Major Bleeding With Apixaban vs Aspirin

Importance: The Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) randomized clinical trial showed that in patients with subclinical atrial fibrillation (SCAF) apixaban, compared with aspirin, reduced stroke/systemic embolism but increased major bleeding. Objectives: To characterize major bleeding events (site and severity) and identify factors associated with major bleeding. Design, Setting, and Participants: This was a prespecified subanalysis of the ARTESiA population who received treatment. This was an international, double-blind, double-dummy randomized clinical trial. Included were patients with 1 or more episodes of SCAF lasting 6 minutes to 24 hours with stroke risk factors (CHA2DS2-VASc score ≥3) or prior stroke without other risk factors. Study data were analyzed from August to November 2024. Interventions: Apixaban, 5 mg, twice daily (2.5 mg twice daily when indicated) or aspirin, 81 mg, once daily. Main Outcomes and Measures: Major bleeding adjudicated by a blinded committee according to International Society on Thrombosis and Hemostasis criteria. Results: A total of 3961 patients (mean SD age, 76.8 7.6 years; 2535 male 64%) were included in this analysis. After a mean (SD) follow-up of 3.5 (1.8) years, 1 or more major bleeding episodes occurred in 133 patients, 86 of 1989 taking apixaban and 47 of 1972 taking aspirin (1.71 vs 0.94 per 100-patient-years; hazard ratio HR, 1.80; 95% CI, 1.26-2.57). The rates of intracranial (0.33 vs 0.40 per 100 patient-years; HR, 0.82; 95% CI, 0.43-1.57) and fatal (0.10% vs 0.16% per 100 patient-years; HR, 0.63; 95% CI, 0.20-1.91) bleeding were similar in the apixaban and aspirin groups, whereas the rate of gastrointestinal bleeding was higher in the apixaban group (0.89% vs 0.40% per 100 patient-years; HR, 2.23; 95% CI, 1.32-3.78). Among 133 index major bleeding events, those that occurred with apixaban were less likely to occur at critical sites (27.9% 24 of 86 vs 46.8% 22 of 47; P = .03) including intracranial (18.6% 16 of 86 vs 42.6% 20 of 47; P = .003). Most major bleeding events were nonemergencies characterized by decreased hemoglobin greater than or equal to 2 g/dL. Factors associated with major bleeding included nonsteroidal anti-inflammatory drug (NSAID) use (HR, 10.25; 95% CI, 6.57-15.99), cancer (HR, 2.87; 95% CI, 1.49-5.53), randomization to apixaban (HR, 1.84; 95% CI, 1.29-2.63), and age (HR, 1.47; 95% CI, 1.28-1.67, per 5-year increase). Conclusions and Relevance: Results of this subanalysis of the ARTESiA randomized clinical trial found that although the rate of major gastrointestinal bleeding was higher in patients with SCAF who were treated with apixaban vs aspirin, rates of fatal and intracranial bleeding were not different. Most major bleeding events were nonemergencies characterized by a decrease in hemoglobin level greater than or equal to 2 g/dL. NSAID use, cancer, randomization to apixaban, and increasing age were associated with an increased risk of major bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT01938248.