A New Drug for Heart Failure with Preserved Ejection Fraction?

By Michael H. Crawford, MD, Editor

SYNOPSIS: The addition of the nonsteroidal mineralocorticoid receptor antagonist finerenone to standard therapy reduced the incidence of recurrent heart failure and death compared to placebo in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction and was generally well tolerated.

SOURCE: Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Eng J Med. 2024; Sep 1. doi: 10.1056/NEJMoa2407107. [Online ahead of print].

Steroidal mineralocorticoid receptor antagonists (MRAs) have been demonstrated to reduce morbidity and mortality in patients with heart failure (HF) with reduced left ventricular ejection fraction (EF), but their efficacy and safety in patients with HF and mildly reduced or preserved EF is not clear. Thus, the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) is of interest.

FINEARTS-HF is an international, multicenter, parallel group, event-driven, double-blind, randomized trial supported by Bayer. Patients ≥ 40 years of age with symptomatic HF, an EF ≥ 40%, evidence of structural heart disease, and elevated levels of natriuretic peptides were randomized to finerenone 20 mg/day or 40 mg/day, depending on the baseline estimated glomerular filtration rate (eGFR), or placebo in addition to their usual therapy. The primary outcome was a composite of worsening HF events and cardiovascular (CV) death.

Secondary endpoints included the components of the primary endpoint, the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, New York Heart Association (NYHA) functional class, change in eGFR, and adverse events. The statistical analysis was based on intention-to-treat, and various prespecified subgroups were assessed.

In 2020 through 2022, a total of 6,001 patients were enrolled and 5,982 finished the median 32-month follow-up. Their mean age was 72 years, 45% were women, 79% were white, 69% were NYHA class II, and 85% were taking a beta-blocker. About one-third of the patients were taking either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, and 14% were taking a sodium glucose cotransporter-2 (SGLT2) inhibitor.

The primary outcome occurred in 21% of the finerenone group and 24% of the placebo group (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.74-0.95; P = 0.007). Worsening HF also was reduced in the finerenone group (HR, 0.82; 95% CI, 0.71-0.94; P = 0.006). Mortality was 8.1% and 8.7%, respectively, which was not significantly different.

Finerenone increased the KCCQ score more than the placebo (8.0 vs. 6.4 points, P < 0.001), but improvement in NYHA classification was similar between the two groups. Decreases in eGFR and increases in potassium were more common in the finerenone group, but hypokalemia was less common. Mean systolic blood pressure at six months was lower in those taking finerenone (-3.4 mmHg), and values < 100 mmHg were more frequent (18.5% vs. 12.4%).

The authors concluded that finerenone significantly reduced the rate of worsening heart failure and CV death compared to placebo in patients with HF with mildly reduced or normal EF.

Commentary

The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial of the steroidal MRA spironolactone is the only other study of MRA in HF with mildly reduced or preserved EF. It failed to show that the primary outcome of CV death, aborted cardiac arrest, or recurrent HF was significantly different from placebo. However, post hoc analyses revealed that there were geographic differences in important study details in this international trial and that there was a suggestion of benefit in the Americas. This has led to a soft indication for spironolactone or eplerenone treatment of heart failure with preserved ejection fraction (HFpEF) in the United States.

Accordingly, this study of a nonsteroidal MRA in HFpEF is timely. Although finerenone showed a modest improvement in HF outcomes and the KCCQ score, there was no improvement in the NYHA classification or mortality, and it was at the expense of an increase in renal dysfunction and hyperkalemia. Although there were no deaths or hospitalizations related to hyperkalemia, the reduction in kidney function is concerning. Also, it is surprising, since a prior study of finerenone in patients with type 2 diabetes and chronic kidney disease showed a reduction in similar kidney outcomes.¹

There were limitations to FINEARTS-HF. This was largely a white population with very few Black patients (1.5%). Also, all the subgroups were underpowered, so it is not surprising that none showed any different results compared to the main trial. In addition, only 14% were taking an SGLT2 inhibitor, which is one of the few drugs with a strong recommendation in guidelines for the treatment of patients with HFpEF.

Finally, the authors dismissed the lack of improvement in NYHA classification with finerenone as an illustration of the insensitivity of this physician-determined measure. It could just as easily represent the marginal benefit of finerenone, since most drugs recommended for the treatment of HF do improve NYHA classification.

Finerenone is marketed by Bayer as Kerendia, and it is U.S. Food and Drug Administration-approved for the prevention of kidney disease progression and cardiovascular risk reduction in people with type 2 diabetes with chronic kidney disease based in part on two trials in these patients.^1,2 Personally, I would like to see more convincing data before prescribing it off-label to patients with HFpEF.

REFERENCES

1. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229.
2. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252-2263.

Michael H. Crawford, MD, is a Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.