FINEARTS-HF: Benefit of Finerenone Extends to HFmrEF and HFpEF Patients

LONDON, England—Use of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone cuts the risk of worsening HF events and cardiovascular mortality in patients who have heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), full results of the FINEARTS-HF study show.

The topline results were announced 1 month ago, as reported by TCTMD, but lead investigator Scott Solomon, MD (Brigham and Women’s Hospital, Boston, MA), presented a complete rundown of the data at one of today’s Hot Line sessions at the European Society of Cardiology Congress 2024. The reduction in the study’s primary endpoint was driven by a reduction in total worsening HF events.

“We did not see significant reductions—although numerically [it went] in the right direction—for cardiovascular death,” said Solomon during a media briefing.

Nonetheless, Solomon said FINEARTS-HF, which was published simultaneously in the New England Journal of Medicine, supports the use of finerenone (Kerendia; Bayer AG) for this difficult-to-treat patient population.

“Heart failure with mildly reduced or preserved ejection fraction accounts for about half of patients living with heart failure,” he said. “Despite the recent availability of several therapeutic options in these patients, including SGLT2 inhibitors, there remains enormous unmet need in this population.”

While MRAs have been shown to reduce the risk of hospitalizations and mortality in patients with HF with reduced ejection fraction (HFrEF), that same benefit hasn’t been extended to those with mildly reduced or preserved LVEF. The lone study to date in this population, TOPCAT with spironolactone, was a neutral study.

Harriette Van Spall, MD (Hamilton Health Sciences/McMaster University, Hamilton, Canada), who wasn’t involved in the study, noted that TOPCAT was a controversial trial, with questions about whether all randomized patients in Russia or Georgia had a true HF diagnosis and received the treatment as allocated. There was also evidence of heterogeneity by region in TOPCAT, with low event rates and no treatment benefit in Russia/Georgia but a therapeutic benefit from spironolactone in the Americas.

“So, this is a really welcome addition to the breadth of evidence that supports the use of MRAs,” she told TCTMD, noting that finerenone, a nonsteroidal MRA, is more selective and has a better side-effect profile than older agents. FINEARTS-HF, she said, “also answers the question definitively” about whether MRAs reduce the risk of cardiovascular death or heart failure events in those with HFmrEF/HFpEF.

“We know from other trials that patients with HFpEF also have comorbidities, such as diabetes and kidney disease, that portend a worse overall prognosis,” Van Spall noted. “We know from the FIGARO-DKD and FIDELIO-DKD trials of finerenone that patients with these comorbidities also experience a benefit.”

Despite the recent availability of several therapeutic options in these patients, including SGLT2 inhibitors, there remains enormous unmet need in this population. Scott Solomon

Theresa A. McDonagh, MD (King’s College Hospital, London, England), the discussant following Solomon‘s presentation, called the trial “a masterpiece,” noting this is the first trial of an MRA to meet its primary endpoint in HF patients with LVEF > 40%.

Two meta-analyses rounded out the Hot Line session, the first examining the risks and benefits of MRAs across the spectrum of HF patients and the second looking the benefits of finerenone in HF patients with chronic kidney disease and type 2 diabetes.

Less Worsening HF Events

In 2021, the US Food and Drug Administration approved finerenone for patients with chronic kidney disease (CKD) associated with type 2 diabetes. That approval was based on results from FIGARO-DKD and FIDELIO-DKD, two randomized, controlled trials of patients with type 2 diabetes with a broad spectrum of kidney disease.

The FINEARTS-HF study included 6,001 patients with symptomatic HF and LVEF 40% or greater (mean LVEF 53%) as well as elevated levels of natriuretic peptides and evidence of structural heart disease. The majority of patients had NYHA functional class II symptoms, and 20.3% were enrolled within 7 days after a HF event. Those treated with finerenone received either a 20-mg or 40-mg dose depending on baseline estimated glomerular filtration rate (eGFR).

There were 1,083 primary-outcome events—a composite of cardiovascular mortality or total worsening HF events—in 624 patients treated with finerenone compared with 1,283 events in 719 patients given placebo (RR 0.84; 95% CI 0.74-0.95). First worsening HF events or death from cardiovascular causes was similarly reduced with finerenone (RR 0.84; 95% CI 0.76-0.94).

Overall, total worsening HF events were reduced by 18% with finerenone (RR 0.82; 95% CI 0.71-0.94), but the difference in cardiovascular mortality was not significant (242 vs 260 deaths in the finerenone and placebo groups, respectively). Treatment with finerenone improved patient health status as assessed by the change in KCCQ symptom score at 6, 9, and 12 months. There was no improvement in NYHA functional class.

The risk of hyperkalemia—defined as serum potassium levels > 5.5 mmol/L—was more than doubled in the finerenone group (14.3% vs 6.9%), but Solomon said there were no deaths and few hospitalizations resulting from hyperkalemia. The rate of hypokalemia was lower in the finerenone-treated patients.

Van Spall said severe hyperkalemia can increase the risk of mortality, and that this side effect is one reason physicians have been cautious about using the drug class. Hyperkalemia can often be managed by adding potassium-binding agents, adjusting the MRA dose, or in some cases, withholding the medication and then rechallenging the patient after several days. She noted that while finerenone was associated with increased risk of hyperkalemia, severe cases were rare and risks of hypokalemia, which is also associated with worse outcomes, was lower with finerenone.

“It’s not to say there is no risk,” said Van Spall. “It’s a significant concern. Patients in our everyday practice have comorbidities which can put them at increased risk of hyperkalemia without the use of these agents. So, we have to be cautious, to monitor labs, and to follow the protocols that were implemented in these trials.”

Role in Light of SGLT2 Inhibitors

In recent years, the EMPEROR Preserved and DELIVER trials showed that treatment with the SGLT2 inhibitors empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) and dapagliflozin (Farxiga; AstraZeneca) reduces the risk of cardiovascular mortality/HF hospitalizations in patients with HFpEF, while also improving health status or quality of life.

McDonagh pointed out that treatment with finerenone yielded a similar magnitude of benefit as the SGLT2 inhibitors in the aforementioned HFpEF trials. 

As a reflection of the trial’s time line, just 13.6% of patients in FINEARTS-HF received a SGLT2 inhibitor, although the number of patients taking these drugs increased over the study period, said Solomon. In the subgroup analysis, the reduction in the primary endpoint was seen in those taking SGLT2 inhibitors at baseline and those not taking the drugs.

“We started this study well before it was clear that SGLT2 inhibitors would be beneficial in this patient population,” Solomon told TCTMD. “Fourteen percent at baseline, but we also had drop-ins.” The group plans to present more data at the upcoming Heart Failure Society of America scientific meeting at the end of September showing the consistent benefit of finerenone on top of SGLT2 inhibition, he said.

This is a really welcome addition to the breadth of evidence that supports the use of MRAs. Harriette Van Spall

Van Spall said there aren’t a wide variety of treatments to improve clinical outcomes in HFpEF patients, adding that the disease itself is heterogenous. Therapies that have proven effective, such as SGLT2 inhibitors, reduce HF hospitalizations and improve health status; in pooled analyses, they also reduce CV death. She also noted that patients with HFpEF have a higher incidence of death from noncardiovascular causes than those with HFrEF.

“Cardiovascular death is a hard needle to move in these patients without a pooled analysis due to relatively low event rates in any individual trial,” she told TCTMD.

McDonagh thought along the same lines, noting the lack of mortality benefit with finerenone may be the result of statistical power, pointing out that rates for mortality, including cardiovascular, are lower in patients with HFmrEF/HFpEF. “That’s why heart failure trials in patients with ejection fractions greater than 40% have to be bigger than trials in HFrEF,” she said.

The current European guidelines state 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 in HFpEF. The US guidelines also offer tepid recommendations in those with HFmrEF and HFpEF (class IIb, level of evidence B).

“I think we can see a stronger recommendation for MRAs and finerenone put forward in this space, at least class 2a, of course depending on other studies reported in the interim,” said McDonagh. 

Patient-Level Meta-analyses

For the first meta-analysis, researchers led by Pardeep Jhund, MBChB, PhD (University of Glasgow, Scotland), analyzed outcomes of 13,846 patients in four trials: RALES and EMPHASIS-HF, with spironolactone and eplerenone, respectively, in patients with HFrEF, plus TOPCAT and FINEARTS-HF, with spironolactone and finerenone, respectively, in those with HFmrEF/HFpEF.

There was a 23% reduction in the risk of cardiovascular death or HF hospitalization with MRA treatment, but there was a statistically significant interaction by trials and treatment owing to the larger benefit seen in HFrEF patients. Cardiovascular and all-cause mortality were reduced in the HFrEF trials, but not in those with HFmrEF/HFpEF.

The analysis, which was published in the Lancet, showed the risk of hyperkalemia was higher for finerenone compared with placebo, but hypokalemia was cut in half.

Maja Cikes, MD, PhD (University of Zagreb School of Medicine, Croatia), said that despite MRAs having a strong recommendation for use in patients with HFrEF, the drugs remain underutilized. As the discussant after Jhund’s presentation, Cikes said there is now “compelling evidence supporting the use of these drugs in patients with chronic heart failure across the ejection fracture spectrum, and it is our duty to overcome inertia and optimize implementation strategies.”

In the second meta-analysis, which was published in Nature Medicine, Muthiah Vaduganathan, MD (Brigham and Women’s Hospital, Boston, MA), combined data from FINEARTS-HF, FIDELIO-DKD, and FIGARO-DKD. Here, the primary endpoint of cardiovascular death was not reduced with finerenone, although there was a signal of benefit (HR 0.89; 95% CI 0.78-1.01), including when researchers counted cardiovascular deaths and those from undetermined causes. (HR 0.88; 95% CI 0.79-0.98). 

Secondary endpoints of HF hospitalizations and a composite kidney endpoint (sustained eGFR decline > 50%, kidney failure, or death due to kidney failure), were both significantly reduced with the nonsteroidal MRA.

Not to be outdone by the flurry of finerenone and MRA studies, the Journal of the American College of Cardiology also published viewpoints on the challenges of modifying kidney disease progression in patients with HF as well as the challenges of reducing mortality in patients with HFmrEF/HFpEF.