"Enalapril for Chronic Heart Failure with Reduced Ejection Fraction". The New England Journal of Medicine. 1991. 325(5):293-302.

Clinical Question

Does enalapril reduce mortality and hospitalization in patients with chronic congestive heart failure and low ejection fractions (≤0.35)?

Bottom Line

Enalapril, in addition to conventional therapy for heart failure, significantly reduced both mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and low ejection fractions.

Major Points

Congestive heart failure (CHF) carries a high mortality rate and frequent hospitalizations. Previous studies suggested benefits from vasodilator therapy. This study aimed to assess the effect of the ACE inhibitor enalapril on mortality in patients with CHF and ejection fractions ≤0.35.

Guidelines

No specific guidelines were mentioned in this study.

Design

Multicenter, double-blind, randomized, placebo-controlled trial.

Population

Patients with CHF (n=2569; placebo=1284, enalapril=1285) with ejection fractions ≤0.35.

Inclusion Criteria:
- CHF on conventional therapy, not including ACE inhibitors.
- Ejection fractions ≤0.35 by various measures (radionuclide, contrast angiography, or echocardiography).
- Enrolled between June 1986 and March 1989.

Exclusion Criteria:
- Over 80 years, hemodynamically significant valvular disease, unstable angina, recent MI (<1 month), severe pulmonary disease, creatinine >2 mg/dL, and other conditions limiting survival or trial participation.

Interventions

- Placebo or enalapril 2.5 to 20 mg per day, with titration based on tolerability.
- Initial two-week dosing, followed by 14-17 days of placebo for stabilization.

Outcomes

Primary Outcomes:
- Total mortality: 510 deaths (39.7%) in placebo vs. 452 (35.2%) in enalapril group (risk reduction 16%; P=0.0036).
- Death attributed to progressive heart failure was reduced by 22% (P=0.0045).

Secondary Outcomes:
- Fewer patients in the enalapril group (n=613) died or were hospitalized for worsening CHF compared to placebo (n=736); risk reduction 26% (P<0.0001).

Criticisms

- The effect of enalapril was less clear in patients with ejection fractions >0.30 and those in NYHA class IV.
- Open-label ACE inhibitors were allowed during the trial, potentially confounding results.
- Higher incidence of non-fatal gastrointestinal system neoplasms in the enalapril group, although this may have been due to detection bias.

Funding

National Heart, Lung and Blood Institute and a gift from Merck Sharp and Dohme, which did not participate in the study design, conduct, monitoring, or analysis.

Further Reading

No further readings were provided.