Carvedilol or Metoprolol European Trial (COMET)

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Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.
Authors	Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, et al.
Journal	Lancet
Year/Volume(Issue)/Pages	2003;362(9377):7-13
Original Article Abstract
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Contents 1 Quick Summary 2 Hypothesis/Objectives 3 Methods/Design 3.1 Inclusion criteria 3.2 Exclusion criteria (major) 3.3 Design 4 Results 4.1 Baseline characteristics 4.2 Primary endpoint results 4.3 Other 5 Limitations

Quick Summary

• This study was performed as a survival study to determine if there were differences between two β-blocker treatments approved to treat chronic heart failure (CHF).
• Carvedilol 25 mg BID was compared to metoprolol tartrate 50 mg BID.
• Researchers found a statistically significant difference in all-cause mortality in favor of the carvedilol regimen.

Hypothesis/Objectives

The objective in this study was to directly compare carvedilol and metoprolol (in its short-acting formulation) in their effects on mortality and morbidity in patients with mild to severe symptomatic CHF. Participants in this study were already stabilized on ACE-inhibitor and diuretic treatment, unless contraindicated.

Methods/Design

		Y	Randomized?
		N	Controlled?
		N	Placebo-controlled?
		Y	Prospective?
		Y	Double-blind?
		*U = not reported

Inclusion criteria

• symptomatic (New York State Heart Association Class II-IV) CHF
• on stable (at least 4 weeks) ACE-inhibitor treatment unless contraindicated
• on diuretic (≥40 mg furosemide or equivalent) for at least 2 weeks
• LVEF ≤35% measured within the previous three months OR left ventricular end diastolic diameter > 6cm and a fractional shortening <20% as seen on EKG
• at least one cardiovascular hospital admission in the 2 years prior to study

Exclusion criteria (major)

• contraindication to β-blockers (e.g. asthma, COPD, heart block, etc.)
• unstable treatment regimen (change within the prior two weeks)
• treatment with non-dihydropyridine calcium channel blockers, class-I antiarrhythmic drugs, or amiodarone in a dose above 200 mg/day
• unstable angina, MI, coronary revascularization, or stroke within 2 previous months
• uncontrolled hypertension (systolic >170 mmHg and/or diastolic >105 mmHg)

Design

This was a parallel-group trial. Subjects were randomized to receive either 3.125 mg carvedilol twice daily or 5 mg metoprolol tartrate twice daily, which was subsequently titrated upward every two weeks as tolerated as follows: 3.125 mg to 6.25 mg to 12.5 mg to 25 mg for carvedilol; 5 mg to 12.5 mg to 25 mg to 50 mg for metoprolol. Investigators were encouraged to change ACE-inhibitor and diuretic doses in order to get the β-blocker to the maximal tolerated dose. Digoxin, angiotensin II receptor blockers, and other vasodilators could be used during the study. The goal time of follow-up was 5 years.

Results

Baseline characteristics

There were no reported differences in baseline characteristics between the two study groups. Authors did note an even distribution of NYHA class scores, mean age, and mean ejection fraction between groups.

Primary endpoint results

In regard to the first primary endpoint of all-cause mortality, 512 of 1511 (34%) subjects on carvedilol died, while 600 of 1518 (40%) on metoprolol died. This was a statistically significant difference in favor of carvedilol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). A mortality benefit was seen at the 6-month time point. With regard to the second primary endpoint of all-case mortality plus all-cause hospital admission, there was no difference between groups (74% carvedilol; 76% metoprolol, p=0.122).

Other

There was a statistically significant difference between groups in cardiovascular deaths in favor of carvedilol (29% versus 35% for metoprolol, hazard ratio 0.80 [95% CI 0.70-0.90], p=0.0004). Percentage of subjects taking maximal study doses of each drug was similar (75% for carvedilol, 78% for metoprolol). There were also similar rates of adverse events and discontinuations not due to death between groups.

Limitations

• There is concern over whether the proper maximal dose of metoprolol was used in this trial - the maximal dose of carvedilol indicated for CHF is 100 mg/day, while the maximal dose of metoprolol succinate, which is indicated for CHF, is 200 mg/day
• GlaxoSmithKline, maker of Coreg (brand name of carvedilol) did support this study
• β-blockers are common drugs used post-MI or in unstable angina patients; these patients were excluded in this trial
• Metoprolol tartrate is not available in a tablet less than 25 mg, making an initial dose of 5 mg in practice technically impossible to achieve