Do β-Blockers Prolong Survival in Heart Failure only by Inhibiting the β1-Receptor? A Perspective on the Results of the COMET Trial

Milton Packer

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Experimental and clinical studies indicate that carvedilol exerts multiple antiadrenergic effects in addition to β1-receptor blockade, but the prognostic importance of these actions has long been debated. This controversy has now been substantially advanced by the results of the recently completed Carvedilol Or Metoprolol European Trial (COMET), which showed that carvedilol (25 mg twice daily) reduced mortality by 17% when compared with metoprolol (50 mg twice daily), P = .0017-a result that was consistent with the differences seen across earlier controlled trials with β-blockers in survivors of an acute myocardial infarction and in patients with chronic heart failure. Questions have been raised about the interpretation of these findings in view of the fact that the trial did not use the dose or formulation of metoprolol that was shown to prolong life in a placebo-controlled trial (ie, Metoprolol CR/XL [Controlled Release] Randomized Intervention Trial in Heart Failure). Pharmacokinetic and pharmacodynamic analyses, however, indicate that the dosing regimen of metoprolol selected for use in the COMET trial produces a magnitude and time course of β1-blockade during a 24-hour period that is similar to the dose of carvedilol targeted for use in the trial. These analyses suggest that the observed difference in the mortality effects of metoprolol and carvedilol is not related to a difference in the magnitude or time course of their β1-blocking effects but instead reflect antiadrenergic effects of carvedilol in addition to β1-blockade.

Original languageEnglish (US)
Pages (from-to)429-443
Number of pages15
JournalJournal of Cardiac Failure
Issue number6
StatePublished - Dec 2003


  • Carvedilol
  • Dose-response relations
  • Metoprolol
  • β-adrenergic blockade

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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