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.
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