title: Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study.
abstract: BACKGROUND
  The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo.
  
  
  METHODS
  Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations.
  
  
  RESULTS
  The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone.
  
  
  CONCLUSIONS
  Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.
authors.affiliation: Monash University, Melbourne, Australia. henry.krum@med.monash.edu.au
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Paul
authors.initials: P
authors.lastname: Mohacsi
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Michael
authors.initials: M
authors.lastname: Tendera
authors.forename: Jean-Lucien
authors.initials: JL
authors.lastname: Rouleau
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fowler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Coats
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Roecker
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D011412:Propanolamines / Q000627:therapeutic use*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013148:Spironolactone / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D000451:Mineralocorticoid Receptor Antagonists; D011412:Propanolamines; D000077261:Carvedilol; D013148:Spironolactone