Benefits of Finerenone Similar in Women and Men, Analysis Finds

It’s known that women are not well-represented in studies for heart medications, even though heart failure is rising more quickly in women than in men, especially heart failure with preserved ejection fraction (HFpEF).

That’s why Sunday’s prespecified analysis of the FINEARTS-HF study offered something exciting.¹ In September, findings showed that finerenone (Kerendia, Bayer) caused a significantly lower rate of a composite of cardiovascular death and worsening of HF than placebo.² That study evaluated the nonsteroidal mineralocorticoid receptor antagonists (MRA) in patients with a HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), ≥40%.

The new analysis, presented at the 2024 American Heart Association (AHA) Scientific Sessions in Chicago, IL, broke out results for women and men, highlighting that 45.5% of the trial’s participants were women—more than double the historic levels. This was 1 of 3 abstracts with follow-up results for FINEARTS-HF presented in the Sunday morning session on HFpEF.

Misato Chimura, MD, of the Department of Cardiovascular Medicine, Osaka University, Japan, shared enrollment data that showed 2732 women and 3269 men were randomized in FINEARTS-HF. Women, she said, were older and had higher rates of obesity than men, with a lower average estimated glomerular filtration rate, worse NY Heart Association functional class, and lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). Of note, women had a mean left ventricle ejection fraction (LVEF) of 55%, while men had an LVEF of 51%.

Chimura reported that compared with placebo, “finerenone reduced the risk of the primary outcome to a similar extent in both men and women.” The rate ratio (RR) for women was 0.78 (95% Ci, 0.65-0.95) in women, while the RR for men was 0.88 (0.74-1.04), with P for interaction = 0.41. Detailed data for women and men in the finerenone group showed the following:

• Total HF events favored women (0.76; 0.62-0.94), over men (0.86; 0.70-1.04), P for interaction = 0.45
• While women and men had the same RR for first HF event (0.81), the data favored women for cardiovascular death (0.87 for women vs 0.96 for men) but slightly favored men for all-cause death (0.94 for women vs 0.92 for men).

In the abstract, investigators reported that the mean improvement in the KCCQ-TSS from baseline to 12 months was greater with finereone than placebo, irrespective of gender, although during the question-and-answer period it was noted that women came out slightly lower; Chimura explained that this pattern in KCCQ-TSS scores is seen across multiple HF trials.

“To summarize, almost half of the patient in the FINEARTS-HF trial were women, making it one of the few cardiovascular trials with a substantial representation of women,” Chimura said.

Using Win Statistics to Evaluate FINEARTS-HF by Clinical Importance

Composite end points are common in HF trials, but how can clinicians or payers tease out which factors are of greatest relevance? Toru Kondo, MD, of the School of Cardiovascular and Metabolic Health at the University of Glasgow, offered a different look at the FINEARTS-HF results through the lens of “win” statistics, a complex, alternative method of evaluating a trial by comparing participants in treatment group with the control group across a series of endpoints.³

For this analysis, Kondo evaluated endpoint components in the following order: cardiovascular death (Tier 1); total HF hospitalizations, which factored in both the number and time to HF event (Tier 2); and total urgent HF visits (Tier 3). This type of analysis can offer insight not only into the number of events, but also when they occur.

“The total events approach has the limitation of giving equal statistical weight to clinically less important events,” he said. “The win statistics approach can integrate all these outcomes into a single end point."

Kondo described what he called an “extended hierarchical standpoint,” and went into detail to show how win statistics are calculated. The analysis calculated 3 measures for 6001 participants, randomized to finerenone (3003) or placebo (2998):

• win ratio, which is a ratio of wins to losses,
• win odds, a modification of win ratio that factors in ties and as well as the likelihood that the treatment group will have better outcomes than the control group, and
• net benefit, which the authors said corresponds to absolute risk difference. This was calculated over a fixed period of 24 months.

Results. The finerenone group had 825 events, compared with 1012 events for the placebo group, for a win ratio of 1.17 (95% CI, 1.04-1.32; P = .01). The win odds were 1.05 (95% CI, 1.01-1.09, P = .01), and the net benefit was 2.6%, (95% CI, 0.6-4.5%).

Of note, the win ratio stayed above 1.0 starting at 60 days after randomization and hit a plateau at the 12-month mark. Losses for total HF hospitalizations contributed more to overall totals than cardiovascular death, which is consistent with reports from recent trials that HF hospitalization events drive results more than CV deaths.

Evaluating Hyperkalemia Risk in FINEARTS-HF

Orly Vardeny, PharmD, MS, professor of Medicine, University of Minnesota, gave an overview of hyperkalemia risk relative to benefit for HF patients enrolled in FINEARTS-HF. According to the abstract, the review examined predictors of hyperkalemia as well as the treatment effects of finerenone “based on post-randomization potassium levels,”⁴ and concluded in an article published in JAMA Cardiology that use of finerenone in patients with HFmrEF / HFpEF offers a favorable risk to benefit ratio.⁵

“Appropriate dose selection according to baseline kidney function and dose adjustments in response to potassium levels while receiving treatment, in keeping with the trial protocol, may mitigate risks of serious hyperkalemia and optimize treatment continuation in clinical practice,” Vardeny and her coauthors wrote. “These data suggest a favorable risk to benefit ratio for the use of finerenone in select patients with heart failure with mildly reduced or preserved ejection fraction in the setting of protocolized surveillance and follow-up.”⁵

As Vardeny explained during the session, the trial protocol called for investigators to down-titrate or temporarily halt study medication if a patient’s potassium levels reached ≥5.5 mmol/l. At the 1-month mark, those in the finerenone arm had seen an increase in potassium of 0.19 (0.17-0.21) mmol/l, which continued throughout the trial.

Vardeny shared a graphic that showed most patients’ potassium stayed at the 4.6 mmol/l range in the finerenone arm and in the 4.4 mmol/l range in the placebo arm.

Results also showed:

• Men were more likely to have potassium levels reach 5.5 mmol/l regardless of which arm they were assigned.
• Other contributing factors to hyperkalemia were having a history of diabetes, a recent HF worsening event, or a lower baseline kidney function.
• Finerenone elevated the risk of any potassium level going above 5.5mmol/l (14.3% vs 6.9%), and reduced the risks for hypokalemia, which was 3.5 mmol/l or lower (4.4% vs 9.7%).
• Hyperkalemia-related hospitalizations are uncommon in both arms, occurring in 0.5% of the finerenone arm and 0.2% of the placebo arm. There were no hyperkalemia-related deaths in either arm.

“In patients with HFmrEF/HFpEF, finerenone resulted in early modest increases in potassium levels,” Vardeny wrote in the abstract. “However, the clinical benefit of finerenone was maintained even in the setting of moderate hyperkalemia.”

References

1. Chimura M, Jhund PS, Henderson AD, et al. Efficacy and safety of finerenone in patients with heart failure and mildly reduced or preserved ejection fraction: A prespecified sex-specific analysis of the FINEARTS-HF trial. Presented at: American Heart Association Scientific Sessions, November 16-18, 2024; Chicago, IL; Abstr 4170814.
2. Solomon SD, McMurray JV, Claggett B, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction, for the FINEARTS-HF investigators. N Engl J Med. 2024;391(16):1475-1485. DOI: 10.1056/NEJMoa2407107
3. Kondo T, Jhund PS, Henderson AD, et al. Effect of finerenone on a hierarchical composite endpoint analyzed using win statistics in patients with heart failure and mildly reduced or preserved ejection fraction: A prespecified analysis of FINEARTS-HF. Presented at: American Heart Association Scientific Sessions, November 16-18, 2024; Chicago, IL; Abstr 4169904.
4. Vardeny O, Vaduganathan M, Claggett B, et al. Finerenone and risk of hyperkalemia in patients with heart failure with mildly reduced or preserved ejection fraction. A prespecified analysis of FINEARTS-HF. Presented at: American Heart Association Scientific Sessions, November 16-18, 2024; Chicago, IL; Abstr 4171315.
5. Vardeny O, Vaduganathan M, Claggett B, et al.Finerenone, serum potassium, and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction JAMA Cardiol. Published online November 17, 2024. doi:10.1001/jamacardio.2024.4539