % among controls -RRB- , atenolol -LRB- 3.2 % vs. 3.6 % -RRB- , sotalol -LRB- 1.9 % vs. 1.5 % -RRB- , and propranolol -LRB- 0.9 % vs. 0.9 % -RRB- . The adjusted ORs for current use of metoprolol and atenolol were 0.79 -LRB- 95 % CI 0.69 -- 0.90 -RRB- and 0.89 -LRB- 95 % CI 0.77 -- 1.04 -RRB- , respectively . Current use of propranolol -LRB- adjusted OR = 0.98 , 95 CI 0.74 -- 1.21 -RRB- and sotalol -LRB- adjusted OR = 1.15 , 95 % CI 0.93 -- 1.42 -RRB- were not associated with a protective effect of hip/femur fracture . Categorizing β-blockers according to their lipophilicity , receptor selectivity , or last prescribed daily dose did not reveal major differences in effect -LRB- Table 2 -RRB- , nor did stratification according to age and gender -LRB- Table 3 -RRB- . Table 3 . Current use of β-blockers and risk of hip/femur fractures in patient subgroupsCurrent use of β-blockersGPRDPHARMO RLSCases -LRB- % -RRB- Controls -LRB- % -RRB- Crude OR -LRB- 95 % CI -RRB- Adjusted OR -LRB- 95 % CI -RRB- aCases -LRB- % -RRB- Controls -LRB- % -RRB- Crude OR -LRB- 95 % CI -RRB- Adjusted OR -LRB- 95 % CI -RRB- aGender Men3 .44.50.68 -LRB- 0.55 -- 0.84 -RRB- 0.77 -LRB- 0.60 -- 0.98 -RRB- 10.112.00.83 -LRB- 0.70 -- 0.98 -RRB- 0.77 -LRB- 0.64 -- 0.93 -RRB- Women4 .86.30.71 -LRB- 0.64 -- 0.78 -RRB- 0.83 -LRB- 0.74 -- 0.93 -RRB- 13.314.40.93 -LRB- 0.95 -- 1.02 -RRB- 0.90 -LRB- 0.82 -- 1.00 -RRB- Age -LRB- years -RRB- < 652.93.10.93 -LRB- 0.68 -- 1.26 -RRB- 0.91 -LRB- 0.62 -- 0.91 -RRB- 5.07.21.04 -LRB- 0.80 -- 1.35 -RRB- 0.94 -LRB- 0.70 -- 1.27 -RRB- 65 -- 807.09.10.71 -LRB- 0.62 -- 0.80 -RRB- 0.84 -LRB- 0.73 -- 0.98 -RRB- 14.516.80.84 -LRB- 0.58 -- 1.12 -RRB- 0.80 -LRB- 0.70 -- 0.91 -RRB- 80 +3.54.60.65 -LRB- 0.57 -- 0.75 -RRB- 0.77 -LRB- 0.66 -- 0.91 -RRB- 12.413.50.94 -LRB- 0.84 -- 1.06 -RRB- 0.94 -LRB- 0.83 -- 1.07 -RRB- History of any use of other antihypertensive drugs No2 .22.40.89 -LRB- 0.77 -- 1.04 -RRB- 0.97 -LRB- 0.82 -- 1.14 -RRB- 8.38.11.02 -LRB- 0.85 -- 1.23 -RRB- 1.01 -LRB- 0.90 -- 1.14 -RRB- Yes9 .714.70.60 -LRB- 0.53 -- 0.67 -RRB- 0.73 -LRB- 0.64 -- 0.83 -RRB- 20.926.90.73 -LRB- 0.65 -- 0.83 -RRB- 0.76 -LRB- 0.67 -- 0.86 -RRB- a Adjusted for use of other antihypertensive drugs and general risk factors for falls and fractures -LRB- see Materials and Methods -RRB- Percentages represent the proportion of current beta-blocker within each subcategory -LRB- e.g. male gender -RRB- The protective effect of β-blockers was only present among patients who had been treated with other antihypertensive agents -LRB- e.g. , low-ceiling diuretics , calcium antagonists , RAAS inhibitors -RRB- , either concurrently or in the past -LRB- Table 3 -RRB- . This finding was consistent in both the GPRD -LRB- adjusted OR = 0.73 , 95 % CI 0.64 -- 0.83 -RRB- and PHARMO RLS -LRB- adjusted OR = 0.76 , 95 % CI 0.67 -- 0.86 -RRB- . Among patients using only β-blockers , the adjusted ORs were close to unity . In both data sets , the interaction term between current use of β-blockers and use of other antihypertensive drugs was statistically significant -LRB- P < 0.05 -RRB- . Furthermore , no effect of cumulative dose was found in either current users of β-blocker only or in current β-blocker users with a history of using other antihypertensive drugs -LRB- Fig. 2 -RRB- . Further stratification according to high or low average daily dose during the study period indicated no effect of the intensity of β-blocker use on the risk estimates . Fig. 2 . Spline visualization of cumulative dose among current ß - blocker users , stratified according to patients not having -LRB- A -RRB- or having a history of other antihypertensive drugs -LRB- B -RRB- -LRB- GPRD , dashed line , solid circles ; PHARMO RLS , solid line , open circles -RRB- . Cumulative dose is expressed in DDDs -LRB- 1,000 DDDs are equivalent to 150 g of metoprolol -RRB- . Odds ratios were adjusted for the same confounders as in Table 2 , except for the use of antihypertensive drugs . Discussion In both the GPRD and PHARMO RLS data sets , current use of β-blockers was associated with a decreased risk of hip/femur fractures . However , there was no reduced risk of hip/femur fractures among patients who did not have a history of using other antihypertensive drugs : a protective effect of β-blockers was only observed for patients with current or prior use of other antihypertensive agents . Even within this group of patients , no dose-response relationship with β-blocker use was found . The effect was constant with cumulative dose and the OR was below 1.0 even among patients who had just started treatment with β-blockers . As the mechanism by which β-blockers could influence BMD is likely to need some time to exert a clinically relevant effect , this finding suggests that the association between β-blockers and fracture risk is not causal . Based on in vivo and in vitro studies and the discovery that the central nervous system is involved in the regulation of bone , β-blockers have been implicated in a preventive role in patients with osteoporosis . Central effects of leptin have been found to be mediated by the sympathetic nervous system , acting via β receptors on osteoblasts -LSB- 3 -RSB- . β agonists stimulate bone-resorption activity in osteoclasts -LSB- 24 -RSB- . Previous data have shown that systemic application of β agonists had a negative effect on bone mass in mice -LSB- 25 -RSB- , whereas β antagonists stimulated bone formation in rats -LSB- 6 -RSB- . Several epidemiological studies have reported discrepant results on the association between use of β-blockers and risk of fracture -LSB- 7 -- 12 -RSB- , including a study that also used data from the GPRD -LSB- 8 -RSB- . The reason for the discrepancy is unclear . Emerging data from randomized controlled trials also support a lack of effect of β-blockers on the risk of fracture . Recently , a clinical trial among 41 normal postmenopausal women found no evidence that propranolol stimulates bone formation , as measured by bone turnover markers -LSB- 26 -RSB- . Furthermore , pooled data from nine clinical trials investigating the nonselective β-blocker carvedilol in the management of congestive heart failure did not provide evidence in support of an effect of β-blockers on fracture risk reduction -LSB- 10 -RSB- . The data from this meta-analysis are consistent with the results of our study as no effect on fracture was observed in patients treated with β-blockers without history of other antihypertensive drug use . Therapeutic uses of β-blockers include the treatment of hypertension as well as heart failure and secondary prevention post-myocardial infarction , - cardiac dysrhythmia , and - angina pectoris . Cardiovascular disease , heart failure , and hypertension have all been linked with decreased BMD -LSB- 27 -- 30 -RSB- . Because thiazides , calcium channel blockers , and inhibitors of the renin-angiotensin system have also been associated with beneficial effects on bone -LSB- 31 -RSB- , we stratified in our study on history of use of other antihypertensive drugs to separate the effect of current use of β-blockers from that of other antihypertensive agents . This method of stratification was not applied in earlier epidemiological studies on β-blockers and fractures . The strength of our study is that it was population-based . Furthermore , we found the same results in both the UK and Dutch data sets . The prevalence of β-blocker use was nearly three times as high in the PHARMO RLS compared to the GPRD . In 2002 , 5.1 million prescriptions for β-blockers were issued in The Netherlands -LRB- population 16 million -RRB- -LSB- 32 -RSB- compared to 22.4 million prescriptions in the United Kingdom in the same year -LRB- population 59 million -RRB- -LSB- 33 -RSB- . Taking into account that prescriptions in the United Kingdom are usually for 30 days and those in The Netherlands for 90 days , we can conclude that the observed difference in exposure prevalence is in line with prescribing data volumes in both countries . Observational studies like ours have potential for bias and confounding and can fuel debates on study interpretation and credibility -LSB- 34 -- 36 -RSB- . Various drugs with effects on the central nervous system are known to increase the risk of falls and thereby fracture risk . Also , there are likely to be complex interactions between vascular disease and fracture risk , operating through falls risk , BMD , or common genetic or lifestyle factors . In this study , we had no information on BMD and we can not exclude the possibility that cases and controls were different with respect to BMD . However , given that initiation of antihypertensive treatment in daily clinical practice will usually be independent of patient BMD , major confounding seems unlikely . Variables included in the final regression models were slightly different between the two data sets due to the nature of the data collections . However , multivariate adjustment had only modest effects on the OR of the exposure of interest . Information on smoking and BMI was not available in the PHARMO RLS database , but adjustment for these factors in the GPRD had no influence on risk estimates -LRB- smoking was not retained in the model -RRB- . Data on BMI were missing for 58 % of the GPRD study population , so we can not exclude the concern that adjustment was suboptimal . We had no data on physical activity , diet , or socioeconomic status as such information is not available in the databases used in our studies -LSB- 37 -RSB- . Furthermore , we can not exclude the possibility that residual confounding can explain part of our results . An alternative explanation for our findings could be that the protective effect of β-blockers on fractures is an artifact caused by selective underuse in patients with an unmeasured comorbidity , a problem that has been described by Glynn et al. in a study on cardiovascular drug use and mortality -LSB- 38 -RSB- . In their study , among elderly subjects in the United States , they found that users of drugs from seven commonly prescribed therapeutic classes , including β-blockers , thiazide diuretics , and angiotensin-converting enzyme inhibitors , had reduced rates of death compared to nonusers , which was more likely to be explained by selective prescribing and nonadherence . A potential limitation is that we confined our study to hip/femur fractures and did not evaluate other type of fractures . It is possible that potential beneficial effects of β-blockers are present only at sites other than the hip/femur , but there is no evidence to support this . In conclusion , the reduction in hip/femur fracture risk was not related to cumulative dose of β-blockers and was only present in patients using β-blockers with a history of using other antihypertensive drugs as well . This suggests that the effect of β-blockers on hip/femur fracture is not causal .

O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O


Impact

of

a

programme

of

mass

mammography

screening

for

breast

cancer

on

socio-economic

variation

in

survival

a

population-based

study

Background

After

a

systematic

mass

mammography

breast

cancer

screening

programme

was

implemented

between

and

-LRB-

attendance

-RRB-

we

evaluated

its

impact

on

survival

according

to

socioeconomic

status

-LRB-

SES

-RRB-

Introduction

Mammography

screening

aims

at

early

detection

of

breast

cancer

so

that

adequate

treatment

will

eventually

lower

breast

cancer

mortality

In

a

mass

screening

programme

it

is

therefore

especially

important

to

reach

women

who

have

the

highest

chance

of

being

diagnosed

with

advanced

stage

or

have

the

lowest

survival

rates

Women

from

lower

socio-economic

strata

are

less

likely

to

attend

population

screening

programmes

-LSB-

-RSB-

and

are

also

more

likely

to

present

with

unfavourable

stage

at

diagnosis

-LSB-

-RSB-

although

not

all

studies

confirm

this

-LSB-

-RSB-

Lower

breast

cancer

survival

rates

among

the

disadvantaged

are

usually

attributed

to

advanced

stage

at

presentation

but

also

to

suboptimal

access

to

adequate

treatment

A

recent

population-based

study

in

Switzerland

found

social

class

to

be

an

independent

prognostic

factor

-LSB-

-RSB-

The

mass

breast

cancer

screening

programme

was

introduced

in

for

women

of

years

and

became

fully

implemented

in

in

the

south

of

the

Netherlands

covered

by

the

population-based

Eindhoven

Cancer

Registry

with

a

continuous

high

participation

rate

Based

on

previous

work

-LSB-

-RSB-

and

a

new

postcode-based

indicator

of

socio-economic

status

-LRB-

SES

-RRB-

introduced

by

Statistics

Netherlands

-LSB-

-RSB-

we

were

able

to

investigate

survival

according

to

SES

for

a

sufficient

period

of

time

after

introduction

We

studied

whether

survival

according

to

SES

was

affected

differentially

by

the

implementation

of

the

screening

programme

Methods

The

Eindhoven

Cancer

Registry

records

data

on

all

patients

newly

diagnosed

with

cancer

in

the

south

eastern

part

of

the

Netherlands

an

area

with

now

million

inhabitants

-LRB-

about

of

the

Dutch

population

-RRB-

and

only

general

hospitals

Trained

registry

personnel

actively

collect

data

on

diagnosis

staging

and

treatment

from

the

medical

records

after

notification

by

pathologists

and

medical

registration

offices

In

the

area

of

the

Eindhoven

Cancer

Registry

a

biennial

breast

cancer

screening

programme

for

women

aged

years

was

started

in

and

fully

implemented

in

The

attendance

rate

was

more

than

-LSB-

-RSB-

For

our

analyses

we

included

all

patients

age

years

diagnosed

in

with

invasive

breast

cancer

in

the

eastern

part

of

the

registration

area

-LRB-

about

million

inhabitants

-RRB-

This

population

has

been

followed-up

for

vital

status

up

to

Information

on

the

vital

status

of

all

patients

was

obtained

initially

from

the

municipal

registries

and

since

from

the

Central

Bureau

for

Genealogy

These

registers

provide

virtually

complete

coverage

of

all

deceased

Dutch

citizens

An

indicator

of

socioeconomic

status

was

developed

by

Statistics

Netherlands

-LSB-

-RSB-

being

based

on

individual

fiscal

data

from

the

year

on

the

economic

value

of

the

home

and

household

income

and

provided

at

aggregated

level

for

each

postal

code

-LRB-

average

of

households

-RRB-

Socioeconomic

status

was

categorized

according

to

quintiles

ranging

from

-LRB-

low

-RRB-

to

-LRB-

high

-RRB-

with

a

separate

class

for

postal

codes

with

a

care-providing

institution

-LRB-

such

as

a

nursing

home

-RRB-

This

measure

is

assumed

to

be

valid

ten

years

before

and

after

the

basic

year

-LRB-

-RRB-

so

for

patients

diagnosed

before

we

used

a

measure

which

was

also

based

on

postal

code

of

residence

but

socio-economic

status

-LRB-

five

categories

-RRB-

was

based

on

data

from

a

marketing

agency

-LRB-

self-reported

occupation

and

education

define

social

classes

collapsed

into

a

indicator

based

on

average

number

of

years

of

education

-RRB-

as

described

before

-LSB-

-RSB-

We

also

used

both

SES

indicators

for

the

whole

study

period

-LRB-

-RRB-

to

make

sure

any

effect

of

diagnostic

period

was

not

attributable

to

the

indicator

we

used

We

calculated

distribution

of

age

and

stage

of

disease

according

to

period

of

diagnosis

Stage

was

categorized

according

to

the

TNM

classification

-LSB-

-RSB-

Patients

with

either

positive

lymph

nodes

or

metastases

were

considered

to

have

advanced

disease

Chi-square

test

was

performed

of

changes

in

the

distribution

across

the

three

diagnostic

periods

T-tests

were

performed

of

differences

between

two

groups

Crude

survival

analyses

were

performed

The

log-rank

test

was

used

to

evaluate

significant

differences

between

survival

curves

in

univariate

analyses

We

used

Cox

regression

models

to

compute

multivariate

rates

The

proportional

hazard

assumption

of

the

predictor

was

evaluated

by

applying

Kaplan

Meier

Curves

The

predictor

satisfied

the

assumption

of

proportionality

as

the

graphs

of

the

survival

function

versus

the

survival

time

resulted

in

graphs

with

parallel

curves

as

did

the

graphs

of

the

log

-LRB-

log

-LRB-

survival

-RRB-

-RRB-

versus

log

of

survival

time

The

independent

prognostic

effect

of

SES

was

investigated

adjusting

for

age

and

stage

of

disease

and

stratified

according

to

period

of

diagnosis

-LRB-

-RRB-

We

also

calculated

the

age

and

stage-adjusted

effect

of

period

of

diagnosis

stratified

according

to

SES

Results

Median

age

was

similar

for

all

three

periods

of

diagnosis

-LRB-

and

years

respectively

-RRB-

Patients

diagnosed

between

and

had

a

significantly

more

favourable

stage

at

diagnosis

than

patients

diagnosed

in

earlier

periods

-LRB-

P

-RRB-

the

proportion

diagnosed

with

stage

I

-LRB-

tumour

smaller

than

cm

no

axillary

lymph

nodes

involved

-RRB-

increased

from

in

to

in

and

in

more

recent

years

-LRB-

Table

-RRB-

The

proportion

with

advanced

disease

i.e.

stage

III

or

IV

was

significantly

lower

in

the

most

recent

period

-LRB-

-RRB-

compared

to

-LRB-

-RRB-

and

-LRB-

P

-RRB-

Treatment

varied

over

time

with

a

large

proportion

receiving

systemic

therapy

in

recent

years

-LRB-

vs.

and

-RRB-

Table

of

all

women

age

years

diagnosed

with

invasive

breast

cancer

between

in

Southeastern

n

n

n

Treatment

S

S

RT

S

ST

alone261.7231.5231.3721.5Other583.8211.4130.7921.9Socio-economic

-LRB-

low

-RRB-

-LRB-

high

-RRB-

institution

S

Surgery

RT

Radiotherapy

ST

Systemic

therapy

#institution

care-providing

institution

such

as

a

nursing

home

The

proportion

of

patients

from

the

lowest

socio-economic

class

decreased

from

in

to

in

and

in

-LRB-

P

-RRB-

whereas

the

proportion

from

in

the

higher

social

classes

increased

Stage

distribution

improved

significantly

over

time

for

each

social

class

-LRB-

P

-RRB-

It

was

similar

for

all

SES

groups

in

-LRB-

P

Fig.

-RRB-

although

the

proportion

with

stage

IV

was

somewhat

lower

in

the

highest

classes

The

stage

distribution

was

marginally

more

favourable

for

high

SES

compared

to

the

lowest

SES

group

in

both

and

-LRB-

P

both

periods

-RRB-

although

the

overall

effect

of

SES

on

stage

was

not

significant

in

the

last

period

of

time

-LRB-

P

-RRB-

Fig.

distribution

according

to

socio-economic

status

and

period

of

diagnosis

of

patients

age

years

with

invasive

breast

cancer

in

Southeastern

Netherlands

Survival

improved

for

all

socio-economic

strata

over

time

-LRB-

Fig.

-RRB-

Survival

rates

did

not

differ

among

patients

from

each

of

the

socio-economic

classes

diagnosed

in

the

period

-LRB-

P

-RRB-

survival

rates

being

and

for

patients

from

the

lowest

to

the

highest

social

class

respectively

For

patients

diagnosed

in

survival

of

patients

with

a

high

SES

was

better

than

that

of

all

other

socio-economic

strata

-LRB-

P

-RRB-

survival

rates

being

and

respectively

For

patients

diagnosed

in

an

increasing

gradient

in

survival

was

observed

-LRB-

P

-RRB-

ranging

from

the

lowest

rates

for

the

lowest

SES

group

to

the

highest

for

the

higher

classes

-LRB-

and

respectively

-RRB-

Fig.

in

survival

according

to

socio-economic

status

for

all

women

age

years

diagnosed

with

invasive

breast

cancer

in

Southeastern

Netherlands

Multivariate

analysis

-LRB-

Table

-RRB-

showed

that

patients

diagnosed

between

and

from

the

lower

social

classes

had

a

higher

risk

of

death

compared

to

the

highest

socio-economic

group

after

adjusting

for

age

and

stage

at

diagnosis

-LRB-

HR

for

the

lowest

versus

the

highest

SES

group

CI

-RRB-

The

risk

of

death

for

low

SES

patients

diagnosed

since

was

twice

as

high

as

that

for

the

highest

SES

group

-LRB-

HR

CI

-RRB-

The

overall

effect

of

socio-economic

status

was

significant

in

the

last

period

-LRB-

P

-RRB-

Additional

adjustment

for

treatment

did

not

change

risk

estimates

more

than

-LRB-

data

not

shown

-RRB-

Table

regression

analysis

of

survival

of

breast

cancer

patients

age

years

according

to

period

of

diagnosis

Southeastern

HR

CIHR

CIHR

CIAge

-LRB-

continuous

-RRB-

-LRB-

low

-RRB-

-LRB-

high

-RRB-

Χ2

-LRB-

P

-RRB-

-LRB-

P

-RRB-

-LRB-

P

-RRB-

TNM

HR

Hazard

Ratio

CI

Confidence

IntervalaAdjusted

for

all

variables

listedbReference

Age

and

stage-adjusted

survival

improved

over

time

for

all

socioeconomic

strata

-LRB-

Table

-RRB-

the

largest

improvements

were

found

for

the

highest

social

classes

Table

regression

analysis

of

survival

according

to

socio-economic

status

-LRB-

SES

-RRB-

of

breast

cancer

patients

age

years

in

Southeastern

-LRB-

low

-RRB-

-LRB-

high

-RRB-

HR

CIHR

CIHR

CIHR

CIHR

CIPeriod

of

-LRB-

P

-RRB-

-LRB-

P

-RRB-

-LRB-

P

-RRB-

-LRB-

P

-RRB-

-LRB-

P

-RRB-

HR

Hazard

Ratio

CI

Confidence

IntervalaAdjusted

for

age

at

diagnosis

and

stage

of

diseasebReference

Discussion

We

found

that

the

proportion

of

breast

cancer

patients

with

a

low

SES

has

decreased

since

the

introduction

of

a

mass

biennial

mammography

screening

programme

with

high

response

rates

Although

stage

distribution

improved

for

all

socio-economic

groups

the

proportion

with

advanced

disease

decreased

the

most

in

the

highest

socio-economic

group

In

the

survival

was

similar

for

all

socio-economic

groups

but

since

the

introduction

of

screening

the

survival

of

women

with

a

high

SES

has

improved

more

than

that

for

low

socio-economic

classes

also

after

adjustment

for

age

and

stage

We

used

an

indicator

of

socio-economic

status

based

on

the

postal

code

of

a

residential

area

This

aggregate

covers

a

relatively

small

geographical

area

and

thus

represents

a

reliable

approximation

of

individual

socio-economic

status

Furthermore

routinely

collected

income

tax

data

-LRB-

no

questionnaires

or

interviews

-RRB-

have

been

found

to

provide

reliable

estimates

of

household

income

Previous

studies

have

proven

that

socio-economic

differences

based

on

neighbourhood

data

tend

to

reflect

socio-economic

differences

well

at

the

individual

level

-LSB-

-RSB-

Furthermore

this

objective

measure

of

SES

is

also

applicable

for

older

women

-LRB-

born

before

-RRB-

whose

occupation

or

education

does

not

always

properly

reflect

their

social

class

-LSB-

-RSB-

We

also

repeated

the

analyses

comparing

both

SES

indicators

if

they

were

applied

for

the

whole

study

period

-LRB-

-RRB-

to

ensure

any

that

effect

of

diagnostic

period

was

not

attributable

to

the

indicator

we

used

and

it

was

not

The

lower

proportion

of

patients

with

a

low

SES

since

the

introduction

of

screening

is

not

likely

to

reflect

the

higher

attendance

rate

of

women

from

a

higher

social

class

because

of

the

very

high

participation

rate

although

this

is

not

known

according

to

social

class

Studies

from

other

countries

have

shown

that

SES

does

play

a

role

in

participation

in

the

screening

programme

-LSB-

-RSB-

sometimes

-LSB-

-RSB-

but

not

always

-LSB-

-RSB-

due

to

the

costs

of

a

screening

mammogram

However

the

costs

for

the

mass

screening

programme

in

the

Netherlands

are

completely

covered

by

public

funds

Furthermore

the

mean

attendance

rate

in

the

Netherlands

has

always

been

rather

high

-LRB-

about

-RRB-

-LSB-

-RSB-

and

in

our

study

area

even

higher

than

the

national

mean

-LRB-

in

-RRB-

-LSB-

-RSB-

Foreign-born

women

are

more

likely

to

be

non-attenders

in

the

Netherlands

-LSB-

-RSB-

as

well

as

in

Sweden

-LSB-

-RSB-

Australia

-LSB-

-RSB-

and

the

US

-LSB-

-RSB-

for

a

variety

of

reasons

However

the

incidence

of

breast

cancer

among

these

groups

of

migrants

is

relatively

low

in

the

Netherlands

and

the

stage

distribution

is

comparable

to

that

of

women

born

in

the

Netherlands

-LSB-

-RSB-

So

this

is

unlikely

to

have

affected

survival

rates

in

our

study

A

lower

attendance

rate

of

low

social

classes

will

result

in

more

advanced

disease

stages

at

presentation

-LSB-

-RSB-

Before

the

start

of

the

mammography

screening

programme

we

found

that

the

stage

distribution

for

breast

cancers

diagnosed

in

was

slightly

more

favourable

for

the

highest

socio-economic

group

-LSB-

-RSB-

We

have

now

shown

that

this

was

also

true

after

the

introduction

of

screening

although

the

differences

were

small

In

fact

we

found

that

although

stage

distribution

became

more

favourable

for

all

socio-economic

groups

the

proportion

with

advanced

disease

decreased

less

in

the

lower

socio-economic

group

This

differential

stage

distribution

was

also

described

in

a

recent

Danish

study

-LSB-

-RSB-

although

our

differences

were

smaller

The

variation

in

survival

according

to

SES

may

also

be

related

to

differences

in

treatment

which

depends

on

the

disease

stage

and

varies

over

time

The

use

of

surgery

and

radiotherapy

was

similar

across

SES

groups

However

we

found

that

the

administration

of

adjuvant

chemotherapy

varied

across

the

social

strata

among

stage

II

patients

-LRB-

of

the

lowest

SES

group

versus

of

the

highest

SES

group

P

-RRB-

Patients

with

a

higher

SES

seem

to

have

benefited

more

from

the

general

trend

towards

more

adjuvant

chemotherapy

independent

of

the

disease

stage

This

may

explain

at

least

in

part

the

diverging

trend

in

survival

rates

Another

explanation

for

differential

survival

could

be

socio-economic

variations

in

lifestyle

Smoking

has

become

relatively

more

prevalent

among

low

SES

groups

-LSB-

-RSB-

This

may

have

had

an

adverse

effect

on

survival

due

to

a

poor

general

health

while

undergoing

breast

cancer

treatment

or

to

smoking

related

diseases

-LRB-

such

as

chronic

obstructive

pulmonary

diseases

-LRB-

COPD

-RRB-

or

cardiovascular

disease

-RRB-

Also

related

to

an

unhealthy

lifestyle

is

obesity

which

has

become

an

increasingly

important

problem

in

the

last

decade

-LSB-

-RSB-

especially

among

women

from

the

lower

social

classes

-LSB-

-RSB-

Serious

concomitant

diseases

besides

breast

cancer

also

affect

survival

rates

-LSB-

-RSB-

which

may

explain

differences

in

survival

if

comorbidity

occurs

more

frequently

in

low

SES

groups

Since

the

Eindhoven

Cancer

Registry

has

recorded

comorbidity

for

all

newly

diagnosed

patients

since

we

checked

whether

the

prevalence

varied

across

socioeconomic

strata

Indeed

the

proportion

of

patients

with

comorbidity

was

higher

among

those

with

a

lower

SES

-LRB-

of

patients

in

the

lowest

SES

group

had

one

or

more

concomitant

conditions

compared

to

of

the

high

SES

group

-RRB-

In

particular

the

prevalence

of

diabetes

and

cardiovascular

disease

was

highest

in

the

low

SES

groups

-LRB-

diabetes

in

with

low

SES

and

with

high

SES

cardiovascular

disease

and

respectively

-RRB-

Several

studies

have

reported

increased

survival

rates

after

the

introduction

of

breast

cancer

screening

As

far

as

we

know

no

studies

describe

a

differential

effect

of

the

introduction

of

screening

on

survival

rates

for

socio-economic

strata

However

socioeconomic

inequalities

in

mortality

have

been

widening

in

recent

decades

in

western

European

countries

-LSB-

-RSB-

In

fact

socio-economic

differences

in

breast

cancer

mortality

increased

between

and

among

women

in

Finland

and

Italy

-LRB-

Turin

-RRB-

but

remained

stable

in

Denmark

and

decreased

somewhat

in

Norway

where

a

mass

screening

programme

was

only

introduced

later

-LSB-

-RSB-

In

conclusion

despite

a

very

high

participation

rate

women

from

lower

socio-economic

strata

clearly

benefited

less

from

the

introduction

of

the

breast

cancer

screening

programme

than

those

with

a

lower

SES

probably

due

to

a

higher

prevalence

of

comorbidity

and

suboptimal

treatment

-LRB-

for

both

the

cancer

and

the

concomitant

disease

-RRB-

O O O O O O O O O B I O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


The association of heart rate recovery immediately after exercise with coronary artery calcium : the coronary artery risk development in young adults study We tested whether slower heart rate recovery -LRB- HRR -RRB- following graded exercise treadmill testing -LRB- GXT -RRB- was associated with the presence of coronary artery calcium -LRB- CAC -RRB- . Participants -LRB- n = 2,648 -RRB- ages 18 -- 30 years at baseline examination underwent GXT , followed by CAC screening 15 years later . Slow HRR was not associated with higher odds of testing positive -LRB- yes/no -RRB- for CAC at year 15 -LRB- OR = 0.99 , p = 0.91 per standard deviation change in HRR -RRB- . Slow HRR in young adulthood is not associated with the presence of CAC at middle age . Introduction The prognostic value of slow heart rate recovery -LRB- HRR -RRB- after exercise in predicting cardiovascular disease -LRB- CVD -RRB- events has been established -LSB- 5 , 11 , 12 , 13 , 15 -RSB- . Initial increases in heart rate with exercise are due to parasympathetic withdrawal while sympathetic activation is responsible for heart rates greater than a 100 beats/minute . In the first two minutes following cessation of exercise , the rapid decrease in heart rate is principally determined by parasympathetic reactivation -LSB- 1 , 8 -RSB- . Although slow HRR is associated with less autonomic nervous system responsiveness , the underlying mechanisms linking slow HRR to increased cardiovascular morbidity are not well understood . It is possible that slow HRR is associated with a higher susceptibility for atherosclerosis . Prior studies of patients referred for cardiac angiography for suspected ischemic heart disease -LRB- IHD -RRB- suggest an association between slow HRR and higher atherosclerotic burden -LSB- 15 -RSB- . Further , slow HRR has been observed to be associated with several risk factors for atherosclerosis -LSB- 2 , 3 , 10 -RSB- . However , the relationship between HRR and atherosclerosis in the general population has not been studied using a prospective study design . In a cohort of healthy young adults , we investigated whether slow HRR following a graded exercise treadmill test -LRB- GXT -RRB- was associated with the presence of coronary artery calcium -LRB- CAC -RRB- , a marker of subclinical atherosclerosis , when assessed 15 years later . Methods and statistical analysis The Coronary Artery Risk Development in Young Adults study -LRB- CARDIA -RRB- is a longitudinal study designed to investigate the origins of cardiovascular disease in young adulthood -LSB- 6 -RSB- . Beginning in 1985 , 5,115 African-American and Caucasian individuals -LSB- -LRB- African-American -LRB- 52 % -RRB- and women -LRB- 54 % -RRB- -RSB- ages 18 -- 30 were recruited at sites in Birmingham , Alabama ; Chicago , Illinois ; Minneapolis , Minnesota ; and Oakland , California . All participants gave informed consents prior to enrollment . At baseline , a symptom-limited maximal GXT was administered using the Balke protocol -LSB- 14 -RSB- . The test included nine 2-minute stages of increasing difficulty with participants encouraged to exercise to exhaustion , followed by a recovery period at a speed of 3.2 km/hour at 0 % grade . HRR was defined as the difference between the maximum HR and HR at 2-minutes into recovery -LSB- 10 -RSB- . Participants were ineligible for exercise testing if they were on cardioactive medications , had a resting systolic or diastolic pressure > 160 or > 100 mmHg , or were febrile at time of examination . The rate of energy expenditure for the completion GXT was estimated and reported in metabolic equivalents -LRB- METs -RRB- , as previously described -LSB- 14 -RSB- . Information on physical activity was collected by interview using a standardized questionnaire . At the year 15 follow-up examination , returning participants -LRB- n = 3,043 -RRB- underwent coronary artery computed tomography -LRB- CT -RRB- scanning for the measurement of CAC . Mean HRR did not differ between those who did and did not return to the year 15 examination -LRB- 42.8 versus 42.5 bpm , respectively ; p = 0.55 -RRB- . Details of the scanning procedures have been described elsewhere -LSB- 4 -RSB- . Briefly , using standardized protocols , two scans were obtained for each participant -LRB- 1 -- 2 minutes apart -RRB- using electron beam CT scanners at the Chicago and Oakland sites and multidetector-row CT scanners at the Birmingham and Minneapolis sites . Calcium scores were calculated across each coronary artery and then summed across all the arteries . The final CAC score of positive scans was calculated as the mean of the two CAC scores obtained from each of the scans . Participants were sequentially excluded from this analysis for the following reasons : use of medications that affect heart rate -LRB- HR -RRB- -LRB- n = 27 -RRB- , unavailable GXT or CAC data -LRB- n = 661 -RRB- , missing data on blood pressure , lipids , glucose , or smoking -LRB- n = 353 -RRB- , pregnancy -LRB- n = 27 -RRB- or those absent at the year 15 exam -LRB- n = 1,399 -RRB- . Following exclusions , 2,648 participants remained . Baseline characteristics were compared across sex-specific HRR tertiles . For continuous variables , test for linear trend was performed with HRR as a continuous variable using linear regression models . The Cochran-Armitage test was used to check for linear trend in binomial proportions across the HRR categories . Next , logistic regression was used to estimate the odds of the presence of CAC -LRB- defined as a CAC score > 0 -RRB- in relation to year 0 HRR -LRB- independent variable -RRB- . HRR was modeled both as a continuous variable and in tertiles -LRB- fastest HRR tertile as the reference -RRB- . Statistical significance was determined at P < 0.05 . All analyses were conducted using SAS version 9.1 -LRB- SAS Institute Inc , Cary , NC -RRB- . Results Demographic characteristics of the study sample , by 2-minute HRR tertiles , are presented in Table 1 . Mean 2-minute HRR -LRB- standard deviation -RRB- for men and women were 44.3 -LRB- 11.4 -RRB- and 41.7 -LRB- 11.5 -RRB- bpm , respectively . Participants with slower HRR had less favorable GXT performance characteristics , a higher resting heart rate -LRB- both at year 0 and year 15 -RRB- and reported less physically activity -LRB- both at year 0 and year 15 -RRB- . Table 1Baseline characteristics according to tertiles of 2-minute heart rate recovery -LRB- N = 2,648 -RRB- aBaselineBaseline sex-specific HRR tertiles1 -LRB- slow -RRB- 23 -LRB- fast -RRB- P trendNumber of women479463521NANumber of men392391402NAHRR -LRB- median -LSB- min , max -RSB- -RRB- Women31 .0 -LRB- 1.0 , 36.0 -RRB- 41.0 -LRB- 37.0 , 45.0 -RRB- 51.0 -LRB- 46.0 , 116.0 -RRB- NAMen34 .0 -LRB- − 6.0 , 39.0 -RRB- 44.0 -LRB- 40.0 , 48.0 -RRB- 54.0 -LRB- 49.0 , 97.0 -RRB- NAAge -LRB- years -RRB- 25.4 -LRB- 3.5 -RRB- 25.1 -LRB- 3.6 -RRB- 25.0 -LRB- 3.6 -RRB- 0.003African-American , N -LRB- % -RRB- 360 -LRB- 41.3 -RRB- 383 -LRB- 44.9 -RRB- 435 -LRB- 47.1 -RRB- 0.014 Body Mass Index kg/m224 .9 -LRB- 5.2 -RRB- 24.1 -LRB- 4.2 -RRB- 23.8 -LRB- 4.0 -RRB- < 0.001 Resting heart rate -LRB- bpm -RRB- at year 071.5 -LRB- 11.4 -RRB- 69.3 -LRB- 10.2 -RRB- 66.1 -LRB- 9.7 -RRB- < 0.001 Resting heart rate -LRB- bpm -RRB- at year 1568.3 -LRB- 10.8 -RRB- 68.2 -LRB- 12.1 -RRB- 66.5 -LRB- 11.3 -RRB- < 0.001 Maximum heart rate -LRB- bpm -RRB- 180.1 -LRB- 15.8 -RRB- 180.0 -LRB- 14.6 -RRB- 181.0 -LRB- 13.9 -RRB- 0.001 Estimated METs at peak exercise11 .8 -LRB- 3.0 -RRB- 12.1 -LRB- 2.7 -RRB- 12.5 -LRB- 2.7 -RRB- < 0.001 Total physical activity score -LRB- exercise units -RRB- at year 0375.8 -LRB- 273.0 -RRB- 428.6 -LRB- 317.5 -RRB- 459.7 -LRB- 307.3 -RRB- < 0.001 Total physical activity score -LRB- exercise units -RRB- at year 15325.4 -LRB- 278.1 -RRB- 346.9 -LRB- 288.0 -RRB- 382.4 -LRB- 296.6 -RRB- < 0.001 aValues are expressed as mean -LRB- standard deviation -RRB- unless otherwise indicated . HRR = heart rate recovery . NA = not applicable . METs = metabolic equivalents The prevalence of CAC in the study sample was 9.0 % -LRB- n = 239 -RRB- . Mean HRR at year 0 did not differ between those who had positive CAC scores versus those who had a CAC score of 0 at year 15 -LRB- 42.8 bpm , for both -RRB- . The unadjusted odds ratio -LRB- OR -RRB- for having a CAC score > 0 for those in the slowest HRR tertile compared to those in the fastest HRR tertile was not significantly greater than 1.00 -LRB- Table 2 -RRB- . Similar findings were observed when HRR was studied as a continuous variable . Table 2Unadjusted odds ratio -LRB- 95 % confidence interval -RRB- for the presence of coronary artery calcium -LRB- score > 0 -RRB- at year 15 by baseline 2-minute heart rate recoveryTotal sampleCaucasian menCaucasian womenAfrican-American menAfrican-American womenOdds Ratio -LRB- 95 % CI -RRB- for threshold models based on HRR tertilesTertile 1 -LRB- slow -RRB- 1.13 -LRB- 0.81 -- 1.57 -RRB- 0.90 -LRB- 0.54 -- 1.50 -RRB- 1.12 -LRB- 0.53 -- 2.33 -RRB- 1.11 -LRB- 0.52 -- 2.36 -RRB- 1.44 -LRB- 0.60 -- 3.49 -RRB- Tertile 21.20 -LRB- 0.87 -- 1.66 -RRB- 0.90 -LRB- 0.54 -- 1.50 -RRB- 0.90 -LRB- 0.41 -- 2.01 -RRB- 1.55 -LRB- 0.78 -- 3.09 -RRB- 1.37 -LRB- 0.57 -- 3.32 -RRB- Tertile 3 -LRB- fast -RRB- 1.00 -LRB- Ref -RRB- 1.00 -LRB- Ref -RRB- 1.00 -LRB- Ref -RRB- 1.00 -LRB- Ref -RRB- 1.00 -LRB- Ref -RRB- Odds Ratio -LRB- 95 % CI -RRB- for HRR as continuous variablePer SD change in HRRa0 .99 -LRB- 0.87 -- 1.13 -RRB- 1.04 -LRB- 0.84 -- 1.28 -RRB- 0.86 -LRB- 0.65 -- 1.15 -RRB- 0.95 -LRB- 0.70 -- 1.30 -RRB- 0.88 -LRB- 0.60 -- 1.27 -RRB- HRR = heart rate recovery . CAC = coronary artery calcium . CI = confidence interval . SD = standard deviation aSD of HRR was 11.5 bpm In secondary analysis , similar findings were observed when the presence of higher CAC burden -LRB- defined as a score > 100 -LSB- n = 34 -RSB- -RRB- was studied , as well as when quartiles or quintiles of 2-minute HRR were analyzed . Lastly defining HRR at 1-minute into recovery also did not result in any association between HRR and CAC . Conclusion Slower HRR in young adulthood is not associated with the presence of CAC when assessed 15 years later in middle age -LRB- average age 40 years -RRB- . Moreover , mean HRR at baseline did not differ between those with and without measurable CAC at year 15 . While previous studies have examined the relationship of HRR with CAD events this study is first to investigate the relationship of HRR with a measure of subclinical atherosclerosis . Slow HRR has been associated with higher incident all-cause mortality , sudden cardiac death -LRB- SCD -RRB- , and CVD events ; however , the underlying mechanisms that link these relationships together are not known -LSB- 5 -RSB- . Morshedi-Meibodi et al. -LSB- 12 -RSB- using data from the Framingham Heart Study -LRB- FHS -RRB- observed slow HRR to be associated with coronary heart disease events -LRB- defined as acute coronary syndromes or SCD -RRB- , suggesting a possible relationship between slow HRR and ischemic processes . Similarly , slow HRR has been observed to be associated with several risk factors for atherosclerosis -LSB- 2 , 3 , 10 -RSB- . In contrast to findings from the FHS , Jouven et al. -LSB- 9 -RSB- observed slow HRR to be related only to SCD and not death from myocardial infarction . Due to over lapping and discrepancy in clinical end points used in prior HRR studies , it can not be determined whether slow HRR is associated with atherosclerosis or an increased susceptibility to lethal cardiac arrhythmias . The ability of coronary CT to assess the global burden of atherosclerosis in young adults is uncertain , and CAC is only a subset of atherosclerosis , representing calcified plaques which tend to be more stable than their lipid-rich counterparts -LSB- 7 -RSB- . Despite these limitations , our study suggests that slow HRR in young adulthood is not related to subclinical atherosclerosis at middle age , which supports the hypothesis that slow HRR is associated with mechanisms related to cardiac arrhythmia rather than atherosclerosis .

O O O B I O O O O O B I I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O

sudden cardiac death
atherosclerosis
heart rate
autonomic nervous system
coronary artery calcium


Antioxidant intervention in rheumatoid arthritis : results of an open pilot study There is evidence that reactive oxygen species play a causal role in auto-immune diseases , such as rheumatoid arthritis -LRB- RA -RRB- . Despite the supporting evidence for a beneficial effect of antioxidants on clinical characteristics of RA , the right balance for optimal effectiveness of antioxidants is largely unknown . To determine the potential beneficial effects of an antioxidant intervention on clinical parameters for RA , an open pilot study was designed . Eight non-smoking female patients with rheumatoid factor + RA and a Disease Activity Score -LRB- DAS 28 -RRB- higher than 2.5 were enrolled in the study . Patients had to be receiving stable non-steroidal anti-inflammatory drug treatment and/or ` second line ' medication for at least 3 months . The pilot group consumed 20 g of antioxidant-enriched spread daily during a period of 10 weeks . The intervention was stopped after 10 weeks and was followed by a ` wash-out ' period of 4 weeks . At t = 0 , t = 10 weeks and t = 14 weeks , patients ' condition was assessed by means of DAS . In addition , standard laboratory analyses were performed , and blood-samples for antioxidants were taken . The antioxidant-enriched spread was well tolerated . All laboratory measures of inflammatory activity and oxidative modification were generally unchanged . However , the number of swollen and painful joints were significantly decreased and general health significantly increased , as reflected by a significantly improved -LRB- 1.6 -RRB- DAS at t = 10 weeks . The antioxidant effect was considered beneficial as , compared to the scores at t = 0 , the DAS significantly reduced at t = 10 weeks . Increase of the DAS -LRB- 0.7 -RRB- after the `` wash-out period '' at t = 14 confirmed a causal relation between changes in clinical condition and antioxidants . This open pilot study aimed to assess the clinical relevance of an antioxidant intervention as a first step in assessing potential beneficial effects of antioxidants on rheumatoid arthritis . These conclusions need to be validated in a larger controlled study population . Introduction In spite of the great advances that have been made in the development of new drugs for the treatment of patients with rheumatoid arthritis -LRB- RA -RRB- , many patients are interested in alternative treatments like dietary therapy . Although the aetiology of rheumatoid arthritis is still unknown , the inflammation resulting from the immunological reaction is quite well described . It is known that neutrophil granulocytes , macrophages and lymphocytes are activated , and that reactive oxygen and nitrogen species -LRB- RS -RRB- are produced -LSB- 1 , 2 -RSB- . These RS can react with lipid , protein and nucleic acids and are thought to be of importance for the aetiology and chronicity of the inflammatory rheumatic diseases -LSB- 3 , 4 -RSB- . One approach to counteract this oxidative stress situation is the use of antioxidants as therapeutic agents . There is some evidence for a positive effect of antioxidants on clinical symptoms of RA -LSB- 5 , 6 -RSB- . However , this evidence is weak , and information about the most effective antioxidants , antioxidant doses or combinations is lacking The intervention studies that have been conducted have tested vitamin E exclusively -LSB- 6 , 7 -RSB- . Against this background , an open -LRB- uncontrolled -RRB- pilot study was designed to assess if effects of antioxidants on the clinical parameters of patients with RA could be confirmed and if these effects would associate with changes in a selected number of molecular markers related to human antioxidant defence system status . Further , a mix of antioxidants was to be tested rather than a single high-dosed compound . Materials and methods The open study was approved by the ethical committee . Eight patients with rheumatoid factor + RA , as defined by the ARA revised criteria were enrolled in the study . To avoid influences of gender , only female patients participated . Inflammatory disease activity was defined as a Disease Activity Score -LRB- DAS -RRB- higher than 2.5 . Inclusion criteria included non-smoking and no serious co-morbidity . Patients had to be receiving stable non-steroidal anti-inflammatory drug -LRB- NSAID -RRB- treatment and/or ` second line ' medication for at least 3 months . Those taking antioxidant supplements were excluded from the study . During a period of 10 weeks , patients consumed 20 g of antioxidant-enriched margarine daily . The spread contained a mix of a-tocopherol -LRB- 400 mg -RRB- , lycopene -LRB- 10 mg -RRB- , palm oil carotenoids -LRB- 5 mg ; mainly α-carotene -RRB- and lutein -LRB- 10 mg -RRB- . Further , patients received vitamin C -LRB- 200 mg daily -RRB- as a supplement . The intervention of 10 weeks was followed by a ` wash-out ' period of 4 weeks . At t = 0 , t = 5 weeks , t = 10 weeks and t = 14 weeks , patients ' condition was assessed by means of morning stiffness , visual analogue scale pain , general health score and DAS 28-score -LRB- including the following parameters : pain , swelling of joints , erythrocyte sedimentation rate -LRB- ESR -RRB- , general feeling of well-being -RRB- . At t = 0 , t = 10 weeks and at t = 14 weeks , blood was collected , and standard clinical laboratory analyses -LRB- ESR , C-reactive protein , hemoglobin , leucocytes , thrombocytes , serum values of creatinine and transaminases -RRB- were performed . In addition , blood antioxidant status and markers of antioxidant capacity -LSB- ferric reducing ability of plasma -LRB- FRAP -RRB- -RSB- and oxidative stress -LRB- 8-epi F2-isoprostane -RRB- levels were determined . Determination of vitamin A , not present in the spread , was used as a control . Serum was collected immediately after blood sampling and stored in liquid nitrogen . The potential antioxidant effect was defined as beneficial if the DAS score would significantly improve > 1.2 at t = 10 weeks as compared to the scores at t = 0 . At t = 14 weeks , a ` wash-out '' effect was assessed using the same parameters . Return of the clinical condition of the pilot group to that at t = 0 may indicate a causal relation between changes in clinical condition and antioxidant intake , although a placebo-controlled intervention would be better required for this assessment . Statistical analyses were done using a paired t test . Results The antioxidant-enriched spread was well tolerated . None of the patients withdrew from the study because of adverse reactions . The number of swollen and painful joints were significantly decreased , and general health significantly increased at t = 10 weeks . This was shown by a significantly decreased DAS -LRB- − 1.6 -RRB- at 10 weeks . After the `` wash-out period '' , the DAS score was increased again by 0.6 -LRB- Figs. 1 and 2 -RRB- . Fig. 1Clinical condition by Disease Activity ScoreFig . 2Mean Disease Activity Score The standard laboratory measures of inflammatory activity were relatively unchanged . Levels of plasma vitamin E , lutein , lycopene and alpha-carotene were significantly increased at 10 weeks . No significant changes were seen in vitamin A and vitamin C levels -LRB- Fig. 3 -RRB- . Fig. 3Plasma antioxidant status in eight patients Markers of antioxidant capacity and oxidative stress displayed trends for differences , but none of these reached statistical significance -LRB- Fig. 4 -RRB- . Fig. 4Markers of antioxidant capacity and oxidative stress Discussion This pilot study was conducted to obtain some first indications for potential beneficial effects of an antioxidant intervention on clinically relevant parameters for rheumatoid arthritis . In our present study , a significant reduction in Disease Activity Score -LRB- DAS -RRB- was observed following antioxidant intervention of 10 weeks . This was accompanied by significant increases in blood levels of antioxidants administered . The reduction of DAS is remarkable as all patients had an active -LRB- high initial mean DAS of 5.8 -RRB- longstanding disease and had tried all kinds of disease-modifying anti-rheumatic drugs , including combination therapy . The unchanged level of vitamin A , not present in the spread , reinforces the significance of the increased levels of the blood antioxidant status . As NSAIDs can influence the absorption of vitamin C , this could explain the non-significant changes of the serum concentration of this antioxidant . A limited number of clinical intervention studies is available which support the therapeutic or prophylactic activity of antioxidants in the pathogenesis of RA . These studies were all conducted with an oral intake of 1,200 mg/day of vitamin E. Edmonds et al. -LSB- 6 -RSB- reported that the antioxidant a-tocopherol significantly reduced pain parameters in a placebo-controlled double-blind trial following a 3-week supplementation period . Results from a randomised double-blind parallel group comparison study with a-tocopherol and diclophenac showed that the clinical parameters assessed , e.g. morning stiffness , Ritchie joint index , grip strength and pain , were significantly reduced by vitamin E , with similar effectivity and less side effects as compared to regular drug therapy by diclofenac -LSB- 7 -RSB- . Results from other intervention studies have generally been in line with these observations -LSB- 8 , 9 -RSB- . In our study , not only the effect of vitamin E on the inflammatory response and clinical symptoms was evaluated but also the interactions with bioavailable natural antioxidants such as carotenoids , vitamin C and others . In view of the limited number of controlled studies , the supporting evidence for beneficial effects of antioxidants on clinical characteristics of rheumatoid arthritis may be considered limited but promising . Another point is that the potential mechanism of action of antioxidants in rheumatoid arthritis needs further attention . The aspect of damage by RS and loss of critical functions can be analysed by use of ` molecular markers ' . These markers may include antioxidant status , products which arise as a consequence of oxidative damage to lipid , protein and DNA and tissue damage -LRB- as assessed by lactic dehydrogenase release -RRB- or cytokine levels -LRB- cq anti-TNFα -RRB- . Although markers are very informative from a mechanistic point of view , a drawback is that none of them has been validated against clinical conditions of patients with RA . In this study , a trend for reduced levels of measures of antioxidant capacity and of ` footprints ' of oxidative stress was observed , e.g. statistically non-significant increase in FRAP and reduction in F2-isoprostane levels . Furthermore , these markers showed a trend for correlation with clinical conditions . The data indicate that statistically significant effects may be observed when the number of patients enrolled is increased . This open pilot study therefore should be viewed as a first step in assessing potential beneficial effects of the antioxidants tested on rheumatoid arthritis . The data indicate there may be potential in using mixes of antioxidants in the treatment of RA alongside drug treatment so that drug dosage may be reduced while hopefully retaining efficacy . Further , multi-drug/antioxidant therapy could be used to reduce drug dose and thus side effects of treatment . In conclusion , our present pilot study indicated that intervention with antioxidant-enriched margarine in RA results in consistent and significant relief of clinical symptoms . Furthermore , increases in blood antioxidant status and indications for effects on oxidative stress markers were observed . These data are promising and indicate need for a double-blind , placebo-controlled randomised human trial to establish effect and demonstrate causality .

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antioxidants
clinical parameters
intervention
rheumatoid arthritis