Ximelagatran versus Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty

Ximelagatran versus Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty

A Randomized, Double-Blind Trial

From University of Rochester School of Medicine and Dentistry, Rochester, New York; University of Washington School of Medicine and Swedish Medical Center, Seattle, Washington; AstraZeneca, Wilmington, Delaware; University of Pennsylvania, Philadelphia, Pennsylvania; McMaster University, Hamilton, Ontario, Canada; University of California, Los Angeles, Los Angeles, California; and Scripps Clinic and Research Foundation, La Jolla, California.

Abstract

Background: Warfarin is used for prophylaxis of venous thromboembolism in patients undergoing total knee arthroplasty. However, it is associated with rates of deep venous thrombosis (DVT) of approximately 38% to 55% and requires routine coagulation monitoring and frequent dose adjustment. Ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and tolerability in patients undergoing total hip or knee arthroplasty.

Objective: To compare the efficacy and safety of ximelagatran and warfarin for prophylaxis of venous thromboembolism after total knee arthroplasty.

Design: Randomized, double-blind, parallel-group trial.

Setting: 74 North American hospitals.

Patients: 680 patients who had undergone total knee arthroplasty.

Intervention: 7 to 12 days of treatment with oral ximelagatran, 24 mg twice daily, starting on the morning after surgery, or warfarin (target international normalized ratio, 2.5 [range, 1.8 to 3.0]), starting on the evening of the day of surgery.

Measurements: Principal end points were asymptomatic DVT on mandatory venography; symptomatic DVT confirmed by ultrasonography or venography; symptomatic, objectively proven pulmonary embolism; and bleeding. All were assessed by blinded adjudication locally and at a central study laboratory.

Results: On central adjudication, incidence of venous thromboembolism was 19.2% (53 of 276 patients) in the ximelagatran group and 25.7% (67 of 261 patients) in the warfarin group (difference, −6.5 percentage points [95% CI, −13.5 to 0.6 percentage points]; P = 0.070). On local assessment, incidence was 25.4% in the ximelagatran group and 33.5% in the warfarin group (P = 0.043). In the ximelagatran and warfarin groups, respectively, major bleeding occurred in 1.7% and 0.9% of patients and minor bleeding occurred in 7.8% and 6.4% of patients. No variables related to bleeding differed significantly between the two groups.

Conclusions: For prophylaxis of venous thromboembolism, fixed-dose ximelagatran started the morning after total knee arthroplasty is well tolerated and at least as effective as warfarin, but it does not require coagulation monitoring or dose adjustment.

Article and Author Information

Potential Financial Conflicts of Interest:Employment: S.D. Berkowitz, A.K. Webster, J.P. Whipple, G.R. Peters; Consultancies: C.W. Francis, B.L. Davidson, S.D. Berkowitz, P.A. Lotke, J.S. Ginsberg, J.R. Lieberman; Honoraria: C.W. Francis, B.L. Davidson, S.D. Berkowitz, J.R. Lieberman; Stock ownership: S.D. Berkowitz, A.K. Webster; Grants received: J.S. Ginsberg, C.W. Colwell Jr.
Requests for Single Reprints: Charles W. Francis, MD, Hematology/Oncology Unit, Department of Medicine, University of Rochester Medical Center, Box 610, 601 Elmwood Avenue, Rochester, NY 14642; e-mail, charles_francis{at}urmc.rochester.edu.
Current Author Addresses: Dr. Francis: Hematology/Oncology Unit, Department of Medicine, University of Rochester Medical Center, Box 610, 601 Elmwood Avenue, Rochester, NY 14642.
Dr. Davidson: University of Washington School of Medicine and Swedish Medical Center, 801 Broadway, Suite 915, Seattle, WA 98122.
Dr. Berkowitz, Ms. Webster, Mr. Whipple, and Dr. Peters: DCC2, 1800 Concord Pike, Wilmington, DE 19850.
Dr. Lotke: University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104.
Dr. Ginsberg: McMaster University Medical Centre, Room 3X28, 1200 Main Street West, Hamilton, Ontario L87 3Z5, Canada.
Dr. Lieberman: UCLA Medical Center, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095.
Dr. Colwell: Scripps Clinic, 10666 North Torrey Pines, La Jolla, CA 92037.
Author Contributions: Conception and design: C.W. Francis, B.L. Davidson, P.A. Lotke, J.S. Ginsberg, J.P. Whipple, G.R. Peters, C.W. Colwell Jr.
Analysis and interpretation of the data: C.W. Francis, B.L. Davidson, S.D. Berkowitz, P.A. Lotke, J.S. Ginsberg, J.R. Lieberman, J.P. Whipple, G.R. Peters, C.W. Colwell Jr.
Drafting of the article: C.W. Francis, B.L. Davidson, S.D. Berkowitz, P.A. Lotke, J.S. Ginsberg, G.R. Peters.
Critical revision of the article for important intellectual content: C.W. Francis, B.L. Davidson, S.D. Berkowitz, P.A. Lotke, J.R. Lieberman, G.R. Peters, C.W. Colwell Jr.
Final approval of the article: C.W. Francis, B.L. Davidson, P.A. Lotke, J.S. Ginsberg, J.R. Lieberman, G.R. Peters, C.W. Colwell Jr.
Provision of study materials or patients: B.L. Davidson, P.A. Lotke.
Statistical expertise: B.L. Davidson, J.P. Whipple.
Obtaining of funding: G.R. Peters.
Administrative, technical, or logistic support: B.L. Davidson, A.K. Webster, G.R. Peters.
Collection and assembly of data: B.L. Davidson, S.D. Berkowitz, G.R. Peters.