These trials suggest that VKA therapy increases the risk of nonfatal major extracranial bleeding by about 50% compared with aspirin (pooled risk ratio, 1.42; 95% CI, 0.89-2.29), but the quality of evidence was rated down to moderate because of imprecision. Indirect evidence from RCTs of adjusted- dose VKA therapy vs aspirin in other populations suggest that VKA therapy is likely associated with a true twofold to 2.5-fold increase in major bleeding risk.78,79 For the outcomes of death and systemic embolism, pooled estimates of treatment effect from trials of VKA therapy in patients with AF were impre- cise, leaving uncertainty about the impact of VKA therapy on these outcomes compared with antiplate- let monotherapy. 2.1.4 VKAs vs Dual Antiplatelet Therapy With Aspirin and Clopidogrel: The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) W trial assessed dual antiplatelet therapy with aspirin and clopidogrel as a potential alternative to VKA therapy (INR 2.0-3.0).80 The trial was stopped early because of ndings of superiority of VKA therapy (for their primary out- come of stroke, systemic embolism, MI, or vascular death) and did not nd evidence of a difference in the risk of major bleeding (Table 6). Most patients (77%) were receiving VKA therapy before randomi- zation, raising some concerns about generalizability of these ndings to patients with AF who are being newly started on VKA therapy (ie, by enrolling mostly The studies also provide moderate-quality evidence that VKA therapy reduces the risk of systemic embo- lism (rated down for imprecision). 2.1.2 Antiplatelet Monotherapy (Aspirin) vs No Therapy: Several RCTs of antiplatelet monotherapy vs no therapy in patients with AF have shown that antiplatelet therapy leads to, at best, a modest reduc- tion in the risk of nonfatal stroke. 