Enalapril increased survival in patients with reduced left ventricular ejection fraction and congestive heart failure
ACP J Club. 1991 Nov-Dec;115:67. doi:10.7326/ACPJC-1991-115-3-067
The Studies of Left Ventricular Dysfunction Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991 Aug 1;325:293-302.
To investigate whether an angiotensin-converting-enzyme inhibitor, enalapril, increases survival and reduces the frequency of hospitalization in patients with mild-to-moderate congestive heart failure and ejection fractions ≤ 0.35.
Randomized, double-blind, placebo-controlled study.
23 centers including 83 hospitals in North America and Belgium.
39 924 patients with an ejection fraction ≤ 0.35 were screened between April 1986 and March 1989. Patients were excluded for contraindications for use of angiotensin-converting-enzyme inhibitors, age > 80 years, valvular disease requiring surgery, unstable angina pectoris, angina requiring revascularization, myocardial infarction in previous month, severe pulmonary disease, serum creatinine level > 177 µmol/L, presence of any other disease that would curtail follow-up, or an inability to tolerate the drug or comply during a run-in period. 2569 patients were randomized; 2 patients were lost to follow-up.
Patients received either placebo (n = 1284) or enalapril (n = 1285), 2.5 mg or 5 mg twice daily, titrated to a maximum of 10 mg twice daily in the absence of symptomatic hypotension or worsening renal function. Follow-up visits were after 2, 6, and 16 weeks, then every 4 months.
Main outcome measures
Death and number of hospitalizations.
Length of follow-up ranged from 22 to 55 months. There were 452 deaths in the enalapril group and 510 in the placebo group during 48 months of follow-up (risk reduction 16%, 95% CI 5% to 26%, P = 0.004). There were 399 and 461 cardiovascular deaths in the enalapril and placebo groups, respectively (risk reduction 18%, CI 6% to 28%). 48% of the enalapril group and 57% of the placebo group died or were hospitalized for worsening congestive heart failure (risk reduction 26%, CI 18% to 34%, P < 0.001). The mortality difference was seen only in patients who were hospitalized at least once. Benefit was seen with enalapril independent of baseline sodium level, use of other vasodilators, and cause of congestive heart failure. Benefit was less among patients with ejection fractions between 30% and 35%.
The addition of enalapril, an angiotensin-converting-enzyme inhibitor, to conventional therapy for heart failure caused led to an increase in survival and a reduction in hospitalizations among patients with ejection fractions ≤ 0.35 and congestive heart failure.
Sources of funding: National Heart, Lung, and Blood Institute and Merck Sharp & Dohme.
Address for article reprint: Dr. S. Yusuf, Clinical Trials Branch, National Heart, Lung, and Blood Institute, Federal Building, Room 5CO8, 7550 Wisconsin Avenue, Bethesda, MD 20892, USA.
This large, important, and well-designed clinical trial significantly extends knowledge gained from the first Cooperative North Scandinavian Enalapril Survival Study (1), which showed improved survival when enalapril was added to standard therapy for severe heart failure. Now, enalapril has been shown to be effective in decreasing hospitalizations and extending survival in persons with mild-to-moderate heart failure. In another important trial also involving persons with mild-to-moderate heart failure, the second Vasodilator-Heart Failure Trial (2), enalapril was superior to a combination regimen of hydralazine and nitrates in enhancing survival. These 3 critical studies cement enalapril as a cornerstone therapy for persons with symptomatic heart failure.
Several issues are worth noting in the present study. 80% of subjects were white men. 11% of screened subjects had contraindications to use of ACE inhibitors, and 4% of those meeting initial eligibility criteria were excluded during a run-in phase because of worsening renal function, symptomatic hypotension, or noncompliance. Side effects such as dizziness, fainting, or cough were reported in 87% of patients receiving enalapril compared with 82% receiving placebo. Finally, one third of those originally assigned to enalapril had stopped taking blinded medication by the end of the study, and 49% of the remainder were receiving enalapril doses of 10 mg twice daily, the maximum dose.
Enalapril is an important therapeutic agent that improves survival in a broad spectrum of patients with symptomatic congestive heart failure.
Cynthia Mulrow, MD, MSc
Audie L. Murphy Memorial Veterans HospitalSan Antonio, Texas, USA
1. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-35.