Do beta-blockers prolong survival in heart failure only by inhibiting the beta1-receptor? A perspective on the results of the COMET trial.

Experimental and clinical studies indicate that carvedilol exerts multiple antiadrenergic effects in addition to beta(1)-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 beta-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 beta(1)-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 beta(1)-blocking effects but instead reflect antiadrenergic effects of carvedilol in addition to beta(1)-blockade.

RCT Entities:   Population Interventions Outcomes