The effect of spironolactone on morbidity and mortality in patients with severe heart failure

Background and Methods Aldosterone is important in the pathophysiology of h eart failure, In a double-blind study, we enrolled 1663 patients who had se vere heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an a agiotensin-converting-enzy me inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 pa tients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was e fficacious, There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduct ion in the risk of death among patients in the spironolactone group was att ributed to a lower risk of both death from progressive heart failure and su dden death from cardiac causes. The frequency of hospitalization for worsen ing heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confi dence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failu re, as assessed on the basis of the New York Heart Association functional c lass (P<0.001). Gynecomastia or breast pain was reported in 10 percent of m en who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was m inimal in both groups of patients. Conclusions Blockade of aldosterone receptors by spironolactone, in additio n to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure. (N Engl J Med 1999:341:709 -17.) (C)1999, Massachusetts Medical Society.