Background: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation (AF) who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI. Methods: Using a 2x2 factorial design we compared apixaban with vitamin K antagonists (VKA) and aspirin with placebo in patients with AF who had ACS or were undergoing PCI and were receiving a P2Y12 inhibitor. We explored bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in three pre-specified subgroups: patients with ACS treated medically, ACS treated with PCI, and those undergoing elective PCI. Results: Of 4614 patients enrolled, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Apixaban compared with VKA reduced ISTH major or CRNM bleeding in patients with ACS treated medically (HR 0.44, 95% CI 0.28-0.68), ACS treated with PCI (HR 0.68, 95% CI 0.52-0.89), and undergoing elective PCI (HR 0.82, 95% CI 0.64-1.04) (pinteraction=0.052); and reduced death or hospitalization in ACS treated medically (HR 0.71, 95% CI 0.54-0.92), ACS treated with PCI (HR 0.88, 95% CI 0.74-1.06), and elective PCI (HR 0.87, 95% CI 0.72-1.04) (pinteraction=0.345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events in the ACS treated medically, ACS treated with PCI, and elective PCI groups (pinteraction=0.356). Compared with placebo, aspirin had a higher rate of bleeding than placebo in patients with ACS treated medically (HR 1.49, 95% CI 0.98-2.26), ACS treated with PCI (HR 2.02, 95% CI 1.53-2.67) and elective PCI groups (HR 1.91, 95% CI 1.48-2.47) (pinteraction=0.479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization (pinteraction=0.787) and death and ischemic events (pinteraction=0.710). Conclusions: An antithrombotic regimen consisting of apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with AF who have ACS, whether managed medically or with PCI, or those undergoing elective PCI than regimens that include VKAs, aspirin, or both.