The role of aldosterone receptor antagonists in the management of heart failure: An update

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.