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March 28, 2026JAMA Cardiology
Biomarker, Functional Status, and Quality-of-Life Trajectories Before Modes of Death in Heart Failure
H LuAnnamária KosztinBrian L. ClaggettAlberto FoàMaria PabónA S DesaiPardeep S. JhundAlasdair D. HendersonBela MerkelyCarolyn S. P. LamMichele SenniSanjiv J. ShahA W VoorsFaiez ZannadBertram PittFlaviana AmaranteRiitta SaarinenYoriko De SanctisAndrea GlasauerJohn J. V. McMurrayMuthiah VaduganathanScott D. Solomon
Key result
Sudden death in HFmrEF/HFpEF is preceded by an ~8-point KCCQ drop and worsening symptoms.
- n=6,001
Figures
Why the study?
Sudden death remains a leading cause of mortality in HFmrEF and HFpEF, but whether these events are preceded by clinical deterioration remains unclear.
Are sudden deaths in patients with HFmrEF or HFpEF preceded by distinct trajectories of functional status, quality of life, and natriuretic peptide levels compared with other modes of death and survival?
Key Points
- To characterize clinical trajectories of functional status, health status, and natriuretic peptide levels preceding sudden death compared with other modes of death and survival in patients with HFmrEF or HFpEF.
- Post hoc analysis of 6001 patients (mean age, 72.0 years; 54% male) enrolled in the global, event-driven FINEARTS-HF randomized clinical trial comparing finerenone with placebo.
- Eligible patients had symptomatic heart failure, left ventricular ejection fraction of 40% or greater, NYHA class II to IV, and elevated NT-proBNP, followed for a median of 2.7 years.
- Longitudinal trajectories of physician-assigned NYHA class, KCCQ-TSS, and NT-proBNP levels were evaluated preceding adjudicated modes of death using linear mixed-effects models with restricted cubic splines.
- Among 215 sudden deaths, the preceding 6 months showed a slight worsening in NYHA class (from approximately 2.3 to 2.4), an approximately 8-point decline in KCCQ-TSS, and an increase in NT-proBNP levels from approximately 1800 to 2000 pg/mL.
- In contrast, surviving patients demonstrated an improvement in NYHA class (from approximately 2.3 to 2.1), an increase in KCCQ-TSS (from approximately 68 to 77), and a decline in NT-proBNP (from approximately 800 to 650 pg/mL) over the preceding 18 months.
- Heart failure-related deaths showed more severe preceding deterioration than sudden death, with NYHA class worsening from approximately 2.4 to 2.8, KCCQ-TSS declining from approximately 70 to 50, and NT-proBNP rising from approximately 2000 to 3000 pg/mL.
Study Design
Type
Observational (n=6,001)
Blinding
Blinded outcome adjudication
Multicenter
Yes
Structured PICO
Are sudden deaths in patients with HFmrEF or HFpEF preceded by distinct trajectories of functional status, quality of life, and natriuretic peptide levels compared with other modes of death and survival?
P
Population
6,001 adults (mean age 72.0 years, 46% female) with symptomatic HFmrEF or HFpEF (LVEF >=40%), NYHA class II-IV, and elevated natriuretic peptides from the FINEARTS-HF trial, followed for a median of 2.7 years.
E
Exposure
Finerenone (evaluated in the parent FINEARTS-HF trial; this post hoc analysis evaluated longitudinal clinical trajectories preceding sudden death).
C
Comparator
Placebo (in the parent FINEARTS-HF trial; this post hoc analysis compared trajectories preceding sudden death with trajectories in survivors and patients who died of HF-related, nonsudden cardiovascular, or noncardiovascular causes).
O
Outcome
Longitudinal trajectories of physician-assigned New York Heart Association (NYHA) functional class, patient-reported Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels in the 18 months preceding blindly adjudicated modes of death (sudden death, HF-related death, nonsudden cardiovascular death, noncardiovascular death) or end of follow-up over a median follow-up of 2.7 years.
Limitations
- Post hoc analysis of a clinical trial; results should be considered hypothesis-generating
- Potential misclassification of deaths despite blinded adjudication due to insufficient documentation around unexpected deaths
- Trajectories were estimated at the population level rather than the individual level
- NT-proBNP levels were only measured at a limited number of follow-up visits, potentially missing rapid or transient changes
- Serial imaging and ECG parameters were not evaluated
- Assessments followed a fixed trial schedule rather than continuous monitoring, potentially missing short-term changes around acute hospitalizations or terminal events
- Post hoc analysis of a clinical trial, so results should be considered hypothesis generating
- Potential misclassification of deaths despite adjudication if unexpected deaths lacked sufficient documentation
- Trajectories were integrated across multiple time points providing population-level rather than personalized individual-level estimates
- NT-proBNP levels were only measured at a limited number of follow-up visits, possibly missing rapid or transient changes
- Imaging and ECG measures were not serially evaluated, and scheduled assessments rather than continuous monitoring may not capture short-term changes around acute events
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“These trajectories may reflect heightened near-term vulnerability to death more broadly, which may help identify patients at increased overall risk rather than guide sudden death–specific preventive strategies.”
“However, the nonspecific nature of these changes limits their immediate clinical actionability, particularly in guiding decisions about preventive therapies.”
Implication
Worsening KCCQ, NYHA, and NT-proBNP precede sudden death in HFmrEF/HFpEF; nonspecific patterns leave open utility for broad risk stratification.
Abstract
Importance 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. Objective To characterize clinical trajectories preceding sudden death in patients with HFmrEF or HFpEF and compare them with trajectories before other modes of death and survival. Design, Setting, and Participants This was a post hoc analysis of the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial evaluating trajectories of functional status, patient-reported health status, and natriuretic peptide levels preceding adjudicated modes of death. This was a global, event-driven clinical trial. Patients with symptomatic HF, left ventricular EF of 40% or greater, New York Heart Association class (NYHA) II to IV, and elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) were enrolled between September 14, 2020, and January 10, 2023. Data analysis was conducted in December 2025. Interventions Finerenone vs placebo. Main Outcomes and Measures Longitudinal trajectories of NYHA class, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and NT-proBNP levels preceding sudden death were compared with trajectories in survivors and those who died of HF-related, nonsudden cardiovascular, or noncardiovascular causes, using linear mixed-effects models with restricted cubic splines. Results Included in this analysis were 6001 patients (mean [SD] age, 72.0 [9.6] years; 3269 male [54%]). Over a median (IQR) follow-up of 2.7 (1.9-3.0) years, 215 sudden deaths occurred. In the 6 months before death, sudden death was preceded by a slight worsening in physician-assigned NYHA class (from approximately 2.3 to 2.4), worsening self-reported health status (an approximately 8-point decline in KCCQ-TSS), and a gradual rise in NT-proBNP levels (from approximately 1800 to 2000 pg/mL). In contrast, among patients who survived, NYHA class improved (from approximately 2.3 to 2.1), KCCQ-TSS increased (from approximately 68 to 77), and NT-proBNP levels declined (from approximately 800 to 650 pg/mL) over the 18 months before the end of follow-up. Comparable patterns of deterioration to those preceding sudden death, often more pronounced, were observed before other modes of death. Conclusions and Relevance 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. However, similar deterioration preceding other modes of death suggests limited specificity for sudden death. Trial Registration ClinicalTrials.gov Identifier: NCT04435626
Cite This Study
Lu et al. (2026) conducted an observational in Heart failure with mildly reduced or preserved ejection fraction (HFmrEF or HFpEF) (n=6,001). Sudden death (post hoc trajectory analysis of FINEARTS-HF trial of finerenone vs placebo) vs. Survivors and other modes of death (HF-related, nonsudden cardiovascular, and noncardiovascular death) was evaluated on Longitudinal trajectories of NYHA functional class, KCCQ-TSS, and NT-proBNP levels in the 6 months preceding sudden death vs survival. Sudden death in HFmrEF/HFpEF was preceded by a 6-month KCCQ-TSS decline of ~8 points, NYHA worsening (2.3 to 2.4), and NT-proBNP rise (1800 to 2000 pg/mL), unlike improvements in survivors.