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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres
Regular Article
Safety and efficacy of edoxaban in patients undergoing hip fracture surgery
Takeshi Fuji a,*< Satoru Fujita b, Yohko Kawaic, Mashio Nakamura d, Tetsuya Kimura e, Yuichi Kiuchif, Kenji Abe g, Shintaro Tachibana h
a Department of Orthopaedic Surgery, Osaka Koseinenkin Hospital, Osaka, Japan b Department of Orthopaedic Surgery, Takarazuka Daiichi Hospital, Takarazuka, Japan c International University of Health and Welfare, Tokyo, Japan
d Department of Clinical Cardiovascular Research, Mie University Graduate School of Medicine, Tsu, Japan e Clinical Planning Department, Daiichi Sankyo Co. Ltd, Tokyo, Japan f New Drug Regulatory Affairs Department, Daiichi Sankyo Co. Ltd, Tokyo, Japan g Clinical Data & Biostatistics Department, Daiichi Sankyo Co. Ltd, Tokyo, Japan h Department of Orthopaedic Surgery, Mishuku Hospital, Tokyo, Japan
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ARTICLE INFO
ABSTRACT
Article history:
Received 6 January 2014
Received in revised form 24 February 2014
Accepted 3 March 2014
Available online 6 March 2014
Keywords: Edoxaban Enoxaparin Factor Xa
Hip fracture surgery Venous thromboembolism
Introduction: Edoxaban is an oral, direct, once-daily factor Xa inhibitor. This study evaluated the safety and efficacy of edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery. Materials and methods: In this multicenter, randomized, open-label, active-comparator, phase 3 trial, 92 patients were randomized 2:1 to receive edoxaban 30 mg once daily (n = 62) or enoxaparin sodium (enoxaparin) 2000IU (equivalent to 20 mg) twice daily (n = 30) for 11 to 14 days. The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and incidence of any bleeding events (major, CRNM, or minor bleeding). Secondary efficacy endpoints included the incidence of thromboembolic events, venous thromboembolism-related deaths, and all-cause deaths. Additional adverse events were recorded throughout the study.
Results: In the edoxaban and enoxaparin treatment groups, the incidence of major or CRNM bleeding was 3.4% and 6.9%, respectively, while any bleeding event occurred in 25.4% and 17.2% of patients, respectively. The incidence of thromboembolic events was 6.5% in the edoxaban group and 3.7% in the enoxaparin group. All events were asymptomatic deep vein thrombosis. The incidence of adverse events was 72.9% and 82.8% in the edoxaban and enoxaparin groups, respectively.
Conclusions: Compared to subcutaneous enoxaparin 2000 IU twice daily, oral edoxaban 30 mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery.
Clinical trials registration number: NCT01181141.
© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).
Abbreviations: ADR, adverse drug reactions; AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, every 12 hours; CI, confidence interval; CRNM, clinically relevant non-major; CT, computed tomography; DVT, deep vein thrombosis; GCP, good clinical practice; GI, gastrointestinal; HFS, hip fracture surgery; LLOS, lower-limb orthopedic surgeries; LMWH, low-molecular weight heparin; PD, pharmaco-dynamic; PE, pulmonary embolism; PK, pharmacokinetic; PT, prothrombin time; PT-INR, prothrombin time expressed as international normalized ratio; aPTT, activated partial thromboplastin time; SAE, serious adverse event; sc, subcutaneous injections; THA, total hip arthroplasty; TKA, total knee arthroplasty; ULN, upper limit of normal; VTE, venous thromboembolism.
* Corresponding author at: Osaka Koseinenkin Hospital, 4-2-78, Fukushima, Fukushima-ku,Osaka,553-0003,Japan.Tel.: +81 6 6441 5451; fax: +81 664458900.
E-mail address: fuji-th@umin.ac.jp (T. Fuji).
Introduction
Patients undergoing lower-limb orthopedic surgeries (LLOS) are at an increased risk for developing deep vein thrombosis (DVT) and pulmonary embolism (PE) if they are not provided with timely and adequate thromboprophylaxis [1,2]. The incidence of postoperative DVT is relatively high among patients who do not receive thromboprophylaxis undergoing total knee arthroplasty (TKA; 41%-85%), total hip arthroplasty (THA; 42%-57%), and hip fracture surgery (HFS; 46%-60%) [3]. PE, which in most cases is caused by DVT, can be fatal and is associated with a 14% in-hospital mortality rate; in serious cases accompanied by shock, the mortality rate is approximately 30% [4]. It has been reported that approximately 40% of patients who die of a PE do so within 1 hour of onset [5]. PE has been recognized as a significant
http://dx.doi.org/10.1016/j.thromres.2014.03.009
0049-3848/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
cardiovascular disease in Japan in recent years [2]. As such, current guidelines from the Japanese Circulation Society and the American College of Chest Physicians underscore the importance of preventing postoperative thrombosis and strongly recommend the use of adequate anticoagulant therapy soon after surgery [1,2].
Traditional anticoagulants (like heparin and warfarin) have limited use for venous thromboembolism (VTE) prevention in Japan because little is known about their efficacy in postoperative DVT prevention, adverse drug reactions (ADRs), and bleeding risks in this patient population. Enoxaparin, a low-molecular weight heparin (LMWH), and fondaparinux, an indirect factor Xa inhibitor, are efficacious in preventing VTE in patients undergoing LLOS, compared to placebo [6,7], and have both been approved in Japan for thromboprophylaxis in patients undergoing lower-limb orthopedic surgery [2]. Both drugs require subcutaneous injections (sc) administered once or twice daily, which may hinder patient adherence to therapy [8,9].
Edoxaban is an oral, once-daily, selective, direct factor Xa inhibitor that demonstrates a linear pharmacokinetic (PK) profile, a rapid onset of action with approximately 62% oral bioavailability [10], and low intra-subject variability [11]. Previous phase 2 studies in patients undergoing TKA [12] and THA [13,14] have demonstrated that edoxaban is associated with dose-dependent reductions in VTE with a low incidence of bleeding events that do not significantly increase with dose. In addition, edoxaban demonstrated efficacy and safety profiles similar to sc enoxaparin sodium for the prevention of thromboembolic events in patients undergoing THA [13]. The objective of this phase 3 study was to investigate the safety and efficacy of edoxaban in Japanese patients undergoing HFS.
Materials and Methods
Study Design
This was a multicenter, open-label, active-comparator, phase 3 trial (ClinicalTrials.gov Identifier: NCT01181141). Japanese patients were randomized 2:1 to receive an oral dose of edoxaban 30 mg once daily or the active control, enoxaparin 2000 IU sc every 12 hours (BID), which is the approved dosing regimen in Japan [15]. Edoxaban was initiated within 6 to 24 hours after surgery; enoxaparin was initiated within 24 to 36 hours after surgery (the standard of care in Japan). Both treatments were continued for 11 to 14 days. Concomitant use of mechanical physiotherapy (intermittent pneumatic compression or elastic stockings) was permitted.
Venography of both lower limbs was performed within 24 hours after the end of study treatment or treatment discontinuation; however, if it could not be performed within 24 hours for reasons such as difficulty establishing an intravenous line, it was performed within 96 hours. If DVT was suspected during the study, it was visually confirmed with diagnostic imaging. Similarly, suspected PE was confirmed by pulmonary scintigraphy or arteriography, computed tomography (CT) scan, or other appropriate imaging techniques. Study treatment was immediately discontinued if a suspected DVT or PE was confirmed and appropriate interventions were taken.
Investigations, observations, examinations, and urine and blood sample collections (for urinalysis, edoxaban plasma concentration measurements, pharmacodynamic [PD] indices assessments, and hematology tests) were performed during the presurgical evaluation, pretreatment (postsurgery), on day 7, and on the completion day of treatment. Follow-up examinations were performed 25 to 35 days after the last dose of the study drug. The occurrence of thromboembolic events, bleeding, and all other adverse events (AEs) were recorded throughout the study and the follow-up period. If applicable, site, duration, and total time of physiotherapy use were recorded throughout the course of the study. The study was conducted in compliance with the ethical principles in the Declaration of Helsinki, the Pharmaceutical Affairs Law Articles 14-3 and 80-2, and the Ministry of Health and Welfare Ordinance
on Good Clinical Practice (GCP). All study protocols, information for patients, and informed consent forms received approval from an independent review board.
Patient Selection
Men and women of at least 20 years of age who provided written informed consent and were scheduled to undergo surgery within 10 days for inner or outer femoral neck (trochanteric or subtrochanteric) fracture were eligible for enrollment. Prior to surgery, patients were considered ineligible if they were at increased risk for bleeding (e.g., a history of intracranial bleeding or recent gastrointestinal [GI] bleeding) or increased risk for VTE (i.e., had a prior VTE, history of fracture or prosthetic replacement of lower limbs within 6 months, or recent occurrence of myocardial infarction, cerebral infarction, or transient ischemic attack). Additional reasons for exclusion included body weight of <40 kg, current use of antithrombotic therapy for another indication, severe renal impairment (creatinine clearance <30 mL/min) or evidence of hepatic impairment, conditions preventing bilateral venography, pregnancy or lactation, and any contraindications to enoxaparin. After surgery, patients could also be excluded if they experienced any abnormal bleeding at the site of spinal anesthesia administration, experienced abnormal or excessive bleeding during or immediately after surgery, were unable to take oral medications, or required additional surgery after the initial HFS until the start of study drug administration.
Study Endpoints
The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and the incidence of any bleeding event (major, CRNM, or minor bleeding) from the start of treatment to completion day of treatment, inclusive. Secondary safety endpoints included the incidence of individual bleeding events, AEs, ADRs, vital signs and laboratory test data. AEs were reported from the start of the treatment up to the end of the follow-up period (25-35 days after treatment).
Secondary efficacy endpoints included the proportion of patients who experienced the composite of asymptomatic DVT detected by the end-of-study venography, confirmed symptomatic DVT, or confirmed symptomatic PE; the proportion of patients who experienced the composite of symptomatic or proximal DVT, symptomatic PE, or VTE-related mortality; the incidence of asymptomatic or symptomatic DVT; the incidence of symptomatic or proximal DVT; the incidence of confirmed, symptomatic PE; the incidence of VTE-related mortality; and the incidence of all-cause mortality. To ensure objectivity, independent committees assessed bleeding events and thromboembolic events under blinded conditions.
Major bleeding was defined as fatal bleeding, clinically overt bleeding accompanied by a decrease in hemoglobin of >2 g/dL, clinically overt bleeding requiring transfusion (excluding predonated autologous blood) with more than 4 units of blood (1 unit = approximately 200 mL), retroperitoneal bleeding, intracranial bleeding, intraocular bleeding or intrathecal bleeding, and bleeding requiring repeat surgery. CRNM bleeding was defined as bleeding that did not fall under the category of major bleeding but corresponded to any of the following: hematoma of > 5 cm in longest diameter, epistaxis or gingival bleeding that occurred in the absence of external factors and lasts > 5 minutes, GI bleeding, gross hematuria that is persistent after 24 hours of onset, and other bleeding that was assessed to be clinically significant by the investigator or sub-investigator. Any bleeding event that did not meet major or CRNM criteria was categorized as a minor bleeding event.
In addition to safety and efficacy outcomes, PD indices (prothrombin time [PT], prothrombin time expressed as international normalized ratio [PT-INR], and activated partial thromboplastin time [aPTT]), and edoxaban plasma concentrations were measured at various time points as described below.
Blood Sampling for Pharmacodynamic and Edoxaban Plasma Concentration Measures
Blood sampling for measurement of edoxaban plasma concentrations was performed on day 7 of study treatment (predose and 1-3 hours postdose), at the completion of study treatment (predose), or at discontinuation. The concentration was measured by liquid chromatography tandem mass spectrometry (Quotient Bioresearch [Rushden] Ltd.; Northamptonshire, United Kingdom). The lower limit of quantification was 1 ng/ml.
Blood sampling for measurement of PD indices was performed at the following time points: presurgical examination, pretreatment, day 7 of study treatment (predose and 1-3 hours postdose), predose on completion day of study treatment, and at the time of discontinuation. While presurgical PD measurements were made at the study sites, measurements during the treatment were performed at a central laboratory (SRL, Inc; Tokyo, Japan) and were not to be made at the investigation site to avoid effects on assessment (unless they were for treatment of an AE or an emergency occurred).
Statistical Analysis
The full analysis set was defined as all patients enrolled in the study who received at least 1 dose of study drug and had no significant GCP violations. Patients who did not develop symptomatic DVT or PE, but in whom venography was not appropriately performed, were excluded from this group. The per-protocol set was defined as patients in the full analysis set, but excluded those with who had any violations of the inclusion and exclusion criteria, who took prohibited concomitant medications or therapies, or who had a study treatment compliance rate of < 80%. The safety analysis set included all patients who received at least 1 dose of study drug, had safety data, and had no significant GCP violations. The PD and PK analysis sets comprised those patients
in the per-protocol set with at least 1 set of valid PD index or plasma drug concentration data, respectively.
Baseline demographics and characteristics are reported here for the safety analysis set and were reported by summary statistics according to treatment group. Between-treatment comparisons were made using the x2 test or Fisher's exact test for categorical data, the Wilcoxon rank-sum test for ordinal data, and the 2-sample t-test for continuous data.
Primary analyses of the primary and secondary safety endpoints were performed for the safety analysis set. Primary analyses of the efficacy endpoints were performed for the full analysis set. Incidence of major or CRNM bleeding or any bleeding (primary safety endpoints) 95% confidence intervals (CIs) were calculated by treatment group, as well as the differences between treatment groups and the corresponding 95% CIs. For the secondary endpoints of individual bleeding events, AEs, ADRs, and thromboembolic events, incidences and 95% CIs were calculated by treatment group. In addition, for the incidence of individual bleeding events and thromboembolic events, the differences between treatment groups and corresponding 95% CIs were determined. Laboratory data, vital signs, and other observations were reported using summary statistics calculated by treatment group.
PD indices were reported for the corresponding PD analysis set using summary statistics for measured values. Changes from pretreatment were calculated for each parameter by treatment group at each time point. Similarly, summary statistics of edoxaban plasma concentrations were calculated for the PK analysis set.
The sample size (N = 90) for this analysis was determined to ensure that a major or CRNM bleeding event would occur in at least 1 patient with an 80% or higher probability in any situation for the edoxaban (n > 41) and enoxaparin (n > 28) groups. This determination was based on the assumption that these bleeding events would occur at a similar rate, as has been previously reported for edoxaban and enoxaparin. However, the target number of patients was set at 60
Patients randomized (N=92)
Fig. 1. Patient disposition. aMultiple answers were allowed; patients with multiple reasons for exclusion were counted once for each reason.
Table 1
Baseline demographics and characteristics.3
Characteristic
Edoxaban (N = 59)
Enoxaparin (N = 29)
Sex Men Women Age, y (mean ± SD) <75 >75
Weight, kg (mean ± SD) <50 >50 Site of surgery Medial femoral neck
Lateral femoral neck (trochanteric section) Lateral femoral neck (subtrochanteric section) Method of surgery Femoral head replacement Prosthetic joint replacement Osteosynthesis
Duration from the end of surgery to the start of study treatment, h:min (mean ± SD) >6 to < 12 >12 to < 18 >18 to <24 >24 to < 30 >30 to < 36 Creatinine clearance, mL/min (mean ± SD) <50
>50 to < 80 >80
Use of physiotherapy Intermittent pneumatic compression Foot sole
Lower legs and thigh Elastic stockings Concomitant NSAID use
11 (18.6) 48 (81.4) 76.5 ±11.0
20 (33.9) 39 (66.1) 52.3 ± 8.4
21 (35.6) 38 (64.4)
30 (50.8)
26 (44.1) 3(5.1)
21 (35.6) 0 (0.0) 38 (64.4) 20:01 ± 2:47 0 (0.0) 18 (30.5) 41 (69.5)
63.7 ± 22.4 24 (40.7) 23 (39.0) 12 (20.3)
16 (27.1)
13 (22.0)
47 ( 79.7) 59 (100.0)
7(24.1)
22 ( 75.9) 75.6 ± 12.0 12 (41.4)
17 (58.6) 55.1 ± 10.0 10 (34.5) 19 (65.5)
10 (34.5)
18 (62.1) 1 (3.4)
6 (20.7)
0 (0.0)
23 (79.3) 27:02 ± 2:56
24 (82.8) 5 (17.2) 73.2 ± 30.8 8 (27.6)
10 (34.5)
11 (37.9)
8 (27.6) 7(24.1) 20 (69.0) 29 (100.0)
Data provided as n (%) unless indicated otherwise. SD = standard deviation; NSAID = non-steroidal anti-inflammatory drug. a Safety analysis set.
(edoxaban) and 30 (enoxaparin) so that the total number of patients could be randomly assigned to a 2:1 ratio (edoxaban:enoxaparin).
Results
Patients
Between October 2008 and August 2009,92 patients were randomized and 76 completed the study. Among the 16 patients who did not complete the study, 12 were in the edoxaban treatment group and 4 received enoxaparin. One patient each discontinued due to a DVT or PE, major bleeding, an AE, or were lost to follow-up, 2 patients were discontinued at the investigators discretion, and 3 patients each voluntarily withdrew or became ineligible for continued participation during the course of the study. In the enoxaparin group, reasons for discontinuation were an AE, voluntary withdrawal, ineligibility, or lost to follow up, 1 patient each. Four patients did not receive study drug and 19 were not assessable by venography, leaving 88 and 73 patients in the safety and full analysis sets, respectively. An additional 5 patients
were excluded from the per-protocol set due to various protocol violations (Fig. 1). No additional patients were excluded from the PK or PD analysis sets (edoxaban only, n = 42). Baseline characteristics were similar between the treatment groups, although creatinine clearance was lower in the edoxaban group (63.7 ± 22.4 mL/min) than in the enoxaparin group (73.2 ± 30.8 mL/min); however, this difference was not statistically significant (Table 1). Overall, the majority of patients were female (79.5%) and > 75 years of age (63.6%). Approximately one-third of patients had a body weight < 50 kg (35.2%) and creatinine clearance < 50 mL/min (36.4%). The mean duration of treatment with edoxaban or enoxaparin was 12.1 and 12.2 days, respectively.
Primary Safety Endpoints
The incidence of major or CRNM bleeding was observed in 3.4% (2/59; 95% CI 0.9-11.5) of patients in the edoxaban group and 6.9% (2/29; 95% CI 1.9-22.0) in the enoxaparin group (Table 2). The absolute difference (defined as the difference in the incidence of bleeding events between the edoxaban group and the enoxaparin group, the same
Table 2
Incidence of bleeding events during the treatment period.a
Bleeding Event Edoxaban (N = 59) Enoxaparin (N = 29) Absolute Difference
nb % (95% CI) nb % (95% CI) % (95% CI)
Major or CRNM bleeding 2 3.4 (0.9 to 11.5) 2 6.9 (1.9 to 22.0) -3.5 (-18.8 to 6.0)
Any bleeding 15 25.4(16.1 to 37.8) 5 17.2 (7.6 to 34.5) 8.2 (-11.5 to 23.9)
Major bleeding 1 1.7(0.3 to 9.0) 1 3.4 (0.6 to 17.2) -1.8 (-15.6 to 6.1)
CRNM bleeding 1 1.7 (0.3 to 9.0) 1 3.4 (0.6 to 17.2) -1.8 (-15.6 to 6.1)
Minor bleeding 13 22.0 (13.4 to 34.1) 3 10.3 (3.6 to 26.4) 11.7 (-6.5 to 25.5)
CI = confidence interval; CRNM = clinically relevant non-major. a Safety analysis set. Number of subjects with events.
Table 3
Incidence of adverse events, serious adverse events, and drug reactions, from the start of treatment to the end of follow-up period.a
Treatment Group
Edoxaban (N = 59) Enoxaparin (N = 29)
Adverse events n
% (95% CI) Serious adverse events n
% (95% CI) Adverse drug reactions n
% (95% CI)
72.9 (60.4 to 82.6) 82.8 (65.5 to 92.4)
5.1 (1.7 to 13.9) 10.3 (3.6 to 26.4)
37.3 (26.1 to 50.0) 37.9 (22.7 to 56.0)
Adverse events reported by >10% of patients in either treatment group, n (%)b
Urinary tract infections 7 (11.9)
Diarrhea 3 (5.1)
Decubitus ulcer 0
Alanine aminotransferase increased 0
Aspartate aminotransferase increased 2 (3.4)
Y-Glutamyltransferase increased 2 (3.4)
Blood urine present 9 (15.3)
4(13.8)
3 (10.3) 3 (10.3) 4(13.8)
5 (17.2) 3 (10.3)
4(13.8)
CI = confidence interval; breported by MedDRA preferred term. a Safety analysis set.
hereinafter) was — 3.5% (95% CI —18.8-6.0). The incidence of any bleeding event (major, CRNM, and minor bleeding) was 25.4% (15/59; 95% CI 16.1-37.8) and 17.2% (5/29; 95% CI 7.6-34.5) in the edoxaban and the enoxaparin groups, respectively. The absolute difference was 8.2% (95% CI —11.5-23.9).
Secondary Safety Endpoints
individual Bleeding Events
The incidence of major bleeding was 1.7% (1/59; 95% CI 0.3-9.0) and 3.4% (1/29; CI 0.6-17.2) in the edoxaban and enoxaparin groups, respectively. The absolute difference was —1.8% (95% CI, —15.6-6.1; Table 2). The major bleeding events included GI hemorrhage in the edoxaban group and postprocedural hematoma in the enoxaparin group. Both events were classified as clinically overt bleeding accompanied by a decrease in hemoglobin of > 2 g/dL. The percentage of patients who had a CRNM bleeding event was 1.7% (1/59; 95% CI 0.3-9.0; GI hemorrhage) and 3.4% (1/29; 95% CI 0.6-17.2; postprocedural hematoma of > 5 cm in diameter) in the edoxaban and enoxaparin groups, respectively. The absolute difference was — 1.8% (95% CI, —15.6-6.1). The incidence of minor bleeding was 22% (13/59; 95% CI 13.4-34.1) and 10.3% (3/29; 95% CI 3.6-26.4) in the edoxaban and enoxaparin groups, respectively. The absolute difference was 11.7% (95% CI — 6.525.5).
Adverse Events
The incidence of AEs was 72.9% (43/59; 95% CI 60.4-82.6) in the edoxaban group and 82.8% (24/29; 95% CI 65.5-92.4) in the enoxaparin group (Table 3). The most frequently reported AEs (reported by > 10% of patients in either treatment group) included blood urine present, urinary tract infections, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase, diarrhea, decubitus ulcer, and Y-glutamyltransferase increase (Table 3). Increased ALT and AST levels were reported more frequently in the enoxaparin group compared to the edoxaban group. Subcutaneous hemorrhage was reported for 4 (6.8%) patients in the edoxaban treatment group and 1 (3.4%) patient in the enoxaparin treatment group. The majority (> 70%) of AEs were mild in intensity. The incidence of AEs, excluding bleeding events and hepatic dysfunction, was 57.6% (34/59) and 69.0% (20/29) for the edoxaban and enoxaparin treatment groups, respectively.
The incidence of ADRs was 37.3% (22/59; 95% CI 26.1-50.0) in the edoxaban group and 37.9% (11/29; 95% CI 22.7-56.0) in the enoxaparin group. The most common ADRs, which occurred in > 5% of patients in either the edoxaban or enoxaparin groups, included ALT increase (0% and 10.3%, respectively), AST increase (0% and 13.8%, respectively), Y-glutamyltransferase increase (3.4% and 10.3%, respectively), blood urine present (6.8% and 3.4%, respectively), and postprocedural hematoma (1.7% and 6.9%, respectively).
Serious AEs (SAEs) occurred in 5.1% (3/59; 95% CI 1.7-13.9) and 10.3% (3/29; 95% CI 3.6-26.4) of the patients in the edoxaban and enoxaparin groups, respectively. Fracture displacement occurred in 2 patients in the edoxaban group (1 event each) while it occurred twice in 1 patient in the enoxaparin group. Other SAEs included 1 subdural hematoma in the edoxaban group and 1 each of postoperative wound infection and thoracic vertebral fracture (2 different patients) in the enoxaparin group. Of the SAEs, subdural hematoma in the edoxaban group and postoperative wound infection in the enoxaparin group were considered treatment related. No deaths occurred during the study. Three AEs led to treatment discontinuation: 2 patients receiving edoxaban experienced GI bleeding and 1 patient receiving enoxaparin experienced a postoperative wound infection.
Secondary Efficacy Endpoints
The efficacy endpoint of composite thromboembolic events (asymptomatic DVT detected by the end-of-study venography, confirmed symptomatic DVT, or confirmed symptomatic PE) occurred in 6.5% (3/46; 95% CI, 2.2-17.5) of patients in the edoxaban group and 3.7% (1/27; 95% CI, 0.7-18.3) in the enoxaparin group (Table 4). All events were asymptomatic distal DVT; there were no occurrences of asymptomatic proximal DVT, symptomatic PE or DVT, or death in either treatment group.
Table 4
Incidence of venous thromboembolism during the treatment period.a
Thromboembolic Event Edoxaban (N = 46) Enoxaparin (N = 27) Absolute Difference
nb % (95% CI) nb % (95% CI) % (95% CI)
Composite VTE (symptomatic or asymptomatic DVT, symptomatic PE) 3 6.5 (2.2 to 17.5) 1 3.7 (0.7 to 18.3) 2.8 ( — 12.4 to 14.2)
Composite of symptomatic or proximal DVT, symptomatic PE, or VTE-related death 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
Any DVT 3 6.5 (2.2 to 17.5) 1 3.7 (0.7 to 18.3) 2.8 ( — 12.4 to 14.2)
Asymptomatic DVT 3 6.5 (2.2 to 17.5) 1 3.7 (0.7 to 18.3) 2.8 ( — 12.4 to 14.2)
Asymptomatic proximal 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
Asymptomatic distal 3 6.5 (2.2 to 17.5) 1 3.7 (0.7 to 18.3) 2.8 ( — 12.4 to 14.2)
Symptomatic DVT 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
Symptomatic or proximal DVT 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
Symptomatic PE 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
VTE-related death 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
All-cause death 0 0.0 (0.0 to 7.7) 0 0.0 (0.0 to 12.5) 0.0 ( — 12.5 to 7.7)
CI = confidence interval; VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism; NC = not calculated. a Full analysis set. b Number of subjects with events.
Clinical Laboratory Tests
One (1.7%) patient in the edoxaban group and 5 (17.2%) patients in the enoxaparin group had elevated ALT levels > 1.5 times the upper limit of normal (ULN). Two patients in the edoxaban group and 6 patients in the enoxaparin group had elevated AST > 1.5 times the ULN. Elevations in ALT/AST were seen in 4 patients (13.8%) in the enoxaparin group. No patient in the edoxaban group experienced ALT, AST, or ALT/AST elevations > 3 times the ULN or total bilirubin elevations > 2 times the ULN. ALT was elevated > 3 times the ULN in 1 (3.4%) patient in the enoxaparin group.
Pharmacokinetic and Pharmacodynamic Analyses
The mean (standard deviation) plasma edoxaban concentrations were 24.3 (12.5) ng/mL, 129.9 (111.1) ng/mL, and 23.3 (11.1) ng/mL at predose on day 7,1 to 3 hours postdose on day 7, and at predose on the completion day of treatment, respectively.
In the edoxaban group, PT, PT-INR, and aPTT were prolonged at 1 to 3 hours postdose on day 7 of treatment compared with those at pre-treatment. No prolongation was observed in the enoxaparin group (Fig. 2). The observed increases in PT, PT-INR, and aPTT values from pretreatment levels were nearly linear to the observed increase in edoxaban plasma concentrations at 1 to 3 hours postdose on day 7 (data not shown).
Discussion
In Japanese patients undergoing HFS, VTE prophylaxis with oral edoxaban 30 mg once daily led to similar rates of major or CRNM bleeding events compared to sc enoxaparin 20001U BID, while the incidence of any bleeding event (major bleeding, CRNM bleeding, or minor bleeding) was higher in the edoxaban group (absolute difference 8.2%). Although the incidence of major or CRNM bleeding in the edoxaban group in this study was low (3.4%) and in line with rates reported in phase 2b and phase 3 studies in Japanese patients undergoing TKA [12,16] or THA [13,17,18], the incidence of any bleeding event (15/59; 25.4%) was higher than that reported for the edoxaban 30 mg treatment group in the phase 2b dose-rangingJapanese TKA study (10.7%, 11/103) [12]. These data suggest that the difference in overall bleeding rates observed in the current study may be attributed to higher rates of minor bleeding. The increased incidence of any bleeding event, primarily minor bleeding, may be due to the characteristics of patients undergoing HFS who were enrolled in this study; they were of lower body weight compared to the patients enrolled in the phase 2b TKA study (52.3 vs 60.1 kg, respectively) [12] and 40.7% had a creatinine clearance of < 50 mL/min. These patient characteristics, low body weight and decreased renal function, have been shown to increase edoxaban concentrations in patients with atrial fibrillation [19].
Additional safety assessments showed no clear differences in the incidence of AEs between the 2 treatment groups (72.9% and 82.8% in the edoxaban and enoxaparin groups, respectively). Among the common AEs observed in both treatment groups, none were specific to the edoxaban group, while elevated liver function tests occurred at a higher rate in the enoxaparin group. It should be noted that elevated serum transaminase levels are a recognized class-effect of heparins. These elevations are reversible and considered benign [20]. AEs not inclusive of bleeding or hepatic dysfunction were reported by 57.6% and 69.0% patients in the edoxaban and enoxaparin treatment groups, respectively, and therefore made up the majority of all AEs reported in this study.
The incidence of VTE was lower in the enoxaparin treatment group than observed in the edoxaban treatment group. All occurrences of VTE were asymptomatic distal DVT and the rate of VTE occurrence was comparable between the 2 groups. The rate of VTE in the edoxaban group in this study was low and similar to those reported in previous phase 2b and phase 3 Japanese LLOS studies [12,13,16,17]. The
Edoxaban Enoxaparin
At pre-surgical examination
Pre-treatment Day 7 of study Day 7 (1 to 3 hr Completion day of treatment post-dose) treatment
Edoxaban Enoxaparin
At pre-surgical Pre-treatment Day 7 of study Day 7 (1 to 3 hr Completion day of examination treatment post-dose) treatment
Edoxaban Enoxaparin
At pre-surgical examination
Pre-treatment
Day 7 of study treatment
Day 7 (i to 3 hr Completion day of post-dose) treatment
Fig. 2. Time course analyses3 ofPT, PT-INR, and aPTT. EDX = edoxaban; ENX = enoxaparin; PT = prothrombin time; PT-INR = prothrombin time expressed as international normalized ratio; aPTT = activated partial thromboplastin time. Pharmacodynamic analysis set. Error bars represent standard deviation.
incidence of VTE in a Japanese phase 3, placebo-controlled study of enoxaparin 2000 IU BID was 20.0% for THA patients and 29.8% for TKA patients [6]. As such, adequate prophylaxis of thromboembolic events was achieved in both edoxaban and enoxaparin groups in the present study.
Prolongation of mean edoxaban PT, PT-INR, and aPTT values were observed at 1 to 3 hours postdose on day 7 and coincide with a corresponding increase in mean edoxaban concentrations. The PD results observed in this study are very similar to those reported for the phase 2b Japanese TKA study [12].
Enoxaparin and fondaparinux have been evaluated in placebo-controlled, double-blind studies in Japanese patients undergoing major orthopedic surgery [6,7]. However, sc administration of enoxaparin and fondaparinux may involve clinical implications that can restrict their use in patients undergoing orthopedic surgeries. Additionally, the long-term use of enoxaparin or fondaparinux requires that patients be administered daily injections in an outpatient setting. This is often seen as an inconvenience and could lead to reduced patient compliance and decreased efficacy [8,9]. Edoxaban is the only new oral anticoagulant that has been studied for the prevention of VTE in patients undergoing HFS. Its ease of administration may offer an attractive thromboprophylactic option for patients who cannot tolerate or comply with enoxaparin or fondaparinux therapies.
This study does have some potential limitations. It was a small study, conducted only in 92 Japanese patients. The small study size does not provide power for a statistical comparison between groups. This study was in part designed to confirm that the edoxaban dose of 30 mg once daily, identified in phase 2b studies as the appropriate dose in Japanese patients undergoing TKA or THA [12,13], was also appropriate for patients undergoing HFS. As such, the sample size was set at 90 to ensure that a major or CRNM bleeding event would occur in at least 1 patient with an 80% or higher probability in either treatment group. Sixteen of 92 (17%) patients did not complete the study; the majority of reasons for discontinuation were voluntary withdrawal and ineligi-bility to continue in the study. However, 88 patients were included in the safety analysis set to assess the primary endpoint of major, CRNM, or minor bleeding.
Conclusions
The results of this study show that a once-daily oral dose of edoxaban 30 mg was comparable to sc enoxaparin 2000 1U BID with regards to the safety/efficacy balance for the prophylaxis of thromboembolic events in patients who underwent HFS for medial or lateral femoral neck fracture. This study, along with phase 3 studies in patients undergoing TKA or THA, provided data that led to the approval in Japan of once-daily, oral edoxaban 30 mg for the prevention of VTE in patients undergoing LLOS [21].
Conflict of Interest Statement
T. Fuji has been a consultant for Daiichi Sankyo, Bayer, Astellas, GlaxoSmithKline, Kaken, and Ono Pharmacy, and also has received Royalties from Century Medical and Showa Ikakogyo. S. Fujita has been a consultant for Daiichi Sankyo, Astellas, and GlaxoSmithKline. Y. Kawai has been a consultant for Daiichi Sankyo and Toyama Chemical. M. Nakamura has been a consultant for Daiichi Sankyo. S. Tachibana has been a consultant for Daiichi Sankyo and GlaxoSmithKline. T. Kimura, Y. Kiuchi, and K. Abe are employees of Daiichi Sankyo Co., Ltd.
Acknowledgements
This study (ClinicalTrials.gov Identifier: NCT01181141) was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). The study sponsors were involved in the design of the study and the analysis of the data. Editorial support was provided by Deepa Mothey, PhD, and Meryl Gersh, PhD, of AlphaBioCom, LLC (King of Prussia, PA, USA).
Appendix
Thromboembolic Event Assessment Committee: H. Nakamura, K. Nakamura, S. Fujita, S. Nakata; The Bleeding Event Assessment Committee: S. Fujita, Y. Kawai; Study Investigators: Y. Kamo, K. Asami, T. Kontani, H. Matsumoto, S. Katsuo, H. Seki, S. Kitamura, T. Sato, T. Yamakawa, M. Kakiuchi, S. Nozaki, Y. Tsukamoto, S. Ishii, T. Tsujimura, I. Nakayama, S. Kuratsu, H. Nagano, T. Mae, Y. Doiguchi, K. Akasaki, T. Ikeda, M. Nagayama, S. Shirota; Sponsor Representatives: T. Kimura (Project Leader), Y. Kiuchi (Study Leader), K. Abe (statistician).
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