Matsumoto S, Henderson AD, Shen L, et al. Mineralocorticoid Receptor Antagonists in Patients With Heart Failure and Impaired Renal Function. J Am Coll Cardiol. 2024 Jun 18;83(24):2426-2436. doi: 10.1016/j.jacc.2024.03.426. Epub 2024 May 12.

BACKGROUND: Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy.

OBJECTIVES: This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction.

METHODS: We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization.

RESULTS: Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4 mL/min/1.73 m2 vs 70.5 ± 21.8 mL/min/1.73 m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95% CI: 2.01-3.08; P < 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95% CI: 0.56-0.71) (Pinteraction = 0.87). In patients with a decrease in eGFR to <30 mL/min/1.73 m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0 mmol/L).

CONCLUSIONS: Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation.

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Comments from MORE raters

Cardiology rater

Based on the post hoc analysis of two landmark studies with mineralocorticoid receptor antagonists (MRAs) in heart failure, this article sheds more light on the safety of starting or continuing this life-saving therapy in these patients despite kidney dysfunction and on therapy decrease of eGFR below 30 mL/min/1.73M2. From the safety endpoint, the incidence of severe hyperkalemia and increase in serum creatinine was low, and counterbalanced by the net benefit in clinical outcomes (death or rehospitalization). This suggests that these patients may benefit from continuing MRA medications.

Cardiology rater

Very reassuring data about the safety of mineralocorticoid receptor antagonists in patients with impaired renal function. The availability of modern treatments of hyperkalemia should allow implementation of mineralocorticoid receptor in larger subsets of patients with heart failure.

Nephrology rater

These findings are not surprising since most nephrologists know that patients with eGFR &lt;30 ml/min are at particularly high risk of most adverse outcomes. I expected this analysis would demonstrate that MRA may provide a benefit in patients at high risk, but they did not show this but it was observed.