Elsevier

The Lancet

Volume 362, Issue 9377, 5 July 2003, Pages 7-13
The Lancet

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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

https://doi.org/10.1016/S0140-6736(03)13800-7Get rights and content

Summary

Background

β blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome.

Methods

In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat.

Findings

The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 [95% CI 0·74–0–93], p=0–0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 [0·86–1–02], p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups.

Interpretation

Our results suggest that carvedilol extends survival compared with metoprolol.

Introduction

Chronic heart failure is common,1 readily diagnosed, the cause of disabling symptoms, has a poor prognosis, and consumes about 2% of the total health budget in developed countries.

Therapeutic strategies for chronic heart failure are based on the notions of restriction of fluid retention and inhibition of activation of neurohumoral systems, notably the renin-angiotensin pathway and the sympathetic system. Guidelines recommend a combination of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and β blockers with or without digoxin as a basis for treatment.2 Aldosterone inhibitors are often used in patients with more severe heart failure. Results of large clinical trials have shown that although treatment with ACE inhibitors lessens admissions and improves survival,3 morbidity and mortality remain high. Addition of a β blocker further reduces mortality4, 5, 6, 7, 8 and has various effects on symptoms.9, 10, 11 Many mechanisms for the benefits of these drugs have been put forward.

β blockers have different pharmacological profiles, for example adrenergic receptor selectivity and the presence of ancillary properties. Metoprolol and bisoprolol have a high specificity for the β-1 adrenergic receptor. Carvedilol blocks β-1, β-2, and α-1 adrenergic receptors.12 Bucindolol did not have a mortality benefit in chronic heart failure.13 Results of a meta-analysis14 suggested that carvedilol was associated with a greater increase in left-ventricular ejection fraction than metoprolol. Several other small studies12, 15, 16, 17 have suggested that carvedilol is more effective than metoprolol in terms of remodelling and central haemodynamics, but the two drugs are similar in their effect on quality of life10 or peak oxygen consumption.15,16 Carvedilol has several other effects that might be advantageous in heart failure. It increases insulin sensitivity whereas metoprolol has the opposite effect.18 The antioxidant action of carvedilol19 might improve endothelial dysfunction and prevent apoptosis, mechanisms that could be important in the progression of chronic heart failure.20

We designed the Carvedilol Or Metoprolol European Trial (COMET) to compare directly the effects of carvedilol and metoprolol on mortality and morbidity in patients with mild to severe chronic heart failure.

Section snippets

Design

COMET was a multicentre, randomised, double-blind, parallel-group trial to compare the effect on mortality and morbidity of carvedilol and metoprolol in patients with chronic heart failure. A detailed description of the study design has been published, including the method of randomisation, monitoring, and follow-up.21 The study was done in 15 European countries, involving 341 centres, of which 317 contributed at least one patient. During the trial one centre was withdrawn from the study

Results

Of 3029 patients, 1511 (50%) were assigned to treatment with carvedilol and 1518 (50%) to metoprolol (figure 1). The mean study duration was 58 months (SD 6). Five patients were lost to follow-up and a further 28 patients withdrew their consent to further follow-up during the course of the study. All other patients were followed up to death or study end.

Table 1 shows the baseline characteristics. The mean age was 62 years (11) and the mean ejection fraction 0·26 (0·07). Patients were evenly

Discussion

Our results suggest that carvedilol used for treatment of chronic heart failure, in patients optimally treated with diuretics and ACE inhibitors, has a significantly greater beneficial effect on survival than metoprolol. The absolute reduction in mortality over 5 years was 5·7%. Survival times were consistent with a constant hazard in each group permitting estimation of median survival. Extrapolation from the survival curves suggested that carvedilol extended median survival by 1·4 years (95%

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