Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial

Charles W Francis, Bruce L Davidson, Scott D Berkowitz, Paul A Lotke, Jeffrey S Ginsberg, Jay R Lieberman, Anne K Webster, James P Whipple, Gary R Peters, Clifford W Colwell
Annals of Internal Medicine 2002 October 15, 137 (8): 648-55

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.

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