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Carvedilol Or Metoprolol European Trial - COMET
Description:
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).
Hypothesis:
Investigators sought to compare the effects of carvedilol with metoprolol on the risk of death and death or hospitalization in patients with CHF.
Study Design
Study Design:
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
Female: 20%
Mean Ejection Fraction: Mean 26% at baseline
Patient Populations:
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%
Exclusions:
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
Primary Endpoints:
All-cause mortality; all-cause mortality or all-cause hospitalization
Secondary Endpoints:
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
Drug/Procedures Used:
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.
Concomitant Medications:
Diuretic (99% of patients), and angiotensin-converting enzyme (ACE) inhibitor (91% of patients)
Principal Findings:
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.
Interpretation:
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.
References:
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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