Risk and benefits of baseline antiplatelet therapy in 58,598 patients with atrial fibrillation randomized to NOACs vs warfarin

Abstract Background The efficacy and safety of NOAC versus warfarin (W) may differ in AF pts receiving antiplatelet therapy (APT) at baseline. Moreover, prior individual trial-specific analyses examining the treatment effect of NOAC vs. W as a function of APT are underpowered for interaction testing. Purpose We evaluated outcomes by randomized anticoagulant stratified by baseline APT in a pooled individual pt-level meta-analysis of 4 pivotal RCTs of NOAC vs. W in AF: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. Methods Pts were stratified by use of APT vs. no APT at baseline. Pts randomized to low-dose NOAC not globally approved (edoxaban 30/15 mg or dabigatran 110 mg) were excluded. The primary efficacy and safety outcomes were stroke/systemic embolic events (S/SEE) and major bleeding, respectively; ischemic stroke (IS), intracranial hemorrhage (ICH), major GI bleeding and all-cause mortality (ACM) were secondary outcomes. Each outcome was assessed by randomized treatment using a Cox model stratified by trial with adjustment for age, sex, weight, CrCl, smoking status, HTN, DM, CAD, prior MI, PAD, and prior stroke. Interaction testing was performed by APT at baseline. Results Of 58,598 pts, 19,774 (34%) were on APT at baseline (92% aspirin only, 5% P2Y12 only, 3% DAPT). Pts treated with APT had greater prevalence of CAD (41% vs. 24%), prior MI (22% vs. 11%), and PAD (6% vs. 4%) (p<0.001 for each). Reflective of these baseline differences, the annualized event rate for each outcome was higher in the APT vs. no APT group (Figure). The treatment effect (HR) of NOAC vs. W for all 6 clinical outcomes was consistent irrespective of baseline APT (p-interaction [aHR] for each = NS; Figure). However, the absolute risk reduction (ARR) for NOAC vs. W differed for ICH and major GI bleeding as a function of baseline APT (Figure). Specifically, for ICH, a greater absolute benefit was seen with NOAC vs. W in those on APT at baseline (ARR 0.6% vs. 0.3%; p-int = 0.007). Conversely, for major GI bleeding, NOAC vs. W was associated with greater absolute risk in those on APT (ARR -0.6% vs. -0.2%; p-int = 0.04). Conclusions The treatment effect of NOAC vs. W is consistent irrespective of APT at baseline for S/SEE, major bleeding, and ACM. Given higher rates of bleeding in AF pts treated with both APT and anticoagulation, concomitant APT should be avoided when possible. In pts requiring concomitant APT, NOAC instead of W should be considered owing to greater absolute safety benefit for ICH, which should be weighed against individual patient-specific risk factors for GI bleeding.