The FINEART of finerenone: A new option for HFmrEF/HFpEF?

Full results of the phase III FINEARTS-HF trial have shown that finerenone cuts the risk of worsening heart failure (HF) events and cardiovascular (CV) death in symptomatic HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF).

The trial was positive, with a 16 percent overall reduction (p=0.007) in the primary endpoint, driven by the reduction in total worsening HF events.

“If we look at the endpoint in the traditional way as a time to the first event, it’s the exact same hazard ratio and an even better p value,” said principal investigator Profesor Scott Solomon from Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, US, who presented the data at ESC 2024. [Hot Line 7]

Overall, total worsening HF events were reduced by 18 percent with finerenone (relative risk [RR] 0.82), but the difference in CV death was not significant (242 vs 260 deaths in the finerenone and placebo groups, respectively).

“We did not see a benefit in mortality. But things went in the right direction for both CV death and all-cause mortality — a 7-percent reduction and numerically fewer deaths, which is good knowing you’re not harming patients,” he added. “In HFpEF trials, we’ve never been able to get mortality down. This is because the event rates in these patients were low, we would have to do trials twice as long or twice as big.”

FINEARTS-HF is the first trial of a nonsteroidal, selective mineralocorticoid receptor antagonist (nsMRA) to show CV benefit, setting the stage for finerenone in this difficult-to-treat population.

Difference with steroidal MRA

While MRAs have been shown to reduce the risk of hospitalization and mortality in patients with HF with reduced ejection fraction (HFrEF), that same benefit did not extend to HFpEF.

In TOPCAT, the only study to date in this population, with 3,445 patients from six countries followed for 3.3 years, spironolactone, a steroidal MRA, did not significantly reduce the composite primary endpoint of death from CV causes, aborted cardiac arrest, or hospitalization for HF.

“There was an attenuation of treatment benefit as you go up in the ejection fraction with TOPCAT. But I’m pleased to say we did not see that in FINEARTS-HF. There was no heterogeneity in this trial,” Solomon shared.

“Finerenone is quite distinct chemically. It has a shorter half-life and is more selective for MR than spironolactone,” he explained. “Additionally, finerenone has a more balanced distribution between the heart and the kidney receptors than any steroidal MRAs do. So, the properties are different. It doesn’t have any of those nasty sex hormone-related  side effects that you get with spironolactone.”

HFmrEF or HFpEF accounts for about half of patients living with HF. “Despite the availability of several therapeutic options for these patients, including SGLT2 inhibitors, there remains an enormous unmet need in this population,” Solomon pointed out.

A masterpiece of a trial

Study discussant Dr Theresa McDonagh from the King’s College Hospital, London, UK described FINEARTS-HF as “a masterpiece,” drumming into what Solomon had highlighted in his presentation. “Again, this is the first trial of an MRA to meet its primary endpoint in HF with an LVEF of >40 percent.”

As for the lack of mortality benefit with finerenone, she said it may be a result of low statistical power, pointing out that the rates of mortality, including for CV, are lower in patients with HFmrEF/HFpEF. “That’s why HF trials in patients with ejection fractions >40 percent have to be bigger than trials in HFrEF,” she commented.

The FINEARTS-HF study included 6,001 patients (mean age 72 years, 46 percent women) with symptomatic HF and an LVEF of ≥40 percent. All had elevated levels of natriuretic peptides and evidence of structural heart disease, with diuretic use for at least the previous 30 days. The majority of patients had NYHA functional class II symptoms and 20.3 percent were enrolled within 7 days after an HF event.

Patients were randomized to finerenone, titrated to a maximum of 40 mg once daily based on baseline eGFR, or a matching placebo.

Overall, there were 1,083 primary-outcome events in 624 patients treated with finerenone vs 1,283 events in 719 patients given a placebo (RR, 0.84).

Hyperkalaemia outcomes

Hyperkalaemia (serum potassium levels >5.5 mmol/L) is one reason physicians have been cautious about using MRAs. True enough, the risk for hyperkalaemia was more than doubled with finerenone in FINEARTS-HF, at 14.3 percent vs 6.9 for placebo.

“We had a total of 16 people who were hospitalized for hyperkalaemia in the finerenone group vs 6 in the placebo group, but there were no deaths related to that in either group,” said Solomon. “I think we can mitigate the risk for severe hyperkalaemia with this drug.”

The risk for hypokalemia, which is also associated with worse outcomes, was higher in the placebo group.

The risk for hypokalaemia, which is also associated with worse outcomes, was higher in the placebo group.

Current European guidelines assert that an MRA may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death (class IIb recommendation, level of evidence B), but make no recommendations on the use of MRA in HFpEF. [Eur J Heart Fail 2022;24:4-131] The US guidelines also offer tepid recommendations for those with HFmrEF and HFpEF (class IIb, level of evidence B). [Eur Heart J 2023;44:3627-3639]

“I think we can see a stronger recommendation for MRAs and finerenone put forward in this space, at least a class IIa, but that depends on other studies reported in the interim,” commented McDonagh.