Ashton E. Beggs, PharmD

	Oral anticoagulant therapy is the cornerstone for the prevention and treatment of arterial and venous thrombosis.

 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).

 This review is to help guide clinicians on edoxaban’s use and place in therapy.

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

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.

 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 (

<.001 for noninferiority). High-dose edoxaban had an annualized hemorrhagic stroke rate of 0.26%, (

<.001), which was greater than low-dose edoxaban (0.16%, 

<.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 (

<.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.

	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.

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.

 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 (

	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 (

=.004 for superiority). Major bleeding occurred in 1.4% and 1.6% in the edoxaban- and warfarin-treated groups, respectively (

=.35 for superiority). There was no statistically significant difference in the number of deaths between the edoxaban and the warfarin groups.

	Edoxaban’s safety was evaluated in a total of 18,132 patients in 2 phase 3 clinical trials: ENGAGE AF-TIMI 48 and Hokusai-VTE.

	Pharmacokinetic data indicate patients with creatinine clearance (CrCl) higher than 95 mL/min have lower plasma edoxaban levels. ENGAGE AF-TIMI 48 found an increased rate of ischemic stroke in patients with a CrCl higher than 95 mL/min receiving edoxaban compared to patients receiving warfarin. Unless bleeding occurs or therapy is completed, edoxaban should not be discontinued without adequate alternative anticoagulation.

	As expected, the most common adverse effect in the trials was bleeding. In both trials compared to warfarin, however, edoxaban was associated with consistently lower rates of any type of bleeding, with the exception of slightly higher rates of gastrointestinal (GI) bleeding with edoxaban 60 mg versus warfarin in the Hokusai-VTE trial (Table 1).

	The most common nonbleeding adverse reactions occurring in 1% or more of the study population were rash, abnormal liver function tests (LFTs), and anemia.

 The rise in LFTs seen with edoxaban was similar to the warfarin group and did not correlate with significant hepatotoxicity.

	No reversal agent or reliable laboratory parameter for monitoring exists; thus edoxaban should be discontinued in patients with active bleeding. Conventional reversal strategies are not expected to reverse edoxaban’s anticoagulant activity.

Rates of bleeding with edoxaban and warfarin

	Abbreviations: CRNM, clinically relevant nonmajor bleeding; GI, gastrointestinal; ICH, intracranial hemorrhage

	Edoxaban was shown to be at least as effective as warfarin in clinical trials.

 Although the new oral anticoagulants (NOACs) are distinguishably different from each other, common characteristics are shared. No NOACs are approved for use in AF patients with either mechanical valves or bioprosthetic valves. Each carries varying degrees of adjustment for renal dysfunction, as all are renally excreted to an extent. Compared to warfarin, each has a rapid onset of action and a shorter half-life. Each demonstrates a linear and predictable pharmacokinetic profile and does not require monitoring. Not surprisingly, each NOAC carries a risk of bleeding, although all agents have demonstrated significantly less intracranial hemorrhage compared with warfarin. Currently, there are no approved reversal agents for any NOAC. 

	Dabigatran was the first NOAC to demonstrate superiority compared to warfarin for reducing stroke in patients with NVAF. In the RE-LY trial, dabigatran significantly reduced the risk of stroke or systemic embolism compared to warfarin (1.11% vs 1.69%; 

 Dabigatran also showed a significantly lower incidence of annual hemorrhagic stroke. While no difference was detected in major bleeding, dabigatran had significantly higher rates of GI bleeding than warfarin. Apixaban was also found to be superior compared to warfarin for stroke prevention. The ARISTOTLE trial not only demonstrated apixaban’s ability to significantly reduce stroke and systemic embolism compared to warfarin but also apixaban had less major bleeding than warfarin.

 In the ROCKET-AF trial, rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism, with no significant difference in major bleeding.

NEXT: Conclusion on oral anticoagulant therapy efficacy and safety

	As with rivaroxaban and dabigatran, edoxaban demonstrated noninferiority to warfarin in the ENGAGE-AF TIMI 48 trial. It is important to note that although the 60 mg daily and 30 mg daily treatment groups both demonstrated noninferiority, notable differences were observed between doses and efficacy. The 60 mg dose trended toward superiority in stroke prevention compared to warfarin, while warfarin approached superiority over the 30 mg dose.

 On further subgroup analysis, it appeared renal function played a significant role in the efficacy of edoxaban. Although the aggregate results for ENGAGE-AF TIMI 48 showed noninferiority for the primary endpoint, there was a clear separation between patients with a CrCl higher than 95 mL/min and those with a CrCl of 95 mL/min or lower. In the group with impaired renal clearance, edoxaban 60 mg daily demonstrated favorable efficacy results compared to warfarin for stroke and systemic embolism, ischemic stroke, and hemorrhagic stroke. In patients with normal renal function, edoxaban 60 mg daily was inferior to warfarin for stroke, systemic embolism, and ischemic stroke.

 This presents a clinical dilemma for practitioners, limiting use in AF patients to those with impaired renal function. The other NOACs do not carry restrictions for normal renal function.

	Interestingly, the Hokusai-VTE trial did not show a difference in regard to renal function for the treatment of DVT and PE. The majority of patients had a CrCl higher than 50 mL/min and the dose was adjusted from 60 mg to 30 mg for those with a CrCl 30 to 50 mL/min. In both groups, edoxaban was noninferior to warfarin for treatment of VTE and major bleeding.

	No head-to-head studies of the NOACs have been conducted, making direct comparisons difficult. Data are available, however, for comparison of each agent against warfarin (Table 2). Indirect comparisons should be made with caution due to differences in trials, including patient demographics and trial design.     

Efficacy and safety outcomes in trials of newer oral anticoagulants* 

	Edoxaban is a direct factor Xa inhibitor with an efficacy and safety profile comparable to warfarin. The agent offers once-daily administration without need for routine laboratory monitoring. Edoxaban has a niche in therapy, as efficacy is slightly better in patients with renal dysfunction when it is prescribed to reduce the risk of stroke and systemic embolism in NVAF. Future studies will further elucidate potential risks and benefits of this NOAC.

	1. Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. 

	2. Savaysa [package insert]. Tokyo, Japan: Daiichi Sankyo Co., LTD; 2015.

	3. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. 

	4. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. 

	5. Fukuda T, Honda Y, Kamisato C, et al. Reversal of anticoagulant effect of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. 

Ashton E. Beggs, PharmD

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Edoxaban: An oral inhibitor of factor Xa