Sudden Death in HFpEF Often Preceded by Clinical Decline

Sudden death has long been considered an abrupt and unpredictable event in patients with heart failure (HF). But a new post hoc analysis of the FINEARTS-HF randomized clinical trial challenges that assumption, finding that most sudden deaths in patients with HF with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) are preceded by measurable clinical deterioration in the months before death.

The study, published in JAMA Cardiology, examined longitudinal trajectories of functional status, patient-reported health status, and natriuretic peptide levels in 6001 patients enrolled in FINEARTS-HF, a global clinical trial evaluating finerenone vs placebo in patients with symptomatic HF and left ventricular ejection fraction (LVEF) of 40% or greater. Over a median follow-up of 2.7 years, 215 adjudicated sudden deaths occurred.

Warning Signs Before Sudden Death

Investigators tracked 3 clinical parameters at regular intervals: New York Heart Association (NYHA) functional class, the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. In the 6 months preceding sudden death, patients showed only a slight worsening in NYHA class, from approximately 2.3 to 2.4, but experienced a meaningful decline in patient-reported health status, with KCCQ-TSS falling by approximately 8 points. NT-proBNP levels also rose gradually, from roughly 1800 to 2000 pg/mL.

By contrast, patients who survived improved across all 3 measures during the same timeframe. NYHA class declined from approximately 2.3 to 2.1, KCCQ-TSS rose from approximately 68 to 77, and NT-proBNP fell from roughly 800 to 650 pg/mL.

“Sudden death remains a leading cause of mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), but whether these events are preceded by clinical deterioration remains unclear,” wrote the researchers of the study.

Overlap With Other Modes of Death Limits Specificity

A critical finding of the study is that similar—and often more pronounced—deterioration was observed before other causes of death, including HF-related death, nonsudden cardiovascular death, and noncardiovascular death. Patients who died of HF-related causes, for example, showed steeper worsening across all 3 domains: NYHA class rose from approximately 2.4 to 2.8, KCCQ-TSS fell steadily from roughly 70 to 50 over 18 months, and NT-proBNP climbed from approximately 2000 to 3000 pg/mL.

The researchers caution that these trajectories may reflect heightened near-term vulnerability to death more broadly, rather than being specific to sudden death. This limits their utility for guiding targeted sudden death prevention strategies such as implantable cardioverter-defibrillator (ICD) placement.

This challenge is well recognized in the literature. A pooled individual patient-level analysis of 5 randomized clinical trials, including CHARM-Preserved, I-Preserve, TOPCAT Americas, PARAGON-HF, and DELIVER, found that sudden death accounted for 39% of cardiovascular deaths among patients with HFmrEF/HFpEF, especially in male patients and patients with ischemic heart disease, and that combining clinical risk factors with NT-proBNP may be an efficient strategy for identifying high-risk patients.² Despite that burden, current professional society guidelines do not recommend ICDs for primary prevention in HFpEF, citing a lack of demonstrated clinical benefit and inadequate risk stratification tools.

Patient Characteristics and Study Context

Patients who experienced sudden death were predominantly male (61.9%) and had a lower mean LVEF (50.7%) compared with those who survived (52.6%) or died of HF-related causes (52.8%).¹ They were also more likely to have a history of myocardial infarction and were more frequently enrolled from Eastern Europe. Notably, those who died of sudden death were younger on average than those who died of HF-related causes (mean age, 71.6 vs 75.9 years), suggesting that HF-related death may involve age-driven processes like frailty, while sudden death may reflect earlier disease-specific triggers.

Implications for Practice

The investigators acknowledge several limitations, including the post hoc design, potential misclassification of deaths, and the limited number of NT-proBNP measurement time points. Still, the findings carry meaningful implications.

“Results of this post hoc analysis of the FINEARTS-HF randomized clinical trial reveal that in this contemporary HFmrEF or HFpEF cohort, sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels, suggesting many of these events may not have been entirely sudden,” wrote the researchers. “However, similar deterioration preceding other modes of death suggests limited specificity for sudden death.”

References

1. 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. Published online March 28, 2026. doi:10.1001/jamacardio.2026.0682
2. Ariss RW, Claggett BL, Vaduganathan M, et al. Sudden death in heart failure with mildly reduced or preserved ejection fraction: a pooled individual patient-level analysis of five randomized clinical trials. J Card Fail. 2025;31(1):187. doi:10.1016/j.cardfail.2024.10.025