Systemic, noncerebral, arterial embolism in 21,105 patients with atrial fibrillation randomized to edoxaban or warfarin: results from the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 trial.

Background: Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking.
Methods and Results: We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01).
Conclusion: Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin.
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