Incidence and predictors of major bleeding among patients receiving apixaban or aspirin for subclinical atrial fibrillation: insights from the ARTESiA sub-analysis

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.

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.

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).

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.