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Effects of Initiating Carvedilol in Patients With Severe Chronic Heart Failure
Results From the COPERNICUS Study
Henry Krum, MB, BS, PhD;
Ellen B. Roecker, PhD;
Paul Mohacsi, MD;
Jean L. Rouleau, MD;
Michal Tendera, MD;
Andrew J. S. Coats, MD;
Hugo A. Katus, MD;
Michael B. Fowler, MD;
Milton Packer, MD;
for the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group
JAMA. 2003;289:712-718.
Context  -Blockers remain underused despite their established utility for improving outcome in heart failure. Concerns that initiation of treatment produces few immediate benefits and may have important risks may be deterring widespread use.
Objective To evaluate the early effects of the -blocker carvedilol in patients with severe heart failure.
Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21 countries among 2289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25%.
Intervention Patients were randomly assigned to receive carvedilol, with start dosage of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for heart failure.
Main Outcome Measures Death, hospitalization, or permanent withdrawal from study drug, as well as adverse events during the first 8 weeks of treatment.
Results The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%).
Conclusions These data suggest that, in clinically euvolemic patients, the relation of benefit to risk during initiation of treatment with carvedilol is similar to that seen during long-term therapy with the drug. Our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of long-term clinical trials.
Author Affiliations: Monash University, Melbourne, Victoria, Australia (Dr Krum); University of Wisconsin, Madison (Dr Roecker); University Hospital, Bern, Switzerland (Dr Mohacsi); Silesian School of Medicine, Katowice, Poland (Dr Tendera); University Health Network and Mt Sinai Hospital, Toronto, Ontario, Canada (Dr Rouleau); Royal Brompton Hospital, London, England (Dr Coats); Universitaets Klinikum Luebeck, Luebeck, Germany (Dr Katus); Stanford University Medical Center, Stanford, Calif (Dr Fowler); and the College of Physicians and Surgeons, Columbia University, New York, NY (Dr Packer).
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