Effects of Metoprolol and Carvedilol on Cause-Specific Mortality
Effects of Metoprolol and Carvedilol on Cause-Specific Mortality
Background: β-Blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the β1-blocker metoprolol tartrate and the β1-, β2-, and a1-blocker carvedilol.
Methods: In a randomized double-blind design, 3029 patients with chronic congestive heart failure requiring diuretic therapy and with left ventricular dysfunction were randomized to treatment with carvedilol (n = 1511) or metoprolol tartrate (n = 1518) and titrated to target doses of 25 mg of carvedilol twice daily or 50 mg of metoprolol tartrate twice daily. The main outcome measures were total mortality and the combination of mortality or hospitalization for any cause. Secondary end points were cardiovascular death, combinations of morbidity and mortality, New York Heart Association class, worsening of heart failure, hospitalizations, and discontinuation of study therapy.
Results: A total of 512 and 600 patients in the carvedilol group and metoprolol group, respectively, died (hazard ratio [HR] 0.83, 95% CI 0.74-0.93, P = .0017). Cardiovascular death was reduced by carvedilol (HR 0.80, 95% CI 0.70-0.90, P = .0004). There were fewer sudden deaths and deaths caused by circulatory failure or by stroke in the carvedilol group. There was no difference in all-cause hospitalizations or in worsening heart failure between treatment groups. The incidence of fatal or nonfatal acute myocardial infarction was significantly lower in the carvedilol group (HR 0.71, 95% CI 0.52-0.97, P = .03). Discontinuations of study therapy were similar in the 2 groups.
Conclusion: Compared with metoprolol tartrate, carvedilol reduced cardiovascular mortality, sudden death, death caused by circulatory failure, death caused by stroke, as well as fatal and nonfatal myocardial infarctions.
β-Receptor blockers were considered several years ago to be contraindicated in chronic heart failure because of their negative inotropic effect. Waagstein et al reported a beneficial effect in patients with chronic heart failure caused by idiopathic dilated cardiomyopathy in 1975, and the first report of improved survival was published in 1979. Further studies of metoprolol and bisoprolol indicated benefit, but these studies included < 500 patients and were not sufficiently powered to demonstrate an effect on survival. Finally, an array of large trials has demonstrated a major mortality benefit by carvedilol, bisoprolol, and metoprolol-controlled release (CR) on survival of patients with chronic stable heart failure. Furthermore, both metoprolol CR and carvedilol have been shown to reduce hospitalizations and to improve symptoms assessed by New York Heart Association (NYHA) class. Another agent, bucindolol, did not reduce mortality in a large study of high-risk patients, and a study of xamoterol ended prematurely because of excess mortality. The 3 β-blockers that have demonstrated survival benefits have different β-adrenergic receptor actions. Metoprolol and bisoprolol are highly selective β1-receptor antagonists, whereas carvedilol, in addition to β1-receptor blockade, blocks β2- and α1-receptors. Given these potentially important differences, the COMET was designed to evaluate whether treatment with carvedilol would result in further improvement in mortality and morbidity when compared with metoprolol tartrate. The main result has previously been reported. In the current report, we describe the results of prespecified secondary end points.
Background: β-Blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the β1-blocker metoprolol tartrate and the β1-, β2-, and a1-blocker carvedilol.
Methods: In a randomized double-blind design, 3029 patients with chronic congestive heart failure requiring diuretic therapy and with left ventricular dysfunction were randomized to treatment with carvedilol (n = 1511) or metoprolol tartrate (n = 1518) and titrated to target doses of 25 mg of carvedilol twice daily or 50 mg of metoprolol tartrate twice daily. The main outcome measures were total mortality and the combination of mortality or hospitalization for any cause. Secondary end points were cardiovascular death, combinations of morbidity and mortality, New York Heart Association class, worsening of heart failure, hospitalizations, and discontinuation of study therapy.
Results: A total of 512 and 600 patients in the carvedilol group and metoprolol group, respectively, died (hazard ratio [HR] 0.83, 95% CI 0.74-0.93, P = .0017). Cardiovascular death was reduced by carvedilol (HR 0.80, 95% CI 0.70-0.90, P = .0004). There were fewer sudden deaths and deaths caused by circulatory failure or by stroke in the carvedilol group. There was no difference in all-cause hospitalizations or in worsening heart failure between treatment groups. The incidence of fatal or nonfatal acute myocardial infarction was significantly lower in the carvedilol group (HR 0.71, 95% CI 0.52-0.97, P = .03). Discontinuations of study therapy were similar in the 2 groups.
Conclusion: Compared with metoprolol tartrate, carvedilol reduced cardiovascular mortality, sudden death, death caused by circulatory failure, death caused by stroke, as well as fatal and nonfatal myocardial infarctions.
β-Receptor blockers were considered several years ago to be contraindicated in chronic heart failure because of their negative inotropic effect. Waagstein et al reported a beneficial effect in patients with chronic heart failure caused by idiopathic dilated cardiomyopathy in 1975, and the first report of improved survival was published in 1979. Further studies of metoprolol and bisoprolol indicated benefit, but these studies included < 500 patients and were not sufficiently powered to demonstrate an effect on survival. Finally, an array of large trials has demonstrated a major mortality benefit by carvedilol, bisoprolol, and metoprolol-controlled release (CR) on survival of patients with chronic stable heart failure. Furthermore, both metoprolol CR and carvedilol have been shown to reduce hospitalizations and to improve symptoms assessed by New York Heart Association (NYHA) class. Another agent, bucindolol, did not reduce mortality in a large study of high-risk patients, and a study of xamoterol ended prematurely because of excess mortality. The 3 β-blockers that have demonstrated survival benefits have different β-adrenergic receptor actions. Metoprolol and bisoprolol are highly selective β1-receptor antagonists, whereas carvedilol, in addition to β1-receptor blockade, blocks β2- and α1-receptors. Given these potentially important differences, the COMET was designed to evaluate whether treatment with carvedilol would result in further improvement in mortality and morbidity when compared with metoprolol tartrate. The main result has previously been reported. In the current report, we describe the results of prespecified secondary end points.
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