IMPORTANCE Patients with acute coronary syndrome (ACS) remain at high risk for experiencing recurrent ischemic events. Direct oral anticoagulants (DOAC) have been proposed for secondary prevention after ACS. OBJECTIVE To evaluate the safety and efficacy of DOAC in addition to antiplatelet therapy (APT) after ACS, focusing on treatment effects stratified by baseline clinical presentation (non-ST-segment elevation ACS [NSTE-ACS] vs ST-segment elevationmyocardial infarction [STEMI] ). DATA SOURCES PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched from inception to March 1, 2017. STUDY SELECTION Randomized clinical trials on DOAC after ACS were evaluated for inclusion. Overall, 473 studies were screened, 19 clinical trials were assessed as potentially eligible, and 6 were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to abstract data and assess quality and validity. The risk of bias tool, version 2.0 (Cochrane) was used for risk of bias assessment. Data were pooled using random-effects models. MAIN OUTCOMES AND MEASURES The prespecified primary efficacy end pointwas the composite of cardiovascular death,myocardial infarction, and stroke. The prespecified primary safety end point was major bleeding. RESULTS Six trials that included 29 667 patients were identified (14 580 patients [49.1%] with STEMI and 15 036 [50.7%] with NSTE-ACS). The primary efficacy end point risk was significantly lower in patients who were treated with DOAC as compared with APT alone (odds ratio [OR], 0.85; 95%CI, 0.77-0.93; P < .001). This benefit was pronounced in patients with STEMI (OR, 0.76; 95%CI, 0.66-0.88; P < .001), while no significant treatment effect was observed in patients with NSTE-ACS (OR, 0.92; 95%CI, 0.78-1.09; P = .36; P for interaction = .09). With respect to safety, DOACs were associated with a higher risk of major bleeding as compared with APT alone (OR, 3.17; 95%CI, 2.27-4.42; P < .001), with consistent results in patients with STEMI (OR, 3.45; 95%CI, 1.95-6.09; P < .001) and NSTE-ACS (OR, 2.19; 95%CI, 1.38-3.48; P < .001; P for interaction = .23). CONCLUSIONS AND RELEVANCE To our knowledge, these findings are the first evidence to support differential treatment effects of DOAC in addition to APT according to ACS baseline clinical presentation. In patients with NSTE-ACS, the risk-benefit profile of DOAC appears unfavorable. Conversely, DOAC in addition to APT might represent an attractive option for patients with STEMI. © 2018 American Medical Association. All Rights Reserved.