Carvedilol Or Metoprolol European Trial - COMET
The goal of the Carvedilol Or Metoprolol European Trial (COMET) was to evaluate mortality and morbidity between the multiple adrenergic inhibitor carvedilol and the beta-1-selective agent metoprolol among patients with moderate and severe chronic heart failure (CHF).
Investigators sought to compare the effects of carvedilol with metoprolol on the risk of death and death or hospitalization in patients with CHF.
Patients Enrolled: 3,029
NYHA Class: 48% NYHA class II; 48% class III; 4% class IV
Mean Follow Up: Mean 58 months
Mean Patient Age: Mean age 62 years
Mean Ejection Fraction: Mean 26% at baseline
NYHA class II-IV; cardiovascular event within the prior two years; stable diuretic treatment ≥2 weeks; ACE inhibitor ≥4 weeks prior to study entry; and left ventricular ejection fraction ≤35%
Cerebrovascular accident, acute MI or unstable angina in prior two months; untreated valve disease or arrhythmias; other life-threatening disease; and contraindication to beta-blocker therapy
All-cause mortality; all-cause mortality or all-cause hospitalization
Composite of all-cause mortality or cardiovascular hospitalization; composite of cardiovascular death, nonfatal acute myocardial infarction (MI), or heart transplantation; worsening of heart failure; cardiovascular death; and New York Heart Association (NYHA) class
Patients were randomized to carvedilol (target dose 25 mg twice daily; n=1,511) or metoprolol tartrate (target dose 50 mg twice daily; n=1,518). The metoprolol was an immediate-release formulation. The average daily dose of carvedilol received in the trial was 42 mg, and the average daily dose of metoprolol was 85 mg.
Diuretic (99% of patients), and angiotensin-converting enzyme (ACE) inhibitor (91% of patients)
The primary endpoint of all-cause mortality was lower in the carvedilol arm compared with the metoprolol arm (33.9% vs. 39.5%, hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.74-0.93, p=0.0017). Similar benefit was observed in the subgroup analyses. The co-primary endpoint of all-cause mortality or all-cause hospitalization did not reach statistical significance (73.9% vs. 76.4%, HR 0.93, 95% CI 0.86-1.10, p=0.1222). The annual mortality rate was 10% in the metoprolol arm versus 8.3% in the carvedilol arm, which resulted in a median 1.4 years' prolongation of survival in the trial.
Adverse events (AE) potentially related to beta-blockade were similar in both arms (bradycardia AE 9.5% vs. 8.9% and hypotension AE 14.2% vs. 10.5% for carvedilol and metoprolol, respectively). Secondary endpoint data have not yet been reported.
Among patients with moderate and severe CHF, treatment with carvedilol was associated with a significantly lower rate of the primary endpoint of all-cause mortality, but was not associated with a difference in the co-primary endpoint of all-cause mortality or all-cause hospitalization.
The COMET trial is the first randomized mortality trial to compare two beta-blockers in patients with CHF. The authors suggested that the lack of significant benefit in the co-primary endpoint of all-cause mortality or all-cause hospitalization may be in part due to the high proportion of patients who reached this endpoint, making it difficult to detect a difference between the two groups.
While the reduction in mortality in the carvedilol arm was highly significant, there has been some criticism of the immediate-release formulation of metoprolol tartrate used in the trial, which differs from the controlled-release formulation of metoprolol succinate used in the MERIT HF trial, the main trial showing a benefit of metoprolol compared with placebo in heart failure patients. Metoprolol differs from carvedilol in that metoprolol is a beta-1 blockade agent and carvedilol is a multiple adrenergic inhibitor.
1. Lancet 2003; 362: 7–13. Final results.
2. Presented at the European Heart Failure 2003, by Prof. Philip Poole-Wilson.
3. Poole-Wilson PA, Cleland JG, Di Lenarda A, et al. Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur J Heart Fail 2002;4:321-9.
4. Presented at the European Society of Cardiology, Vienna, Austria, September 2003.
Keywords: Diuretics, Hypotension, Propanolamines, Heart Rate, Adrenergic Antagonists, Carbazoles, Heart Failure, Stroke Volume, Bisoprolol, Bradycardia, Metoprolol, Hospitalization
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