Enalapril for Congestive Heart Failure John Kjekshus, MD, PhD, and Karl Swedberg, MD, PhD, for The Consensus Trial Study Group In a randomized, double-blind trial, 253 patients with congestive heart failure (New York Heart As- sociation class IV) received either enalapril (n = 127) or placebo (n = 126) in addition to their exist- ing therapeutic regimens (consisting of digitalis, diuretics, and vasodilators other than angiotensin- converting enzyme inhibitors). The study was dis- continued prematurely for ethical reasons because of the much lower mortality among the patients re- ceiving enalapril (n = 50) than among those receiv- ing placebo (n = 68) (p <0.003). The important re- duction in mortality was observed among patients dying from progressive heart failure. Follow-up ranged from 1 day to 20 months (average IS8 days). The reduction in mortality was associated with general improvements in the symptoms and signs of left and right ventricular heart failure, re- duction of heart size, improvements in New York Heart Association classification, reduction of con- current cardiovascular medication, and reduction of hospital admissions and days spent in the hospital. The overall withdrawal rate was low, and was com- parable in the 2 treatment groups (16%; enalapril, n = 22, placebo, n = 18). Symptomatic hypotension was observed in 17% (n = 21) of the enalapril group vs 0% of the placebo group. Hypotension was the reason for withdrawal of enalapril therapy in 7 patients. After the initial dose of enalapril was reduced to 2.5 mg in high-risk patients, hypoten- sion necessitated withdrawal in only 3.2% of the patients. Hyperkalemia was observed exclusively among patients with concurrent use of potassium- sparing agents. At initiation of therapy, serum cre- atinine levels increased more frequently in the ena- lapril group than in the placebo group, but was the reason for withdrawal of treatment in only 3 and 2 patients, respectively. A long-term progressive in- crease in serum creatinine levels was not observed. Hyponatremia at baseline was associated with an increased risk for mortality in patients receiving placebo, but not in those receiving enalapril. It is concluded that enalapril, added to conventional therapy, reduces morbidity and mortality from se- vere progressive heart failure. (Am J Cardiol 1989;63:26D-32D) From the Department of Medicine, N-13 16 Baerum Hospital, Norway. This work was supported by a grant from Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey. Address for reprints: John Kjekshus, MD, PhD, Department of Medicine, N-1316 Baerum Hospital, Sandrika, Norway. 26D THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63 I n patients with congestive heart failure (CHF), the administration of angiotensin-converting enzyme in- hibitors (ACE) has been associated with hemody- namic and symptomatic improvement with long-term use.’ Furberg and Yusuf,2 pooling data from several stud- ies, found no conclusive effect on survival, but suggested that ACE inhibitors might improve prognosis. The study described here details the effect of enalapril on mortality in patients with severe CHF; the main results of this study have been published elsewheres3 METHODS This was a double-blind, parallel, randomized, place- bo-controlled, multicenter study conducted in Finland, Norway and Sweden. Patients were included if they were in New York Heart Association (NYHA) class IV CHF. The study was performed under the auspices of an inde- pendent Ethical and Safety Review Committee and a separate Steering Committee to handle administrative responsibilities. The active treatment period for each pa- tient was to last a minimum of 6 months and until the last patient entered had completed 6 months, The study was stopped prematurely by the Ethical and Safety Review Committee for ethical reasons after approximately 20 months. Treatment with enalapril or identically matched pla- cebo was begun in the hospital with 5 mg administered twice daily after informed consent had been obtained. After 67 patients had been randomized, the protocol was changed and high-risk patients (those with a serum sodi- um level <130 mmol/liter, a serum creatinine level of 150 to 300 pmol/liter, an increased dose of diuretics within the previous weeks, or treatment with potassium- sparing agents) were given an initial dose of 2.5 mg/day. If hypotension or an increase in serum creatinine levels did not occur after 3 to 4 days, the dose was increased to 2.5 mg twice daily for the remainder of the first week. After 1 week, therapy was increased to 10 mg twice daily if the patient was not symptomatically hypotensive or had other adverse effects. According to clinical response, a further increase could occur, up to a maximum dose of 20 mg twice daily. The patients were evaluated after 1, 2, 3, 6 and 16 weeks and thereafter at 6,9 and 12 months, as well as at the end of the study. If, at any time after week 3, the patient’s condition was deteriorating to a degree that the investigator be- lieved additional therapy was required, vasodilator thera- py (other than an ACE inhibitor) could be initiated in patients not already receiving such treatment, or a second vasodilator could be added to the regimens of those pa- tients already receiving vasodilatory therapy. A second vasodilator could be added only if the patient had re-