The coagulation system contributes greatly to the evolution of myocardial infarction (MI). Anticoagulation may reduce the occurrence of MI as monotherapy or with concomitant use of aspirin. Activated factor X antagonists (anti-Xa) and direct thrombin inhibitors have promising results in various indications in non-inferiority trials. However, results regarding their cardiovascular safety are heterogeneous. We systematically evaluated the risk of MI and mortality in patients receiving the new-generation oral anti-Xa agent apixaban. Electronic databases were searched to find prospective, randomized, controlled clinical trials (RCT) that evaluated the clinical impact of apixaban. Efficacy measures included frequency of MI, cardiovascular and overall mortality. Outcome parameters of RCTs were pooled with a random-effects model. Between January 2000 and December 2013, 12 RCTs comprising 54,054 patients were identified. Based on the pooled results, there was no increase in the risk of MI in patients treated with apixaban [odds ratio (OR) 0.90; 95 % confidence interval (CI) 0.77-1.05; p = 0.17] compared to different controls. Cardiovascular and overall mortality with apixaban was comparable to the control groups (OR 0.88; 95 % CI 0.72-1.06; p = 0.18, OR 0.89; 95 % CI 0.77-1.03; p = 0.11, respectively). The pooled risk of major bleeding was lower in the apixaban treated groups (OR 0.84; 95 % CI 0.62-1.12; p = 0.23) however this reached significant level only in subgroup analysis of trials with anticoagulant regimes in the control (OR 0.66; 95 % CI 0.51-0.87; p = 0.003). In a broad spectrum of patients and compared to different controls apixaban treatment was not associated with an increase in MI or mortality.