Fast track — ArticlesEffect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF)
Introduction
Chronic heart failure is a major disorder that is becoming increasingly prevalent as the proportion of elderly in the population increases.1 Although inhibitors of angiotensin-converting enzyme (ACE) have improved the treatment of heart failure, mortality related to this disorder remains unacceptably high.2, 3, 4 Prevalence remains high partly because current standard therapy does not prevent sudden cardiac death, which constitutes a high proportion of all deaths in patients with chronic heart failure.2, 3, 4
Results from studies started more than 25 years ago in Sweden suggested that long-term therapy with β-blockers, including metoprolol, could improve haemodynamics and increase survival in patients with heart failure secondary to idiopathic dilated cardiomyopathy.5, 6 Subsequent studies, including other β-blockers such as propranolol, timolol, bisoprolol, and carvedilol, corroborated and extended these early observations also in patients with ischaemic heart disease.7, 8, 9, 10, 11, 12 When the current study was planned there was no previously published study with power to prove survival benefit.
Metoprolol is a lipophilic β1-selective antagonist with no intrinsic sympathomimetic activity. In patients with chronic heart failure, metoprolol improves cardiac function, left-ventricular remodelling, and capacity for physical exercise, and lessens the symptoms of heart failure.9, 13 As with all β-blockers, patients can experience an initial negative inotropic effect that necessitates a low starting dose and an up-titration schedule.1
We did a large-scale randomised placebo-controlled trial to investigate whether metoprolol controlled release/extended release (CR/XL) once daily added to optimum standard therapy lowers mortality in patients with decreased ejection fraction and symptoms of heart failure.
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Patients and methods
We did the study at 313 investigational sites in 13 European countries and in the USA, according to a previously published description of the study design.14 The study was approved by local ethics committees. All patients gave written informed consent.
Results
The international steering committee stopped the study on Oct 31, 1998, on the recommendation of the independent safety committee. The second preplanned interim analysis (50%) showed that the predefined criterion for ending the study had been met and exceeded (Z=3·807 vs a boundary value of 2·98). 3980 patient-years were accumulated and the mean follow-up time was 1 year.
The two study groups were similar for baseline characteristics and concomitant therapies at entry (table). No patient was
Discussion
Once-daily metoprolol CR/XL added to optimum standard treatment with primarily ACE inhibitors and diuretics lessened all-cause mortality by 34% in clinically stable patients with symptomatic chronic heart failure and lowered ejection fraction in NYHA functional classes II-IV. Therefore, treatment of 27 patients with metoprolol CR/XL for 1 year can prevent one death.
Meta-analyses of previous smaller randomised placebo-controlled studies in heart failure patients, in which primary endpoints were
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Investigators and committee members listed at end of paper