Beta-Blockers to Reduce Mortality in Patients with Systolic Dysfunction A Meta-Analysis
STUDY DESIGN: A systematic review was performed with meta-analysis where appropriate. We reviewed clinical trials with respect to the quality of the research methods, including patient population and end points. Two independent reviewers calculated relative risk, relative risk reduction, absolute risk reduction, and number needed to treat for the total mortality end point reported in each trial. A meta-analysis was performed.
DATA SOURCES: We searched pertinent indexing services and references from published articles for relevant literature. The selected clinical trials were randomized, double-blinded, and controlled, and included patients with systolic heart failure. Mortality was assessed as a primary or secondary end point.
OUTCOMES: measured The primary outcome was mortality.
RESULTS: Statistically and clinically significant improvement, including a statistically significant reduction in mortality, has been noted in patients receiving therapy with either bisoprolol, carvedilol, or metoprolol. Pooled analysis revealed a statistically significant reduction in the risk of total mortality (odds ratio [OR] MH=0.66; 95% confidence interval [CI], 0.58-0.75) and sudden death (ORMH=0.61; 95% CI, 0.5-0.75) for patients receiving b-blocker therapy.
CONCLUSIONS: All patients with New York Heart Association class II and III heart failure should receive b-blocker therapy with bisoprolol, carvedilol, or metoprolol. Additional clinical trials are ongoing and will provide further data on which patients receive the greatest benefit from therapy and which b-blocker may be preferred.
The annual mortality in patients with mildly symptomatic heart failure ranges from 5% to 10%. However, as symptoms progress in severity, annual mortality may reach 30% to 40%.1 Mortality remains high in patients maintained on standard therapy (including an angiotensin-converting enzyme [ACE] inhibitor1,2) in large part because of the impact of sudden cardiac death in patients with heart failure.3 Additional therapeutic agents are needed to improve survival for this patient population.1,3
Heart failure may be associated with either systolic or diastolic dysfunction. Patients with systolic dysfunction have poor left ventricular wall motion and an ejection fraction of less than 40%. Patients with diastolic dysfunction have a normal ejection fraction but a noncompliant left ventricular wall that impairs diastolic filling. The etiology of heart failure may be ischemic or nonischemic.1 Coronary artery disease,14 and hypertension are common etiologic factors.1
Beta-blocker therapy results in an acute negative inotropic effect.5 This acute effect led to the conventional belief that b-blockers were contraindicated in patients with heart failure.2,4 However, clinical trials have demonstrated beneficial effects of long-term b-blockade in patients with heart failure, including improvements in clinical status,6 heart failure symptoms,1 ventricular function,5 disease progression,7,8 and hospitalization.8-12 As a result of the identification of these beneficial effects, clinical trials have been conducted to assess the impact of b-blocker therapy on mortality.3,4,9,11-15 Our goal for this systematic review was to synthesize available data and determine whether b-blocker therapy reduces the risk of mortality in patients with systolic dysfunction.
Methods
Literature Search
Two independent searches of MEDLINE (1966 to February 2000) were conducted to identify published randomized double-blind controlled trials of b-blockers in patients with chronic heart failure. We used both Medical Subject Heading (MeSH) terms and key words to provide a broad search. The results were limited to English language articles involving human subjects and the publication type “clinical trial.” In addition to MEDLINE, we searched several other databases for relevant literature, including International Pharmaceutical Abstracts, Iowa Drug Information Service, Current Contents, and The Cochrane Library. We examined references from published clinical trials and reviewed articles to identify further potential articles for inclusion in our evaluation. Finally, the manufacturers of metoprolol (Novartis Pharmaceuticals Corporation, East Hanover, NJ), carvedilol (SmithKline Beecham Pharmaceuticals, Philadelphia, Pa), and bisoprolol (Lederle Laboratories, Philadelphia, Pa) were contacted in an effort to ensure that pertinent articles were identified and included.
We determined the criteria for inclusion before conducting the literature searches. Clinical trials were included if they were randomized, double-blinded, and controlled; if the patients had a diagnosis of systolic heart failure; and if they assessed mortality as a primary or secondary end point. They were excluded if the study duration was shorter than 3 months or if publication occurred before 1975.
We examined 280 articles or abstracts for our review. Although several clinical trials were not included because of study design issues (eg, lack of randomization or blinding), the majority (approximately 95%) were excluded because they lacked a mortality end point. None of the identified trials used an active comparator; therefore, all trials were placebo controlled. Ultimately, we identified 6 clinical trials3,9,11-14 meeting the criteria and used them in our analysis.
