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NewsletterSpironolactone for the Treatment of Congestive Heart FailureSCA Newsletter -- October 2001Reviewers: D. Joshua Mancini and Albert T. Cheung, MD
Congestive heart failure (CHF) affects approximately 400,000 new patients every year and has a prevalence of approximately 4.6 million patients.1 Despite advances in care, patients with CHF require frequent hospitalizations and have an average 5 year survival rate of only 50%. Recent studies have established an important role of neurohumoral factors in the pathophysiology of CHF. Medical therapy directed at attenuating the neuroendocrine responses to heart failure such as beta-adrenergic antagonists and angiotensin converting enzyme (ACE) inhibitors have already demonstrated improved survival and reductions in morbidity. Although activation of the renin-angiotensin-aldosterone system has been well recognized as an important contributor to the development of heart failure, the potential benefits of blocking aldosterone in this disease has only recently been explored. It was originally believed that ACE inhibitors suppressed the release of aldosterone, but recent evidence indicated that aldosterone levels increased in patients with CHF despite suppression of angiotensin II. This aldosterone escape was believed to be caused by the other activators of aldosterone release such as increased serum potassium levels and salt restriction combined with decreased hepatic clearance of aldosterone in CHF. 1,2 Aldosterone was traditionally believed to act only on the kidneys to increase sodium and bicarbonate retention, promote potassium and hydrogen excretion, and exert a relatively minor role in water retention. It is now understood that aldosterone has profound and wide ranging actions on the cardiovascular system. 1,2,3 Aldosterone has been shown to mediate myocardial and vascular fibrosis, endothelial dysfunction, baroreceptor dysfunction, thrombotic phenomena, catecholamine potentiation, parasympathetic suppression, sodium retention, potassium and magnesium loss, and central pressor effects. These actions of aldosterone can contribute to hypertension, cardiac arrhythmias, ventricular remodeling, and fluid retention associated with heart failure. Spironolactone, with the trade name, Aldactone, was originally developed in the early 1970's as a competitive antagonist of aldosterone for the treatment of hyperaldosteronism, edematous states, and hypokalemia.3 Spironolactone has a chemical structure similar to other steroids but with a lactone substituent at C-17. It has excellent oral bioavailability of 90%, a limited first pass effect, and a steady state half-life of approximately 1.4 hours. Canrenoate and canrenone are its principal pharma-cologically active metabolites. Spironolactone acts not only to competitively inhibit aldosterone but also reacts with testosterone and progesterone receptors causing side effects of impotence, gynecomastia and menstrual irregularities. A selective aldosterone receptor blocker, eplerenone, is currently in development. The most serious adverse effect of spironolactone is hyperkalemia. To test the effectiveness of spironolactone for the treatment of heart failure, the Randomized Aldactone Evaluation Study (RALES) enrolled 1663 patients with NYHA class III or IV heart failure in a multi-center, double blind, placebo controlled trial.4 Patients enrolled in the study all had a left ventricular ejection fraction of 35% or less and were being treated with an ACE inhibitor and a loop diuretic. Patients were randomly assigned to receive either placebo or spironolactone 25mg once daily. The dose of spironolactone could be increased to 50 mg per day if there was CHF progression and the plasma potassium level was not elevated. The placebo and spironolactone groups were well matched in terms of disease severity, background characteristics, and medication profiles. The study was terminated early because interim analysis showed spironolactone to be efficacious at reducing mortality. At a mean follow-up of 24 months, there were 386 deaths in the placebo group (46%) compared with 284 deaths in the group receiving spironolactone (35%), equivalent to a 30% reduction in the risk of death (P<0.001). There was also a 30% reduction in the risk of hospitalization for cardiac causes in the spironolactone group (P<0.001). Improve-ments in symptoms of heart failure determined by changes in NYHA status were observed in 33% of the placebo group compared to 41% in the spironolactone group (P<0.001). Hyperkalemia was not a significant problem and occurred in 2% of the spironolactone group compared to 1% of the placebo group (P=0.42). The main side effects of the spironolactone therapy were gynecomastia and breast pain. The effectiveness of the relatively low dose of spironolactone used in the RALES trial suggested that spironolactone acted by mechanisms beyond its diuretic actions. Cardiac fibrosis as a result of myocardial infarction or ventricular remodeling can lead to systolic and diastolic dysfunction and serve as a substrate for cardiac arrhythmias. Evidence that spironolactone decreased collagen biosynthesis in the heart was observed in a study that examined 261 patients from the RALES trial. 5 In that subgroup, it was found that elevated baseline serum markers of cardiac extracellular matrix turnover were associated with an increased risk of death and hospitalization. Markers of collagen synthesis decreased only in response to treatment with spironolactone and the effect of spironolactone on outcome was significant only in patients with elevated levels of these markers at baseline. Evidence supporting a beneficial action of spironolactone on vascular compliance was observed in a clinical study of patients with CHF that found spironolactone increased nitric oxide bioactivity and suppressed vascular angiotensin I to angiotensin II conversion. 6 Finally, experimental evidence has demonstrated that the combined actions of ACE inhibitors and spironolactone have additive effects on promoting renal sodium and water excretion in heart failure. 7 The RALES trial exemplifies the paradigm shift in the therapeutic approach to heart failure and lends additional support for the complex role of neuroendocrine responses in the pathophysiology of CHF. In addition to beta-blockers and ACE inhibitors, spironolactone appears to be a potent, inexpensive and effective addition to the therapy of CHF. Future studies need to address the benefits and safety of combining spironolactone and beta-blockers in CHF. Because surgical stress elicits neuroendocrine responses similar to those that occur in response to heart failure, the safety and efficacy of spironolactone for the prevention and treatment of perioperative cardiac complications needs to be examined. REFERENCES
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