Introduction
Sudden death continues to be a major cause of mortality among patients living with heart failure characterized by mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF). These subtypes involve patients whose hearts eject blood at rates near or above 40%, yet they still suffer considerable morbidity and mortality risks. Understanding whether sudden death is truly abrupt or preceded by clinical deterioration is critical to improving patient surveillance and outcomes.
This post hoc analysis of the FINEARTS-HF trial sought to explore the patterns of clinical parameters, including functional status, patient-reported quality-of-life, and biomarker levels, prior to different modes of death in patients with HFmrEF or HFpEF. The goal was to characterize the trajectories leading up to sudden death and contrast these with trajectories before other types of death or survival.
Study Design and Participants
The analysis leveraged data from the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF), a global, event-driven randomized clinical trial. Participants included adults with symptomatic heart failure, a left ventricular ejection fraction of 40% or higher, and a New York Heart Association (NYHA) functional class ranging from II to IV, indicating mild to severe functional impairment.
Additionally, patients had elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker reflecting cardiac stress and damage. Enrollment occurred between September 2020 and January 2023, with data analysis completed in December 2025. Treatment arms compared finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, to placebo.
Measures and Outcomes
The key metrics tracked over time included the NYHA functional class assessed by physicians, patient-reported outcomes through the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and circulating NT-proBNP levels. These measures were analyzed longitudinally using advanced statistical models — specifically, linear mixed-effects models with restricted cubic splines — to identify trends and changes leading up to events classified as sudden death, heart failure-related death, other cardiovascular death, non-cardiovascular death, or survival.
Findings
This study encompassed 6,001 patients, with an average age of 72 years, 54% of whom were male. During a median follow-up period of 2.7 years, 215 sudden deaths were recorded.
Importantly, in the six months preceding sudden death, patients exhibited mild but noticeable declines in clinical status: the physician-assessed NYHA class worsened slightly from about 2.3 to 2.4, while patient-reported health status declined by roughly 8 points on the KCCQ-TSS scale. Correspondingly, NT-proBNP levels rose gradually from approximately 1800 to 2000 pg/mL.
Contrastingly, surviving patients over the prior 18 months showed improvements: their NYHA class improved from roughly 2.3 to 2.1, KCCQ-TSS scores increased from around 68 to 77, and NT-proBNP levels decreased from about 800 to 650 pg/mL.
Notably, patterns of clinical deterioration similar to or more pronounced than those preceding sudden death were observed before other modes of death, including heart failure-related and other cardiovascular deaths. This implies that while deterioration occurs before sudden death, these changes are not unique to sudden cardiac events.
Implications and Interpretation
These findings challenge the traditional perception that sudden death in HFmrEF or HFpEF patients happens abruptly without warning. Instead, many cases appear to be preceded by modest worsening of symptoms, declining quality of life, and rising levels of cardiac biomarkers. This gradual decline may provide opportunities for intervention.
However, because similar deterioration patterns were noted before other types of death, the predictive specificity of these trajectories for sudden death is limited. Therefore, while ongoing monitoring of functional status, quality of life, and biomarkers remains vital, clinicians should be cautious in interpreting these signals as specific predictors of sudden death.
Treatment Context
Finerenone, investigated in this trial, functions by blocking the mineralocorticoid receptor, reducing inflammation and fibrosis, and improving cardiac remodeling. Although this analysis focused on pre-death trajectories, finerenone has established benefits in heart failure management, particularly among patients with preserved or mildly reduced ejection fraction.
Consistent monitoring and timely adjustment of therapy in response to worsening clinical or biomarker profiles remain essential strategies to reduce adverse outcomes, including sudden death.
Conclusion
This post hoc examination of the FINEARTS-HF trial provides novel insights into the clinical course leading up to sudden death in patients with HFmrEF or HFpEF. Sudden death frequently follows a period of gradual decline in symptoms, quality of life, and NT-proBNP levels rather than occurring abruptly. Awareness of these changes can aid clinicians in patient risk stratification and may guide more proactive therapeutic interventions.
Further research is warranted to enhance the specificity of predictive markers and to develop targeted strategies aimed at preventing sudden death in this high-risk population.
Trial Registration
ClinicalTrials.gov Identifier: NCT04435626
References
Lu H, Kosztin A, Claggett BL, et al. Biomarker, Functional Status, and Quality-of-Life Trajectories Before Modes of Death in Heart Failure: Post Hoc Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2026 Jun 1;11(6):574-582. PMID: 41903171.
