In the realm of treatment options for heart failure with reduced ejection fraction (HFrEF), mineralocorticoid receptor antagonists (MRAs) added to standard HF medications have been proven to reduce mortality and hospitalization, but their use remains suboptimal when compared to standard therapy, like angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), and beta adrenergic receptor blocking agents (beta-blockers). This underuse may be due to the fear of inducing hyperkalemia or worsening renal failure (WRF) in patients with HFrEF.

In a recent JACC article, Romain Eschalier, MD, and colleagues conducted a subanalysis of the EMPHASIS-HF trial, examining the safety and efficacy of the MRA eplerenone in pre-specified high-risk subgroups—patients aged ≥75 years, with diabetes mellitus, chronic kidney disease (CKD; an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m²), and systolic blood pressure (SBP) <123 mm Hg. There were no significant clinical differences between the larger EMPHASIS-HF patient group and the specified subgroups. Groups received either placebo or eplerenone started at a dose of 25 mg, and carefully uptitrated to 50 mg.

At the trial cut-off date, the study drug had been stopped due to at least one adverse event in 118 patients (13.8%) receiving eplerenone and 222 patients (16.2%) receiving placebo in the overall population. The percentages of patients who discontinued either study drug due to adverse events in each of the high-risk subgroups were similar, with a slight advantage for eplerenone:

• 18.2% for eplerenone vs. 19.0% for placebo in patients ≥75 years
• 16.6% vs. 18.0% in patients with SBP <123 mm Hg
• 16.1% vs. 22.3% in CKD patients
• 15.1% vs 18.1% in patients with diabetes mellitus

Overall, eplerenone was effective at reducing the risk of CV death or HF hospitalization in the high-risk subgroups, which, the authors noted, was consistent with results in the general EMPHASIS-HF population (HR = 0.63; p < 0.001). Compared to placebo, odds of reaching the primary efficacy outcome with eplerenone was significantly reduced.

The risk-benefit profile was favorable in carefully selected and monitored patients, even those at increased risk of renal dysfunction, hyperkalemia, and hypotension because of advanced age, diabetes, CKD, or low SBP. Importantly, the benefit of reduced incidence of CV death or HF hospitalization was preserved in all the high-risk subgroups studied, without an increase in the risk of serious hyperkalemia and worsening renal function in any subgroup.

Ultimately, the authors concluded, the risk-benefit ratio of eplerenone observed in the present study “presents compelling evidence for its use in all patients with HFrEF meeting the inclusion and exclusion criteria of EMPHASIS-HF.” However, serum potassium and renal function have to be attentively monitored in these carefully-selected patients.