This post hoc analysis of the FINEARTS-HF randomized clinical trial investigated if sudden deaths in patients with heart failure with mildly reduced or preserved ejection fraction are preceded by identifiable clinical deterioration compared with other modes of death.
Key Points
Question
Are sudden deaths in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF) preceded by identifiable clinical deterioration compared with other modes of death?
Findings
In this 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 including 6001 patients with HFmrEF or HFpEF, sudden death was preceded by modest worsening in New York Heart Association class, substantial declines in patient-reported health status, and rising N-terminal pro–B-type natriuretic peptide levels in the months before death, suggesting that many events may not have been entirely sudden or unexpected. Similar or more pronounced patterns were observed before other cardiovascular and noncardiovascular deaths.
Meaning
Study findings reveal that although sudden death in HFmrEF or HFpEF is often preceded by clinical deterioration—suggesting that many events may not be entirely sudden or unexpected— these clinical signals lack specificity and are unlikely to meaningfully inform targeted prevention strategies.
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
Introduction
Despite recent advances and the emergence of disease-modifying therapies for patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), the burden of cardiovascular death remains substantial in this population.
Sudden death is a leading mode of death in HFpEF trials, accounting for up to 25% to 30% of total deaths, exceeding the rate of deaths related to pump failure. Despite this, current professional society guidelines do not recommend implantable cardioverter-defibrillators (ICDs) for primary prevention in HFpEF, given the lack of appropriate risk stratification and insufficient evidence demonstrating clinical benefit. While often presumed to be abrupt and unpredictable, the clinical course preceding sudden death has not been well characterized. Identifying whether sudden death is preceded by distinct clinical and biological deterioration, compared with other modes of death, may help refine risk prediction and prevention strategies for patients at high near-term risk.
In this 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, we examined temporal patterns of physician-assigned functional status (New York Heart Association [NYHA]), a patient-reported quality-of-life outcome (Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and a biomarker (N-terminal pro–B-type natriuretic peptide [NT-proBNP]) in the months preceding adjudicated sudden death. These parameters were selected because of their established prognostic and clinical significance in HFpEF. Trajectories preceding sudden death were compared with those observed in patients who remained alive through follow-up, as well as in those who died of HF-related, nonsudden cardiovascular, and noncardiovascular causes, to assess whether patterns preceding sudden death are distinct or overlap with trajectories observed prior to other modes of death.
Methods
Trial Design
The FINEARTS-HF trial design has been described in detail previously. In brief, FINEARTS-HF was a multicenter, event-driven, randomized clinical trial evaluating the efficacy and safety of finerenone compared with placebo in patients with HF and a left ventricular EF (LVEF) greater than or equal to 40%. Key inclusion criteria included an age 40 years or older, NYHA functional class II or higher, elevated natriuretic peptide levels—defined as NT-proBNP greater than or equal to 300 pg/mL or BNP greater than or equal to 100 pg/mL (to convert to nanograms per liter, multiply by 1) in patients in sinus rhythm (≥900 pg/mL or ≥300 pg/mL, respectively, in those in atrial fibrillation)—along with evidence of structural heart disease (left atrial dilation or LV hypertrophy), and recent use of diuretics. Patients were excluded if they had an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73 m2 at screening or randomization. The trial protocol is shown in Supplement 1. Written informed consent was obtained from all participants, and the study protocol received approval from institutional review boards or ethics committees at each site. Participants self-reported the following races and ethnicities: Asian, Black, White, and other, which included American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or unreported. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Definition of Outcomes
The mode of death was blindly adjudicated by a clinical end point committee using standardized criteria, as previously described.
Cardiovascular death included any death resulting from an acute myocardial infarction, sudden death, death due to HF, death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other cardiovascular causes. Sudden death was defined as unexpected death in an otherwise stable individual, either witnessed or occurring within 24 hours of the participant last being seen alive. HF-related death was defined as death occurring in the context of clinically worsening symptoms and/or signs of HF without evidence of another cause of death. Nonsudden cardiovascular death was defined as any cardiovascular death that did not meet criteria for sudden death. Noncardiovascular death was defined as death resulting from causes not attributable to a cardiovascular etiology as previously defined. Deaths with undetermined causes were not included in the analyses because they were categorized separately.
All parameters of interest were assessed at randomization and regular intervals during follow-up: NT-proBNP level was assessed at 3 and 12 months after randomization; NYHA functional class was evaluated at 1 month, then at 3, 6, 9, and 12 months, and subsequently every 2 months up to 42 months; and KCCQ-TSS was collected at 6, 9, 12, 16, 24, 32, and 40 months after randomization.
Statistical Analysis
Baseline characteristics according to subsequent mode of death were summarized as frequencies with percentages, means with SD, or medians with IQR. Differences in baseline characteristics were tested using the χ2 test for binary or categorical variables and the Wilcoxon test and 2-sample t test for nonnormally and normally distributed continuous variables, respectively.
We used linear mixed-effects models with random patient-level intercepts and restricted cubic splines to assess the longitudinal trajectories of the 3 parameters of interest over time. These models incorporate all available repeated measurements and inherently accommodate unbalanced data without requiring formal imputation. The number of knots was selected based on minimization of the Akaike information criterion and the clinical interpretability of the resulting figures, models with 3 to 6 knots were tested. These analyses evaluated changes in the selected parameters preceding adjudicated sudden death and compared these trajectories with those observed before end of follow-up among survivors, as well as before HF-related death, nonsudden cardiovascular death, and noncardiovascular death. Because time to event or end of follow-up differed between groups, we adjusted the follow-up period for control patients, ensuring a comparable follow-up time (18 months) across groups. NYHA functional class, KCCQ-TSS, and NT-proBNP levels were each plotted relative to the number of months before the outcome of interest or end of follow-up. For comparisons, 2 P values were reported: 1 assessing whether the trajectories over time were identical (ie, superimposable) and another evaluating whether the trajectories differed in shape over time (ie, nonparallel trajectories reflecting a group × time interaction). Statistical analyses were carried out using Stata, version 19 (StataCorp). All P values were 2-sided, and P values <.05 were considered statistically significant. Data analysis was conducted in December 2025.
Results
Included in this analysis were 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 female [46%]; 3269 male [54%]) (eFigure 1 in Supplement 2). Participants self-reported the following races and ethnicities: 996 Asian (16.6%), 88 Black (1.5%), 4735 White (78.9%), and 182 other (3.0%). Over a median (IQR) follow-up time of 2.7 (1.9-3.0) years, a total of 1013 deaths occurred, of which 502 (49.6%) were adjudicated as cardiovascular deaths, including 215 (21.2%) sudden death and 163 (16.1%) HF-related deaths.
Compared with patients who remained alive, those who died of HF—but not those who experienced sudden death—were older (mean [SD] age, HF death, 75.9 [9.9] years vs alive, 71.4 [9.6] years) (Table). Women were less frequently represented among patients who experienced sudden death (82 of 215 [38.1%]) or HF-related death (69 of 163 [42.3%]) than among those who remained alive (2313 of 4988 [46.4%]). Sudden death occurred more commonly among patients enrolled in Eastern Europe (113 of 215 [52.6%] vs Asia, 37 [17.2%]; Latin America, 23 [10.7%]; North America, 9 [4.2%]) and was associated with lower LVEF (mean [SD], 50.7% [7.9%]) compared with both HF death (52.8% [8.3%]) and survival (52.6% [7.8%]). Patients who died of HF had a higher prevalence of prior HF hospitalization (128 of 163 [78.5%]), lower systolic blood pressure (mean [SD], 124.7 [16.1] mm Hg), worse kidney function (mean [SD] serum creatinine, 1.3 [0.4] mg/dL; to convert to micromoles per liter, multiply by 88.4), and higher NT-proBNP concentrations (median [IQR], 2381 [1412-4109] pg/L) than the other groups, and were more likely to have diabetes (82 of 163 [50.3%]) and atrial fibrillation (81 of 163 [49.7%]). Patients who remained alive were more likely to be in a lower NYHA functional class (class II, 3552 of 4988 [71.2%] vs class IV, 26 of 4988 [0.5%]). Finally, from a therapeutic standpoint, use of guideline-directed medical therapy differed modestly across groups, with lower use of β-blockers (128 of 163 [78.5%]) and angiotensin receptor blockers (45 of 163 [27.6%]), and higher use of sodium-glucose cotransporter 2 inhibitors (32 of 163 [19.6%]) among patients who died of HF.
Table. Baseline Characteristics of Patients Who Experienced Sudden Death vs Those Who Remained Alive During Follow-Up.
| Characteristic | Sudden death (n = 215) | Heart failure death (n = 163) | Remained alive (n = 4988) |
|---|---|---|---|
| Age, mean (SD), y | 71.6 (9.6) | 75.9 (9.9) | 71.4 (9.6) |
| Sex, No. (%) | |||
| Female | 82 (38.1) | 69 (42.3) | 2313 (46.4) |
| Male | 133 (61.9) | 94 (57.7) | 2675 (53.6) |
| Race | |||
| Asian | 37 (17.2) | 26 (16.0) | 840 (16.8) |
| Black | 3 (1.4) | 1 (0.6) | 77 (1.5) |
| White | 1 (0.5) | 4 (2.5) | 163 (3.3) |
| Othera | 174 (80.9) | 132 (81.0) | 3908 (78.3) |
| Region | |||
| Asia | 37 (17.2) | 26 (16.0) | 828 (16.6) |
| Eastern Europe | 113 (52.6) | 56 (34.4) | 2227 (44.6) |
| Latin America | 23 (10.7) | 17 (10.4) | 528 (10.6) |
| North America | 9 (4.2) | 18 (11.0) | 376 (7.5) |
| Western Europe, Oceania and others | 33 (15.3) | 46 (28.2) | 1029 (20.6) |
| Any previous hospitalization for HF | 141 (65.6) | 128 (78.5) | 2930 (58.7) |
| SBP, mean (SD), mm Hg | 127.5 (14.6) | 124.7 (16.1) | 129.6 (15.2) |
| BMI, mean (SD)b | 29.7 (6.4) | 29.8 (6.7) | 30.0 (6.0) |
| Serum creatinine, mean (SD), mg/dL | 1.2 (0.4) | 1.3 (0.4) | 1.1 (0.4) |
| eGFR, mean (SD), mL/min/1.73 m2 | 59.7 (20.0) | 50.5 (17.1) | 63.5 (19.6) |
| Serum sodium, mean (SD), mEq/L | 140.1 (3.5) | 140.3 (3.5) | 140.7 (2.9) |
| Serum potassium, mean (SD), mEq/L | 4.4 (0.5) | 4.3 (0.6) | 4.4 (0.5) |
| Hemoglobin, mean (SD), g/dL | 13.3 (1.9) | 13.0 (1.7) | 13.5 (1.6) |
| UACR, median (IQR), mg/g | 32.0 (9.0-136.0) | 52 (15-142) | 17.0 (6.0-56.0) |
| NT-proBNP, median (IQR), pg/L | 1505 (775-2948) | 2381 (1412-4109) | 935 (410-1760) |
| LVEF, mean (SD), % | 50.7 (7.9) | 52.8 (8.3) | 52.6 (7.8) |
| LVEF categories, No. (%) | |||
| <50% | 105 (48.8) | 60 (36.8) | 1779 (35.7) |
| ≥50% to <60% | 75 (34.9) | 67 (41.1) | 2244 (45.1) |
| ≥60% | 35 (16.3) | 36 (22.1) | 958 (19.2) |
| NYHA functional class, No. (%) | |||
| II | 124 (57.7) | 93 (57.1) | 3552 (71.2) |
| III | 86 (40.0) | 67 (41.1) | 1409 (28.3) |
| IV | 5 (2.3) | 3 (1.8) | 26 (0.5) |
| HFimpEF | 6 (2.8) | 11 (6.7) | 232 (4.7) |
| Medical history, No. (%) | |||
| Hypertension | 188 (87.4) | 144 (88.3) | 4419 (88.6) |
| Type 2 diabetes | 101 (47.0) | 82 (50.3) | 1948 (39.1) |
| Atrial fibrillation on ECG | 92 (42.8) | 81 (49.7) | 1854 (37.2) |
| Stroke | 24 (11.2) | 20 (12.3) | 570 (11.4) |
| Myocardial infarction | 70 (32.6) | 47 (28.8) | 1245 (25.0) |
| KCCQ-TSS | 58.6 (26.3) | 59.6 (24.6) | 68.4 (23.4) |
| Medication use, No. (%) | |||
| β-Blocker | 177 (82.3) | 128 (78.5) | 4259 (85.4) |
| ACEi | 78 (36.3) | 57 (35.0) | 1787 (35.8) |
| ARB | 71 (33.0) | 45 (27.6) | 1791 (35.9) |
| ARNi | 17 (7.9) | 16 (9.8) | 436 (8.7) |
| Calcium channel blocker | 65 (30.2) | 46 (28.2) | 1660 (33.3) |
| SGLT2 inhibitor | 28 (13.0) | 32 (19.6) | 680 (13.6) |
| Loop diuretic | 196 (91.2) | 156 (95.7) | 4306 (86.3) |
| Thiazide diuretic | 29 (13.5) | 11 (6.7) | 724 (14.5) |
| GLP-1 receptor agonist | 5 (2.3) | 7 (4.3) | 135 (2.7) |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; GLP-1, glucagonlike peptide 1; HF, heart failure; HFimpEF, heart failure with improved ejection fraction; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire Total Symptom Score; LVEF, left ventricle ejection fraction; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; UACR, urinary albumin-creatinine ratio.
SI conversion factors: To convert creatinine to micromoles per liter, multiply by 88.4; sodium and potassium to millimoles per liter, multiply by 1; hemoglobin to gram per liter, multiply by 10.
Other race includes American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or unreported.
Calculated as weight in kilograms divided by height in meters squared.
In the 6 months preceding sudden death, there was only a slight worsening in physician-assigned NYHA class (from approximately 2.3 to 2.4) but a marked deterioration in patient-reported health status, reflected by an approximately 8-point decline in KCCQ-TSS, along with a gradual increase in NT-proBNP levels (from roughly 1800-2000 pg/mL) (Figure 1). In contrast, among patients who survived, NYHA class improved over time (from approximately 2.3 to approximately 2.1), KCCQ-TSS increased (from approximately 68 to approximately 77), and NT-proBNP levels steadily declined (from approximately 800 to approximately 650 pg/mL) during the 18 months preceding the end of follow-up.
Figure 1. Cubic Splines Depicting Trajectories in the Period Preceding Sudden Death vs in Patients Who Remained Alive Throughout Follow-Up.
A, New York Heart Association (NYHA) functional class. B, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). C, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level. The dashed line denotes timing of sudden death or end of follow-up (FU). The shading represents 95% CIs. The number in parentheses is the number of patients in each group who had the parameter measured at least once within 18 months before sudden death or end of FU. P equality assesses whether the trajectories over time were identical (ie, superimposable). P interaction assessed whether the trajectories differed in shape over time (ie, nonparallel trajectories reflecting a group × time interaction).
Compared with patients who experienced sudden death, NYHA class worsened more markedly in the 6 months preceding HF-related death (rising from a mean of approximately 2.4 to approximately 2.8) (Figure 2). Declines in KCCQ-TSS were also more pronounced and sustained, with mean scores falling steadily from approximately 70 to approximately 50 over the 18 months before death. Likewise, NT-proBNP levels were already higher (approximately 2000 pg/mL) 18 months before death and exhibited a continuous rise, reaching approximately 3000 pg/mL at the time of death.
Figure 2. Cubic Splines Depicting Trajectories in the Period Preceding Sudden Death vs Heart Failure–Related Death.
A, New York Heart Association (NYHA) functional class. B, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). C, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level. The dashed line denotes timing of sudden death or heart failure (HF)–related death. The shading represents 95% CIs. The number in parentheses is the number of patients in each group who had the parameter measured at least once within 18 months before sudden death or heart failure–related death. P equality assesses whether the trajectories over time were identical (ie, superimposable). P interaction assessed whether the trajectories differed in shape over time (ie, nonparallel trajectories reflecting a group × time interaction).
Compared with patients who experienced sudden death, those who died of nonsudden cardiovascular causes exhibited trajectories characterized by progressive deterioration across all 3 domains, following patterns generally similar to those observed before HF-related death (Figure 3).
Figure 3. Cubic Splines Depicting Trajectories in the Period Preceding Sudden Death vs Nonsudden Cardiovascular Death.
A, New York Heart Association (NYHA) functional class. B, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). C, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level. The dashed line denotes timing of sudden death or nonsudden cardiovascular (CV) death. The shading represents 95% CIs. The number in parentheses is the number of patients in each group who had the parameter measured at least once within 18 months before sudden death or nonsudden CV death. P equality assesses whether the trajectories over time were identical (ie, superimposable). P interaction assessed whether the trajectories differed in shape over time (ie, nonparallel trajectories reflecting a group × time interaction).
Compared with trajectories preceding sudden death, noncardiovascular death was preceded by more modest clinical changes (eFigure 2 in Supplement 2). NYHA functional class worsened slightly in the 6 months before death, increasing from approximately 2.3 to approximately 2.4 to 2.5, whereas KCCQ-TSS declined in the final 6 months from approximately 65 to approximately 56 to 57. In contrast to sudden death, NT-proBNP levels remained largely unchanged over time, averaging approximately 1500 pg/mL, with no clear increase preceding noncardiovascular death.
The degree of missingness for the 3 variables of interest was generally similar over follow-up across the different modes of death and among patients who remained alive during follow-up (eTable in Supplement 2).
Discussion
In this large cohort of well-characterized patients with HFmrEF or HFpEF, clinical trajectories differed substantially between those who experienced sudden death and those who remained alive throughout follow-up. Sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels, whereas these parameters generally improved among survivors. In contrast, patients who died of other causes—including HF-related nonsudden cardiovascular death and noncardiovascular death—also demonstrated deterioration across these domains, although changes were more modest before noncardiovascular death. These data suggest that many sudden events in HFmrEF or HFpEF may not in fact be sudden or entirely unexpected but preceded by meaningful and identifiable clinical deterioration. Importantly, these changes are not specific for sudden death, as similar—and often more pronounced—declines in patient-reported health status and rises in natriuretic peptide levels occur before HF-related and other nonsudden cardiovascular deaths, limiting the clinical actionability of these observations.
The identification of individuals with HFmrEF or HFpEF who are at a high risk for sudden death remains challenging. Although sudden death accounts for roughly a quarter of all deaths in HFpEF, current guidelines do not recommend ICD therapy for primary prevention because of inadequate risk stratification and lack of demonstrated benefit. Prior risk models in HFpEF, such as those derived from the Irbesartan in Heart Failure With Preserved Ejection Fraction trial (I-Preserve) trial, have incorporated baseline clinical variables, comorbidities, electrocardiogram (ECG) findings (eg, left bundle branch block), and natriuretic peptide levels to estimate sudden death risk, but have not been widely adopted in clinical practice and do not integrate dynamic changes over time. In a secondary analysis of the Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT)–Americas trial, male sex and insulin-treated diabetes were identified as predictors of sudden death or aborted cardiac arrest, although the model demonstrated only modest discriminatory performance (C statistic = 0.65). Our findings suggest that even subtle worsening in functional status, quality of life, and natriuretic peptide levels may signal heightened vulnerability to sudden death. However, similar patterns of deterioration were also observed before other major modes of death. Thus, these signals appear to reflect heightened overall mortality risk rather than risk specific to sudden death.
The mechanisms contributing to sudden death in HFpEF are more diverse than in HFrEF, where most sudden death are presumed to be due to ventricular tachyarrhythmias. Consistent with this, a contemporary cohort of 113 patients with systematic rhythm monitoring has demonstrated a low incidence of sustained ventricular tachyarrhythmias, with most sudden death not clearly attributable to ventricular arrhythmias. In our cohort, patients dying of sudden death were younger than those dying of HF-related causes, suggesting that progressive HF death may be driven by age-related processes such as frailty, whereas sudden death may reflect disease-specific vulnerability or earlier transient triggers. Nevertheless, in HFpEF, progressive HF with multiorgan dysfunction, biventricular dysfunction, and pulmonary hypertension may still underlie sudden events, precipitated by transient triggers (such as ischemia or electrolyte disturbance) but occurring on a background of subacute decline. As such, similar mechanistic pathways of disease progression may underlie these seemingly distinct modes of death in HFpEF.
Limitations
This study has several potential limitations. First, it is a post hoc analysis of a clinical trial, and results should be considered hypothesis generating. Second, despite adjudication of end points, some misclassification of deaths may have occurred, because some deaths that occurred unexpectedly without sufficient documentation around the circumstances of the death may have been classified as sudden death. Third, trajectories of the variables of interest were integrated across multiple time points during follow-up—providing estimates at the population level rather than the individual level. This approach leveraged the random timing of study visits and clinical events, allowing for the construction of aggregated population-level trends rather than personalized trajectories. Moreover, NT-proBNP levels were only measured at a limited number of follow-up visits, possibly missing rapid or transient changes before events or end of follow-up. Some parameters of interest—particularly imaging and ECG measures—that may change dynamically before sudden death were not serially evaluated in our study. Finally, because assessments followed the trial schedule rather than continuous monitoring, trajectories may not capture short-term changes around acute hospitalizations or terminal events.
Conclusions
Results of this post hoc analysis of the FINEARTS-HF randomized clinical trial reveal that in this large, contemporary cohort with HFmrEF or HFpEF, sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels. These data suggest that many sudden events in this population occur in the context of subacute clinical deterioration rather than as entirely abrupt events. However, similar—often more pronounced—changes were observed before other major modes of death, underscoring the limited specificity of these commonly assessed clinical parameters for sudden death alone. Instead, 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.
Trial Protocol.
eFigure 1. Patient Flow
eFigure 2. Trajectories of NYHA Functional Class, KCCQ-TSS, and NT-proBNP in the Period Preceding Sudden Death vs Noncardiovascular Death
eTable. Missing Data at 12 Months for NYHA Functional Class, KCCQ-TSS, and NT-proBNP
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
eFigure 1. Patient Flow
eFigure 2. Trajectories of NYHA Functional Class, KCCQ-TSS, and NT-proBNP in the Period Preceding Sudden Death vs Noncardiovascular Death
eTable. Missing Data at 12 Months for NYHA Functional Class, KCCQ-TSS, and NT-proBNP
Data Sharing Statement.
