Pharmacodynamics of beta-blockers in heart failure: lessons from the carvedilol or metoprolol European trial.

Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of beta-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the beta1-/beta2-/alpha1-adrenergic receptors with carvedilol versus selective beta1-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between beta-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all beta-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and dosage forms) that have been proven to reduce mortality in this patient population.