Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan T. Fuji MD, PhD, C.J. Wang MD, S. Fujita MD, PhD, Y. Kawai MD, PhD, T. Kimura MS, S. Tachibana MD, PhD PII: DOI: Reference:
S0883-5403(14)00403-3 doi: 10.1016/j.arth.2014.05.029 YARTH 54031
To appear in:
Journal of Arthroplasty
Received date: Accepted date:
25 March 2014 8 May 2014
Please cite this article as: Fuji T, Wang CJ, Fujita S, Kawai Y, Kimura T, Tachibana S, Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan, Journal of Arthroplasty (2014), doi: 10.1016/j.arth.2014.05.029
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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SC
Running title: Edoxaban in total hip arthroplasty
RI P
T
Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan
ED
MA
Authors: T. Fuji, MD, PhD*; C.J. Wang, MD†; S. Fujita MD, PhD‡; Y. Kawai, MD, PhD¶; T. Kimura, MS**; S. Tachibana, MD, PhD§
AC
CE
PT
Affiliations: *Department of Orthopedic Surgery, Osaka Koseinenkin Hospital, Osaka, Japan; †Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; ‡Department of Orthopedic Surgery, Takarazuka Daiichi Hospital, Hyogo, Japan; ¶International University of Health and Welfare, Tokyo, Japan; **Clinical Planning Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan; §Director, Mishuku Hospital, Tokyo, Japan
Corresponding author: Takeshi Fuji Mailing address: 4-2-78 Fukushima, Fukushima-ku, Osaka 553-0003, Japan Email: [email protected] Phone: 81-6-6441-5451 Fax: 81-6-6445-8900
1
ACCEPTED MANUSCRIPT Abstract Edoxaban, an oral direct factor Xa inhibitor, has proven antithrombotic efficacy. In a
T
multicenter, parallel-group, phase II study, 264 total hip arthroplasty (THA) patients randomly
RI P
received edoxaban 15-mg or 30-mg once-daily or enoxaparin 2000 IU (20-mg) twice-daily for
SC
11–14 days. Thromboembolic event incidences (primary efficacy outcome) were 3.8% (3/78), 2.8% (2/72), and 4.1% (3/74) for edoxaban 15-mg, 30-mg, and enoxaparin, respectively
NU
(P=1.00). Edoxaban-induced prolongation of prothrombin time, international normalized ratio, and activated partial thromboplastin time were proportional to plasma edoxaban concentration.
MA
Major or clinically relevant non-major bleeding incidences (primary safety outcome) were 2.2% (2/89), 1.2% (1/85), and 2.3% (2/87) for edoxaban 15-mg, 30-mg, and enoxaparin,
ED
respectively (P=1.00). Once-daily edoxaban showed similar efficacy and safety to enoxaparin
CE
PT
for prevention of thromboembolic events in patients undergoing THA.
enoxaparin
AC
Key words: edoxaban, factor Xa inhibitor, thromboembolic events, total hip arthroplasty,
2
ACCEPTED MANUSCRIPT Introduction Patients undergoing major orthopedic surgery are at high risk of postoperative venous
T
thromboembolism (VTE). The incidence of asymptomatic deep vein thrombosis (DVT) and
RI P
symptomatic VTE in patients undergoing elective total hip arthroplasty (THA) is 40% to 60% and 2% to 5%, respectively [1]. Therefore, aggressive prophylaxis with anticoagulants including
SC
low-molecular-weight heparins (LMWHs), fondaparinux, or vitamin K antagonists (eg, warfarin)
NU
is recommended for patients following major orthopedic surgery [1]. The occurrence of VTE post surgery in the Japanese population had been perceived to
MA
be considerably low; however, more recent data have demonstrated an increasing incidence of VTE in patients undergoing orthopedic surgery [2, 3]. In a prospective, epidemiologic study, the
ED
incidence of DVT was 22.6% in patients undergoing THA without prophylactic anticoagulation [2]. Similarly, in a recent randomized clinical trial, the incidence of VTE in Japanese patients
PT
undergoing THA was 33.8% in the placebo group [3]. The anticoagulants enoxaparin sodium
CE
and fondaparinux sodium have been approved in Japan at doses of 20 mg twice daily and 2.5 mg once daily, respectively, for the prevention of VTE in patients undergoing orthopedic surgery
AC
of the lower limbs such as THA, total knee arthroplasty (TKA), and hip fracture surgery [4, 5]. The currently available anticoagulants, however, are associated with several limitations. LMWHs and fondaparinux require parenteral administration, and vitamin K antagonists display an unpredictable pharmacokinetic (PK)/pharmacodynamic (PD) profile, numerous food and drug interactions, and genetic variability in patient responses, necessitating frequent monitoring and dosage adjustments [6, 7]. Consequently, there is a need for new anticoagulants that can be administered orally, have more predictable PK/PD, and have comparable or better safety and efficacy than the existing anticoagulants.
3
ACCEPTED MANUSCRIPT Edoxaban is an oral, selective, direct FXa inhibitor [8] in advanced clinical development for the prevention and treatment of thromboembolic events [9, 10]. Edoxaban is rapidly
T
absorbed with an oral bioavailability of approximately 60% and a half-life of 8 to 10 hours, and
RI P
it demonstrates predictable and linear PK/PD [11, 12]. Previous phase II studies in patients undergoing THA [9] and TKA [13] demonstrated that edoxaban was safe and effective for
SC
thromboprophylaxis across a wide range of doses. The aim of the present study was to evaluate
NU
the efficacy, safety, and dosage regimen of edoxaban in patients undergoing THA in Japan and
MA
Taiwan.
Materials and Methods
ED
Study design
This was a randomized, active-controlled, multicenter, parallel-group, double-blind,
PT
phase II trial, conducted in Japan and Taiwan, to assess the safety and efficacy of edoxaban
CE
relative to enoxaparin sodium for the prevention of VTE after THA. The study was conducted in compliance with the Declaration of Helsinki Guidelines for Good Clinical Practice or Guidelines
AC
for the Conduct of Clinical Trials of Drugs. The protocol and informed consent forms were reviewed and approved by the institutional review board. All patients provided written informed consent before undergoing any study-related examinations.
Study population Patients aged 20 to
S0883-5403(14)00403-3 doi: 10.1016/j.arth.2014.05.029 YARTH 54031
To appear in:
Journal of Arthroplasty
Received date: Accepted date:
25 March 2014 8 May 2014
Please cite this article as: Fuji T, Wang CJ, Fujita S, Kawai Y, Kimura T, Tachibana S, Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan, Journal of Arthroplasty (2014), doi: 10.1016/j.arth.2014.05.029
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
NU
SC
Running title: Edoxaban in total hip arthroplasty
RI P
T
Safety and efficacy of edoxaban, an oral factor Xa inhibitor, for thromboprophylaxis after total hip arthroplasty in Japan and Taiwan
ED
MA
Authors: T. Fuji, MD, PhD*; C.J. Wang, MD†; S. Fujita MD, PhD‡; Y. Kawai, MD, PhD¶; T. Kimura, MS**; S. Tachibana, MD, PhD§
AC
CE
PT
Affiliations: *Department of Orthopedic Surgery, Osaka Koseinenkin Hospital, Osaka, Japan; †Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; ‡Department of Orthopedic Surgery, Takarazuka Daiichi Hospital, Hyogo, Japan; ¶International University of Health and Welfare, Tokyo, Japan; **Clinical Planning Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan; §Director, Mishuku Hospital, Tokyo, Japan
Corresponding author: Takeshi Fuji Mailing address: 4-2-78 Fukushima, Fukushima-ku, Osaka 553-0003, Japan Email: [email protected] Phone: 81-6-6441-5451 Fax: 81-6-6445-8900
1
ACCEPTED MANUSCRIPT Abstract Edoxaban, an oral direct factor Xa inhibitor, has proven antithrombotic efficacy. In a
T
multicenter, parallel-group, phase II study, 264 total hip arthroplasty (THA) patients randomly
RI P
received edoxaban 15-mg or 30-mg once-daily or enoxaparin 2000 IU (20-mg) twice-daily for
SC
11–14 days. Thromboembolic event incidences (primary efficacy outcome) were 3.8% (3/78), 2.8% (2/72), and 4.1% (3/74) for edoxaban 15-mg, 30-mg, and enoxaparin, respectively
NU
(P=1.00). Edoxaban-induced prolongation of prothrombin time, international normalized ratio, and activated partial thromboplastin time were proportional to plasma edoxaban concentration.
MA
Major or clinically relevant non-major bleeding incidences (primary safety outcome) were 2.2% (2/89), 1.2% (1/85), and 2.3% (2/87) for edoxaban 15-mg, 30-mg, and enoxaparin,
ED
respectively (P=1.00). Once-daily edoxaban showed similar efficacy and safety to enoxaparin
CE
PT
for prevention of thromboembolic events in patients undergoing THA.
enoxaparin
AC
Key words: edoxaban, factor Xa inhibitor, thromboembolic events, total hip arthroplasty,
2
ACCEPTED MANUSCRIPT Introduction Patients undergoing major orthopedic surgery are at high risk of postoperative venous
T
thromboembolism (VTE). The incidence of asymptomatic deep vein thrombosis (DVT) and
RI P
symptomatic VTE in patients undergoing elective total hip arthroplasty (THA) is 40% to 60% and 2% to 5%, respectively [1]. Therefore, aggressive prophylaxis with anticoagulants including
SC
low-molecular-weight heparins (LMWHs), fondaparinux, or vitamin K antagonists (eg, warfarin)
NU
is recommended for patients following major orthopedic surgery [1]. The occurrence of VTE post surgery in the Japanese population had been perceived to
MA
be considerably low; however, more recent data have demonstrated an increasing incidence of VTE in patients undergoing orthopedic surgery [2, 3]. In a prospective, epidemiologic study, the
ED
incidence of DVT was 22.6% in patients undergoing THA without prophylactic anticoagulation [2]. Similarly, in a recent randomized clinical trial, the incidence of VTE in Japanese patients
PT
undergoing THA was 33.8% in the placebo group [3]. The anticoagulants enoxaparin sodium
CE
and fondaparinux sodium have been approved in Japan at doses of 20 mg twice daily and 2.5 mg once daily, respectively, for the prevention of VTE in patients undergoing orthopedic surgery
AC
of the lower limbs such as THA, total knee arthroplasty (TKA), and hip fracture surgery [4, 5]. The currently available anticoagulants, however, are associated with several limitations. LMWHs and fondaparinux require parenteral administration, and vitamin K antagonists display an unpredictable pharmacokinetic (PK)/pharmacodynamic (PD) profile, numerous food and drug interactions, and genetic variability in patient responses, necessitating frequent monitoring and dosage adjustments [6, 7]. Consequently, there is a need for new anticoagulants that can be administered orally, have more predictable PK/PD, and have comparable or better safety and efficacy than the existing anticoagulants.
3
ACCEPTED MANUSCRIPT Edoxaban is an oral, selective, direct FXa inhibitor [8] in advanced clinical development for the prevention and treatment of thromboembolic events [9, 10]. Edoxaban is rapidly
T
absorbed with an oral bioavailability of approximately 60% and a half-life of 8 to 10 hours, and
RI P
it demonstrates predictable and linear PK/PD [11, 12]. Previous phase II studies in patients undergoing THA [9] and TKA [13] demonstrated that edoxaban was safe and effective for
SC
thromboprophylaxis across a wide range of doses. The aim of the present study was to evaluate
NU
the efficacy, safety, and dosage regimen of edoxaban in patients undergoing THA in Japan and
MA
Taiwan.
Materials and Methods
ED
Study design
This was a randomized, active-controlled, multicenter, parallel-group, double-blind,
PT
phase II trial, conducted in Japan and Taiwan, to assess the safety and efficacy of edoxaban
CE
relative to enoxaparin sodium for the prevention of VTE after THA. The study was conducted in compliance with the Declaration of Helsinki Guidelines for Good Clinical Practice or Guidelines
AC
for the Conduct of Clinical Trials of Drugs. The protocol and informed consent forms were reviewed and approved by the institutional review board. All patients provided written informed consent before undergoing any study-related examinations.
Study population Patients aged 20 to
