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Clinical Trials and Regulatory Science in Cardiology
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Efficacy Study of the COmbination of Edoxaban and Physiotherapy on the PRevention ofVenous-Thromboembolism in patients after Total Knee Arthroplasty (ESCORT-TKA Trial): Study protocol for a randomized controlled trial
Daisuke Sueta a, Koichi Kaikita a'*, Nobukazu Okamoto b, Soichiro Yamabe b, Masanobu Ishiia, Yuichiro Arima a,
Miwa Ito a, Yu Oimatsu a, Satomi Iwashita a, Aya Takahashia, Kenji Sakamoto a, Kenichi Tsujita a,
Eiichi Nakamura b, Seiji Hokimoto a, Hiroshi Mizuta b, Hisao Ogawa a, for the ESCORT-TKA study investigators
a Department of Cardiovascular Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan b Orthopedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
ARTICLE INFO ABSTRACT
Background: Deep vein thrombosis (DVT) after total knee arthroplasty (TKA) often results in a fatal pulmonary thromboembolism (PTE). Edoxaban is an activated factor X inhibitor, which has been shown to prevent thromboembolic events in venous thromboembolism (VTE). Recently, the Total-Thrombus-formation Analysis System (T-TAS™), a microchip-based flow chamber system capable of evaluating thrombogenicity, was developed. In this study, utilizing the T-TAS™, we will examine the incidence of VTE after TKA and evaluate how thromboses form.
Methods/design: This study will be a prospective, single-center, open-label, randomized, controlled clinical trial aimed at exploring the efficacy of edoxaban in reducing the incidence of VTE after TKA. A total of 80 patients who will undergo TKA will be randomly and evenly divided into groups receiving edoxaban plus physiotherapy or physiotherapy alone. The primary outcome measures will include the incidence rate of VTE as detected by ultrasonography 7 days after TKA and the changes in T-TAS™ parameters. The secondary outcome measures will include the changes in prothrombin time and activated partial thromboplastin time, incidence of major/minor bleeding events and adverse effects of edoxaban.
Discussion: This study will provide clinical evidence on the combined efficacy and safety of edoxaban and physiotherapy compared with that of physiotherapy alone. This is will be the first prospective trial designed to explore how thrombus formation after TKA can be predicted by the T-TAS™.
© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Article history: Received 2 February 2016 Accepted 2 May 2016 Available online xxxx
Keywords:
Randomized controlled trial Total knee arthroplasty Venous thromboembolism
1. Introduction
One of the major complications after orthopedic surgery is venous thromboembolism (VTE). In addition, fetal pulmonary thromboembolism (PTE) often occurs in this surgery. It is thought that most occurrences of PTE are derived from a deep vein thrombosis (DVT). It has been reported that PTE occurs in 50-60% [1,2] of DVT patients and that DVT occurs in 50-80% [3,4] of symptomatic VTE patients. It is important to inhibit the occurrence of PTE and prevent its origin from DVT.
According to Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (Japanese Circulation Society 2009) [5], the incidence rates of DVT in total knee
* Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
E-mail address: kaikitak@kumamoto-u.ac.jp (K. Kaikita).
arthroplasty (TKA) are high, and TKA is considered to be as high a risk factor for VTE as total hip arthroplasty (THA) and hip fracture surgery (HFS). The prevention of VTE due to these high-risk operations by physiotherapy has been recommended, including by the use of elastic stockings [6,7] or intermittent pneumatic compression (IPC) [8-11]. Although the merit of physiotherapy is that there is no possibility of bleeding, the efficacy of physiotherapy is lower than that of anticoagulation therapy [12].
Edoxaban (DU-176b, trade names: Savaysa® and Lixiana®, Daiichi Sankyo, Inc.) is an oral direct factor Xa (FXa) inhibitor [13, 14], which has been shown to be effective in the treatment and prevention of thromboembolic events in atrial fibrillation [15] and VTE [16,17]. A multicenter, phase II study in patients undergoing TKAdem-onstrated that edoxaban was safe and effective for thromboprophylaxis across a wide range of doses [18]. The phase III study (the Studying Thrombosis After Replacement Surgery (STARS) E-3 Trial) demonstrated that edoxaban (30 mg, once daily) was more effective for
http: //dx.doi.org/10.1016/j.ctrsc.2016.05.008
2405-5875/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/40/).
thromboprophylaxis than subcutaneous enoxaparin (2000 IU, twice daily) following TKA and demonstrated a similar incidence of bleeding events in Japanese and Taiwanese patients [19]. However, the evaluations of VTE in edoxaban clinical development tests have been performed using venography, and VTE has not been evaluated by ultrasonography or contrast-enhanced computed tomography (CT) scanning, which is what are used in real clinical situations.
Recently, the Total-Thrombus-formation Analysis System (T-TAS™) [20,21], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for the quantitative analysis ofthrombus formation. We have previously demonstrated the usefulness of the AR10-AUC30 levels determined by the T-TAS™ in distinguishing the pharmacological effects of edoxaban in patients undergoing TKA [22]. However, we did not compare these effects to the results from a control group (non-edoxaban-receiving group). Thus, the possibility that the operation affected the measured outcomes could not be ruled out.
In the present study, we will examine the potential benefits of a combination of edoxaban and physiotherapy on the incidence rate of DVT in the lower extremities following surgery utilizing ultrasonogra-phy and contrast-enhanced CT scanning. Moreover, we will evaluate how well thrombosis formation in the lower extremities following surgery is predicted using the T-TAS™. We will obtain data to test the hypothesis that this combined therapy can ameliorate the incidence rate of VTE in the lower extremities following surgery.
2. Methods/design
2.1. Study design
This study is a prospective, single-center (Kumamoto University Hospital, Kumamoto, Japan), open-label, randomized, controlled trial on the efficacy of edoxaban on preventing VTE in patients who have undergone TKA. Consecutive patients who will undergo TKA will be randomly and evenly assigned to groups receiving edoxaban plus physiotherapy or conventional physiotherapy alone. TKAs will be conducted at the Department of Orthopedic Surgery (Kumamoto University Hospital) as described in detail below. Ultrasonography of the operated lower limb will be performed 7 days after the TKA operation by examiners blinded to the treatment group. The study design is summarized in Fig. 1. This study has been registered at UMIN000020627, according to the statement of the International Committee of Medical Journal Editors.
Fig. 1. Flow chart. (T-TAS™; Total-Thrombosis Analysis System, US; ultrasonography).
22. Recruitment and consent
A target sample size of 80 patients who are scheduled to undergo TKA operations at the Department of Orthopedic Surgery in Kumamoto University Hospital will be recruited. All candidates will go through a standardized interview process and will receive more information about the study and the treatments. The purpose, procedures, and potential risks and benefits of the study will also be thoroughly explained to the participants. The participants will be able to withdraw from the study at any time without any consequences. The entire trial, including enrollment and follow-up, will be conducted from April 2015 to December 2016.
2.3. Ethical consideration
All procedures will be conducted in accordance with the Declaration of Helsinki and its amendments. The study protocol has been approved by the human ethics committee of Kumamoto University and written informed consent will be obtained from each patient or from the family of the patient.
2.4. Inclusion criteria
Participants meeting the following criteria will be included:
• Meet the diagnostic criteria for TKA.
• 16 to 85 years of age
• Willingness to give written informed consent and willingness to participate in, and comply with, the study
2.5. Exclusion criteria
Participants meeting one or more of the following criteria will be excluded:
• Emergent operation
• Serious infection
• Allergy to the drug used in the study
• Current thrombosis
• Taking any anti-thrombotic agents, including aspirin, P2Y12 inhibitor, warfarin, or non-vitamin-K oral anticoagulants (NOACs)
• Unwilling to give informed consent
All TKAs will be performed by the same surgeon, who will use a measured resection technique as previously reported in detail [23]. In brief, the patella will be not resurfaced. Using a mobile-bearing TKA (NexGen LPS Flex Mobile, Zimmer, Warsaw, IN), a device will be employed intra-operatively to place four 0.8-mm tantalum beads at predefined sites in a polyethylene insert. The Hospital for Special Surgery (HSS) score will be used for preoperative and postoperative clinical evaluations. Radiographic evaluations will be performed using standing AP radiographs for the tibiofemoral angle and the Knee Society rating system for component alignment [24].
2.7. Periprocedural anticoagulation regimen and collection of blood samples
Oral administration of edoxaban (30 mg, once daily) will be initiated from the second day after the TKA operation to prevent VTE, as described in the to The STARS E-3 Trial [25]. Blood samples will be obtained the day before (anticoagulant-free point) and 7 days after the TKA operation (trough point).
2.6. Interventions
Blood samples will be collected as previously described in detail [26]. Briefly, blood samples will be collected from the antecubital vein with a 21-gauge butterfly needle into the following containers: a hirudin blood tube (MP0600: Verum Diagnostica, Munich, Germany, final concentration of hirudin: 25 pg/mL), blood collection tubes (VP-CA050K70: Venoject II, Terumo, Japan), and a syringe containing 0.11 ml of 3.8% sodium citrate solution. Each sample will be immediately centrifuged at 1800 xg for 10 minutes (min) at room temperature and the plasma will be collected for biochemical analysis. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) will be measured using commercially available thromboplastin reagents (Coagupia®PT-N for PT; Coagupia®APTT-N for APTT, Sekisui Medical Co., Tokyo, Japan) according to the protocol supplied by the manufacturer.
2.8. Measurement of thrombogenicity by the T-TAS™
The T-TAS™ is an automated microchip-based flow chamber system developed for the easy and quick assessment of platelet thrombus formation under flow conditions [20,26,27] We have previously reported the details of the T-TAS™, including its appearance and components, and have established the validity of the methodology under NOACs use [22]. In brief, this system analyzes different processes of thrombus formation via a simple procedure that uses two microchips with different thrombogenic surfaces. One chip, the platelet (PL)-chip is coated with type I collagen. Inside the microchip, platelets adhere and aggregate on the surface of collagen, and the microchips capillaries are occluded. The other chip, the atheroma (AR)-chip, is coated with type I collagen plus tissue thromboplastin. Inside this microchip, the activation ofplatelets and the coagulation system are triggered simultaneously by collagen and tissue thromboplastin, respectively. The process of thrombus formation inside the two chips can be analyzed by monitoring the change in flow pressure. The area under the flow pressure curve (AUC) is then computed to assess platelet thrombogenicity inside the microchips. AUC10 (the AUC for the first 10 min for the PL-chip, tested at flow rate of 24 pL/min) is described as PL24-AUC10, and AUC30 (the AUC for the first 30 min for the AR-chip, tested at flow rate of 10 ^L/min) is described as AR10-AUC30. We have previously reported the details of the T-TAS™, including its appearance and components, as well as established the validity of the methodology in patients receiving vitamin K antagonist (VKA), NOACs [28] and antiplatelet agents [29].
2.9. Outcome measures
2.9.1. Primary outcome measure
The primary endpoint in determining treatment efficacy in this study will be the prevalence of VTE as shown by a 7 day follow-up ultra-sonography. Ifa symptomatic VTE or PTE is suspected based on signs or symptoms that occur during the period between the initiation of the drug treatment and the ultrasonography at the completion (discontinuation) of the administration of the drug, appropriate imaging will be performed to confirm the event. A suspected VTE will be evaluated by ultrasonography and contrast-enhanced CT scanning. A suspected PTE will be evaluated by contrast-enhanced CT scanning. A definite diagnosis of a symptomatic VTE or PTE will be based on the findings of this clinical imaging. Treatment compliance will be verified in a patient interview and by the assessment of residual drugs. The other primary endpoint in determining treatment efficacy will be the changes in T-TAS™ parameters.
2.9.2. Secondary outcome measures
The secondary endpoints in determining treatment efficacy will be the changes in PT and APTT levels the day before and 7 days after the TKA operation and the safety assessment described below.
2.9.3. Safety assessments
The safety outcomes will include the incidence of all bleeding events (major, clinically relevant non-major or minor bleeding), adverse events and adverse drug. Major bleeding will be defined as life-threatening bleeding, bleeding into critical organs (retroperitoneal, intracranial, intraocular or intraspinal), clinically overt bleeding that will be to a decrease in hemoglobin of >2 g dL-1 or required blood transfusion and/or required repeat surgery.
All subjects will be questioned about adverse events during the treatment at each visit, and all reported adverse events will be analyzed, regardless of the investigators' assessments of causality. Safety will be assessed by the following tests on all subjects: physical examination (including body weight, body surface temperature, blood pressure, heart rate, respiration), complete blood cell count, liver function (alanine aminotransferase (ALT), aspartate aminotransferase(AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and Y-glutamyl transpeptidase (y-GTP)), renal function (blood urea nitrogen (BUN), creatinine (Cr)), and coagulation tests (d-dimer, thrombin-antithrom-bin complex (TAT)) at baseline and at the 7 day follow-up.
2.9.4. Sample size calculation
Patients will randomly be assigned to edoxaban plus physiotherapy or physiotherapy only groups (1:1 ratio). We are planning a study of matched sets of patients receiving the experimental (edoxaban plus physiotherapy group) and control (physiotherapy only group) treatments and with 1 matched control(s) per experimental subject. Prior data indicate that the probability of a treatment failure among controls is 0.48 and the correlation coefficient for exposure between matched edoxaban plus physiotherapy group and physiotherapy only group is 0.388. If the true odds ratio for the incidence rate of VTE in physiotherapy only group relative to edoxaban plus physiotherapy group is 6.54 [18], we will need to study 33 experimental subjects with 1 matched control(s) per experimental subject to be able to reject the null hypothesis that this odds ratio equals 1 with probability (power) 0.9 ((3 = 0.9). The Type I error probability associated with this test of this null hypothesis is 0.05 (a = 0.05). The number of patients actually provides < 80% power, assuming a withdrawal rate of 20%. Therefore, we will recruit a total of 80 patients, 40 patients in each group.
2.10. Statistical analysis
Continuous variables will be described using means and standard deviations, or median and range in cases of an asymmetric distribution of the data. Categorical variables will be presented using frequency distributions. Univariate analyses will be conducted using chi-square tests and t-tests for comparing independent samples. Repeated-measures analysis of variance (ANOVA) will be used to analyze changes in the values of biomarkers, such as the T-TAS™ parameters and the PT and APTT levels between testing time points (baseline and day 7). Multiple logistic regression analyses will be performed as needed. Statistical significance will be considered for P < 0.05. All statistical analyses will be performed using SPSS software version 23 (IBM Corp. Armonk, NY).
3. Discussion
This study will provide clinical evidence for the efficacy of the combination of edoxaban and physiotherapy on preventing VTE in patients who will undergo TKA. Several studies have reported that NOACs, such as dabigatran [30,31], apixaban [32,33], rivaroxaban [34,35] and edoxaban [16,17] are beneficial because they significantly reduce the incidence rate of VTE after orthopedic surgery to a degree comparable to VKA but that there are less complications, such as major bleeding, than observed with VKA. However, few studies have examined the combined effect of NOAC and physiotherapy. Due to the lack of objective evidence, a well-designed, randomized, controlled trial is needed to examine the efficacy and safety of the combination of edoxaban and
physiotherapy on preventing VTE in patients undergoing TKA. Our present work will provide important evidence to determine if the combined use of edoxaban and physiotherapy exerts a synergistic effect on preventing VTE. Furthermore, utilizing the T-TAS™ to obtain a quantitative assessment of whole blood thrombogenicity, we will be able to provide data for the quantitative analysis of thrombus formation. Given that edoxaban and physiotherapy are both recommended for the prevention of VTE, our work will have important clinical implications and will determine if the combination of edoxaban and physiotherapy is a promising therapeutic strategy for preventing VTE in patients undergoing TKA.
Funding sources
This study was supported in part by Grants-in-Aid for Scientific Research (#15K09089) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Potential conflict of interest
Clinical trial registration
This study was registered in the UMIN protocol registration system (identification number UMIN000020627).
Trial status
Recruitment commenced in January 2016, and the trial will be scheduled to end in December 2016.
Acknowledgments
We thank Kazuya Hosokawa and Tomoko Ohnishi from the Research Institute, Fujimori Kogyo Co., Yokohama, Kanagawa, Japan, for their excellent technical support in the measurement of T-TAS™. We also thank all of the paramedical staff and clinical secretaries for their kind support during this work.
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