Impact of Age on Bleeding, Stroke, and Mortality in Edoxaban-Treated Patients with Atrial Fibrillation: Results from the ETAF-TR Registry.

Abstract

Background: Data on age-specific outcomes in patients with atrial fibrillation (AF) treated with edoxaban in real-world settings are limited; this prespecified analysis of the ETAF-TR study aimed to investigate the influence of age on prespecified clinical outcomes, including overt bleeding, major bleeding, ischemic stroke, all-cause mortality, major adverse cardiovascular events (MACE), and net clinical benefit.

Methods: The ETAF-TR study is a prospective, multicenter, observational registry conducted at 50 cardiology clinics across Türkiye. Patients with AF receiving edoxaban (60 mg standard dose or 30 mg reduced dose) were categorized into three age groups: < 65 years (n = 265), 65-74 years (n = 397), and ≥ 75 years (n = 391). Time-to-event outcomes were analyzed using the Kaplan-Meier method and unadjusted Cox proportional hazards models, with the < 65-year age group as the reference.

Results: Of 1053 enrolled patients, 25.1% were aged < 65 years, 37.7% were aged 65-74 years, and 37.1% were aged ≥ 75 years. Older patients had higher Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke, Vascular disease, Age 65-74, Sex category (female) (CHA₂DS₂-VASc) and Hypertension, Abnormal renal/liver function, Stroke, Bleeding history, Labile INR, Elderly, Drugs or Alcohol (HAS-BLED) scores, lower creatinine clearance, and more frequent use of reduced-dose edoxaban. Appropriate edoxaban dosing was documented in 82.2% of patients; 8.0% received an inappropriately low dose and 9.8% an inappropriately high dose. Nonsteroidal antiinflammatory drug (NSAID) use was observed in 8.7%, 5.3%, and 10.2% of patients in the < 65, 65-74, and ≥ 75 groups, respectively, and approximately 12% received concomitant antiplatelet therapy without a documented indication. Major bleeding rates were 0.94, 1.20, and 1.13 per 100 patient-years in the < 65, 65-74, and ≥ 75 groups, respectively. Thromboembolic event rates were 0.38, 0.26, and 1.88 per 100 patient-years, respectively. All-cause mortality increased with age: 2.54, 4.34, and 10.84 per 100 patient-years, respectively; the unadjusted hazard ratio for ≥ 75 versus < 65 years was 4.04 (95% CI 1.69-9.65). Of 56 deaths, 10 (17.9%) were attributed to coronavirus disease 2019 (COVID-19) pneumonia, whereas one death was attributed to ischemic stroke and none to major bleeding. Prespecified descriptive secondary composites, including major adverse cardiovascular events and net clinical benefit, were also higher in the ≥ 75 group.

Conclusions: In this real-world cohort of patients with AF treated with edoxaban, major bleeding rates remained consistent across age groups despite an increased comorbidity burden in older patients. Thromboembolic or hemorrhagic events could not account for the excess mortality observed in the ≥ 75 age group; instead, higher comorbidity burdens and the ongoing COVID-19 pandemic may have played contributory roles. Furthermore, beyond issues related to inappropriate dosing and concomitant NSAID or antiplatelet use, significant prescribing concerns persist in clinical practice.