Carvedilol reduced mortality and hospitalization in chronic heart failure
ACP J Club. 1996 Nov-Dec;125:60. doi:10.7326/ACPJC-1996-125-3-060
Packer M, Bristow MR, Cohn JN, et al., for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996 May 23;334: 1349-55.
To determine the efficacy and safety of carvedilol for reducing mortality and hospitalization for cardiovascular reasons in patients with chronic heart failure (CHF).
Randomized, double-blind, placebo-controlled trial.
65 U.S. study sites.
1197 patients were enrolled and were assessed for carvedilol tolerance; 1094 patients (mean age 58 y, 77% men) were randomized. Inclusion criteria were symptomatic CHF and an ejection fraction of ≥ 2 months of treatment with diuretics and an angiotensin-converting enzyme inhibitor. Exclusion criteria were recent cardiovascular events or major surgery; valvular, hepatic, or renal disease; myocarditis; history of sudden death or advanced heart block; heart rate < 68 beats/min; or current use of calcium channel blockers, α- or β-adrenergic agonists or antagonists, or class Ic or III antiarrhythmic agents.
Usual medications were continued. Patients received open-label carvedilol for 2 weeks before assignment to placebo (n = 398) or carvedilol (n = 696). Patients were stratified into 4 protocol groups (mild heart failure protocol, moderate heart failure with a fixed-dose or a dose-ranging protocol, and severe heart failure protocol) on the basis of their exercise performance. The carvedilol dose was generally titrated up to a target dose of 25 to 50 mg twice daily, depending on drug tolerance.
Main outcome measures
Mortality, hospitalization for cardiovascular reasons, combined death and hospitalization using a time-to-first-event analysis, and adverse events.
Analysis was by intention to treat and used Kaplan-Meier survival curves. The study was stopped early because of reduced mortality; patients in the carvedilol group had lower mortality rates than patients in the placebo group (3.2% vs 7.8%, P < 0.001, a relative risk reduction of 65% [95% CI 39% to 80%]). Patients in the carvedilol group also had fewer hospitalizations for cardiovascular causes (14.1% vs 19.6%, P = 0.04) and a greater reduction in heart rate (P < 0.001). The combined rate for either death or hospitalization for cardiovascular reasons was lower in the carvedilol group (24.6% vs 15.8%, P < 0.001).
Carvedilol reduced mortality and hospitalizations for cardiovascular causes in patients with chronic heart failure.
Sources of funding: Smith Kline Beecham Pharmaceuticals and Boehringer-Mannheim Therapeutics.
For article reprint: Dr. M. Packer, Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. FAX 212-305-7439.
The study by Packer and colleagues provides hope and caution about the role of β-blockers in CHF. The results are intriguing but stop short of providing a clear answer for clinical use.
Previous studies of β-blockers in CHF showed that most patients tolerated a careful initiation of therapy, left ventricular function improved over time, and exercise tolerance was variably affected (1-3). Unfortunately, no large, randomized trial has shown a favorable reduction in mortality.
This study provides strong evidence that carvedilol can have a favorable influence on mortality that goes beyond that provided by conventional therapy. Carvedilol has unique characteristics that distinguish it from other β-blockers, including α-blockade and antioxidant properties. Whether these features account for the benefits reported cannot be determined from current data.
Unfortunately, we must remain cautious in applying these data clinically. The authors give a good rationale for having an open-label run-in phase. 67 patients were withdrawn during this phase because of adverse reactions that included 7 deaths. These 7 deaths, 12% of all deaths in the trial, were not included in the final analysis but cannot be presumed to be unrelated to carvedilol. Further, as the authors point out, this trial was done by a limited number of investigators using strict entry criteria and protocols. The titration of β-blockers in patients with CHF is difficult and requires meticulous attention. Finally, perhaps because few patients with severe CHF were included, only 53 deaths occurred in the entire study. In comparison, more than 1300 deaths occurred in landmark studies of angiotensin-converting enzyme inhibitors (4).
Clearly, carvedilol and β-blockers warrant continued attention and hope, but the data are currently insufficient to broadly change clinical practice. At this writing, carvedilol has not been released in the United States.
Barry K. Rayburn, MD
Bowman Gray School of MedicineWinston-Salem, North Carolina, USA