Cardiology Express Report

Data Presented at a Satellite Symposium titled “Challenging Established Treatment Patterns in Chronic Heart Failure” held during Heart Failure 2003 - European Society of Cardiology and International Society for Heart Research Meeting - Strasbourg, France

Publication date: 2003-08-23

Challenging Established Treatment Patterns: First Results of the COMET Trial

This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director of Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary and Opinion

Professor John GF Cleland, Department of Cardiology, University of Hull, Kingston upon Hull, United Kingdom; COMET Investigator.

The combination of angiotensin converting enzyme (ACE) inhibitors and β-blockers has halved the two-year mortality of patients with heart failure secondary to left ventricular systolic dysfunction. The results of COMET, the longest and largest clinical trial conducted in patients with heart failure, indicate that treatment with carvedilol reduces mortality by a further 17% (P = .0017) over existing therapy and prolonged median survival by a further 1.4 years compared to metoprolol.¹ This suggests that the benefits of treatment with a β-blocker can be increased by a further 50% by using or switching to carvedilol. No effect was observed on time to first all-cause hospitalization. Further analyses on cause-specific hospitalization, total number of hospitalizations, total days in hospital and effects on symptoms and quality of life are awaited. These are the facts, but why was such a difference in mortality observed? There are many possible explanations with varying degrees of plausibility.

The most obvious and most likely reason for the difference in outcome is the pharmacological differences between the agents used. Carvedilol provides comprehensive anti-adrenergic blockade (β₁-, β₂-and α₁-receptors--all of which are expressed on cardiac myocytes) whereas metoprolol only blocks the β₁-receptor. β₁-receptors mediate much, but not all, of the inotropic, chronotropic and arrhythmogenic effects of sympathetic activation. β₂-receptors also mediate some of the inotropic and chronotropic effects of sympathetic activation. Activation of β₂-receptors may also provoke hypokalemia during sympathetic stress (not good) but also peripheral vasodilatation (potentially good). Blockade of α₁-receptors, which probably also mediate some of the inotropic effects of sympathetic activation, are involved in the hypertrophic response and cause peripheral vasoconstriction, may offset the effects of peripheral β₂-receptor blockade. However, the long-term benefit of α-blockade in heart failure remains unknown. Carvedilol and its metabolites are also powerful antioxidants,² which may confer benefits to patients with heart failure who have increased oxidant stress³ and reduced endogenous antioxidant defenses. The significance of this attribute in treating heart failure remains uncertain at this time but it could potentially be of great importance. Carvedilol, like metoprolol, is also lipophilic, a common attribute of all β-blocking agents for which there is robust evidence of a mortality benefit. Thus of all available β-blockers, carvedilol appears to have the most favorable pharmacological profile for the management of heart failure and there should be no surprise that this translates into greater patient benefits.

Those who have invested much time and energy in trials of β₁-receptor blockers have done a great service to patients and are naturally inclined to defend their trials and criticize the results of COMET. It has been said that the doses of metoprolol and carvedilol are not equivalent. This is very hard to prove one way or another. Simple pharmacokinetics suggest no difference. COMET was planned at a time when only four substantial studies were available (the MDC trial with metoprolol in similar doses and the same formulation used in COMET⁴; CIBIS-I, an inconclusive study of bisoprolol⁵; and tw