By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA

The third oral factor Xa inhibitor has been approved by the FDA. Edoxaban is the fourth target-specific oral anticoagulant (TSOA) to enter the market following dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban is manufactured by Tokyo-based Daiichi Sankyo Company and marketed by Daiichi Sankyo as Savaysa.

INDICATIONS

Edoxaban is approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF), as well as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) after initial treatment with a parenteral anticoagulant.1

DOSAGE

The recommended dose for NVAF and DVT/PE is 60 mg daily.1 The dose should be reduced to 30 mg daily in NVAF patients NVAF and a CrCl 15-50 mL/min. For DVT/PE, the dose should be reduced to 30 mg if CrCl is 15-50 mL/min, body weight is 60 kg, or the patient is using certain P-gp inhibitors (e.g., ketoconazole, quinidine, erythromycin, cyclo-sporine).

POTENTIAL ADVANTAGES

Edoxaban is the second TSOA to offer once-a-day dosing, along with rivaroxaban.

POTENTIAL DISADVANTAGES

There is reduced efficacy in patient with creatinine clearance > 95 mL/min.1 Premature discontinuation of edoxaban increases the risk of ischemic events.1 For the acute treatment of DVT/PE, edoxaban (and dabigatran) requires parenteral therapy prior to their initiation. Co-administration with strong P-gp inducers, such as rifampin, should be avoided.

COMMENT

The efficacy and safety of edoxaban were evaluated in two large clinical trials with warfarin as the active control. These were the ENGAGE AF-TIMI 48 study for NVAF (n = 21,105) and the Hokusai-VTE (venous thromboembolism) for DVT/AF (n = 8241).1-3 In the first study, NVAF subjects were randomized to 30 mg edoxaban or 60 mg warfarin. Subjects on warfarin maintained a mean time in therapeutic range (TTR) of the international normalized ratio of 2.0-3.0 to 65%. Subjects were randomized to edoxaban 60 mg, 30 mg, or warfarin. The primary endpoint was first stroke (ischemic or hemorrhagic). The primary analysis was a modified intention-to-treat during on-treatment or within 3 days of the last dose taken. After a median follow-up of 2.8 years, edoxaban 60 mg had a lower incidence of stroke (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.65-0.98). The 60 mg dose was not superior to warfarin. The 30 mg dose was inferior to warfarin.

In a secondary analysis, in all patients randomized during the study period, the incidence of stroke was similar: 1.49% (high-dose edoxaban) compared to 1.69% (warfarin). Intracranial hemorrhages were significantly lower for both doses of edoxaban compared to warfarin. Major bleeding overall was lower with edoxaban, but GI bleeding was higher (HR, 1.40; 95% CI, 1.13-1.73). Subjects who were naïve to vitamin K antagonists fared better than those who were treatment-experienced. Those with CrCl > 95 mL/min had poorer outcomes. For DVT/PE, 4921 subjects with DVT and 3319 with PE were randomized to edoxaban 60 mg (30 mg in those with CrCl 30-50 mL/min) or warfarin. All subjects had received treatment with heparin or low molecular weight heparin for at least 5 days. The primary efficacy endpoint was recurrent symptomatic venous thromboembolism, and the primary safety outcome was major or clinically relevant nonmajor bleeding. Edoxaban was noninferior to warfarin in terms of efficacy but superior to warfarin in terms of safety outcome.

CLINICAL IMPLICATIONS

Edoxaban enters the market as the third anti-Xa inhibitor and the fourth TSOA. Previously approved TSOAs include the Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct thrombin inhibitor dabigatran (Pradaxa). There are currently no published studies among these agents. In a comparative analysis and meta-analysis of major clinical trials in atrial fibrillation with apixaban, edoxaban, rivaroxaban, and warfarin, major bleeding was lower with apixaban and edoxaban compared with warfarin, but not with rivaroxaban.4 In another indirect comparison, edoxaban was not significantly different compared to apixaban in terms of efficacy endpoints, mortality, myocardial infarction, and major bleeding.5

Dabigatran (150 mg twice daily) was associated with lower stroke and systemic embolism compared to edoxaban. For indirect comparison in acute venous thrombosis, there appears to be no difference in recurrent VTE or all-cause mortality among the four agents,6 although edoxaban was associated with a higher risk of major bleeding compared to apixaban. Being the newest agent approved, its role is yet to be determined. Current ACC/AHA/HRS guidelines recommend the thrombin inhibitor (dabigatran) or a factor Xa inhibitor (rivaroxaban or apixaban) in patients with NVAF unable to maintain a therapeutic INR level with warfarin.7 The recommended treatment for acute DVT or PE is initial parenteral anticoagulation (e.g., low molecular weight heparin), followed by warfarin, dabigatran, apixaban, or edoxaban. Rivaroxaban, however, does not require initial therapy with heparin.8 The wholesale monthly cost for edoxaban is $277, compared to $315 for dabigatran, rivaroxaban, and apixaban. 

REFERENCES

1. Savaysa Prescribing Information. Daiichi Sankyo Co., Ltd.
January 2015.

2. Giugliano RP, et al. Stroke 2014;45:2372-2378.

3. Buller HR, et al. N Engl J Med 2013;369:1406-1415.

4. Pedro J, et al. Open Heart 2014;1:e000080.doi:10.1136/openhrt-2014-000080.

5. Skjoth F, et al. Thromb Haemost 2014;111:981-988.

6. Mantha S, Ansell JJ. Thromb Thrombolysis 2014; Jul 3 epub.

7. January CT, et al. J Am Clin Card 2014;64:2246-80.

8. Kearon C, et al. Chest 2012;141:e419s-e494S.