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Sudden Death in Diastolic Heart Failure
Study Questions:
What are the rates and predictors of sudden death (SD) or aborted cardiac arrest (ACA) in heart failure with preserved ejection fraction (HFpEF)?
Methods:
The study cohort was comprised of 1,767 patients with HFpEF (EF ≤45%) enrolled in the Americas region of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. SD was defined as an unexpected death in an otherwise stable patient and was classified as either witnessed (if death was observed or if last seen within 24 hours) or presumed (if last seen ≥24 hours with the clinical context suggestive of SD). ACA, a prespecified component of the primary composite endpoint for the overall TOPCAT trial, was defined as successful resuscitation after cardiac arrest (with or without antecedent myocardial infarction or HF) with meaningful recovery. The study authors identified independent predictors of composite SD/ACA with stepwise backward selection using competing risks regression analysis that accounted for nonsudden causes of mortality.
Results:
The study investigators found that during the median 3-year (25th-75th percentile: 1.9-4.4 years) follow-up, 77 patients (~20%) experienced SD/ACA, and 312 experienced non-SD/ACA. Corresponding incidence rates were 1.4 events/100 patient-years (25th-75th percentile: 1.1-1.8 events/100 patient-years) and 5.8 events/100 patient-years (25th-75th percentile: 5.1-6.4 events/100 patient-years). SD/ACA was numerically lower, but not statistically reduced in those randomized to spironolactone: 1.2 events/100 patient-years (25th-75th percentile: 0.9-1.7 events/100 patient-years) versus 1.6 events/100 patient-years (25th-75th percentile: 1.2-2.2 events/100 patient-years); the subdistributional hazard ratio (sHR) was 0.74 (95% confidence interval, 0.47-1.16; p = 0.19). Treatment effects with spironolactone did not differ by gender or diabetes mellitus (DM) status (all interaction terms, p > 0.05). After accounting for competing risks of non-SD/ACA, male gender (sHR, 2.06 [1.27-3.32]) and insulin-treated DM (sHR, 2.57 [1.568-4.20]) were independently predictive of composite SD/ACA (C-statistic = 0.65). Covariates, including eligibility criteria, age, EF, coronary artery disease, left bundle branch block, and baseline therapies, were not independently associated with SD/ACA. Gender and DM status remained independent predictors in sensitivity analyses, excluding patients with implantable cardioverter-defibrillators and when predicting SD alone. Compared with patients who experienced non-SD/ACA, patients who experienced SD/ACA tended to be younger (70 ± 9 years vs. 75 ± 9 years), men (68% vs. 54%), with higher body mass indexes (35 ± 9 kg/m2 vs. 32 ± 9 kg/m2), and rates of DM (58% vs. 45%) (p ≤ 0.05 for all comparisons).
Conclusions:
The study authors concluded that SD accounted for approximately 20% of deaths in HFpEF. Male gender and insulin-treated DM identified patients at higher risk for SD/ACA with modest discrimination. These data might guide future SD preventive efforts in HFpEF.
Perspective:
The findings of this study are important because it indicates that SD is an important cause of mortality in patients with diastolic HF. Prospective studies are needed to validate these findings and if confirmed, whether neurohormonal blockade, such as beta-blockers, mineralocorticoid antagonists, or neprilysin inhibition, will ameliorate this burden.
Keywords: Adrenergic beta-Antagonists, Bundle-Branch Block, Coronary Artery Disease, Death, Sudden, Defibrillators, Implantable, Diabetes Mellitus, Geriatrics, Heart Arrest, Heart Failure, Insulin, Mineralocorticoid Receptor Antagonists, Myocardial Infarction, Neprilysin, Risk, Spironolactone, Stroke Volume
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