Nonsteroidal MRA Improves Outcomes in HFpEF, HFmrEF

LONDON — The nonsteroidal mineralocorticoid receptor antagonist (MRA) 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 showed.

The drug reduced by 16% the composite risk of urgent or unplanned heart failure care and death from cardiovascular causes (rate ratio 0.84, 95% CI 0.74-0.95, P=0.007), reported Scott Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) meeting. The findings were simultaneously released 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 not statistically significant impact on cardiovascular death (8.1% vs 8.7%, HR 0.93, 95% CI 0.78-1.11).

No randomized controlled trial has yet demonstrated 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 to coincide with the NEJM paper.

“However, this probably reflects the statistical power of trials to date to show 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 as well.

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

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

The data, presented at the same session as FINEARTS-HF and published in The Lancet, still didn’t find a mortality benefit in the HFmrEF or HFpEF population. However, the results were encouraging with regard to potassium levels, which have driven underuse.

MRAs did double the risk of hyperkalemia compared with placebo, but the rate for serious cases reaching over 6.0 mmol/L was low (2.9% vs 1.4%) and the risk of hypokalemia was halved (7% vs 14%, OR 0.51, 95% CI 0.45-0.57).

ESC session discussant for the meta-analysis Maja Cikes, MD, PhD, of University Hospital Centre Zagreb in Croatia, emphasized evidence showing that too low is more dangerous than too high when it comes to potassium and that concomitant use of sodium-glucose cotransporter-2 (SGLT2) inhibitors as recommended for these patients actually is attenuated the risk of MRA-associated hyperkalemia.

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

The international FINEARTS-HF trial included 7,463 patients, ages 40 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 levels of natriuretic peptides. 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 afterward.

The participants were randomized double-blind to receive finerenone at doses up to 20 or 40 mg once daily or matching placebo. This was given atop usual therapy, which comprised 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 on the benefits of SGLT2 inhibitors in this setting accrued during the trial, and the proportion on one of these agents rose from 13.6% at baseline to around 20% during the trial.

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

McDonagh agreed: “The U.S. guidelines do give a recommendation for HFpEF. I think we can see a stronger recommendation for MRAs and finerenone in this space going forward, at least class 2a, of course depending on other studies that report in the interim. So while we wait for guidelines to change, what does this 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.”