Nonsteroidal MRA improves outcomes in HFpEF and HFmrEF

LONDON — The nonsteroidal mineralocorticoid receptor (MRA) antagonist finerenone (Kerendia) improved outcomes driven by soft endpoints in patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF, HFpEF), the FINEARTS-HF trial found.

The drug reduced the composite risk of urgent or unplanned heart failure care and death from cardiovascular causes by 16% (rate ratio 0.84, 95% CI 0.74-0.95, P=0.007), Scott Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, reported at the European Society of Cardiology (ESC) meeting. The findings were published simultaneously in the New England Journal of Medicine (NEJM).

The effect was driven by fewer first or repeat worsening heart failure events with finerenone (RR 0.82, 95% CI 0.71-0.94), with a directionally consistent but statistically non-significant impact on cardiovascular mortality (8.1% versus 8.7%, HR 0.93, 95% CI 0.78-1.11).

No randomized controlled trial to date has shown a statistically significant reduction in mortality in HFmrEF or HFpEF, in contrast to HF with reduced EF (HFrEF), the researchers noted in a special communication in the Journal of the American College of Cardiology coincide with the NEJM paper.

“However, this likely reflects the statistical power of the studies to date to demonstrate an effect on mortality, rather than mechanistic differences between HFmEF/HFpEF and HFrEF or differences in treatment efficacy,” they argued, noting a lower rate of potentially modifiable deaths in HFmrEF and HFpEF.

Still, Theresa McDonagh, MD, of King’s College Hospital in London, the ESC session discussant for the study, called the trial a “masterpiece” as the “first ever trial of an MRA in patients with ejection fractions above 40% to meet the primary endpoint. In fact, the first trial of a renin-angiotensin-aldosterone system inhibitor to do so.”

A patient-level meta-analysis of the MRA drugs (spironolactone in RALES and TOPCAT, eplerenone (Inspra) in EMPHASIS-HF in HFrEF, and finerenone in FINEARTS-HF) showed that the risk of cardiovascular death or hospitalization for heart failure was reduced (HR 0.77, 95% CI 0.72-0.83). This risk was lower when only HFmrEF or HFpEF was considered (0.87, 95% CI 0.79-0.95).

The data, presented at the same session as FINEARTS-HF and published in The Lancetstill found no mortality benefit in the HFmrEF or HFpEF population. However, the results were encouraging with respect to potassium levels, which have caused underuse.

MRAs doubled the risk of hyperkalaemia compared with placebo, but the percentage of severe cases exceeding 6.0 mmol/l was low (2.9% versus 1.4%) and the risk of hypokalaemia was halved (7% versus 14%, OR 0.51, 95% CI 0.45-0.57).

Maja Cikes, MD, PhD, from Zagreb University Hospital in Croatia, moderated the ESC session for the meta-analysis. She highlighted the evidence that low potassium levels are more dangerous than high. She also emphasized that concomitant use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, as recommended for these patients, actually reduces the risk of MRA-associated hyperkalemia.

“Yes, indeed, we all think about hyperkalemia in our patients who are on MRAs, and we should. But when we look at the rates of hyperkalemia in patients who are on different forms of MRA, they are actually lower than in patients who are on an ACE inhibitor in PARADIGM-HF,” she said. “It is our obligation to overcome inertia and optimize implementation strategies.”

The international FINEARTS-HF trial included 7,463 patients aged 40 years or older (mean age 72), who had symptomatic heart failure, a left ventricular EF of 40% or greater (mean 53%), evidence of structural heart disease, and elevated natriuretic peptide levels. Most patients (69.1%) were in New York Heart Association functional class II, and 20.3% were enrolled during a heart failure event or in the week following.

Participants were randomised and treated in a double-blind manner to receive finerenone at doses of up to 20 or 40 mg once daily or matching placebo. This was given on top of usual therapy, which consisted of beta-blockers for 84.9%, ACE inhibitors for 35.9%, angiotensin receptor blockers for 35.0% and angiotensin receptor-neprilysin inhibitors for 8.5%. Notably, evidence of the benefit of SGLT2 inhibitors in this setting built up during the trial, and the percentage on one of these agents increased from 13.6% at baseline to around 20% during the trial.

Solomon said the point estimates were consistent regardless of SGLT2 inhibitor use. While more data on this subgroup will be forthcoming, he said, “I think there’s reason to think there’s an incremental benefit beyond SGLT2 inhibitors based on these data.”

McDonagh agreed: “The US guidelines do recommend it for HFpEF. I think we may see a stronger recommendation for MRAs and finerenone in this space in the future, at least class 2a, depending of course on other studies that report in the meantime. So while we wait for the guidelines to change, what does that mean? Well, I think for clinical practice we now have another option to give patients with ejection fractions above 40% in addition to SGLT2 inhibitors.”