Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.
BACKGROUND
In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin.


METHODS
This randomized, double-blind trial compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures.


RESULTS
Among the 1851 patients in the efficacy analysis, oral ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thromboembolism and death from all causes (20.3 percent vs. 27.6 percent; P=0.003). There were no significant differences between these two groups with respect to major bleeding (incidence, 0.8 percent and 0.7 percent, respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7 percent vs. 4.1 percent; P=0.17).


CONCLUSIONS
The efficacy of oral ximelagatran, administered starting the morning after total knee replacement, was superior to that of warfarin for prevention of venous thromboembolism. Rates of hemorrhagic complications with the two drugs were similar.
Department of Medicine, University of Rochester, Rochester, NY, USA. charles_francis@urmc.rochester.edu
Charles W
CW
Francis
Scott D
SD
Berkowitz
Philip C
PC
Comp
Jay R
JR
Lieberman
Jeffrey S
JS
Ginsberg
Guy
G
Paiement
Gary R
GR
Peters
Anne W
AW
Roth
Jennifer
J
McElhattan
Clifford W
CW
Colwell
D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D019645:Arthroplasty, Replacement, Knee; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001596:Benzylamines; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000517:prevention & control; D013923:Thromboembolism / Q000517:prevention & control*; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000453:epidemiology / Q000517:prevention & control; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C426686:ximelagatran; D014859:Warfarin