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    Edoxaban: An oral inhibitor of factor Xa

    Oral anticoagulant therapy is the cornerstone for the prevention and treatment of arterial and venous thrombosis.1 Anticoagulation therapy is commonly prescribed to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE).

    Factor Xa remains an attractive target for drug development, as activated factor X plays a key role in the coagulation cascade by connecting the intrinsic and extrinsic pathways, as well as being the rate limiting step in thrombin production. Edoxaban (Savaysa) is a once-daily oral selective reversible inhibitor of factor Xa approved by the FDA in January 2015. Edoxaban is approved for reduction of stroke risk and systemic embolism in NVAF and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).2 This review is to help guide clinicians on edoxaban’s use and place in therapy.

    Clinical trials

    Two phase 3 trials evaluating the use of edoxaban are published: one in patients with NVAF and the other in patients with VTE. 

    Atrial fibrillation. The ENGAGE AF-TIMI 48 was a randomized, double-blind, double-dummy, multicenter trial of 21,105 moderate- to high-risk atrial fibrillation (AF) patients.  Patients were randomized in a 1:1:1 fashion to high-dose edoxaban (60 mg), low-dose edoxaban (30 mg), or warfarin.3 The primary efficacy endpoint of stroke or systemic embolic event occurred less frequently in the high-dose edoxaban arm compared with the low-dose edoxaban or warfarin arm (P<.001 for noninferiority). High-dose edoxaban had an annualized hemorrhagic stroke rate of 0.26%, (P<.001), which was greater than low-dose edoxaban (0.16%, P<.001), yet lower than warfarin (0.47%). Low-dose edoxaban was markedly less effective at preventing ischemic stroke compared to high-dose edoxaban or warfarin (P<.001). Although the high-dose edoxaban group had less ischemic and more hemorrhagic strokes than the low-dose edoxaban group, there was an overall statistically significant reduction in the rate of strokes and systemic embolic events in the high-dose edoxaban arm.3

    High-dose edoxaban was noninferior to warfarin when assessing the primary endpoint of prevention of stroke or systemic embolism. This was accompanied by significantly lower rates of bleeding or death from cardiovascular causes compared to warfarin. Edoxaban had no effect on the rate of myocardial infarction.3

    Venous thromboembolism. The Hokusai-VTE was a randomized, double-blind noninferiority study comparing edoxaban 60 mg or 30 mg once daily to warfarin in 8092 patients with acute VTE who had previously received heparin.4 Patients were randomized to receive low molecular weight heparin (LMWH) and edoxaban or LMWH and warfarin. Recurrent symptomatic thromboembolism was the primary efficacy endpoint, and major bleeding or clinically relevant nonmajor bleeding was the primary safety endpoint. Patients were treated for 3 to 12 months.

    Patients who received 30 mg of edoxaban performed similarly to those receiving 60 mg with respect to efficacy and had less bleeding than the warfarin group. Recurrent VTE occurred in 3.2% of the edoxaban group and 3.5% of the warfarin group (P<.001 for noninferiority).4

    The primary safety endpoint of first major or clinically relevant nonmajor bleeding occurred in 8.5% of the edoxaban group and 10.3% of the warfarin group (P=.004 for superiority). Major bleeding occurred in 1.4% and 1.6% in the edoxaban- and warfarin-treated groups, respectively (P=.35 for superiority). There was no statistically significant difference in the number of deaths between the edoxaban and the warfarin groups.4

     

    NEXT: Edoxaban's safety

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