Fast track — ArticlesComparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial
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%
References (29)
- et al.
Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis
Am Heart J
(2001) - et al.
Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group
J Am Coll Cardiol
(1999) - et al.
Beta-blockade in heart failure: a comparison of carvedilol with metoprolol
J Am Coll Cardiol
(1999) - et al.
Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol
J Am Coll Cardiol
(2000) - et al.
Implications of trial results: the potentially misleading notions of number needed to treat and average duration of life gained
Lancet
(2000) - et al.
Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy
Lancet
(1993) - et al.
Dose of Metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF)
J Am Coll Cardiol
(2002) - et al.
The epidemiology of heart failure
Eur Heart J
(1997) - et al.
Guidelines for the diagnosis and treatment of chronic heart failure
Eur Heart J
(2001) - et al.
Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure: collaborative Group on ACE Inhibitor Trials
JAMA
(1995)
The effect of carvedilol on morbidity and mortality in patients with chronic heart failure
N Engl J Med
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial
Lancet
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
Lancet
Effect of carvedilol on survival in severe chronic heart failure
N Engl J Med
Cited by (1640)
Potential of β<inf>2</inf>AR for added benefit in treating heart failure through a better understanding of signaling
2023, Current Opinion in PhysiologyTip loaded cyclodextrin-carvedilol complexes microarray patches
2023, Carbohydrate PolymersEditorial commentary: Resting heart rate and outcomes: Risk marker or risk factor?
2023, Trends in Cardiovascular Medicine
Members listed at end of report