Regular ArticleSafety and Efficacy of Edoxaban, an Oral Factor Xa Inhibitor, Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty: The STARS E-3 Trial
Introduction
Anticoagulants are administered to reduce the incidence of thromboembolic events after major orthopaedic surgery such as total knee arthroplasty (TKA). In Japan, unfractionated heparin and warfarin are used with caution for venous thromboembolism (VTE) prevention due to limited evidence regarding their efficacy in postoperative deep vein thrombosis (DVT) prevention, adverse drug reactions, and the risk of bleeding in this patient population. Current Japanese guidelines recommend either anticoagulant therapy with the low-molecular weight heparin (LMWH) enoxaparin or the synthetic pentasaccharide indirect factor Xa inhibitor fondaparinux, or intermittent pneumatic compression for patients following orthopaedic surgery [1], [2]. However, enoxaparin and fondaparinux require parenteral administration [3], [4]. As a result, there is a need for more convenient anticoagulants.
Edoxaban is a novel, oral, direct factor Xa inhibitor that has been evaluated for stroke prevention in atrial fibrillation as well as treatment and secondary prevention of recurrent VTE [5], [6]. Edoxaban displays predictable pharmacokinetics (PK) at daily doses of ≤ 150 mg with approximately 62% oral bioavailability [7], [8]. In a phase 2 study of Japanese patients undergoing TKA, edoxaban doses of 5 mg to 60 mg once daily demonstrated significant dose-related reductions in VTE with a low incidence of bleeding that did not increase with increasing dose [9]. Three phase 3 studies have evaluated the safety and efficacy of edoxaban compared with enoxaparin for the prevention of VTE following TKA, total hip replacement, and after hip fracture surgery [10], [11]. The present phase 3 study, Studying Thrombosis After Replacement Surgery (STARS-E3; clinicatrials.gov NCT01181102), was a multicenter, randomized, double-blind trial comparing the efficacy and safety of oral edoxaban 30 mg once daily with subcutaneous enoxaparin 2000 IU (equivalent to 20 mg) twice daily following TKA in Japanese and Taiwanese patients.
Section snippets
Patients
Men and women aged 20 to 84 years who were scheduled to undergo unilateral TKA, excluding revision arthroplasty, were eligible for inclusion in the study. Patients were ineligible if they had increased risk of bleeding; were at high risk for thromboembolism; had a body weight < 40 kg; severe renal impairment (creatinine clearance < 30 mL/min); hepatic dysfunction; or were pregnant or lactating women. Postoperative exclusion criteria included abnormal bleeding from the injection site upon
Outcome Measures
All thromboembolic events were evaluated by the Thromboembolic Events Evaluation Committee based on copies of the clinical findings, such as films, provided by the principal investigator or co-investigator to the sponsor under blinded conditions. Evaluation by the committee was defined as the final evaluation. The primary efficacy endpoint was the composite of symptomatic PE and symptomatic and asymptomatic DVT. A secondary efficacy outcome was the proportion of patients with one or more of the
Efficacy analyses
Primary analysis of the efficacy endpoints was performed on the full analysis set (FAS) and on the per-protocol set (PPS) as a reference. The FAS was defined as all patients who received ≥ 1 dose of study drug but excluded those patients who had significant GCP violations or who had inadequate venography in the absence of symptomatic DVT or PE. The PPS was defined as patients in the FAS but excluded those with a violation of the inclusion or exclusion criteria, or rules for prohibited
Study populations
Between February and October 2009, 716 patients were randomized to edoxaban 30 mg (n = 360) and enoxaparin 2000 IU (n = 356). Patient disposition during the study is shown in Fig. 1. In the edoxaban group, 36 and 19 patients were excluded from the FAS because venography was either not performed or was uninterpretable, respectively. Similarly, 37 and 17 patients had no venography or uninterpretable venography, respectively, in the enoxaparin group and thus were excluded from the FAS analysis set. A
Discussion
In this STARS E-3 trial of thromboprophylaxis after TKA, oral edoxaban 30 mg once daily was more effective than subcutaneous enoxaparin 2000 IU twice daily for the prevention of VTE. Edoxaban reduced the incidence of the primary efficacy outcome (symptomatic PE, symptomatic DVT, or asymptomatic DVT) from 13.9% to 7.4%; the 95% CI for the difference was -11.5 to -1.6, indicating non-inferiority (P < 0.001) and superiority (P = 0.010) of edoxaban relative to enoxaparin. Most of the documented VTEs were
Disclosure of conflict of interest
T. Fuji has been a consultant for Daiichi Sankyo Co., Ltd. and Ono Pharmacy, received royalties from Century Medical and Showa Ikakogyo, and received compensation for speaker’s bureau/paid presentations from Daiichi Sankyo Co., Ltd. Century Medical, Ono Pharma and Bayer. S. Fujita has been a consultant for Daiichi Sankyo Co., Ltd., Astellas, and GlaxoSmithKline. Y. Kawai has been a consultant for Daiichi Sankyo Co., Ltd. and Toyama Chemical. M. Nakamura has been a consultant for Daiichi Sankyo
Acknowledgments
This study (ClinicalTrials.gov Identifier: NCT01181102) was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). The authors would like to acknowledge writing assistance provided by Scarlett Geunes-Boyer, PhD, of AlphaBioCom, LLC, which was funded by Daiichi Sankyo.
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Dr Fuji and Dr Wang contributed equally to this article.
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