Mariusz Kowalewski

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials

Objective To assess the benefits and risks of short term (<12 months) or extended (>12 months) dual antiplatelet therapy (DAPT) versus standard 12 month therapy, following percutaneous coronary intervention with drug eluting stents. Design Meta-analysis of randomised controlled trials. Data sources PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major congress proceedings, searched from 1 January 2002 to 16 February 2015. Review methods Trials comparing short term (<12 months) or extended (>12 months) DAPT regimens with standard 12 month duration of therapy. Primary outcomes were cardiovascular mortality, myocardial infarction, stent thrombosis, major bleeding, and all cause mortality. Results 10 randomised controlled trials (n=32 287) were included. Compared to 12 month DAPT, a short term course of therapy was associated with a significant reduction in major bleeding (odds ratio 0.58 (95% confidence interval 0.36 to 0.92); P=0.02) with no significant differences in ischaemic or thrombotic outcomes. Extended versus 12 month DAPT yielded a significant reduction in the odds of myocardial infarction (0.53 (0.42 to 0.66); P<0.001) and stent thrombosis (0.33 (0.21 to 0.51); P<0.001), but more major bleeding (1.62 (1.26 to 2.09); P<0.001). All cause but not cardiovascular death was also significantly increased (1.30 (1.02 to 1.66); P=0.03). Conclusions Compared with a standard 12 month duration, short term DAPT (<12 months) after drug eluting stent implementation yields reduced bleeding with no apparent increase in ischaemic complications, and could be considered for most patients. In selected patients with low bleeding risk and very high ischaemic risk, extended DAPT (>12 months) could be considered. The increase in all cause but not cardiovascular death with extended DAPT requires further investigation.

Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis

Objectives To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES). Design Network meta-analysis of randomised controlled trials. Data sources and study selection Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES. Primary outcomes Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond. Results 60 randomised controlled trials were compared involving 63 242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles. Conclusions The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date.

Off-pump coronary artery bypass grafting improves short-term outcomes in high-risk patients compared with on-pump coronary artery bypass grafting: Meta-analysis

OBJECTIVES To assess the benefits and risks of off-pump coronary artery bypass (OPCAB) versus coronary artery bypass grafting (CABG) through a meta-analysis of randomized controlled trials (RCTs), and to investigate the relationship between outcomes and patient risk profile. METHODS PubMed, Embase, the Cumulative Index of Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major conference proceedings databases were searched for RCTs comparing OPCAB and CABG and reporting short-term (≤ 30 days) outcomes. Endpoints assessed were all-cause mortality, myocardial infarction (MI), and cerebral stroke. RESULTS The meta-analysis included 100 studies, with a total of 19,192 subjects. There was no difference between the 2 techniques with respect to all-cause mortality and MI (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.71-1.09; P = .25; I(2) = 0% and OR, 0.90; 95% CI, 0.77-1.05; P = .19; I(2) = 0%, respectively). OPCAB was associated with a significant 28% reduction in the odds of cerebral stroke (OR, 0.72; 95% CI, 0.56-0.92; P = .009; I(2) = 0%). A significant relationship between patient risk profile and benefits from OPCAB was found in terms of all-cause mortality (P < .01), MI (P < .01), and cerebral stroke (P < .01). CONCLUSIONS OPCAB is associated with a significant reduction in the odds of cerebral stroke compared with conventional CABG. In addition, benefits of OPCAB in terms of death, MI, and cerebral stroke are significantly related to patient risk profile, suggesting that OPCAB should be strongly considered in high-risk patients.

Comprehensive Meta-Analysis of Safety and Efficacy of Bivalirudin Versus Heparin With or Without Routine Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndrome

OBJECTIVES The aim of this meta-analysis was to compare the 30-day safety and efficacy of bivalirudin with those of heparin with or without routine administration of a glycoprotein IIb/IIIa inhibitor (GPI) in patients with acute coronary syndrome (ACS). BACKGROUND Bivalirudin has been a mainstay of anticoagulation in patients with ACS compared with heparin. The extent to which trial results have been affected by the coadministration of heparin with a GPI, however, remains unclear. METHODS A total of 13 randomized, controlled trials involving 24,605 patients were included. RESULTS There was no significant difference in 30-day mortality or myocardial infarction rate with bivalirudin compared with heparin with or without routine GPI administration. A reduction of 30-day major bleeding was observed with bivalirudin compared with heparin that was significant when GPI was routinely administered (odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.45 to 0.60), p < 0.001) but not with provisionally administered GPI (OR: 0.66, 95% CI: 0.33 to 1.32; p = 0.24). The occurrence of stent thrombosis (ST) at 30 days was significantly increased with bivalirudin compared with heparin plus routinely administered GPI (OR: 1.67, 95% CI: 1.13 to 2.45, p = 0.02), but not compared with heparin plus provisionally administered GPI (OR: 2.08, 95% CI: 0.35 to 12.32, p = 0.42). The rate of acute ST (≤ 24 h), however, was almost 4.5-fold higher with bivalirudin compared with heparin with or without GPI, whereas the rate of subacute ST (24 h to 30 days) did not differ significantly. CONCLUSIONS Overall, bivalirudin in ACS patients is associated with a significant reduction of major bleeding compared with heparin plus routinely administered GPI, but with a marked increase in ST rates compared with heparin with or without GPI.

First-generation versus second-generation drug-eluting stents in current clinical practice: updated evidence from a comprehensive meta-analysis of randomised clinical trials comprising 31 379 patients

Background First-generation drug-eluting stents (DES) have become the most widely used devices worldwide for management of coronary artery disease. As remote follow-up data were becoming available, concerns emerged in regard to their long-term safety. Second-generation DES were designed to overcome safety issues, but the results of randomised clinical trials remain conflicting. Methods We compared the safety and efficacy of first-generation versus second-generation Food and Drug Administration approved DES; the following devices were included: first-generation sirolimus-eluting stent (SES) and paclitaxel-eluting stents (PES); second-generation everolimus-eluting stent (EES), zotarolimus-eluting stent Endeavor and ZES-Resolute (ZES-R). Prespecified safety end points comprised ≤1 and >1 year: overall and cardiac mortality, myocardial infarction (MI), definite/definite or probable ST; efficacy end points were target lesion revascularisation and target vessel revascularisation. Composite end points were analysed as well. Results 33 randomised controlled trials involving 31 379 patients with stable coronary artery disease or acute coronary syndrome undergoing DES implantation were retrieved. No differences in mortality among devices were found. In the overall class comparison, second-generation DES were associated with a 22% reduction of odds of MI at short-term OR 0.77 (95% CI 0.68 to 0.89) p=0.0002; EES reduced the odds of definite-probable ST compared with PES: OR 0.33 (95% CI 0.15 to 0.73) p=0.006; First-generation SES along with second-generation EES and ZES-R showed similar efficacy in decreasing the odds of repeat revascularisation. Conclusions Second-generation EES and ZES-R offer similar levels of efficacy compared with first-generation SES, but are more effective than PES; however, only second-generation EES significantly reduced the incidence of MI and ST, and therefore should be perceived as the safest DES to date.

Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Patients with acute coronary syndromes (ACSs) still experience high rates of recurrent coronary events, particularly, early in their presentation. Statins yield substantial cardiovascular benefits, but the optimal timing of their administration, before or after percutaneous coronary intervention (PCI), remains unclear. We aimed to perform a meta-analysis of randomized controlled trials of statin administration before or after PCI versus no statin or low-dose statin in patients with ACS. Primary end points were 30-day all-cause mortality and 30-day myocardial infarction (MI) stratified by pre- and post-PCI statin administration. Secondary end points were major adverse cardiac events (MACEs) or major adverse cardiac and cerebrovascular events (MACCEs). Long-term analysis beyond 30 days was also performed. Twenty randomized controlled trials enrolling 8,750 patients were included. At 30 days, the rate of MI was significantly lower in the statin group (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.53 to 0.84, p = 0.0007) with a trend toward reduced mortality (p = 0.06) and significant reductions in MACE and MACCE compared with no or low-dose statin. The 30-day incidence of MI was markedly lower when statins were administered before PCI (OR 0.38, 95% CI 0.24 to 0.59, p <0.0001) rather than after PCI (p = 0.28). The direction and magnitude of the estimates for before and after PCI versus no statin or low-dose statin were sustained at long term, not reaching statistical significance for MI (OR 0.81, 95% CI 0.65 to 1.01, p = 0.06) but with significant reductions in MACE (p = 0.0002). By meta-regression, earlier statin administration correlated significantly with lower risk of MI, MACE, and MACCE at 30 days. In conclusion, the present meta-analysis indicates a time-related impact of statin therapy on clinical outcomes of patients with ACS undergoing PCI: the earlier the administration before PCI, the greater the benefits.

Complete revascularisation in ST-elevation myocardial infarction and multivessel disease: meta-analysis of randomised controlled trials

Background Current guidelines recommend culprit-only revascularisation (COR) in haemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel (MV) disease. Contrarily, growing body of evidence available from recent randomised controlled trials (RCTs) demonstrates improved outcomes with complete MV-percutaneous coronary intervention (PCI). Methods and results We performed a meta-analysis of RCTs comparing complete MV-PCI with non-complete MV-PCI in STEMI and MV disease. Complete MV-PCI was defined as revascularisation to non-infarct-related artery lesions during index procedure, non-complete MV-PCI-encompassed COR and staged approaches. Multiple databases and congress proceedings from major cardiovascular societies’ meetings were screened for relevant studies. Primary endpoint was the composite of major adverse cardiac events (MACE) typically defined as death, recurrent myocardial infarction (MI) and repeat revascularisation. Secondary endpoints were cardiovascular mortality, recurrent MI and repeat revascularisation. Outcomes were analysed at longest available follow-up with differences accounted for with adjusted models by person-years. Seven RCTs (N=1303) were included. The median follow-up was 12 months. Complete MV-PCI reduced the odds of MACE compared with non-complete MV-PCI (OR (95% CIs) 0.59 (0.36 to 0.97), p=0.04) driven by reduction in recurrent MI (0.48 (0.27 to 0.85), p=0.01) and repeat revascularisation (0.51 (0.31 to 0.84), p=0.008). Complete MV-PCI was associated with a non-significant trend towards reduced cardiovascular mortality (0.54 (0.26 to 1.10), p=0.09) as well. In a sensitivity analysis, none of the baseline clinical variables significantly influenced overall estimates. Conclusions In STEMI and MV disease, complete MV-PCI as compared with non-complete strategy reduces MACE by 41%, driven by a 52% reduction in recurrent MI and 49% reduction in repeat revascularisation.

Gentamicin-collagen sponge reduces the risk of sternal wound infections after heart surgery: Meta-analysis.

OBJECTIVES Sternal wound infections are serious postoperative complications that increase the length of hospital stay and healthcare costs. The benefit of implantable gentamicin-collagen sponges in reducing sternal wound infections has been questioned in a recent multicenter trial. We aimed to perform a comprehensive meta-analysis of studies assessing the efficacy of implantable gentamicin-collagen sponges in sternal wound infection prevention. METHODS Multiple databases were screened for studies assessing the efficacy of implantable gentamicin-collagen sponges after heart surgery. The primary end point was sternal wound infection, and secondary end points were the occurrence of deep sternal wound infection, superficial sternal wound infection, mediastinitis, and mortality. Randomized controlled trials and observational studies were analyzed separately. By means of meta-regression, we examined the correlation between sternal wound infection and extent to which the bilateral internal thoracic artery was harvested. RESULTS A total of 14 studies (N = 22,135, among them 4 randomized controlled trials [N = 4672]) were included in the analysis. Implantable gentamicin-collagen sponges significantly reduced the risk of sternal wound infection by approximately 40% when compared with control (risk ratio [RR], 0.61; 95% confidence interval [CI], 0.39-0.98; P = .04 for randomized controlled trials and RR, 0.61; 95% CI, 0.42-0.89; P = .01 for observational studies). A similar, significant benefit was demonstrated for deep sternal wound infection (RR, 0.60; 95% CI, 0.42-0.88; P = .008) and superficial sternal wound infection (RR, 0.60; 95% CI, 0.43-0.83; P = .002). The overall analysis revealed a reduced risk of mediastinitis (RR, 0.64; 95% CI, 0.45-0.91; P = .01). The risk of death was unchanged. A significant positive linear correlation (P = .05) was found between the log RR of sternal wound infection and the percentage of patients receiving bilateral internal thoracic artery grafts. CONCLUSIONS Implantable gentamicin-collagen sponges significantly reduce the risk of sternal wound infection after cardiac surgery, with evidence consistent in randomized and observational-level data. However, the extent of this benefit might be attenuated in patients receiving bilateral internal thoracic artery grafts.

Cerebrovascular Events After No-Touch Off-Pump Coronary Artery Bypass Grafting, Conventional Side-Clamp Off-Pump Coronary Artery Bypass, and Proximal Anastomotic Devices: A Meta-Analysis.

Background Off‐pump coronary artery bypass (OPCAB) has been shown to reduce the risk of neurologic complications as compared to coronary artery bypass grafting performed with cardiopulmonary bypass. Side‐clamping of the aorta while constructing proximal anastomoses, however, still carries substantial risk of cerebral embolization. We aimed to perform a comprehensive meta‐analysis of studies assessing 2 clampless techniques: aortic “no‐touch” and proximal anastomosis devices (PAD) for OPCAB. Methods and Results PubMed, CINAHL, CENTRAL, and Google Scholar databases were screened for randomized controlled trials and observational studies comparing “no‐touch” and/or PAD with side‐clamp OPCAB and reporting short‐term (≤30 days) outcomes: cerebrovascular accident and all‐cause mortality. A total of 18 studies (3 randomized controlled trials) enrolling 25 163 patients were included. Aortic “no‐touch” was associated with statistically lower risk of cerebrovascular accident as compared to side‐clamp OPCAB: risk ratio 95% CI: 0.41 (0.27–0.61); P<0.01; I2=0%. Event rates were 0.36% and 1.28% for “no‐touch” and side‐clamp OPCAB, respectively. No difference was seen between PAD and side‐clamp OPCAB: 0.71 (0.33–1.55); P=0.39; I2=39%. A trend towards increased 30‐day all‐cause mortality with PAD and no difference with “no‐touch” were observed when compared to side‐clamp OPCAB. In a subset analysis, “no‐touch” consistently reduced the risk of cerebrovascular accident regardless of patients’ baseline risk characteristics. A benefit with PAD was observed in low‐risk patients. Conclusions Aortic “no‐touch” technique was associated with nearly 60% lower risk of postoperative cerebrovascular events as compared to conventional side‐clamp OPCAB with effect consistent across patients at different risk.

Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis

Sudden death accounts for approximately half the deaths in patients with left ventricular systolic dysfunction. Life-threatening ventricular arrhythmias are the cause of most sudden deaths. Randomized clinical trials have shown that the implantable cardioverter-defibrillator (ICD) is the most effective current therapy to prevent sudden death by terminating ventricular arrhythmias. Moreover, ICD versus no ICD placement has been shown to improve survival among patients with heart failure and reduced ejection fraction (HeFrEF), with or without nonsustained ventricular tachycardia or symptoms (1). As a result, contemporary European and American guidelines assign a class I recommendation for prophylactic ICD therapy in patients with HeFrEF (24). The benefits of ICD therapy are most pronounced in the secondary prevention of life-threatening arrhythmias among high-risk patients with ischemic heart disease and ventricular dysfunction, although implantation is not recommended soon after acute myocardial infarction or in patients with an expected survival of less than 1 year (5). For primary prevention, the main indications for an ICD are related to the prevention of fatal outcomes in patients at increased risk for life-threatening ventricular tachycardia or ventricular fibrillation. In this setting, controversy recently was sparked by the findings of a clinical study questioning the benefits of ICDs and emphasizing the medical improvements in heart failure management (6). In light of this uncertainty, we aimed to systematically address, through a meta-analysis of randomized trials, the effect of ICD therapy versus conventional care for primary prevention of death of various causes in patients with ischemic or nonischemic cardiomyopathy. Methods The present meta-analysis was performed according to established methods recommended by the Cochrane guidelines and in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement (7, 8). The protocol, although not registered, was developed on 20 September 2016, with final amendments on 31 March 2017. Originally, we aimed to assess both primary and secondary prevention settings; the current article, however, focuses only on primary prevention. Data Sources and Searches MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as the Web sites www.tctmd.com, www.europcr.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, and www.acc.org, were searched, without language restriction, from 1 April 1976 to 31 March 2017. Key words were nonischemic cardiomyopathy, ischemic cardiomyopathy, implantable cardioverter-defibrillator, implantable defibrillator, randomized controlled trials, clinical trials, mortality, death, sudden death, survival, and prevention. (For search strategies, see Supplement Table 1.) Search sources also included previous systematic reviews and abstracts as well as presentations from major cardiovascular medicine meetings. Supplement. Supplement Tables, Figures, and References to Excluded Studies Two authors (M. Koodziejczak and M. Kowalewski) independently assessed titles and abstracts identified by searches, as well as citations mentioned in any relevant systematic reviews or meta-analyses identified in the searches. Citations determined to be potentially eligible by either reviewer were selected for full-text review; both reviewers then independently assessed the full text for eligibility. Study Selection Inclusion criteria were any randomized controlled trial in humans comparing ICD therapy with conventional care (defined as control, contemporary medical therapy, antiarrhythmic medical therapy, or placebo in addition to medical care) and reporting mortality outcomes in the primary prevention setting. No restrictions based on language, follow-up, or study size were applied. Nonrandomized and single-group studies were excluded, as were studies that had a randomized design but compared ICDs with other devices or electrophysiologic procedures. Data Extraction and Quality Assessment Data were abstracted on prespecified forms by 2 independent investigators not involved in any of the retrieved studies. Hazard ratios (HRs) with 95% CIs were abstracted for all available mortality outcomes. When only other summary statistics were available, HRs were calculated according to the method of Parmar and colleagues (7). In SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), patients with ischemic or nonischemic disease were randomly assigned to receive an ICD, amiodarone, or placebo in a 1:1:1 fashion; trial data on all-cause mortality were presented (and extracted) by disease mechanism. Two investigators not involved in any trial (M. Koodziejczak and E.P.N.) independently assessed the risk of bias for each study according to the Cochrane Collaboration guidelines (treatment sequence generation; concealment of treatment allocation; blinding of participants, personnel, and outcome assessors; adequate assessment of incomplete outcome data; selective outcome reporting; other potential sources of bias) (7). Disagreements regarding extraction or risk-of-bias assessments were resolved by discussion with a third investigator (F.A.). Data Synthesis and Analyses We stratified our synthesis and analyses on the basis of the underlying cause of cardiomyopathy, nonischemic or ischemic, and pooled data for mortality outcomes. For the 3-group SCD-HeFT, we considered amiodarone and placebo as conventional care in the main analyses; we also performed a separate all-cause mortality analysis comparing ICD therapy with amiodarone (antiarrhythmic medical therapy). We used time-to-event outcomes reported for the randomly assigned groups (intention-to-treat principle). We used HRs to summarize time-to-event outcomes, because they account for time as well as the number of events (7). Heterogeneity was assessed by using the Cochran Q test (9). Statistical heterogeneity was summarized by the I 2 statistic, which quantifies the percentage of variation in study results caused by heterogeneity rather than chance (9). Pooled HRs were calculated by using the KnappHartung small-sample estimator method (10). Potential publication bias was examined by constructing a funnel plot in which the SE of the log HR was plotted against the HR of the selected outcomes. Prespecified sensitivity analyses were performed for all-cause mortality in subgroups based on age (<65 years and 65 years), sex, ventricular function (ejection fraction <25% and 25%), heart failure (New York Heart Association [NYHA] class I to II and class III to IV), diabetes mellitus, time after myocardial infarction (<18 months and 18 months), and baseline QRS length (<120 ms and 120 ms). Because event rates for subgroup analyses were provided in only 1 study (DANISH [Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality]), exact summary event rates were not calculated; individual study-subgroup data were summarized by using HRs and their respective 95% CIs whenever applicable, by using the random-effects model. Further sensitivity analyses including and excluding studies with early ICD placement after myocardial infarction or coronary bypass surgery were conducted. R, version 3.2.3 (R Foundation), and Comprehensive Meta-analysis software, version 2 (Biostat), were used for statistical computations and graphics. Role of the Funding Source This review received no funding or other support (such as supply of data). No external organizations or patients were involved in defining questions, developing the protocol, carrying out the review, interpreting the data, or deciding to submit the review for publication. Results Study Selection and Patient Population The PRISMA flow chart showing the publication screening process, the search strategies, and a list of excluded studies with reasons for exclusion are provided in Supplement Figure 1 and Supplement Tables 1 and 2. Of 2340 potentially relevant articles, 639 were excluded on the basis of title content and 1656 were excluded after abstract or full-text review. Of the remaining 45 trials, 11 studies, involving 8716 patients, met eligibility criteria (6, 1120). Four trials enrolled 1781 patients with nonischemic cardiomyopathy (6, 1113), 6 trials enrolled 4414 patients with ischemic cardiomyopathy (1520), and 1 trial included 2521 patients with both types of cardiomyopathy (14). Characteristics of the trials and participants are detailed in the Appendix Table and Supplement Table 3. Most of the included studies compared ICD therapy with conventional care; however, 1 study compared ICD therapy specifically with amiodarone (13), and 1 had a 3-group design comparing ICDs, amiodarone, and placebo (14). Mean follow-up was 3.2 years (range, 1.7 to 5.6 years). The earliest trial was published in 1996, but most of the studies were done in the first decade of the 21st century; only 1 study was published in 2016. All trials were funded, at least in part, by industry. Appendix Table. Characteristics of Included Trials: Design, Follow-up, and Timing of Intervention After Diagnosis or Surgery Mean ventricular ejection fraction of trial participants was 26.20%. Most patients had moderately symptomatic heart failure (NYHA class II or III). Only 2 studies included patients with class IV heart failure, who made up 1.0% and 4.6% of the total patient population, respectively (6, 17). Almost half the study population had a history of hypertension, and one third had diabetes mellitus. The lowest burden of comorbid conditions was in DANISH (31.2% and 18.9% had hypertension and diabetes, respectively). Patients included in the studies received several pharmacotherapies: 67.35% received -blockers, 80.12% angiotensin-converting enzyme inhibitors, 62.65% digoxin, and 68.40% diuretics (Supplement Table 4). Pharmacotherapy, however, varied across trials, with -blockers administered