The Blood Saving Effect of Tranexamic Acid in Total Knee Arthroplasty With Rivaroxaban as Thromboprophylaxis

Study Overview
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Brief Summary
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The aim of this study was to conduct a prospective, randomized, double-blind study and assess the efficacy of and safety for thromboprophylaxis of rivaroxaban in total knee arthroplasty patients when tranexamic acid is used for bleeding prophylaxis.

Detailed Description
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Total knee arthroplasty is an effective procedure for end-stage arthritis of the knee in terms of pain relief and functional recovery. However, this procedure is associated with a substantial perioperative blood loss. As high as 69% allogeneic blood transfusion rate was reported in patients receiving total knee arthroplasty when preoperative haemoglabin level was <13 g/dl. Tranexamic acid (TXA), an antifibrinolytic, given intraoperatively, has been reported to be effective in reducing one third of postoperative blood loss in standard total knee arthroplasty. Our previous study showed that TXA reduced total blood loss from 1453mL to 833mL (p<0.001) and the need for transfusion from 20% to 4% (p=0.014) in total knee patients with enoxaparin (Clexane; Glaxo-Smith-Kline, Brentford, United Kindom) for thromboprophylaxis. In recent years, there have been more effective and practical methods for thrombophylaxis in total hip and knee replacement surgeries. Rivaroxaban is one of the first oral factor Xa inhibitors licensed for this regard. The advantages of rivaroxaban include oral administration, no need to monitor blood levels and no dosing adjustments which are convenient for short hospital stay in contemporary total knee arthroplasty. Its efficacy in preventing venous thromboembolism (VTE) after total knee arthroplasty have been extensitvely investigated in RECORD (Regulation of Coagulation in Orthopaedic surgery to prevent Deep-vein thrombosis and pulmonary embolism) 3 and 4 studies, and the results showed that rivaroxaban 10mg once daily was superior to enoxaparin 40mg subcutaneously once daily or 30mg every 12 hours for 10 to 14 days. Despite of its clinical efficacy in VTE prophylaxis, orthopaedic surgeons are still sceptic in routine use of rivaroxaban in knee and hip surgery and concerned about the increased risk of bleeding complications. A higher reoperation rate regarding wound complications within 30 days of hip and knee replacement in the rivaroxaban group than the tinzaparin group (2.94% versus 1.8%) was reported recently. Similar event has been reported in other studies. However, all these studies did not use TXA as bleeding prophylaxis after hip and knee replacement surgery. The risk of increasing VTE by use of TXA, owing to its antifibrinolytic effects, is the cause of concern. The aim of this study was to conduct a prospective, randomized, double-blind study and assess the efficacy of and safety for thromboprophylaxis of rivaroxaban in total knee arthroplasty patients when TXA is used for bleeding prophylaxis.

Official Title
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The Blood Saving Effect and Wound-related Complications of Tranexamic Acid in Mininally Invasive Total Knee Arthroplasty With Rivaroxaban as Thromboprophylaxis

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: Tranexamic Acid 5%,5ml/amp (intraoperative)
* Drug: Tranexamic Acid 5%,5ml/amp (3 hours after operation)
* Drug: 0.9% Normal Saline (intraoperative)
* Drug: 0.9% Normal Saline (3 hours after operation)
* Drug: rivaroxaban (10mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: End-stage arthritis of the knee Failure of medical treatment or rehabilitation Hemoglobin > 10g/dl No use of non-steroid anti-inflammatory agent one week before operation Exclusion Criteria: Preoperative Hemoglobin ≦10 g/dl History of infection or intraarticular fracture of the affective knee Renal function deficiency (GFR < 55 ml/min/1.73m2)which is relative contraindicated for venography Elevated liver enzyme, history of liver cirrhosis, impaired liver function and coagulopathy (including long-term use anticoagulant) History of deep vein thrombosis, ischemic heart disease or stroke

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Group<br>Primary total knee replacement with 0.9% normal saline 20ml administration intravenously twice, five minutes before deflation of the tourniquet and 3 hours after operation Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14 for VTE prophylaxis | Drug: 0.9% Normal Saline (intraoperative)<br>* 0.9% Normal Saline 20ml administered intravenously five minutes before deflation of the tourniquet<br>* Other names: 0.9% sodium chloride;Drug: 0.9% Normal Saline (3 hours after operation)<br>* 0.9% Normal Saline 20ml administered intravenously 3 hours after operation<br>* Other names: 0.9% Normal Saline;Drug: rivaroxaban (10mg)<br>* Oral rivaroxabam (10mg) QD on PostOp Day 1 to 14<br>* Other names: Xarelto;|
| Active Comparator: One-dose TXA Group<br>Primary total knee replacement with 1 g Tranexamic Acid 5%,5ml/amp administrated intravenously five minutes before deflation of the tourniquet. and then 0.9% normal saline 20ml administration intravenously 3 hours after operation Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14 for VTE prophylaxis | Drug: Tranexamic Acid 5%,5ml/amp (intraoperative)<br>* tranexamic acid 1g administered intravenously five minutes before deflation of the tourniquet<br>* Other names: Transamine;Drug: 0.9% Normal Saline (3 hours after operation)<br>* 0.9% Normal Saline 20ml administered intravenously 3 hours after operation<br>* Other names: 0.9% Normal Saline;Drug: rivaroxaban (10mg)<br>* Oral rivaroxabam (10mg) QD on PostOp Day 1 to 14<br>* Other names: Xarelto;|
| Active Comparator: Two-dose TXA Group<br>Primary total knee replacement with 1 g Tranexamic Acid 5%,5ml/amp administrated intravenously twice, five minutes before deflation of the tourniquet and 3 hours after operation Oral rivaroxaban (10mg) QD on PostOp Day 1 to 14 for VTE prophylaxis | Drug: Tranexamic Acid 5%,5ml/amp (intraoperative)<br>* tranexamic acid 1g administered intravenously five minutes before deflation of the tourniquet<br>* Other names: Transamine;Drug: Tranexamic Acid 5%,5ml/amp (3 hours after operation)<br>* tranexamic acid 1g administered intravenously 3 hours after operation<br>* Other names: Transamine;Drug: rivaroxaban (10mg)<br>* Oral rivaroxabam (10mg) QD on PostOp Day 1 to 14<br>* Other names: Xarelto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of any deep-vein thrombosis, non-fatal pulmonary embolism, or all-cause mortality | Primary efficacy outcome is the composite of any deep-vein thrombosis, non-fatal pulmonary embolism, or all-cause mortality | within 15 days after surgery (2 days after the last dose of rivaroxaban ) | 
| Incidence of major bleeding after the first dose of rivaroxaban and all death related to postoperative bleedings | Primary safety outcome is the composite of major bleeding after the first dose of rivaroxaban and all death related to postoperative bleedings. Major bleeding was defined as bleeding that was fatal, that involved a critical organ, or that required reoperation or clinically overt bleeding outside the surgical site that was associated with a decrease in the hemoglobin level of 2 g or more per deciliter or requiring infusion of 2 or more units of blood | within 15 days after surgery (2 days after the last dose of rivaroxaban ) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of major venous thromboembolism | The secondary efficacy outcomes include major venous thromboemolism defined as the composite of proximal deep-vein thrombosis, non-fatal pulmonary embolism, and VTE related death | within 15 days after surgery (2 days after the last dose of rivaroxaban | 
| Secondary safety outcome was composite of any non-major bleeding and all wound complications after operation | Non-major bleeding including hemorrhagic wound complications (excessive wound hematoma or bleeding at the surgical site | within 15 days after surgery (2 days after the last dose of rivaroxaban | 
| Incidence of wound complications after surgery | composite of hematoma, superficial wound infection, and deep infection requiring return to surgery | within 30 days of the procedure | 
| Total blood loss after surgery | Total blood loss was calculated according to Nadler et al., which used maximum postoperative reduction of the Hb level adjust for weight and height of the patient. The formula is as follows, Total blood loss = (Total blood volume x [change in Hb level / preoperative Hb level])x1000+volume transfused | From the operation to the postoperative day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic Acid, Total Knee Arthroplasty, Rivaroxaban