cts treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.
Table 5. Results of COMET
End Point
Carvedilol
n = 1,511
Metoprolol
n = 1,518
Hazard Ratio
(95% CI)
All-cause mortality
34%
40%
0.83
0.74 – 0.93
Mortality + all hospitalization
74%
76%
0.94
0.86 – 1.02
Cardiovascular death
30%
35%
0.80
0.70 – 0.90
Sudden death
14%
17%
0.81
0.68 – 0.97
Death due to circulatory failure
11%
13%
0.83
0.67 – 1.02
Death due to stroke
0.9%
2.5%
0.33
0.18 – 0.62
It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL) with benefits in heart failure.
Severe Heart Failure (COPERNICUS)
In a double-blind trial, 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction less than 25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%), were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol: hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 6.
Table 6. Results of COPERNICUS Trial in Subjects with Severe Heart Failure
End Point
Placebo (n = 1,133)
Carvedilol (n = 1,156)
Hazard Ratio (95% CI)
% Reduction
Nominal P value
Mortality
190
130
0.65
(0.52 – 0.81)
35
0.00013
Mortality + all hospitalization
507
425
0.76
(0.67 – 0.87)
24
0.00004
Mortality + CV hospitalization
395
314
0.73
(0.63 – 0.84)
27
0.00002
Mortality + HF hospitalization
357
271
0.69
(0.59 – 0.81)
31
0.000004
Cardiovascular = CV; Heart failure =
