Finerenone in the Management of HFmrEF and HFpEF: A Comprehensive Synthesis of Evidence from the FINEARTS-HF Trial

Highlights

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), significantly reduces the composite risk of cardiovascular (CV) death and total worsening heart failure (HF) events in patients with LVEF ≥40%.
Treatment benefits are consistent across the ejection fraction spectrum, including the often-overlooked ‘HF with improved EF’ (HFimpEF) population.
Finerenone demonstrates a unique metabolic benefit by reducing the hazard of new-onset diabetes by 24% in patients with HF.
Clinical efficacy remains robust regardless of patient frailty status, BMI, or the presence of comorbidities like COPD and atrial fibrillation.
While an initial decline in eGFR is observed upon treatment initiation, it does not correlate with adverse long-term outcomes and should not trigger premature discontinuation.

Background

Heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) account for approximately half of all heart failure cases worldwide. Unlike heart failure with reduced ejection fraction (HFrEF), therapeutic options for these patients were historically limited until the advent of SGLT2 inhibitors. Mineralocorticoid receptor (MR) overactivation is known to drive myocardial fibrosis, inflammation, and adverse remodeling. Traditional steroidal MRAs (spironolactone and eplerenone) have shown mixed results in HFpEF (e.g., TOPCAT trial) and are often limited by hyperkalemia and hormonal side effects. Finerenone, a nonsteroidal MRA with high potency and selectivity, was recently evaluated in the FINEARTS-HF trial to address this unmet need. The trial successfully met its primary endpoint, marking a significant milestone in cardiovascular medicine.

Key Content

Primary Efficacy and Hierarchical Outcome Analysis

The FINEARTS-HF trial randomized 6,001 patients to finerenone or placebo. The primary endpoint—a composite of CV death and total worsening HF events—showed a significant reduction (Rate Ratio [RR] 0.84; 95% CI 0.74-0.95). To further refine the clinical impact, researchers applied win statistics to a hierarchical composite endpoint (CV death > HF hospitalizations > urgent HF visits). The win ratio was 1.17 (p=0.010), with HF hospitalizations contributing the most to the overall treatment benefit. Gains were observed as early as 60 days post-randomization, emphasizing the rapid onset of finerenone’s protective effects.

Ejection Fraction Spectrum: From HFmrEF to HFimpEF

A crucial finding of FINEARTS-HF is the consistency of benefit across the LVEF spectrum. Sub-analyses categorized patients into LVEF <50%, 50%–60%, and ≥60%. Finerenone reduced the risk of the primary outcome in all groups (P-interaction = 0.70). Furthermore, the trial included patients with HF with improved ejection fraction (HFimpEF), defined as those with a prior LVEF <40% that rose to ≥40%. Despite their ‘improved’ status, these patients remained at high risk for CV events. Finerenone’s treatment benefit in HFimpEF was consistent with the overall population, although these patients showed a higher propensity for hypotension.

Metabolic and Renal Implications

One of the most striking findings from the prespecified analyses is finerenone’s effect on glycemic status. In patients without diabetes at baseline, finerenone reduced the hazard of new-onset diabetes by 24% (HR 0.76). This suggests a potential role for finerenone in modifying metabolic risk beyond its hemodynamic effects. Regarding renal function, finerenone led to a 30% reduction in the urine albumin/creatinine ratio (UACR). While an acute eGFR decline (≥15%) occurred more frequently with finerenone (23% vs 13.4% for placebo), this ‘dip’ was not associated with worse subsequent outcomes, mirroring the renal dynamics seen with SGLT2 inhibitors.

Vulnerable Populations: Frailty and Obesity

Patients with frailty are frequently undertreated due to perceived risks. FINEARTS-HF demonstrated that 37.3% of the study population was ‘most frail’ (Class III). Finerenone’s efficacy and safety (hypotension, hyperkalemia) were not modified by frailty status, supporting its use in elderly and multimorbid populations. Similarly, in patients with obesity, where adipocyte-derived aldosterone may exacerbate HF, the benefit of finerenone was consistent, with data suggesting even greater absolute risk reductions in those with higher BMI (P-interaction as continuous variable = 0.005).

Comorbidities: COPD and Atrial Fibrillation

Chronic obstructive pulmonary disease (COPD) often complicates HF management and worsens prognosis. In FINEARTS-HF, 12.9% of participants had COPD. Finerenone’s benefits on clinical events and symptoms (KCCQ-TSS) were entirely consistent regardless of COPD status, addressing concerns from previous MRA studies that suggested pulmonary disease might modify treatment response. Atrial fibrillation (AF) status also did not alter the efficacy of finerenone. Interestingly, a signal for reduced new-onset AF was observed (SHR 0.77), although it did not reach formal statistical significance (p=0.09).

Expert Commentary

The wealth of data from FINEARTS-HF positions finerenone as a foundational therapy for HFmrEF and HFpEF. The nonsteroidal structure of finerenone translates to a different tissue distribution and safety profile compared to spironolactone, notably with a lower risk of hormonal side effects and potentially more balanced cardio-renal protection.

A key clinical takeaway for practitioners is the management of eGFR. The initial decline should be viewed as a physiological manifestation of reduced intraglomerular pressure—a mechanism that likely contributes to long-term nephroprotection. Discontinuing therapy due to a minor eGFR dip may deprive patients of significant survival and symptomatic benefits. Furthermore, the reduction in new-onset diabetes adds a unique dimension to the MRA class, suggesting that early initiation could have systemic metabolic advantages.

Despite these strengths, the trial was likely underpowered to show a definitive reduction in all-cause mortality or specific modes of death (e.g., sudden death vs. HF death), though the trends were favorable. The higher incidence of hyperkalemia compared to placebo remains a consideration, necessitating routine monitoring of potassium levels, particularly in patients with baseline chronic kidney disease.

Conclusion

Finerenone represents a transformative addition to the armamentarium for heart failure with LVEF ≥40%. The FINEARTS-HF trial evidence confirms that finerenone reduces the burden of worsening heart failure and improves quality of life across the entire clinical spectrum—from the frail elderly to the obese and those with complex comorbidities like COPD and diabetes. Future clinical guidelines are expected to reflect these findings, potentially making nonsteroidal MRAs a standard of care alongside SGLT2 inhibitors for this challenging patient population.

References:

Butt JH, Jhund PS, Henderson AD, Claggett BL, Chiang CE, Linssen GCM, Saldarriaga CI, Saraiva JFK, Sato N, Schou M, von Lewinski D, Lay-Flurrie J, Scalise A, Rohwedder K, Desai AS, Lam CSP, Senni M, Shah SJ, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. Finerenone According to Frailty in Heart Failure: A Prespecified Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2025 Aug 1;10(8):829-840. doi: 10.1001/jamacardio.2025.1775 IF: 14.1 Q1 B1 . PMID: 40531488 IF: 14.1 Q1 B1 ; PMCID: PMC12177723 IF: 14.1 Q1 B1 .

Kondo T, Jhund PS, Henderson AD, Claggett BL, Desai AS, Brinker M, Lay-Flurrie J, Schloemer P, Viswanathan P, Amarante F, Chiang CE, Filippatos G, Lam CSP, Petrie MC, Senni M, Schou M, Verma S, Voors AA, von Lewinski D, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. The efficacy of finerenone on hierarchical composite endpoint analysed using win statistics in patients with heart failure and mildly reduced or preserved ejection fraction: A prespecified analysis of FINEARTS-HF. Eur J Heart Fail. 2025 Aug;27(8):1459-1471. doi: 10.1002/ejhf.3669 IF: 10.8 Q1 B1. Epub 2025 Apr 29. PMID: 40300840 IF: 10.8 Q1 B1; PMCID: PMC12482849 IF: 10.8 Q1 B1.

Butt JH, Jhund PS, Henderson AD, Claggett BL, Desai AS, Lam CSP, Mueller K, Scheerer MF, Viswanathan P, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. Finerenone, chronic obstructive pulmonary disease, and heart failure with mildly reduced or preserved ejection fraction: A prespecified analysis of the FINEARTS-HF trial. Eur J Heart Fail. 2025 Aug;27(8):1444-1458. doi: 10.1002/ejhf.3661 IF: 10.8 Q1 B1. Epub 2025 Apr 13. PMID: 40222820 IF: 10.8 Q1 B1; PMCID: PMC12482838 IF: 10.8 Q1 B1.

Pabon MA, Vardeny O, Vaduganathan M, Desai AS, Claggett BL, Kulac IJ, Jhund PS, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, Saldarriaga CI, Petrie MC, Merkely B, Borentain M, Mueller K, Viswanathan P, Amarante F, Morris A, McMurray JJV, Solomon SD. Finerenone in Heart Failure With Improved Ejection Fraction: The FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2025 Jul 1;10(7):740-745. doi: 10.1001/jamacardio.2025.1101 IF: 14.1 Q1 B1. PMID: 40397470 IF: 14.1 Q1 B1; PMCID: PMC12096322 IF: 14.1 Q1 B1.

Desai AS, Jhund PS, Vaduganathan M, Claggett BL, Cunningham JW, Pabon MA, Lam CSP, Senni M, Shah S, Voors AA, Zannad F, Pitt B, Amarante F, Lay-Flurrie J, Scheerer MF, Lage A, McMurray JJV, Solomon SD. Mode of Death in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2025 Jul 1;10(7):678-685. doi: 10.1001/jamacardio.2025.0860 IF: 14.1 Q1 B1. PMID: 40159247 IF: 14.1 Q1 B1; PMCID: PMC11955905 IF: 14.1 Q1 B1.

Matsumoto S, Henderson AD, Jhund PS, Bauersachs J, Chioncel O, Claggett BL, Comin-Colet J, Desai AS, Filippatos G, Lam CSP, Pitt B, Scheerer MF, Lay-Flurrie J, Amarante F, Brinker M, Schou M, Senni M, Shah SJ, Voors AA, Zannad F, Zieroth S, Vaduganathan M, Solomon SD, McMurray JJV. Finerenone and Atrial Fibrillation in Heart Failure: A Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2025 Jul 1;10(7):696-707. doi: 10.1001/jamacardio.2025.0848 IF: 14.1 Q1 B1. PMID: 40156827 IF: 14.1 Q1 B1; PMCID: PMC11955084 IF: 14.1 Q1 B1.

McDowell K, Docherty KF, Campbell RT, Henderson AD, Jhund PS, Claggett BL, Desai AS, Lay-Flurrie J, Hofmeister L, Scalise A, Lam CSP, Petrie MC, Schou M, Senni M, Shah SJ, Udell JA, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. Finerenone for Heart Failure and Risk Estimated by the PREDICT-HFpEF Model: A Secondary Analysis of FINEARTS-HF. JAMA Cardiol. 2025 Jun 1;10(6):535-544. doi: 10.1001/jamacardio.2025.0025 IF: 14.1 Q1 B1. Erratum in: JAMA Cardiol. 2025 Jun 1;10(6):635. doi: 10.1001/jamacardio.2025.1107 IF: 14.1 Q1 B1. PMID: 40042880 IF: 14.1 Q1 B1; PMCID: PMC11883611 IF: 14.1 Q1 B1.

Butt JH, Jhund PS, Henderson AD, Claggett BL, Desai AS, Viswanathan P, Kolkhof P, Schloemer P, Amarante F, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV; FINEARTS-HF Committees and Investigators. Finerenone and new-onset diabetes in heart failure: a prespecified analysis of the FINEARTS-HF trial. Lancet Diabetes Endocrinol. 2025 Feb;13(2):107-118. doi: 10.1016/S2213-8587(24)00309-7 IF: 41.8 Q1 B1. Epub 2025 Jan 13. PMID: 39818225 IF: 41.8 Q1 B1.

Vaduganathan M, Claggett BL, Desai AS, Jhund PS, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, Borentian M, Lay-Flurrie J, Viswanathan P, Behmenburg FU, McMurray JJV, Solomon SD. Estimated Long-Term Benefits of Finerenone in Heart Failure: A Prespecified Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2025 Feb 1;10(2):176-181. doi: 10.1001/jamacardio.2024.3782 IF: 14.1 Q1 B1. PMID: 39332395 IF: 14.1 Q1 B1; PMCID: PMC11581494 IF: 14.1 Q1 B1.

Matsumoto S, Jhund PS, Henderson AD, Bauersachs J, Claggett BL, Desai AS, Brinker M, Schloemer P, Viswanathan P, Mares JW, Scalise A, Lam CSP, Linssen GCM, Kerr Saraiva JF, Senni M, Troughton R, Udell JA, Voors AA, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. Initial Decline in Glomerular Filtration Rate With Finerenone in HFmrEF/HFpEF: A Prespecified Analysis of FINEARTS-HF. J Am Coll Cardiol. 2025 Jan 21;85(2):173-185. doi: 10.1016/j.jacc.2024.11.020 IF: 22.3 Q1 B1. PMID: 39814476 IF: 22.3 Q1 B1.

Yang M, Henderson AD, Talebi A, Atherton JJ, Chiang CE, Chopra V, Comin-Colet J, Kosiborod MN, Kerr Saraiva JF, Claggett BL, Desai AS, Kolkhof P, Viswanathan P, Lage A, Lam CSP, Senni M, Shah SJ, Rohwedder K, Voors AA, Zannad F, Pitt B, Vaduganathan M, Jhund PS, Solomon SD, McMurray JJV. Effect of Finerenone on the KCCQ in Patients With HFmrEF/HFpEF: A Prespecified Analysis of FINEARTS-HF. J Am Coll Cardiol. 2025 Jan 21;85(2):120-136. doi: 10.1016/j.jacc.2024.09.023 IF: 22.3 Q1 B1. Epub 2024 Sep 29. PMID: 39520455 IF: 22.3 Q1 B1.

Mc Causland FR, Vaduganathan M, Claggett BL, Kulac IJ, Desai AS, Jhund PS, Henderson AD, Brinker M, Perkins R, Scheerer MF, Schloemer P, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, McMurray JJV, Solomon SD. Finerenone and Kidney Outcomes in Patients With Heart Failure: The FINEARTS-HF Trial. J Am Coll Cardiol. 2025 Jan 21;85(2):159-168. doi: 10.1016/j.jacc.2024.10.091 IF: 22.3 Q1 B1. Epub 2024 Oct 25. PMID: 39490700 IF: 22.3 Q1 B1.

Docherty KF, Henderson AD, Jhund PS, Claggett BL, Desai AS, Mueller K, Viswanathan P, Scalise A, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, Vaduganathan M, Solomon SD, McMurray JJV. Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the FINEARTS-HF Trial. Circulation. 2025 Jan 7;151(1):45-58. doi: 10.1161/CIRCULATIONAHA.124.072011 IF: 38.6 Q1 B1. Epub 2024 Sep 29. PMID: 39342512 IF: 38.6 Q1 B1; PMCID: PMC11670913 IF: 38.6 Q1 B1.