Randomized Aldactone Evaluation Study

Abbreviations ACE, angiotensin-converting enzyme AMI, acute myocardial infarction EPHESUS, eplerenone postacute myocardial infarction heart failure efficacy and survival study HF, heart failure LVEF, left ventricular ejection fraction NYHA. New York Heart Association RALES, randomized aldactone evaluation study. 

Pitt B, Zannad F Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N EnglJ Med 1999 341 709-717. 

In the Randomized Aldactone Evaluation Study (RALES) in 1663 patients with New York Heart Association (NYHA) class III (70%) or IV (30%) symptoms and an ejection fraction less than 35%, the addition of spironolactone 25 mg/day to conventional treatment (an ACE inhibitor, a loop diuretic, in most cases digoxin, and in 11% a beta-blocker) for an average of 24 months lowered the risk of all-cause mortality by 30% (from 46% to 35%), death from progressive heart failure, and sudden death (28). There were similar reductions in hospital admissions for worsening heart failure and for all cardiac causes. The magnitude of the overall effect was similar and additional to the proven benefit from ACE inhibition in severe heart failure. 

Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004 351(6) 543-51. 

PURSUIT Platelet Glycoprotein Ilb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy RALES Randomized Aldactone Evaluation Study SL sublingual... 

Zannad F, Alla F, Dousset B, et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure Insights from the randomized aldactone evaluation study. Circulation 2000 102 2700-2706 (erratum appears in Circulation 2001 103 476). 

Apart from the valuable benefit of aldosterone antagonism in hypertension, MR blockade has been shown to substantially reduce both morbidity and mortality among patients with severe chronic heart failure (CHF) and post-myocardial infarction (MI) in clinical trials [17, 18]. The Randomized Aldactone Evaluation Study (RALES) has shown that 26 mg spironolactone on average per day on top of existing standard therapy [i.e. an angiotensin-converting enzyme (ACE) inhibitor, aspirin and a loop diuretic] given to patients with severe heart failure (New York Heart Association class III or IV, left ventricular ejection fraction <35%) results in 30%... 

The sample of patients selected for a clinical trial may not be representative of the entire population of patients with that disease. Patients entered into a trial usually are selected according to the severity of their disease and other characteristics inclusion criteria) or are excluded because of coexisting disease, concurrent therapy, or specific features of the disease itself (exclusion criteria). It always is important to ascertain that the clinical characteristics of an individual patient correspond with those of patients in the trial. For example, the Randomized Aldactone Evaluation Study (RALES) showed that treatment with the mineralocorticoid-receptor antagonist spironolactone was associated with a 30% reduction in death in patients with severe congestive heart failure. Hyperkalemia, a potential adverse effect, was seen only rarely in this study, which excluded patients with serum creatinine levels >2.5 mg/dL. With the expanded use of spironolactone after RALES was published, numerous patients, many of whom did not meet the RALES inclusion criteria, developed severe hyperkalemia. Therefore, knowledge of the criteria for selecting the patients in a trial must inform the application of study results to a given patient. 

Administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients already receiving an ACE inhibitor who have an EF of 40% or less and either heart failure symptoms or a diagnosis of diabetes mellitus to reduce mortality. Aldosterone plays an important role in heart failure and MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, LV hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone blockers have been shown in experimental and human studies to attenuate these adverse effects." As discussed in Chap. 14, the benefit of aldosterone blockade in patients with stable, severe heart failure was highhghted in the Randomized Aldactone Evaluation Shidy (RALES), where spironolactone decreased the risk of all-cause mortahty." ... 

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