HF with reduced ejection fraction
Several large randomized placebo-controlled clinical trials provided the basis for MR antagonists (MRAs) as an essential treatment in patients with HF with reduced ejection fraction (HFrEF) and for their class I recommendation in current HF treatment guidelines (Ponikowski et al., 2016; Berliner et al., 2020; Bozkurt et al., 2021).
The RALES trial (Randomized Aldactone Evaluation Study) was the first study demonstrating that the addition of spironolactone to the standard therapy improved mortality and morbidity in patients with advanced HFrEF (NYHA class III-IV) (Pitt et al., 1999). These results were extended by the EPHESUS trial (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study): in patients with HF after myocardial infarction (MI), the MRA eplerenone, started between day 3 and 14 after MI, in addition to optimal standard therapy, significantly reduced mortality and HF hospitalizations. Earlier eplerenone administration (3-7 days) was associated with more beneficial outcomes compared with later (7-14 days) initiation after acute MI (Pitt et al., 2003). The EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) expanded these findings, showing that eplerenone treatment in addition to standard therapy promoted a highly significant reduction in mortality and HF hospitalizations in patients with NYHA class II HFrEF (Zannad et al., 2011). However, the clinical uptake of MRAs in the treatment of HFrEF have been limited for a long time by the risk of hyperkalemia conferred by combined therapy with an ACE inhibitor, especially in patients with diabetes mellitus and/or chronic kidney disease (Zannad et al., 2012; Agarwal et al., 2021).
More recently, the novel non-steroidal selective MRA, finerenone, also demonstrated beneficial effects in HFrEF patients. In the ARTS-HF trial (Mineralocorticoid Receptor Antagonist Tolerability Study-Heart Failure), finerenone was well tolerated and decreased NT-proBNP levels to a similar extent as eplerenone in HFrEF patients with diabetes mellitus and/or chronic kidney disease and requiring hospitalization (Filippatos et al., 2016). A pre-specified composite clinical endpoint numerically occurred less frequently with finerenone. ARTS-HF was the first clinical trial to compare finerenone with eplerenone in patients with worsening HFrEF at risk for hyperkalemia. In such vulnerable population, finerenone was as effective as steroidal MRAs but was safer in patients with chronic kidney disease (Pei et al., 2018).