Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients With Heart Failure

The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Hjalmarson, Åke MD, PhD
Goldstein, Sidney MD
Fagerberg, Björn MD, PhD
Wedel, Hans PhD
Waagstein, Finn MD, PhD
Kjekshus, John MD, PhD
Wikstrand, John MD, PhD
El Allaf, Dia MD
Vítovec, Jirí MD, PhD
Aldershvile, Jan MD, PhD
Halinen, Matti MD, PhD
Dietz, Rainer MD
Neuhaus, Karl-Ludwig MD
Jánosi, András MD, DSc
Thorgeirsson, Gudmundur MD, PhD
Dunselman, Peter H. J. M. MD, PhD
Gullestad, Lars MD
Kuch, Jerzy MD
Herlitz, Johan MD, PhD
Rickenbacher, Peter MD
Ball, Stephen MD, PhD
Gottlieb, Stephen MD
Deedwania, Prakash MD

Author Affiliations: Department of Cardiology (Drs Hjalmarson, Waagstein, and Herlitz) and Wallenberg Laboratory for Cardiovascular Research (Drs Fagerberg and Wikstrand), Sahlgrenska University Hospital, and the Nordic School of Public Health (Dr Wedel), Göteborg, Sweden; Henry Ford Hospital, Detroit, Mich (Dr Goldstein); Department of Medicine, Rikshospitalet, Oslo, Norway (Drs Kjekshus); Baerums Sykehus, Baerum, Norway (Dr Gullestad); Service de Cardiologie et de Réanimation Cardiaque, Centre Hospitalier Hutois, Huy, Belgium (Dr El Allaf); 2 Interní Klinika, Fakultní Nemocnice, Brno, Czech Republic (Dr Vítovec); Department of Medicine B, Rigshospitalet, Copenhagen, Denmark (Dr Aldershvile); Accident and Emergency Department, Kuopio University Hospital, Kuopio, Finland (Dr Halinen); Franz-Volhard Klinik, Charité Campus, Berlin-Buch, Germany (Dr Dietz); Klinikum-Kassel, Medizinische Klinik II, Kassel, Germany (Dr Neuhaus); Szent János Hospital, Budapest, Hungary (Dr Jánosi); Department of Medicine, Landspítalinn, University Hospital, Reykjavík, Iceland (Dr Thorgeirsson); Department of Cardiology, St Ignatius Ziekenhuis, Breda, the Netherlands (Dr Dunselman); Department of Cardiology, Warsaw School of Medicine, Warsaw, Poland (Dr Kuch); Kardiologie, Kantonsspital Bruderholz, Bruderholz, Switzerland (Dr Rickenbacher); Institute for Cardiovascular Research, Leeds General Infirmary, Leeds, England (Dr Ball); Division of Cardiology, University of Maryland, Baltimore (Dr Gottlieb); and the Department of Veterans Affairs Medical Center, Fresno, Calif (Dr Deedwania).

Corresponding Author/Reprints: Björn Fagerberg, MD, PhD, Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden (e-mail: [email protected]).

JAMA: The Journal of the American Medical Association 283(10):p 1295-1302, March 8, 2000.

Context

Results from recent studies on the effects of β₁-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of β₁-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored.

Objective

To examine the effects of the β₁-blocker controlled-release/extended-release metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure.

Design

Randomized, double-blind controlled trial, preceded by a 2-week single-blind placebo run-in period, conducted from February 14, 1997, to October 31, 1998, with a mean follow-up of 1 year.

Setting

Three hundred thirteen sites in 14 countries.

Participants

Patients (n = 3991) with chronic heart failure, New York Heart Association (NYHA) functional class II to IV, and ejection fraction of 0.40 or less who were stabilized with optimum standard therapy.

Interventions

Patients were randomized to metoprolol CR/XL, 25 mg once per day (NYHA class II), or 12.5 mg once per day (NYHA class III or IV), titrated for 6 to 8 weeks up to a target dosage of 200 mg once per day (n = 1990); or matching placebo (n = 2001).

Main Outcome Measures

Total mortality or any hospitalization (time to first event), number of hospitalizations for worsening heart failure, and change in NYHA class, by intervention group; quality of life was assessed in a substudy of 741 patients.

Results

The incidence of all predefined end points was lower in the metoprolol CR/XL group than in the placebo group, including total mortality or all-cause hospitalizations (the prespecified second primary end point; 641 vs 767 events; risk reduction, 19%; 95% confidence interval [CI], 10%-27%; P<.001); total mortality or hospitalizations due to worsening heart failure (311 vs 439 events; risk reduction, 31%; 95% CI, 20%-40%; P<.001), number of hospitalizations due to worsening heart failure (317 vs 451; P<.001); and number of days in hospital due to worsening heart failure (3401 vs 5303 days; P<.001). NYHA functional class, assessed by physicians, and McMaster Overall Treatment Evaluation score, assessed by patients, both improved in the metoprolol CR/XL group compared with the placebo group (P =.003 and P =.009, respectively).

Conclusions

In this study of patients with symptomatic heart failure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.

JAMA.2000;283:1295-1302