Spironolactone in congestive heart failure

When a large multicenter research trial is abruptly terminated, it is usually a consequence of significant adverse events. In contrast, when the Randomized Aldactone Evaluation Study (RALES) mortality trial was discontinued 18 months early, it was because of the prominent salutary effect of spironolactone, added to standard multidrug therapy consisting of an angiotensin converting enzyme (ACE) inhibitor and loop diuretic (with or without digoxin), in reducing the incidence of death and hospitalization in patients with severe congestive heart failure (CHF). Therapies directed toward suppression of neurohormonal activation have contributed to significant reductions in morbidity and mortality. ACE inhibitors, in particular, have had the largest impact on adverse outcome measures in CHF. Yet despite combined therapy with an ACE inhibitor and loop diuretic, patients on these agents still have an unacceptably high incidence of progressive ventricular failure and death. In the years that followed its discovery in 1954, aldosterone was considered a target for therapy in CHF because of its role in sodium retention. It is now clear that chronic elevations in plasma aldosterone are responsible for many other adverse effects (Fig. 1), including enhanced potassium and magnesium excretion, myocardial fibrosis, inhibition of catecholamine reuptake, endothelial cell and baroreceptor dysfunction, and ventricular arrhythmias. Blockade of aldosterone action is a desirable pharmacologic approach to treating both the underlying pathophysiology of CHF and its clinical consequences. Spironolactone promotes magnesium and potassium retention, increases uptake of myocardial norepinephrine, attenuates formation of myocardial fibrosis, and decreases mortality associated with both progressive ventricular dysfunction and malignant ventricular arrhythmias. Despite the encouraging results seen in the recent RALES mortality trial, a diagnosis of CHF still carries 30% to 40% mortality at 2 years. We need to continue the trend of evaluating newer therapies directed at the pathophysiologic mechanisms of this syndrome, with a goal toward delaying and eventually reversing long-term consequences.