RALES was a double-blind study which enrolled 1.663 patients with severe heart failure and a left ventricular ejection fraction of no more than 35 percent who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic and, in most cases, digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily and 841 to receive placebo. The primary end point of the study was death from all causes. The trial was discontinued early after a mean follow-up of 24 months because an interim analysis determined that spironolactone was efficacious. There were indeed 386 deaths in the placebo group (46%) and 284 in the spironolactone group (35%) (relative risk of death: 0.70; 95% confidence interval, 0.60-0.82; p < 0.001). The reduction of mortality among patients in the spironolactone group was attributable to a lower risk of sudden cardiac death and of death from progressive heart failure. Patients treated by spironolactone had a lower hospitalization rate for worsening heart failure; they also had a significant improvement in the symptoms of heart failure as assessed by the New York Heart Association functional class. Serious hyperkalemia was minimal in both groups of patients. Gynecomastia or breast pain was reported in 10% of men who were treated with spironolactone as compared with 1% of men in the placebo group (p < 0.001).