Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study.
BACKGROUND
Beta-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 beta-blocker carvedilol in patients with severe heart failure.


METHODS
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%.


METHODS
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.


METHODS
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or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03).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.
Krum
Henry
H
Dept of Medicine and Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, 3181 Australia. henry.krum@med.monash.edu.au
Roecker
Ellen B
EB
Mohacsi
Paul
P
Rouleau
Jean L
JL
Tendera
Michal
M
Coats
Andrew J S
AJ
Katus
Hugo A
HA
Fowler
Michael B
MB
Packer
Milton
M
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077261:Carvedilol; D004311:Double-Blind Method; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D011412:Propanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012306:Risk; D016019:Survival Analysis; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol