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Importance: Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up., Objective: To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels., Design, Setting, and Participants: Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included., Intervention: Participants received finerenone or placebo., Main Outcomes and Measures: The primary outcome was a composite of total worsening heart failure events or cardiovascular death., Results: A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L., Conclusions and Relevance: In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.

Importance: People living with heart failure (HF) with mildly reduced or preserved ejection fraction have substantially curtailed life expectancy free from clinical events compared with their peers of comparable age. The nonsteroidal mineralocorticoid receptor antagonist, finerenone, was recently shown to reduce risks of cardiovascular events in this population over a median follow-up of 2.6 years; as patients with HF typically continue treatment beyond this time frame, estimating the potential long-term benefits of finerenone could inform shared clinical decision-making., Objective: To estimate the projected long-term treatment effects of finerenone in patients with HF with mildly reduced or preserved ejection fraction if treated over a patient's lifetime., Design, Setting, and Participants: Prespecified analyses were conducted of the FINEARTS-HF trial, a phase 3 randomized clinical trial conducted across 653 sites in 37 countries. Adults 40 years and older with symptomatic HF and left ventricular ejection fraction of 40% or greater were randomized from September 2020 to January 2023. Median (IQR) follow-up was 2.6 (1.9-3.0) years., Interventions: Finerenone (titrated to either 20 mg or 40 mg) or placebo., Main Outcomes and Measures: The primary composite outcome was time to cardiovascular death or worsening HF event. The long-term gains in survival free from a primary end point with finerenone were iteratively estimated with age-based Kaplan-Meier curves using age at randomization rather than time from randomization. Differences in areas under the survival curves between the finerenone and placebo arms represented event-free survival gains., Results: Among 6001 participants (median [IQR] age, 73 [66-79] years; 3269 male [54.5%]), mean survival free from the primary end point for a 55-year-old participant was 13.6 years (95% CI, 11.9-15.2 years) with finerenone and 10.5 years (95% CI, 6.8-11.3 years) with placebo, representing a gain in event-free survival of 3.1 years (95% CI, 0.8-5.4 years; P = .007). Mean event-free survival for a 65-year-old participant was 11.0 years (95% CI, 10.1-11.9 years) with finerenone and 8.9 years (95% CI, 8.1-9.8 years) with placebo, representing a gain of 2.0 years (95% CI, 0.8-3.3 years; P = .001). Projected mean event-free survival was numerically greater with finerenone than with placebo for every starting age between 50 to 80 years. Lifetime gains in event-free survival were observed even among individuals already treated with a sodium-glucose cotransporter 2 inhibitor (65-year-old participant: 3.1 years; 95% CI, 0.1-6.0 years; P = .04)., Conclusions and Relevance: In this prespecified secondary analysis of the FINEARTS-HF randomized clinical trial, long-term treatment with finerenone was estimated to extend event-free survival by up to 3 years among people with HF with mildly reduced or preserved ejection fraction., Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.