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
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.