This report will be published in the September 2 issue of The New England Journal of Medicine We enrolled 1663 patients with severe heart failure and an EF of no more than 35%. All patients were being treated with an ACE inhibitor, a loop diuretic such as Lasix, and in some cases digoxin. 822 patients took 25mg of spironolactone daily and 841 took placebo. The primary endpoint was death from all causes. The trial was stopped early, after an average follow-up period of 2 years. There were 386 deaths in the placebo group (46%) and 284 deaths in the spironolactone group (35%). This 30% reduction in the risk of death among patients in the spironolactone group was from a lower risk of death from both progressive heart failure and sudden cardiac death. The frequency of hospitalization for worsening heart failure was 35% lower in the spironolactone group than in the placebo group. Also, patients who took spironolactone had a significant improvement in their heart failure symptoms, measured by functional heart class. Breast pain was reported by 10% of men taking spironolactone. CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of complications and death among patients with severe heart failure. ----------------- Aldosterone promotes sodium retention, magnesium and potassium loss, sympathetic activity, vascular fibrosis, baroreceptor dysfunction and impairs arterial compliance. Many doctors have assumed that using an ACE inhibitor to supress the renin-angiotensin-aldosterone system will also suppress aldosterone. Giving an aldosterone-receptor blocker like Aldactone in addition to an ACE inhibitor has been considered incorrect because of the potential for serious potassium level problems (hyperkalemia - too much potassium). However, there is increasing evidence that ACE inhibitors only temporarily suppress aldosterone production. Also, treatment with spironolactone at a daily dose of 12.5 to 25mg, added to standard doses of an ACE inhibitor and a loop diuretic, is well tolerated, lowers atrial natriuretic peptide levels and does not lead to serious potassium level problems. The Randomized Aldactone Evaluation Study (RALES) tested the theory that daily treatment with 25mg of spironolactone would reduce the risk of death from all causes in CHF patients with systolic left ventricular dysfunction and who were receiving standard therapy, including an ACE inhibitor. The trial began on March 24, 1995 and was stopped on August 24, 1998, on the recommendation of the data and safety monitoring board. Patients had class 4 heart failure within the 6 months before enrollment and were in class 3 or 4 at time of enrollment. They were being treated with an ACE inhibitor and a loop diuretic, and had an ejection fraction of no more than 35% in the 6 months before enrollment. Treatment with digoxin and vasodilators was allowed but potassium-sparing diuretics were not permitted. Oral potassium supplements were not recommended unless hypokalemia (too low level of potassium) developed. Patients were randomly assigned to take either 25mg of spironolactone (Aldactone by Searle) once daily or a placebo. After 8 weeks of treatment, the dose could be increased to 50mg once daily if the patient showed signs progressing heart failure without evidence of hyperkalemia. If hyperkalemia developed at any time, the dose could be decreased to 25mg every other day. Laboratory measurements, including measurements of blood potassium level, were done every 4 weeks for the first 12 weeks, then every 3 months for one year, and every 6 months after that until the end of the study. Additional tests were also done at weeks one and 5. The primary endpoint of the study was death from any cause. Secondary endpoints included death from cardiac causes, hospitalization for cardiac causes, and change in heart class. The effect of spironolactone was also measured by: ejection fraction, cause of heart failure, serum creatinine concentration, age, ACE inhibitor use, and digoxin use. 1663 patients from 195 centers in 15 countries participated. 841 took placebo and 822 took spironolactone. During the study, 414 patients (200 in the placebo group and 214 in the spironolactone group) stopped out of treatment because of a lack of response, because of adverse events, or for administrative reasons. Treatment was stopped in another 19 patients due to need for heart transplant. Patients who stopped treatment were followed by means of regular telephone calls to determine their status. After 24 months of follow-up, the average daily drug dose was 31mg in the placebo group and 26mg in the spironolactone group. There were 386 deaths in the placebo group (46%) and 284 deaths in the spironolactone group (35%), representing a 30% reduction in the risk of death. 314 deaths in the placebo group (37%) and 226 deaths in the spironolactone group (27%) were from cardiac causes, representing a 31% reduction in the risk of death from cardiac causes. The reduction in risk of death was studied in respect to gender, heart class, base-line potassium level, use of potassium supplements, and use of beta-blockers. Benefit was the same in each analysis. The benefit was similar across geographic regions. 336 patients in the placebo group and 260 patients in the spironolactone group were hospitalized at least once for cardiac reasons. Altogether, there were 753 hospitalizations for cardiac causes in the placebo group and 515 in the spironolactone group, representing a 30% reduction in hospitalization for cardiac causes among patients in the spironolactone group. Analysis of the combined endpoint of death OR hospitalization for cardiac causes showed a 32% reduction in risk of this endpoint among patients in the spironolactone group compared to the placebo group. We used 3 categories to label changes in CHF symptoms: improvement, no change, and worsening or death. In the placebo group, the condition of 33% of the patients improved; it did not change in 18%, and it worsened in 48%. In the spironolactone group, the condition of 41% of the patients improved; it did not change in 21%, and it worsened in 38%. There were no significant differences between groups in blood sodium level, blood pressure, or heart rate. The average creatinine and potassium levels did not change in the placebo group during the first year of follow-up. During that same period, however, both the average creatinine and potassium levels in the spironolactone group increased. Serious hyperkalemia occurred in 10 patients in the placebo group (1%) and 14 patients in the spironolactone group (2%). Breast pain was reported by 10% of the men in the spironolactone group and one percent of the men in the placebo group. Discussion We found that treatment with spironolactone reduced the risk of death from all causes, death from cardiac causes, hospitalization for cardiac causes, and combined endpoint of death or hospitalization for cardiac causes among patients with severe heart failure, who were receiving standard therapy including an ACE inhibitor. Spironolactone also improved CHF symptoms, as measured by changes in functional heart class. The reductions in the risk of death and hospitalization were seen after 2 to 3 months of treatment and persisted throughout the study. Serious hyperkalemia was uncommon, occurring in one patient in the placebo group and 3 in the spironolactone group. The patients in our study were at higher risk than those in studies of bisoprolol, digoxin, amlodipine, or carvedilol on heart failure, but they were at lower risk than patients in a study of enalapril (Vasotec). Our study results are consistent with the current understanding of the effect of aldosterone in CHF patients. Aldosterone was originally thought to be important in the heart failure only because of its ability to increase sodium retention and potassium loss. However, recent research has shown that aldosterone also causes heart and blood vessel fibrosis, direct blood vessel damage, baroreceptor dysfunction, and prevents the uptake of norepinephrine by the heart. The reduction in risk of death in our study does not seem to be due entirely to an effect of spironolactone on sodium retention or potassium loss. Spironolactone may be cardio-protective. In our previous dose-finding study, a daily 25mg dose of spironolactone had no apparent diuretic effect - that is, there was no change in total body weight, sodium-retention score, or urinary sodium excretion. In the present study, a 26mg daily spironolactone dose did not have much effect on the heart's mechanical functioning. Although we cannot rule out spironolactone having some effect on sodium retention in our study, this effect would be small, compared with the high doses of loop diuretics used. Also, although there was a significant increase in blood potassium levels in our spironolactone group, the change was not clinically important. The 35% reduction in risk of hospitalization for worsening heart failure may be due to spironolactone reducing cardiac and blood vessel fibrosis. Although the exact cause of the risk reduction in our study is unknown, we think that spironolactone can slow progressive heart failure by slowing sodium retention and fibrosis, and prevent sudden death from cardiac causes by slowing potassium loss and by increasing myocardial uptake of norepinephrine. Spironolactone may avert myocardial fibrosis by blocking the effects of aldosterone on the collagen formation, which in turn could reduce risk of sudden death from cardiac causes, since myocardial fibrosis may predispose patients to ventricular arrhythmia. Few patients (11%) in the spironolactone group were taking a beta-blocker at the study's start, and the reduction in risk of death did not differ between those who were treated with a beta-blocker and those who were not. Since our patients were at higher risk than patients in recent studies of beta-blockers in heart failure, more studies are needed to test the tolerability and effectiveness of beta-blockers in such a high-risk population AND the effects of combined spironolactone and beta-blocker use. Our finding that an aldosterone-receptor blocker reduced risk of both complications and death among patients who were taking an ACE inhibitor emphasizes the point that standard doses of an ACE inhibitor may not effectively suppress aldosterone production. Although higher doses of ACE inhibitors are more effective than lower doses in reducing risk in CHF patients, there is no evidence that higher doses suppress aldosterone production more effectively in the long run. ACE inhibitors cannot totally suppress aldosterone production, because other factors besides angiotensin 2 (like blood potassium level) are important and may override the effects of angiotensin 2. Since aldosterone remains in the blood, only the presence of an aldosterone-receptor blocker will completely suppress the effects of this hormone. We found that spironolactone at a dose of 12.5 to 25mg daily was effective in blocking aldosterone receptors and decreasing atrial natriuretic peptide levels, and that serious hyperkalemia happened most often with daily doses of 50mg or greater. It should be noted, however, that a blood creatinine level of more than 2.5mg per deciliter and a blood potassium level of more than 5mmol per liter excluded patients from our study. Also, long-term use of drugs known to interact with spironolactone or increase the risk of hyperkalemia were not allowed. Although potassium supplements were used by 29% of the patients in our spironolactone group, the benefit of the drug in these patients was similar to that in patients who did not use potassium supplements. Overall, spironolactone therapy was tolerated well: 8% of the patients in the spironolactone group stopped treatment due to adverse events, compared to 5% of the placebo patients. This was largely due to breast pain among men in the spironolactone group. The use of a selective aldosterone-receptor antagonist such as eplerenone, which has less affinity for androgen and progesterone receptors, may minimize this side effect. The effectiveness and risks of treatment with spironolactone in patients with less severe heart failure, will require further study. Supported by a grant from Searle, the drug's manufacturer. Preliminary data were presented at the American Heart Association meeting, Dallas, November 8-11, 1998.