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).