Finerenone Benefits Heart Failure With Preserved EF

LONDON — The benefit of mineralocorticoid receptor antagonists (MRAs) for the treatment of patients with heart failure and mildly reduced or preserved ejection fraction has finally been established in the FINEARTS-HF trial.
Full trial results show that finerenone, a third-generation nonsteroidal MRA, reduced the primary endpoint of worsening heart failure events (unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes by 16% compared with placebo (rate ratio, 0.84; P = .007).
The benefit was driven by a clear reduction in worsening heart failure events (rate ratio, 0.82; P = .006); no significant effect was seen on cardiovascular death (hazard ratio, 0.93; 95% CI, 0.78 to 1.11).
“About 64 million patients live with heart failure worldwide, and about half of these have preserved or mildly reduced ejection fraction,” said lead investigator Scott Solomon, MD, from Brigham and Women’s Hospital in Boston, Massachusetts.
“This is a population with enormous unmet need, as there is currently only one guideline-indicated therapy (SGLT2 inhibitors). The FINEARTS-HF trial adds another option, with finerenone, so I think we’ll now be seeing combination therapy in these patients like we already have in patients with heart failure and reduced ejection fraction,” Solomon said here at the European Society of Cardiology (ESC) Congress 2024, where he presented the results, which were simultaneously published in the New England Journal of Medicine.
Patients with heart failure and mildly reduced or preserved ejection fraction have typical symptoms of heart failure, including breathlessness on exertion and swollen ankles, but they often have different risk factors than those with reduced ejection fraction. The mildly reduced or preserved ejection fraction condition is related, in particular, to obesity, hypertension, and diabetes. Patients do not always go on to develop reduced ejection fraction but the condition can still progress and is a major cause of hospitalization.
The FINEARTS-HF Trial
In FINEARTS-HF, 6016 patients with heart failure and a left ventricular ejection fraction of at least 40% (mean, 54%) were randomized to finerenone (at a maximum dose of 20 mg or 40 mg once daily, depending on kidney function) or placebo. Most patients — 69% — were in New York Heart Association functional class II heart failure, and 20% were enrolled during or in the 7 days after a heart failure event. At baseline, 85.0% were being treated with beta-blockers, 36.0% with ACE inhibitors, 35.0% with angiotensin receptor blockers, 8.5% with angiotensin receptor–neprilysin inhibitors, and 14.0% with sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The results for the primary outcome were consistent across all prespecified subgroups, including those defined according to baseline left ventricular ejection fraction and baseline use of SGLT2 inhibitors.
Tracking Hyperkalemia
There has been concern about hyperkalemia with MRAs, and potassium levels greater than 6.0 mmol/L were more common in the finerenone than in the placebo group (3.0% vs 1.4%). However, there were few hospitalizations because of hyperkalemia in the finerenone or placebo groups (0.5% vs 0.2%), and no episodes of hyperkalemia led to death.
Hypokalemia, defined as a potassium level of less than 3.5 mmol/L, was less common with finerenone than placebo (4.4% vs 9.7%).
Mean systolic blood pressure at 6 months was lower in the finerenone than in the placebo group (difference, −3.4 mm Hg), but adjustment for this did not attenuate the observed treatment effect on the primary outcome.
FINEARTS-HF is “a masterpiece,” said Theresa McDonagh, MD, professor of heart failure at King’s College London, UK. It is the first trial of an MRA in patients with heart failure with mildly reduced or preserved ejection fraction to meet its primary endpoint, and also the first trial of a renin-angiotensin-aldosterone system inhibitor to do so, the trial discussant pointed out.
The magnitude of benefit was similar to that seen in trials of SGLT2 inhibitors in similar populations, McDonagh reported. As in those trials, there was no reduction in cardiovascular mortality most likely because of the lack of power in this relatively low-risk group.
The TOPCAT trial of an older steroidal MRA, spironolactone, did not show a clear benefit in patients with heart failure and preserved ejection fraction, but that trial was found to have flaws in the Russian and Eastern European cohorts. When the North American cohort was analyzed separately, spironolactone was found to be beneficial.
Rates of hyperkalemia appear to be lower with finerenone, which is believed to have a better tolerability profile than spironolactone, in the FINEARTS-HF trial than with spironolactone in the North American cohort of TOPCAT, McDonagh explained.
The European guidelines currently give a weak recommendation (level IIb evidence) for the use of MRAs in heart failure patients with mildly reduced ejection fraction, and no recommendation for patients with preserved ejection fraction. The American guidelines do give a recommendation for preserved ejection fraction, “but I think we will see stronger recommendations for MRAs, and finerenone in particular, in this space moving forward,” she said.
“Many of us suspected that MRAs were effective in heart failure with preserved ejection fraction after TOPCAT, but we didn’t have definitive data to prove it. Now we finally have proof that MRAs are effective in this population,” said Christopher Kramer, MD, chief of cardiology at the University of Virginia in Charlottesville.
Despite finerenone not having an effect on cardiovascular death, the clear reduction in heart failure hospitalization is still a valuable finding. “These patients get admitted over and over again with volume overload. We see it all the time,” he said. “This should help.”
The FINEARTS-HF trial has answered an important question, but there are still some issues outstanding, such as whether the drug should be started in hospitalized patients, and whether the benefit is seen on top of SGLT2 inhibitors, said Marc Bonaca, MD, director of vascular research at the University of Colorado in Aurora.
“While subgroup analyses in FINEARTS-HF suggest benefits in both these situations, more data are needed, which will hopefully come from further trials,” he said.
Is It a Class Effect?
The FINEARTS-HF trial gives validation to the TOPCAT North American data, and indicates that the benefit is probably a class effect, said Kramer.
“This begs the question of whether we can just use spironolactone and, yes, I think we probably can. If finerenone is easily available and reasonably priced, I think people will use it. But spironolactone has been around a long time, and will be cheaper, so I think many doctors will use that now with more confidence after this trial,” he said.
Some people may interpret the results that way, but others will prefer to use finerenone, which has clear data and, as a third-generation MRA, has a better tolerability profile, Bonaca said.
Given that MRAs have diuretic and blood-pressure-lowering properties, some have speculated that benefits similar to those seen with finerenone could be achieved with just a diuretic and antihypertensive drugs. This is unlikely, said Bonaca, because studies looking at those agents have not shown the same benefit.
Both Kramer and Bonaca were not overly concerned about the adverse effect of hyperkalemia.
“It is something you must be aware of, especially in patients with baseline renal dysfunction. It is important to monitor electrolytes and treat hyperkalemia when it arises,” Kramer said. But it’s a very treatable side effect, and there were only very few hospitalizations and no deaths due to hyperkalemia in the FINEARTS-HF study.”
The FINEARTS-HF data are “reassuring” with regard to hyperkalemia, said Bonaca. “Yes, finerenone did increase potassium levels, but severe hyperkalemia was not an issue. I am more worried about the risk of low potassium in these patients, and there was significantly less hypokalemia with finerenone,” he added.
 
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