Aldosterone Antagonists in the Treatment of Heart Failure

Todd R. Marcy; Toni L. Ripley


Am J Health Syst Pharm. 2006;63(1):49-58. 

In This Article

Clinical Efficacy of Aldosterone Antagonists

Aldosterone escape and non-ACE pathways for angiotensin II production may explain, at least in part, the continued high mortality rates in heart failure patients despite the advances made in pharmacotherapy. These mechanisms revealed the incomplete blockade of the RAAS with ACE inhibitor and ARB therapy and thus a potential benefit from complimentary RAAS inhibition. The logical target of research was aldosterone antagonism.

Studies in humans and animals have taken place to help establish the mechanisms of benefit of spironolactone in heart failure. Rat studies have linked spironolactone to reduced collagen synthesis,[26] decreased aldosterone-mediated PAI-1 expression,[25] and prevention of aldosteronesalt-induced increase in AT1-receptor density.[24]

Human studies demonstrated reductions in collagen synthesis and left ventricular remodeling after a myocardial infarction (MI)[54,55] and reduced markers of collagen turnover in severe heart failure in patients taking spironolactone.[56,57] Further improvement in endothelial function has been demonstrated through brachial artery blood flow studies in patients with New York Heart Association (NYHA) class II–IV heart failure taking spironolactone.[58,59] Improved nitric oxide activity has been linked to improved endothelial function. Spironolactone has also been associated with improved heart rate variability[56] and decreased ventricular arrhythmias[60] in patients with severe heart failure. Improved left ventricular function and exercise tolerance have been demonstrated in patients with a left ventricular ejection fraction (LVEF) of <45%.[61]

Spironolactone was evaluated in a randomized, dose-finding study of 214 heart failure patients treated with ACE inhibitors.[62] This 12-week study compared spironolactone 12.5, 25, 50, or 75 mg daily with placebo and found that plasma renin activity (PRA) and urinary aldosterone levels increased in a dose-dependent fashion. Further, a significant difference was observed between each treatment group and placebo (p = 0.002 for both groups). No comparisons were made among the various dosages of spironolactone. Peak PRA occurred with a spironolactone dosage of 50 mg daily. Hyperkalemia occurred in all groups, with increasing frequency at higher dosages. The authors recommend an initial dosage of 25 mg daily for patients taking an ACE inhibitor and increasing the dosage to 50 mg daily if serum potassium levels remain normal and the patient shows signs of disease progression.

RALES was the first study to evaluate the effect of aldosterone-receptor blockade on morbidity and mortality in patients with heart failure.[4] Spironolactone 25 mg daily or placebo was randomly added to existing therapy (i.e., an ACE inhibitor and a loop diuretic) in 1663 patients with NYHA class III or IV heart failure and an LVEF of ≤35%. The spironolactone dosage could be increased to 50 mg daily after eight weeks in the absence of hyperkalemia if heart failure symptoms worsened. The primary endpoint of the study was all-cause mortality. The average baseline ejection fraction was about 25% in each group. During the mean 24-month follow-up period, 46% of patients in the placebo group died, compared with 35% in the spironolactone group (relative risk, 0.7; 95% confidence interval [CI], 0.6–0.82) (p < 0.001). The reduction in death was attributed to a reduction in death from progressive heart failure and a reduction in sudden death from cardiac causes. A 30% reduction in hospitalizations for cardiac causes was also noted in the spironolactone-treated group. NYHA functional class improved in 41% of the spironolactone-treated group, compared with 33% in the placebo group (p < 0.001).

The effectiveness of spironolactone demonstrated in RALES is impressive, although the study's results should be interpreted with caution. The study was designed before the emergence of β-blockers as a standard treatment for heart failure. Only 10% of patients in the placebo group and 11% of patients in the spironolactone group were taking a β-blocker. Spironolactone's effects on morbidity and mortality rates in patients receiving β-blocker therapy are unknown. Nonetheless, RALES was a landmark trial in the treatment of heart failure, providing evidence of morbidity and mortality benefits of spironolactone in patients with advanced disease.

A double-blind crossover study evaluated spironolactone's effects on surrogate endpoints (endothelial function, vascular ACE activity, Q–T interval, heart rate variability, plasma brain natriuretic peptide [BNP], and procollagen III N-terminal peptide [PIIINP]) in 43 patients with NYHA class I or II heart failure.[63] Patients were started on spironolactone 25 mg daily. The dosage was increased to 50 mg daily after two weeks in the absence of adverse effects or electrolyte abnormalities. Improvements in endothelial function were demonstrated in brachial artery blood flow studies. Furthermore, significant improvements in BNP, PIIINP, Q–T interval, and ventricular extrasystoles and reduced angiotensin I-induced vasoconstriction were noted. The authors hypothesized that these improvements were due to reduced angiotensin I conversion to angiotensin II. Surprisingly, spironolactone increased angiotensin II-induced vasoconstriction, which the authors suggested may be attributable to the upregulation of AT1 receptors. No improvements were observed in heart rate variability and six-minute walk distance. Scores from the Minnesota Living with Heart Failure questionnaire[64] and Hospital Anxiety and Depression Scale[65] were significantly worse in patients receiving spironolactone. Macdonald et al.[63] suggested that these scores could have been a result of unidentified or unreported adverse drug effects. Adverse effects resulting from the non-selective nature of spironolactone limit its tolerability in some patients. While this study provides preliminary evidence that spironolactone may benefit patients with mild heart failure, morbidity and mortality studies of spironolactone in this population are warranted.

The pharmacologic effects of eplerenone (a selective aldosterone antagonist) have not been studied as extensively as those of spironolactone, particularly in humans. In rats given exogenous angiotensin II and dietary sodium chloride, eplerenone reduced myocardial hypertrophy,[19,21] expression of markers of coronary inflammation,[18,19] and myocardial necrosis.[21] In dogs with heart failure, eplerenone prevented progression of left ventricular dysfunction and remodeling.[66] Young and Funder[67] recently reported that eplerenone reversed established cardiac inflammation and fibrosis in rats treated with a corticosteroid.

Eplerenone and enalapril were evaluated separately and in combination in 202 patients with essential hypertension and left ventricular hypertrophy.[68] Patients were randomized to receive once-daily doses of eplerenone 200 mg, enalapril 40 mg, or eplerenone 200 mg plus enalapril 10 mg for nine months. The primary outcome measure was change in left ventricular mass assessed by magnetic resonance imaging. Left ventricular mass decreased by 19.7 and 14.5 g in the enalapril-only and eplerenone-only groups, respectively (p = 0.258). Combination enalapril–eplerenone resulted in a reduction of 27.2 g, a significantly greater decrease than with eplerenone alone (p = 0.007) but not with enalapril alone (p = 0.107). The study also found a smaller reduction of albuminuria in the combination group than in either monotherapy-treated group. Blood pressure reductions were similar among groups, except for a significant improvement in blood pressure in the combination group when compared with eplerenone alone (p = 0.048). Of note, severe hyperkalemia (≥6.0 mmol/L) developed in 7 patients in the eplerenone group, 2 patients in the enalapril group, and 3 patients in the combination group. The authors concluded that the combination of ACE inhibition and aldosterone antagonism has additive effects on left ventricular mass and may improve patient outcomes.

The second major trial to evaluate aldosterone antagonism on morbidity and mortality in heart failure was EPHESUS.[5] EPHESUS evaluated the efficacy and safety of eplerenone in 6642 patients with left ventricular dysfunction after an MI. Patients initially received eplerenone 25 mg daily or placebo 3–14 days after acute MI complicated by an LVEF of ≤40% and heart failure evidenced by pulmonary rales, chest radiograph showing pulmonary venous congestion, or the presence of a third heart sound. Eplerenone dosage was adjusted to a maximum of 50 mg daily four weeks after therapy initiation. Patients were treated concurrently with standard heart failure therapies, including ACE inhibitors, β-blockers, aspirin, and diuretics. The primary endpoints were time to death from any cause and time to death from cardiovascular causes or first hospitalization for a cardiovascular event. Patients in the treatment group had an average baseline LVEF of 33% and received a mean eplerenone dose of 46 mg daily. During the 16-month follow-up period, 14.4% of patients in the eplerenone-treated group and 16.7% of patients receiving placebo died (relative risk, 0.85; 95% CI, 0.75–0.96) (p = 0.008). Cardiovascular death or hospitalization for a cardiovascular event occurred in 26.7% and 30.0% of patients in the treatment and placebo groups, respectively (relative risk, 0.87; 95% CI, 0.79–0.95) (p = 0.002).

No studies have directly compared spironolactone and eplerenone. The morbidity and mortality benefits found in EPHESUS were approximately half of those seen with spironolactone in RALES.[4,5] However, the patient populations and baseline therapies in these two studies differed considerably. Patients enrolled in RALES had severe heart failure; EPHESUS enrolled patients an average of seven days after MI complicated by heart failure. The presence of heart failure before MI was not part of the inclusion criteria. The LVEF in RALES was 26% at baseline, compared with 33% in EPHESUS. The LVEF would likely have increased in patients enrolled in EPHESUS with revascularization and recovery from the acute event. Patients in EPHESUS were receiving therapy with a β-blocker (75%), aspirin (88%), an ACE inhibitor or ARB (86%), and a statin (47%). In RALES, only 11% of patients treated with spironolactone were taking a β-blocker, 36% were receiving aspirin, and 95% were taking an ACE inhibitor; statin use was not reported. A more widespread use of these agents could have potentially attenuated the benefit seen from spironolactone.