Abstract Background ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Sub-Clinical Atrial Fibrillation) was a randomized double-blind, double-dummy trial which showed that apixaban, compared with aspirin, reduced stroke and systemic embolism, but increased major bleeding in patients aged ≥55 years with subclinical atrial fibrillation (AF) and CHA2DS2-VASc score ≥3. Objectives To characterize major bleeding events, determine the cumulative incidence of major bleeding (overall and by treatment, site, and severity), and determine risk factors associated with major bleeding. Study Design and Methods: We performed a pre-specified sub-analysis of major bleeding events defined as overt bleeding accompanied by a decrease in hemoglobin of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site, or resulting in death (International Society on Thrombosis and Haemostasis criteria) in the on-treatment population. Results After mean follow-up of 3.5 years, major bleeding occurred in 86/1989 patients on apixaban (1.71% per patient-year) and 47/1972 patients on aspirin (0.95% per patient-year) (HR 1.80; 95% CI, 1.26 to 2.57; p=0.001) (Table 1). Gastrointestinal bleeding was most common, representing 52.3% of bleeds in the apixaban group and 42.5% of bleeds in the aspirin group. The frequency of intracranial (0.6% vs. 0.8%, p=0.547) and fatal bleeding (0.3% vs. 0.2%, p=0.40) was low and similar between groups, while major gastrointestinal bleeding was more frequent in patients on apixaban (2.3% vs. 1.0%, p=0.002). The cumulative incidence of major bleeding is shown in Figure 1 according to randomized treatment, bleeding site and severity. Most bleeding events (73.8%) were not considered severe or fatal. Baseline covariates associated with an increased risk of major bleeding included ongoing cancer (HR 3.10, 95%CI 1.61-5.96), randomization to apixaban (HR 1.83, 95%CI 1.28-2.62), and age (HR 1.45, 95%CI 1.27-1.65, for each increase of 5 years). Conclusions The increased risk of major bleeding with apixaban is driven by gastrointestinal bleeding. Almost 75% of major bleeds were not considered emergencies and required only supportive measures. Increasing age and active cancer were associated with increased risk of major bleeding.