Elsevier

Thrombosis Research

Volume 134, Issue 6, December 2014, Pages 1198-1204
Thrombosis Research

Regular Article
Safety and Efficacy of Edoxaban, an Oral Factor Xa Inhibitor, Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty: The STARS E-3 Trial

https://doi.org/10.1016/j.thromres.2014.09.011Get rights and content

Highlights

  • Edoxaban is an oral, once daily, direct factor Xa inhibitor

  • In Japanese and Taiwanese patients after knee replacement surgery:

  • Edoxaban was superior to enoxaparin for VTE prevention

  • Rates of bleeding were similar between edoxaban and enoxaparin

Abstract

Introduction

This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan.

Materials and methods

In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions.

Results

Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction = 46.8%), indicating non-inferiority (P < 0.001) and superiority (P = 0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P = 0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P = 0.129), respectively.

Conclusions

Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events.

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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