Copyright © 1995 by the European Society of Cardiology.
© 1995 The European Society of Cardiology
ACE inhibitor co-therapy in patients with heart failure: Rationale for the Randomized Aldactone Evaluation Study (RALES)
Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School Ann Arbor, Michigan, U.S.A.
Correspondence: Bertram Pitt, MD, Professor and Associate Chariman, Department of Internal Medicine, Director, Cardiology, University of Michigan Medical Center, Room 3910 Taubman, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0366, U.S.A.
Angiotensin converting enzyme (ACE) inhibitor therapy in conjunction with loop diuretics and possibly, digoxin, is associated with a relatively high incidence of recurrent heart failure and death. Even high doses of ACE inhibitors may not completely suppress the renin-angiotensin-aldosterone system; aldosterone ‘escape’ may occur through non angiotensin II dependent mechanisms involving corticotropin, atrial natriuretic peptide, serum potassium, and deficient high-density lipoprotein cholesterol concentrations. Addition of spironolactone (an aldosterone receptor blocker) to an ACE inhibitor regimen causes marked diuresis and symptomatic improvement.
The Randomized Aldactone Evaluation Study (RALES) was organized to explore the role of combination therapy with spironolactone in patients with heart failure. Patients with New York Heart Association Functional Class II–IV heart failure and left ventricular ejection fractions 
40% who were on regimens comprising an ACE inhibitor, loop diuretic, and, possibly, digoxin were randomized to receive placebo or spironolactone in doses of 12·5, 25, 50, or 75 mg per day. Even at the lowest dose of spironolactone, a significant decrease in plasma N-terminal pro-atrial natriuretic peptide occurred, with concomitant increases in concentrations of plasma renin and urinary aldosterone. As prophylaxis for heart failure, a daily dose of 25 mg of spironolactone and monitoring of serwn potassium concentrations are recommended; symptomatic therapy in refractory or severe heart failure may require doses as high as 100 mg b.i.d.
The RALES Mortality Trial will follow up 1400 similar patients for 3 years to determine the effect of the addition of spironolactone on combined mortality and hospitalization for heart failure.
Key Words: Angiotensin converting enzyme inhibitors • aldosterone escape • heart failure • systolic left ventricular dysfunction • RALES • spironolactone
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