THE EFFECT OF CARVEDILOL ON MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC HEART FAILURE

Background. Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined. Methods. We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions 0.35 were randomly assigned to receive either placebo (n 398) or the beta-blocker carvedilol (n 696); background therapy with digoxin, diuretics, and an angiotensin-converting–enzyme inhibitor remained constant. Patients were observed for the occurrence of death or hospitalization for cardiovascular reasons during the following 6 months (12 months for the group with mild heart failure). Results. The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P 0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs. 15.8 percent, P 0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol group than in the placebo group. Conclusions. Carvedilol reduces the risk of death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting–enzyme inhibitor. (N Engl J Med 1996;334:1349-55.)  1996, Massachusetts Medical Society. From the College of Physicians and Surgeons, Columbia University, New York (M.P.); University of Colorado Health Sciences Center, Denver (M.R.B.); University of Minnesota Medical School, Minneapolis (J.N.C.); Boston University School of Medicine, Boston (W.S.C.); Stanford University School of Medicine, Palo Alto, Calif. (M.B.F.); University of Utah School of Medicine, Salt Lake City (E.M.G.); and SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. (N.H.S.). Address reprint requests to Dr. Packer at the Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032. Supported by grants from SmithKline Beecham Pharmaceuticals and Boehringer–Mannheim Therapeutics. *The U.S. Carvedilol Heart Failure Study Group investigators are listed in the Appendix. A CTIVATION of the sympathetic nervous system is one of the cardinal pathophysiologic abnormalities in patients with chronic heart failure. Levels of circulating catecholamines increase in patients with heart failure in proportion to the severity of disease, 1 and those with the highest plasma levels of norepinephrine have the most unfavorable prognosis. 2 These observations have led to the hypothesis that sympathetic activation plays an important part in the progression of heart failure. 3,4 Norepinephrine can exert adverse effects on the circulation, both directly and indirectly, 5,6 and interference with its actions can retard the progression of heart failure in animal models of the disease. 7,8 These findings have led investigators to propose that sympathetic antagonists (e.g., beta-blockers) might be useful in the management of heart failure. Such drugs were previously considered to be contraindicated in this disorder because of their short-term adverse effects, 9 but studies in Sweden in the 1970s raised the possibility that long-term therapy with these drugs might produce hemodynamic and clinical benefits. 10,11 Controlled trials of several different beta-blockers have shown that these drugs can reduce symptoms, improve left ventricular function, and increase functional capacity, 12-18 but recent large-scale studies 19,20 have not clarified the effects of beta-blockers on morbidity and mortality in patients with heart failure. Hence, when a large clinical trial program with carvedilol in heart failure was being designed in 1992, we prospectively defined an overall objective of the program to be an evaluation of the effect of the drug on survival. Our principal goal was to assess the safety of The New England Journal of Medicine Downloaded from nejm.org at VANCOUVER COASTAL HEALTH on July 18, 2011. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 1350 THE NEW ENGLAND JOURNAL OF MEDICINE May 23, 1996 carvedilol while recognizing its potential to prolong life, demonstrated by the results of experimental studies. 7,8,21 Carvedilol is a nonselective b -receptor antagonist that also blocks a 1 -receptors and, unlike other beta-blockers, exerts antioxidant effects, which may contribute to its actions in heart failure. 22-24 This report summarizes the effects of carvedilol on survival and on hospitalization for cardiovascular causes.