title: 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.
abstract: OBJECTIVE
  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-HFs subsets.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wikstrand
authors.forename: H
authors.initials: H
authors.lastname: Wedel
authors.forename: D
authors.initials: D
authors.lastname: Castagno
authors.forename: J J V
authors.initials: JJ
authors.lastname: McMurray
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001578:Benzopyrans / Q000627:therapeutic use; D017298:Bisoprolol / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D000077261:Carvedilol; D003692:Delayed-Action Preparations; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D054143:Heart Failure, Systolic / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D008875:Middle Aged; D000068577:Nebivolol; D011412:Propanolamines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D012720:Severity of Illness Index; D013318:Stroke Volume; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D002227:Carbazoles; D003692:Delayed-Action Preparations; D004983:Ethanolamines; D011412:Propanolamines; D000068577:Nebivolol; D000077261:Carvedilol; D008790:Metoprolol; D017298:Bisoprolol
keywords: beta-blockers; clinical trials; heart failure