The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: Results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF

Aims: The four pivotal beta-blocker trials in heart failure ( HF ) had different inclusion criteria, making comparison difficult without patient stratifying. The aim of this study was to compare, in similar patients, the effects of bisoprolol, metoprolol controlled release/extended release ( CR/XL ), carvedilol and nebivolol on ( i ) total mortality, ( ii ) all-cause mortality or hospitalization due to cardiovascular causes ( time to first event ), ( iii ) all-cause mortality or hospitalization because of HF and ( iv ) tolerability, defined as discontinuation of randomized treatment. Methods: We compared stratified ( s ) subsets in MERIT-HF with patients in CIBIS-II [New York Heart Association ( NYHA ) class III/IV and ejection fraction ( EF ) ≤35%] and COPERNICUS ( NYHA III/IV and EF < 25% ) and in patients with systolic HF in SENIORS-SHF ( age ≥70 years and EF ≤35% ). Results: The annual mortality rates in the placebo and beta-blocker arms were: ( i ) CIBIS-II ( n = 2647 ), 13.2% vs. 8.8% ( relative risk reduction 34%, 95% CI: 19–46, P < 0.0001 ) and MERIT-HFs ( n = 2002 ), 14.8% vs. 8.6% ( relative risk reduction 42%, 95% CI: 24–56, P < 0.0001 ); ( ii ) COPERNICUS ( n = 2289 ), 19.7% vs. 12.8% ( relative risk reduction 35%, 95% CI: 19–48, P = 0.0014 ) and MERIT-HFs ( n = 795 ), 19.1% vs. 11.7% ( relative risk reduction 39%; 95% CI: 11–58, P = 0.0086 ); ( iii ) SENIORS-SHF ( n = 1359 ), 11.3% vs. 9.7% ( relative risk reduction 16%, NS ) and MERIT-HFs ( n = 985 ), 14.8% vs. 10.1% ( relative risk reduction 32%, 95% CI: 2–53, P = 0.038 ). The effects on the other outcomes assessed were similar. Analyses indicated fewer discontinuations from randomized treatment on beta-blockers compared with placebo in COPERNICUS and the MERIT-HFssubsets. Conclusion: The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients with systolic HF, irrespective of NYHA class or ejection fraction. Nebivolol is less effective and not better tolerated.