Mineralocorticoid Antagonism in HF: Key Points
The following are key points to remember from a state-of-the-art review on the established and emerging therapeutic role of mineralocorticoid antagonism in patients with heart failure (HF):
- Large randomized controlled trials in heart failure with reduced ejection fraction (HFrEF) have demonstrated reduction in cardiovascular (CV) mortality and HF hospitalizations with mineralocorticoid receptor antagonists (MRA). Steroidal MRAs (spironolactone and eplerenone) block other steroid receptors including androgen and progesterone receptors leading to gynecomastia, menstrual irregularities, and impotence in addition to hyperkalemia.
- Contemporary HF guidelines recommend MRA in patients with HFrEF with New York Heart Association class II-IV symptoms as a Class 1 recommendation if glomerular filtration rate is >30 mL/min/1.73 m2 and serum potassium is <5 mEq/L. These guidelines also recommend close monitoring of renal function and potassium level at 1 week, 4 weeks, and then every 6 months after initiating or up-titrating MRA.
- For HF with mid-range EF (HFmrEF; EF 41-49%), contemporary guidelines recommend MRA in symptomatic patients as a Class 2b recommendation to reduce hospitalization, especially among patients with left ventricular EF (LVEF) on the lower end of this spectrum.
- The TOPCAT trial with spironolactone in HFmrEF and HF with preserved EF (HFpEF) showed a reduction in HF hospitalizations. However, there were marked differences by geographic location in the trial with lower drug metabolite levels in participants from Russia and Georgia, suggesting dilution of effect due to drug noncompliance. Another trial in HFpEF patients in Europe (Aldo-DHF) showed improvement in diastolic function on echocardiography with spironolactone.
- Nonsteroidal MRAs (finerenone, esaxerenone, and balcinrenone) offer potential advantages over steroidal MRAs including lower risk for hyperkalemia and lack of antiestrogen and antiprogesterone side effects.
- Finerenone is currently Food and Drug Administration approved for chronic kidney disease (CKD) associated with type 2 diabetes based on trial data (FIDELIO-DKD) showing reduction in a composite endpoint for kidney failure. HFrEF patients were excluded in this trial but finerenone also reduced risk for CV events (CV death, myocardial infarction [MI], and HF hospitalization) in this trial. In a similar cohort, the FIGARO-DKD trial showed reduced CV death, MI, HF hospitalization, and stroke with finerenone.
- Phase 2 trial data suggest superiority of finerenone compared with eplerenone in chronic HFrEF and/or CKD with type 2 diabetes with a larger decrease in N-terminal pro–B-type natriuretic peptide (NT-proBNP) level at day 90. A secondary analysis also showed a larger reduction in all-cause mortality, CV hospitalizations, and worsening HF leading to emergency room (ER) visits with finerenone compared with eplerenone. The incidence of hyperkalemia was not different between finerenone and eplerenone groups.
- The FINEARTS-HF trial included HF patients with LVEF >40% randomized to finerenone and placebo. Finerenone was superior to placebo in reducing the composite of CV death and total number of HF hospitalizations/ER visits, without any difference in CV death when considered alone.
- Trials have demonstrated that esaxerenone is superior to placebo in patients with type 2 diabetes and CKD for renal protection and improves myocardial remodeling in HFpEF patients by decreasing BNP. A phase 2 trial comparing balcinrenone with dapagliflozin versus dapagliflozin alone in symptomatic HF patients with LVEF<60% and CKD showed that combination therapy was superior to dapagliflozin monotherapy in reducing urine-albumin-creatinine ratio at 12 weeks.
- Although emerging trials are promising for nonsteroidal MRAs, real-world costs limit their use in contemporary practice. The authors suggest using steroidal MRA in treatment of cardiorenal disease due to cost-effectiveness until there are more data with head-to-head comparison of steroidal versus nonsteroidal MRA.
- Future trials looking at efficacy of nonsteroidal MRA in combination with sodium-glucose luminal cotransporter-2 inhibitors compared with standard care in hospitalized HF patients across the entire spectrum of EF are ongoing. This is in addition to another trial looking at nonsteroidal MRA in HFrEF patients with previous intolerance to steroidal MRA and other trials re-examining efficacy of spironolactone compared with placebo in HF patients with LVEF >40%.
