Elsevier

The Lancet

Volume 353, Issue 9169, 12 June 1999, Pages 2001-2007
The Lancet

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Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF)

https://doi.org/10.1016/S0140-6736(99)04440-2Get rights and content

Summary

Background

Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure.

Methods

We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0·40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12·5 mg (NYHA III-IV) or 25·0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat.

Findings

The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7·2%, per patient-year of follow-up]) vs 217 deaths [11·0 %], relative risk 0·66 [95% CI 0·53–0·81]; p=0·00009 or adjusted for interim analyses p=0·0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0·59 [0·45–0·78]; p=0·0002) and deaths from worsening heart failure (30 vs 58, 0·51 [0·33–0·79]; p=0·0023).

Interpretation

Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated. Lancet 1999;353: 2001–07

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.

Section snippets

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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