The Apixaban vs Acetylsalicylic Acid to Prevent Strokes (AVERROES) RCT compared apixaban 5 mg bid to aspirin in 5,599 patients with AF who were demonstrated or expected to be unsuitable candi- dates for adjusted-dose VKA therapy.86 The trial was stopped early for bene t and was consistent with the trials of VKA therapy vs aspirin (section 2.1.3), reporting that apixaban reduces by one-half the occurrence of the primary outcome of stroke and systemic embolism compared with aspirin (hazard ratio, 0.45; 95% CI, 0.32-0.62). The trial failed to demonstrate or exclude a difference in the risk of major extracranial bleeding with apixaban compared with aspirin (hazard ratio, 1.23; 95% CI, 0.74-2.05), and the results were consistent with those of earlier trials of VKA therapy vs aspirin (section 2.1.3), which suggest an increase in the risk of major extracranial prior users of VKA therapy, the study sample may be more representative of patients in whom VKA therapy is well tolerated). In prespeci ed subgroup analyses, the investigators did not nd evidence of a difference in the effect of VKA therapy on primary outcome in patients who were and were not receiving VKA therapy at study entry. However, there was a signi - cant difference (interaction P5.03) in the effect on major bleeding, depending on whether patients were prior users of VKA therapy. For patients who were not receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 69% relative increase in major bleeding compared with dual antiplatelet therapy, whereas in patients already receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 24% relative decrease in major bleeding compared with dual antiplatelet therapy. 