Studies not in English, abstracts or session presentations Number of included studies: 13 Kim et al. () USA NHMRC Level I AMSTAR: 18% (2/11) Poor quality To discuss the evidence of CMR-derived myocardial scar for the prediction of adverse cardiovascular outcomes in NICM Adult patients with NICM (mostly DCM) Search period: Not reported Databases searched: Not reported Inclusion criteria: Studies evaluating the relationship of myocardial scar and outcomes in NICM Exclusion criteria: None reported Number of included studies: 15 Major cardiovascular events: all-cause mortality arrhythmia events Kuruvilla et al. () USA NHMRC Level I AMSTAR: 55% (6/11) Moderate quality To evaluate the prognostic role of LGE-CMR imaging in patients with NICM Adult patients with NICM (mostly DCM) Search period: Search was conducted in August 2013. Databases searched: PubMed, Cochrane CENTRAL and EMBASE Inclusion criteria: Studies evaluating myocardial fibrosis in patients with NICM using LGE-CMR and inclusion of hard end points Exclusion criteria: Studies that evaluated ICM, acute myocarditis, and HCM and infiltrative CM (including cardiac amyloidosis), and abstracts Number of included studies: 9 Major cardiovascular events: all-cause mortality hospitalisation for HF composite endpoint of SCD, aborted SCD or appropriate ICD therapy Scott et al. NHMRC Level I To better gauge the predictive accuracy of Search period: Arrhythmic endpoints:
Canada NHMRC level II SIGN: acceptable quality with a moderate risk of bias n=70 (22%) LGE– Patient characteristics: age = 62.0 ± 12.9 years; male = 73%; QRS interval = 131.9 ± 31.5 milliseconds; LBBB = 40%; LVEF (CMR) = 32.6 ± 11.9%; history of VA = 11%, ICM = 47%; NYHA class III–IV = 46%; medications: ACE inhibitor = 59%, ARB = 22%, -blockers = 77% n=169 (53%) had NICM n=50 (30%) LGE+ n=119 (70%) LGE– Median follow-up: 467 (IQR 16–1,422) days studied. Systolic dysfunction was defined as an LVEF ≤55% because this value corresponds to the lower limit of the 95%CI in healthy subject. Exclusion criteria: patients clinically suspected to have HCM, restrictive CM (sarcoidosis or amyloidosis), or arrhythmogenic right ventricular CM. Patients were also excluded if standard contraindications to LGE-CMR existed, inclusive of a GFR of ≤30 mL/min/1.73 m2 intervals using a standard SSFP-based cine pulse sequence LGE sequence: phase-sensitive inversion recovery gradient-echo pulse sequence Contrast agent: mmol/kg; Gadovist Time delay: 10–15 minutes LV function: Cine images were examined to determine LV and right ventricular end-systolic volumes and end-diastolic volumes, in addition to LV mass by semi-automated endocardial and epicardial contour tracing. LGE diagnosis: The scoring of all LGE fibrosis patterns was as follows: 1) subendocardial 2) mid-wall striae 3) mid-wall patchy 4) subepicardial 5) right ventricular insertion point 6) diffuse. SCA or appropriate ICD discharge hospitalisation for severe HF non–SCD in LGE+ patients compared with those that are LGE– Buss et al. () Prospective cohort N=210 consecutive patients with DCM Inclusion criteria: consecutive patients with Scanner: 1.5-T scanner with a cardiac phased array receiver coil ICD implantation: Not described
risk of bias male = 71%; median LVEF (CMR) = 39% (IQR 26, 52); CHF = 56% N=215 patients without CAD: n=38 (18%) LGE+ n=177 (82%) LGE– Patient characteristics: age = 51.3 ± 16.0 years; male = 57%; median LVEF (CMR) = 52% (IQR 33, 60); CHF = 33% Median follow-up: 4.4 years LGE sequence: prepared, T1-weighted, gradient-echo sequence Contrast agent: gadolinium chelate, 0.2 mmol/kg Time delay: 15 minutes LV function: Endocardial and epicardial contours were prescribed manually on the series of short-axis cine slices of the LV at end diastole and end systole to obtain end-diastolic volume, volume, LVEF and LV mass. LGE diagnosis: The scoring system used on the LGE data: 1 = no LGE 2 =1–25% LGE (thin subendocardial scar) 3 = 26–50% LGE (dense subendocardial scar) 4 = 51–75% LGE scar) 5 = 76–100% LGE (transmural scar) that are LGE– Chimura et al. () Retrospective cohort N=175 NICM patients with HF who had an LVEF <35% Inclusion criteria: NICM patients who had an LVEF Scanner: 1.5-T scanner with a standardised protocol ICD implantation: ICD implantations were undertaken using standard
Japan NHMRC level SIGN: high quality with a low risk of bias without sustained VT: n=122 (70%) LGE+ n=53 (30%) LGE– n=7 patients received an ICD n=17 patients received a CRT-D Patient characteristics: age = 60 ± 15 years; male = 63%; QRS interval = 121 ± 31 milliseconds; LBBB = 33%; LVEF (Echo) = 29 ± 5.4%; presence of AF = 17%; documentation of VT = 5%; NYHA class: II = 31%, III = 69%; medications: ACE inhibitor/ARB = 95%, = 94% Mean follow-up: 5.1 ± 3.3 years <35% and NYHA class II or III without sustained VT, who were referred with HF at their initial visit between January 2005 and June 2014 Exclusion criteria: contraindications to CMR existed, including significant renal dysfunction (GFR of ≤30 mL/min/1.73 m2) and implanted devices such as pacemakers and/or defibrillators Cardiac function sequence: Cine images were acquired with a steady-state, free-precession sequence in long-axis planes and contiguous short-axis slices. LGE sequence: gradient-echo sequence Contrast agent: 0.1 mmol/kg Time delay: 10 minutes LV function: Details not reported LGE diagnosis: The presence or absence of LGE was visually determined by 2 independent blinded readers and divided into 6 groups according to the LGE pattern: 1) septal subendocardial 2) lateral subendocardial 3) septal mid-wall, 4) lateral mid-wall 5) septal subepicardial 6) lateral subepicardial 7) papillary muscle pattern. techniques at a median of 16 days following the CMR. The ICD devices were programmed to detect VF and VT. Outcomes: HR for likelihood of having: ICD implantation appropriate ICD therapy life-threatening arrhythmic events in LGE+ patients compared with those that are LGE– Cho et al. () Prospective N=79 patients with Inclusion criteria: patients with ECG-proven LV systolic Scanner: Gyroscan Intera system ICD implantation: Presence or
SIGN: high quality with a low risk of bias male = 81%; QRS interval = 136 ± 30 milliseconds; LBBB = 44%; LVEF (CMR) = 26 ± 7%; ICM = 48%; primary prevention ICD = 56%; secondary prevention ICD = 8%; CRT-D implantation = 36%; NYHA class = 2.5 ± 0.9; medications: ACE inhibitor = 71%, ARB = 25%, -blockers = 80% N=59 patients with ICM: all LGE+ N=65 patients with NIDCM: n=46 (71%) LGE+ n=19 (29%) LGE– Mean follow-up: 632 ± 262 days ≥3 months. Prior to enrolment all patients underwent ICA or CTCA to determine CM aetiology. Exclusion criteria: standard contraindications to inclusive of a GFR of ≤30 mL/min/1.73 m2 pulse sequence LGE sequence: standard, segmented inversion recovery gradient-echo pulse sequence Contrast agent: mmol/kg Gadovist Time delay: 10–15 minutes LV function: Cine images were examined to determine the LV end-systolic volume, LV volume and LV mass by semi-automated endocardial and epicardial contour tracing. LGE diagnosis: The presence or absence of any LGE was visually determined by an experienced blinded CMR interpreter, and the most dominant pattern scored: 1) subendocardial based 2) mid-wall 3) subepicardial. HR for likelihood of having: SCD or survived SCA appropriate ICD discharge non-SCD cardiac death in LGE+ patients compared with those that are LGE– HR for likelihood of having: SCD or survived SCA appropriate ICD discharge cardiac death (not SCD) in NIDCM patients compared with ICM patients Gulati et al. () Prospective cohort N=472 consecutive patients with DCM confirmed by CMR Inclusion criteria: patients with DCM of at least 6 months’ duration and Scanner: 1.5-T scanner and a standardised protocol ICD implantation: Not described Outcomes:
history of sustained VT = 18%; CRT-D implantation = 2%; NYHA class III–IV = 68%; medications: ACE inhibitor/ARB = 91%, = 95% Mean follow up: 3.2 years LGE diagnosis: Not reported Looi et al. () New Zealand Prospective cohort NHMRC level II SIGN: unacceptable quality with a high risk of bias N=103 patients with DCM who had a clinical presentation of HF and an ECG demonstrating LVEF <50%: n=31 (30%) LGE+ n=72 (70%) LGE– Patient characteristics: age = 58 ± 13 years; male = 76%; LVEF (CMR) = 32 ± 12%; NYHA class: I = 75%, II = 18%, III = 4% Mean follow-up: 660 ± 346 days Inclusion criteria: Patients with DCM, prospectively identified between 1 December 2003 and 31 August 2006, were included in the analysis if they had a clinical presentation of HF and an ECG demonstrating impaired LV systolic function (LVEF <50%), and had successfully completed an LGE-CMR. Exclusion criteria: patients with ICA-documented significant CAD (>50% DS in any coronary artery), significant valvular disease, CM of known cause including HCM, alcohol- or chemotherapy-induced or infiltrative CM Scanner: 1.5-T scanner with a synergy cardiac coil Cardiac function sequence: Electrocardiographically gated steady-state free-precession cine images were acquired in the 2 and 4 chamber, LV outflow tract and short-axis views. LGE sequence: 3D segmented gradient-echo sequence Contrast agent: 0.15 mmol/kg Gd-based contrast agent (Omniscan) Time delay: 10 minutes LV function: LV end-diastolic and end-systolic volumes, and LVEF were calculated from the cine images. LGE diagnosis: Areas of LGE ICD implantation: Not described Outcomes: HR for likelihood of having: all-cause mortality cardiac death HF VA cardiac transplantation MACE in LGE+ patients compared with those that are LGE–
were defined as subendocardial, mid-myocardial or transmural on visual analysis by a consensus of 2 independent cardiologists Machii et al. () Japan Retrospective cohort NHMRC level SIGN: acceptable quality with a moderate risk of bias N=83 patients with ES-HCM or DCM N=72 patients with DCM: n=48 (67%) LGE+ n=24 (33%) LGE– Patient characteristics: age = 64 ± 14 years; male = 72%; LVEF (CMR) = 34.4 ± 8.3%; BBB = 15%; family history = 11%; syncope = 7%; presence of VT/VF = 29%; presence of AF = 29%; CRT-D/ICD implantation = 10%; NYHA class = 2.5 ± 0.9; medications: ACE inhibitor/ARB = 78%, = 76% Mean follow-up: 39.6 ± Inclusion criteria: patients admitted for treatment of HF and/or for a differential diagnosis of CM who underwent CMR from April 2003 to August 2009, and were diagnosed with and DCM Exclusion criteria: patients diagnosed with cardiac sarcoidosis or with significant CAD (≥50% DS) by ICA Scanner: 1.5-T scanner Cardiac function sequence: Breath-hold cine magnetic resonance images were obtained in contiguous short-axis planes with the patient in a resting state. LGE sequence: inversion recovery prepared fast sequence Contrast agent: 0.2 mmol/kg Time delay: 15 minutes LV function: LV end-diastolic and end-systolic volumes, LVEF and LV mass were acquired from the 2-D FIESTA cine images in view. The values for LV volume and mass were indexed by dividing them with body surface area. LGE diagnosis: 2experienced cardiovascular radiologists interpreted the CMR images without knowledge of clinical findings. Regional analyses of ICD implantation: Not described Outcomes: HR for likelihood of having: cardiac death SCD hospitalisation for HF in LGE+ patients compared with those that are LGE–
arrest with VF N=46 had CRT-D Patient characteristics: age = 56 ± 13 years; male = 62%; history of AF = 16%; QRS interval = 132 ± 32 milliseconds; LVEF (CMR) = 29 ± 12%; NYHA class: I = 32%, II = 37%, III–IV = 31% Median follow-up: 45 months (IQR 23–67) Medical Centre but were followed at another centre; patients with CAD, sarcoidosis, amyloidosis or subendocardial LGE in a coronary artery perfusion territory (Magnevist) Time delay: 15 minutes LV function: The LV and RV and end-systolic endocardial contours were traced on cine images to calculate LV mass, end-diastolic and volumes, and LVEF. LV volumes and mass were normalised to body surface area. LGE diagnosis: Myocardial scar was assessed while the observer was blinded to available diagnostic data and outcome, and was considered to be present only if LGE was visible in 2 orthogonal views. LGE was defined by signal intensity ≥35% of maximal myocardial signal intensity. that are LGE– Shimizu et al. () Japan Prospective cohort NHMRC level II SIGN: high quality with a low risk of bias N=60 consecutively enrolled DCM patients who underwent cardiac assessment: n=11 (18%) ≥10% LGE n=49 (82%) <10% LGE Patient characteristics: age = 59 ± 12 years; male = 77%; disease duration = 2.3 ± Inclusion criteria: consecutively enrolled DCM patients who underwent cardiac assessment in the cardiology department between February 2005 and March 2006 Exclusion criteria: any of the standard contraindications for CMR, such as the presence of a Scanner: 1.5-T scanner with a cardiac-dedicated phased-array coil Cardiac function sequence: CMR studies were ECG-triggered by standard software and images were acquired during diastole to minimise artefacts due to cardiac motion. LGE sequence: gradient-echo (segmented True FISP with ICD implantation: Not described Outcomes: HR for likelihood of having a: cardiac death hospitalisation for HF in LGE+ patients compared with those that are LGE–
4.2 years; LVEF (Echo) = 30 ± 9%; LVEF (CMR) = 23 ± 10; medications: ACE inhibitor/ARB = 43%, = 27% Mean follow up: 406 ± 241 days for LGE+ and 425 ± 174 days for LGE– patients pacemaker, implantable defibrillator and intracerebral aneurysm clips inversion recovery pulse) sequence Contrast agent: 0.2 mmol/kg Time delay: 10 minutes LV function: Not reported LGE diagnosis: All areas of LGE were independently traced by 2 cardiologists who were blinded to the clinical history of the patients. Patients were classified as having advanced LGE when %LGE was ≥10%, and non-advanced LGE when %LGE was <10%. Wang et al. () China Prospective cohort NHMRC level II SIGN: acceptable quality with a moderate risk of bias N=63 consecutive patients diagnosed with DCM: n=31 (49%) LGE+ n=32 (51%) LGE– Patient characteristics: age = 53.9 ± 11.5 years; male = 70%; history of VF or sustained VT = 5%; history of AF = 25%; LBBB = 17%; LVEF (CMR) = 24.4 ± 8.5%; Inclusion criteria: consecutive patients diagnosed with DCM from October 2009 to April 2013 Exclusion criteria: patients with severe valvular disease, active myocarditis, hypertensive heart disease, tachycardia-induced CM, arrhythmogenic RV CM, infiltrative CM, HCM, diabetes mellitus, alcohol abuse, persistent AF, metal fragments in the body, implanted ferromagnetic devices or otherwise Scanner: 1.5-T scanner Cardiac function sequence: Breath-hold retrospective cine true-FISP (fast imaging with steady-state precession) sequence to acquire contiguous short-axis images. LGE sequence: Not reported Contrast agent: Not reported Time delay: Not reported LV function: The LVEF and RVEF were calculated using Simpson’s rule. ICD implantation: Not described Outcomes: HR for likelihood of having a: cardiac death (HF) cardiac transplantation in LGE+ patients compared with those that are LGE–
Study Level Quality appraisal Study population Inclusion criteria / Exclusion criteria / Objective Study Outcomes assessed for change in management Bruder et al. (2013) Europe (57 centres in 15 countries) Prospective multicentre cohort study Level IV: Quality: good Risk of bias: low 3,511 patients undergoing CMR for myocarditis/CM (31.9% of total who underwent CMR) Patient characteristics: age (years) <44 58.2%, 45–59 32.5%, 60–74 21.2%, >75 14.5% Inclusion criteria: Consecutive patients undergoing CMR according to the ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SIR consensus appropriateness criteria for CMR imaging, in centres included in the EuroCMR registry Exclusion criteria: NR Objective: Evaluate indications, image quality, safety and impact on patient management of routine CMR imaging in Europe CMR imaging 88% of patients received a contrast agent (1.28 mmol/kg bodyweight) Myocarditis/CM indication: Total (out of 11,040): Completely new diagnoses Therapeutic consequences: - changes in medication - invasive procedure - hospital discharge - hospital admission Impact on management (new diagnosis and/or therapeutic procedure) Non-invasive imaging ordered after CMR: - transthoracic Echo - transoesophageal Echo - computed tomography Imaging failure rate Note that results are not separated for myocarditis and other CMs. Taylor, AJ et al. (2013) Australia Prospective observational study, single centre Level IV Quality: Good Risk of bias: low Total number of scans = 732 Number of CM scans = 488 (67%) For CM: Patient characteristics: Inclusion criteria: All patients referred to the Alfred Hospital, Melbourne, Australia for clinical CMR between 1 July 2007 and 30 June 2009, referred and funded a under 4 pre-specified clinical pathways: CM, viability, tumour/mass and ARVC CMR imaging: Scanner 1.5-T, cardiac coil, electrocardiographic gating Data collection instrument: Questionnaire sent Number of cardiac surgical interventions averted by CMR (defined as the number of planned interventions who at 6 months post CMR did not undergo, and had no plan to undergo, the intervention that was planned prior to CMR scanning) Change to device plan
age 49.4 ± 16.3 years male = 322 (66%) median NYHA Class (IQR) = 2 (1–2) Exclusion criteria: Patients who were scanned for research purposes or non-funded indications 6 months post CMR procedure Change to surgical plan Note: No specific results for CM; however, the CM population is 67% (449/666) of the total, so could the results be applied to the CM population? Abassi et al. (2013) USA Prospective observational study, single centre Level IV Quality: Good Risk of bias: low N=150 patients with HF referred for CMR over a period Patient characteristics: age (mean) 54 years male 57% LVEF mean 38% (± 11%) Inclusion criteria: LVEF ≤50% by prior imaging studies NYHA class: I = 26%; II = 49%; III = 49%; IV = 1% Exclusion criteria: NR CMR imaging: (using SCMR standardised protocols) Late-Gd enhancement Image analysis was performed by blinded physician. Significant clinical impact (defined as an entirely ‘new diagnosis’ and/or a ‘change in management’ Change in patient management New diagnoses ) Norway Case series Level-III-3 Quality: Moderate: Risk of bias: low N=102 consecutive patients with a diagnosis of idiopathic DCM Patient characteristics: age (mean ± SD) 51 ± 14 years male 73 (74%) NYHA class (n): I = 15; II = 61; III = Inclusion criteria: Suspected DCM, LV end diastolic internal diameter ≥6.5 cm and ejection fraction ≤40% Exclusion criteria: Ischaemic, hypertensive and valvular heart disease, patients with a known or suspected cause of CM including myocarditis, patients with an implanted cardiac device or severe concomitant disease Objective CMR LGE (unless contraindicated) Right-sided heart catheterisation EMB Genetic testing Genomic analysis for viral detection Conventional and Diagnostic yield Therapeutic consequences
mean LVEF = 23 ± 8%; NYHA class: I = 13%, II = 63%, III = 24%; CAD >70% = 11% CAT trial Bänsch et al. (2002) Germany NHMRC Level II SIGN RCT: Adequate quality with a moderate risk of bias N=104 patients with symptomatic DCM and LVEF ≤30% Intervention group: age = 52 ± 10 years; gender = 86% male; median duration of symptoms = 3.0 years; sinus rhythm = 80%; LBBB = 85%; RBBB = 8%; mean LVEF = 24 ± 6%; NYHA class: II = 67%, III = 33%; inducible VT = 6%; inducible VF = 16% Control group: age = 52 ± 12 years; gender = 74% male; median duration of symptoms = Inclusion criteria: symptomatic DCM for ≤9 months, LVEF ≤30%, NYHA class II or III, age years, the absence of CAD Exclusion criteria: patients with CAD, a history of prior MI, myocarditis, excessive alcohol consumption, a history of symptomatic bradycardia, VT and VF, listed for heart transplantation at the time of presentation, significant valvular disease, and hypertrophic or restricted CM Median follow-up: 5.5 ± 2.2 years N=50 Patients assigned to ICD therapy underwent implantation of a transvenous defibrillator system, under general anaesthesia. A defibrillation threshold of <20 J was mandatory. All devices were capable of storing episode data and electrograms. A VT zone with a detection rate of 200 bpm was programmed in all patients. All shocks were programmed to a maximum output of 30 J. The pacemaker rate was programmed to 40 bpm. N=54 Treatment not described Primary endpoint: All-cause mortality at 1 year Secondary endpoint: All-cause mortality at 2 and 6 years Cardiac transplant at 1 year Survival of cardiac arrest Cardiac death at 1 year Sustained VT Sustained VA requiring treatment SCD at 1 year
The GRADE Working Group grades of evidence () presented in the tables below are defined as: ⨁⨁⨁⨁ High quality: We are very confident that the true effect lies close to that of the estimate of effect. ⨁⨁⨁⨀ Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ⨁⨁⨀⨀ Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. ⨁⨀⨀⨀ Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. Table Evidence profile table for the accuracy of LGE-CMR compared with the reference standards for patients with HF symptoms (suspected of DCM) or DCM patients Outcome No. of participants, No. of studies Study design Risk of bias Indirectness Inconsistency Imprecision Other considerations Effect per 1,000 patients/year Study prevalence QoE Importance - LGE-CMR to diagnose DCM (ref. std. = available diagnostic data) - - - - - 39.7% - True positives False negatives N=54 patients K=1 study Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Not serious Not serious Not serious None 330 (282–365) 67 (32–115) High ⨁⨁⨁⨁ True negatives False positives N=82 patients K=1 study Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Not serious Not serious Not serious None 561 (513–585) 42 (18–90) High ⨁⨁⨁⨁ - LGE-CMR to diagnose non-ischaemic - - - - - 63.1% -
DCM (ref. std. = ICA) True positives False negatives N=238 patients K=6 studies cohort- & case-control-type studies Not serious (QUADAS-2 low risk of bias) Serious a Not serious Serious b None 429–631 0–202 Low ⨁⨁⨀⨀ True negatives False positives N=139 patients K=6 studies cohort- & case-control-type studies Not serious (QUADAS-2 low risk of bias) Serious a Not serious Serious b None 262–369 0–107 Low ⨁⨁⨀⨀ - LGE-CMR to diagnose non-ischaemic DCM (ref. std. = available diagnostic data) - - - - - 69.4% - True positives False negatives N=100 patients K=2 studies Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Not serious Not serious Not serious None 590–694 0–104 High ⨁⨁⨁⨁ True negatives False positives N=44 patients K=2 studies Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Not serious Not serious Not serious None 251–269 37–55 High ⨁⨁⨁⨁ - LGE-CMR to diagnose inflammatory cause - - - - - 45.4% -
(ref. std. = EMB) True positives False negatives N=44 patients K=3 studies Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Serious a Not serious Serious b None 263–395 59–191 Low ⨁⨁⨀⨀ True negatives False positives N=53 patients K=3 studies Cross-sectional (cohort-type accuracy study) Not serious (QUADAS-2 low risk of bias) Serious a Not serious Serious b None 180–273 273–366 Low ⨁⨁⨀⨀ a An imperfect reference standard was used. b The confidence intervals of the sensitivity and/or specificity were (too) large. DCM = dilated cardiomyopathy; EMB = endomyocardial biopsy; HF = heart failure; ICA = invasive coronary angiography; LGE-CMR = late gadolinium enhancement cardiac magnetic resonance (imaging); QoE = quality of evidence Table Evidence profile for the SRs investigating the prognostic value of using LGE-CMR to predict health outcomes in patients with DCM Outcome Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Summary of findings HRp, ORp (95%CI) Quality of evidence Importance All-cause mortality K=4 SRs (level I) Not serious (1 low, 2 moderate, 1 high risk) Not serious Not serious Serious (duplication of data) Confounding would suggest spurious effect, while no effect was observed ORp = 3.43 (2.26, 5.22), k=5 HRp = 2.48 [1.78, 3.44] k=3 ORp = 3.27 (1.94, 5.51), k=3 ORp = 1.71 (0.80, 3.68), k=4 Low ⊕⊕⨀⨀ Critical (9/9) SCD K=2 SRs (level I) Not serious (1 low, 1 Not serious Not serious Very serious (duplicated data, wide None ORp = 3.33 (1.80, 6.17), k=9 ORp = 2.05 (0.56, 7.50), k=4 Low ⊕⊕⨀⨀ Critical (9/9)