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

Osteoarthritis, Knee Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02458729
• Other study ID #: NMRPG8B6181
• Status: Completed
• Phase: Phase 4
• First received: May 28, 2015
• Last updated: May 28, 2015
• Start date: August 2012
• Est. completion date: July 2014

Study information

• Verified date: May 2015
• Source: Chang Gung Memorial Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Taiwan: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 294
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Osteoarthritis, Knee

Intervention

Drug:
• Tranexamic Acid 5%,5ml/amp (intraoperative)
tranexamic acid 1g administered intravenously five minutes before deflation of the tourniquet
• Tranexamic Acid 5%,5ml/amp (3 hours after operation)
tranexamic acid 1g administered intravenously 3 hours after operation
• 0.9% Normal Saline (intraoperative)
0.9% Normal Saline 20ml administered intravenously five minutes before deflation of the tourniquet
• 0.9% Normal Saline (3 hours after operation)
0.9% Normal Saline 20ml administered intravenously 3 hours after operation
• rivaroxaban (10mg)
Oral rivaroxabam (10mg) QD on PostOp Day 1 to 14

Locations

Country	Name	City	State
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Koahsiung

Sponsors (1)

Lead Sponsor	Collaborator
Chang Gung Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (23)

Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am. 1999 Jan;81(1):2-10. — View Citation

Clagett GP, Anderson FA Jr, Geerts W, Heit JA, Knudson M, Lieberman JR, Merli GJ, Wheeler HB. Prevention of venous thromboembolism. Chest. 1998 Nov;114(5 Suppl):531S-560S. Review. — View Citation

Friedman RJ, Gallus AS, Cushner FD, Fitzgerald G, Anderson FA Jr; Global Orthopaedic Registry Investigators. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008 Jan;24(1):87-97. — View Citation

Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S. doi: 10.1378/chest.08-0656. — View Citation

Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, Wheeler HB. Prevention of venous thromboembolism. Chest. 2001 Jan;119(1 Suppl):132S-175S. Review. — View Citation

Haas SB, Cook S, Beksac B. Minimally invasive total knee replacement through a mini midvastus approach: a comparative study. Clin Orthop Relat Res. 2004 Nov;(428):68-73. — View Citation

Hiippala S, Strid L, Wennerstrand M, Arvela V, Mäntylä S, Ylinen J, Niemelä H. Tranexamic acid (Cyklokapron) reduces perioperative blood loss associated with total knee arthroplasty. Br J Anaesth. 1995 May;74(5):534-7. — View Citation

Ido K, Neo M, Asada Y, Kondo K, Morita T, Sakamoto T, Hayashi R, Kuriyama S. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg. 2000;120(9):518-20. — View Citation

Jameson SS, Bottle A, Malviya A, Muller SD, Reed MR. The impact of national guidelines for the prophylaxis of venous thromboembolism on the complications of arthroplasty of the lower limb. J Bone Joint Surg Br. 2010 Jan;92(1):123-9. doi: 10.1302/0301-620X.92B1.22751. — View Citation

Jameson SS, Rymaszewska M, Hui AC, James P, Serrano-Pedraza I, Muller SD. Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb arthroplasty. J Bone Joint Surg Am. 2012 Sep 5;94(17):1554-8. — View Citation

Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement, before and after the introduction of rivaroxaban: a retrospective cohort study. J Bone Joint Surg Br. 2011 Jan;93(1):91-5. doi: 10.1302/0301-620X.93B1.24987. — View Citation

Kambayashi J, Sakon M, Yokota M, Shiba E, Kawasaki T, Mori T. Activation of coagulation and fibrinolysis during surgery, analyzed by molecular markers. Thromb Res. 1990 Oct 15;60(2):157-67. — View Citation

Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. doi: 10.1056/NEJMoa076016. — View Citation

Lin PC, Hsu CH, Chen WS, Wang JW. Does tranexamic acid save blood in minimally invasive total knee arthroplasty? Clin Orthop Relat Res. 2011 Jul;469(7):1995-2002. doi: 10.1007/s11999-011-1789-y. Epub 2011 Feb 1. — View Citation

Lin PC, Hsu CH, Huang CC, Chen WS, Wang JW. The blood-saving effect of tranexamic acid in minimally invasive total knee replacement: is an additional pre-operative injection effective? J Bone Joint Surg Br. 2012 Jul;94(7):932-6. doi: 10.1302/0301-620X.94B7.28386. — View Citation

Lotke PA. Rivaroxaban for thromboprophylaxis. N Engl J Med. 2008 Nov 13;359(20):2174; author reply 2175-6. — View Citation

Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962 Feb;51(2):224-32. — View Citation

Patel VP, Walsh M, Sehgal B, Preston C, DeWal H, Di Cesare PE. Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am. 2007 Jan;89(1):33-8. — View Citation

Petäjä J, Myllynen P, Myllylä G, Vahtera E. Fibrinolysis after application of a pneumatic tourniquet. Acta Chir Scand. 1987 Nov-Dec;153(11-12):647-51. — View Citation

Prevention of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol. 1997 Mar;16(1):3-38. Review. — View Citation

Tanaka N, Sakahashi H, Sato E, Hirose K, Ishima T, Ishii S. Timing of the administration of tranexamic acid for maximum reduction in blood loss in arthroplasty of the knee. J Bone Joint Surg Br. 2001 Jul;83(5):702-5. — View Citation

Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-80. doi: 10.1016/S0140-6736(09)60734-0. Epub 2009 May 4. — View Citation

Warwick D, Dahl OE, Fisher WD; International Surgical Thrombosis Forum. Orthopaedic thromboprophylaxis: limitations of current guidelines. J Bone Joint Surg Br. 2008 Feb;90(2):127-32. doi: 10.1302/0301-620X.90B2.20106. Review. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of venographic positive deep-vein thrombosis (any, proximal, distal)		on the second day after last dose of rivaroxaban (POD 15)	No
Other	Incidence of positive finding of pulmonary embolism by computed tomography	In case of suspected pulmonary embolism, computed tomography of the chest was performed	on the second day after last dose of rivaroxaban (POD 15)	No
Primary	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 )	No
Primary	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 )	Yes
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes