Randomized Aldactone Evaluation Study - RALES
RALES assessed the mortality effect of spironolactone, an aldosterone receptor blocker, used with standard therapy, vs placebo in severe heart failure.
Daily treatment with 25 mg of spironolactone would significantly reduce the risk of death from all causes among patients who had severe heart failure as a result of systolic left ventricular dysfunction and who were receiving standard therapy, including an ACE inhibitor if tolerated.
Patients Enrolled: 1,663
NYHA Class: Class III 71%; Class IV 29%
Mean Follow Up: mean follow-up 24 months
Mean Patient Age: not reported
Mean Ejection Fraction: Baseline ejection fraction: placebo arm=25.2%, spironolactone arm=25.6%
NYHA class IV heart failure <=6 months before enrollment NYHA class III or IV at the time of enrollment Given diagnosis of heart failure <=6 weeks before enrollment Current treatment with an ACE inhibitor (if tolerated) and a loop diuretic Left ventricular ejection fraction of <=35 percent within the 6 months before enrollment (with no clinically significant intercurrent event)
Primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure) Congenital heart disease Unstable angina Primary hepatic failure Active cancer Any life-threatening disease (other than heart failure). Heart transplantation or awaiting the procedure. Serum creatinine concentration >2.5 mg/dL Serum potassium concentration >5.0 mmol/L.
Death from any cause
Death from cardiac causes Hospitalization for cardiac causes Combined incidence of death from cardiac causes or hospitalization for cardiac causes Change in the NYHA class
25 mg of spironolactone once daily or a matching placebo. After 8 weeks of treatment, the dose could be increased to 50 mg once daily if the patient showed signs or symptoms of progression of heart failure without evidence of hyperkalemia. If hyperkalemia developed at any time, the dose could be decreased to 25 mg every other day; however, the investigator was encouraged first to adjust the doses of concomitant medications.
ACE inhibitor, loop diuretic, and digoxin
The trial was stopped early because the observed beneficial effect of spironolactone on the risk of death from all causes exceeded the prespecified discontinuation requirements. Mortality was 46% in the placebo group and 35% in the spironolactone group (RR, 0.70, p<0.001). Most of the 30% mortality reduction in the spironolactone group was due to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The mortality reduction in the spironolactone group was similar in analyses of all prespecified subgroups as well as in retrospective analyses performed according to sex, NYHA class, base-line serum potassium concentration, use of potassium supplements, and use of beta-blockers. Hospitalization for worsening heart failure was 35% lower in the spironolactone group than in the placebo group (RR 0.65, p<0.001). Symptoms of heart failure were significantly improved in spironolactone patients (NYHA class improvements, placebo 33% vs spironolactone 41%, p<0.001). Gynecomastia or breast pain was reported in 10% of men treated with spironolactone vs 1% of men in the placebo group (p<0.001). No other differences in safety or adverse event reports were observed.
Use of spironolactone in severe heart failure was associated with a reduction in mortality and rehospitalization and improved symptoms of heart failure without increasing safety events. The 35 percent reduction in the risk of hospitalization for worsening heart failure may be attributable to the ability of spironolactone to reduce myocardial and vascular fibrosis. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, should be considered for the treatment of patients with severe heart failure.
N Engl J Med 1999;341:709-717.
Keywords: Mineralocorticoid Receptor Antagonists, Death, Sudden, Hyperkalemia, Spironolactone, Sodium Potassium Chloride Symporter Inhibitors, Gynecomastia, Potassium, Research Personnel, Receptors, Mineralocorticoid, Heart Failure, Mastodynia, Stroke Volume, Respiratory Sounds, Ventricular Dysfunction, Left
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