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Original Investigation
March 2018

Direct Oral Anticoagulants in Addition to Antiplatelet Therapy for Secondary Prevention After Acute Coronary Syndromes: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
  • 2Cardio Center, Humanitas Research Hospital, Rozzano-Milan, Italy
  • 3Interventional Cardiology Unit, San Raffaele Hospital, Milan, Italy
  • 4Duke Clinical Research Institute, Duke Health, Durham, North Carolina
JAMA Cardiol. 2018;3(3):234-241. doi:10.1001/jamacardio.2017.5306
Key Points

Question  Do direct oral anticoagulants (DOAC) in addition to antiplatelet therapy (APT) safely reduce ischemic events after acute coronary syndromes (ACS), and are there differences according to ACS type?

Findings  In this systematic review and meta-analysis of 6 trials comprising 29 667 patients, direct oral anticoagulants with APT was associated with a reduced risk of ischemic events at the cost of an increase in major bleedings compared with APT alone. Direct oral anticoagulants was associated with a reduction in ischemic events after ST-segment elevation myocardial infarction with no effects after non–ST-segment elevation ACS, while the increased risk of major bleeding was consistent after ST-segment elevation myocardial infarction and non–ST-segment elevation ACS.

Meaning  The risk-benefit profile of direct oral anticoagulants in addition to APT appears to differ by ACS type; direct oral anticoagulants might represent an attractive strategy in patients with ST-segment elevation myocardial infarction.


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 elevation myocardial 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 point was 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.