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Fixed-Dose Ximelagatran as Safe, More Effective Than Warfarin for Postoperative Thromboprophylaxis

The efficacy of oral fixed-dose ximelagatran is superior to that of warfarin for thromboprophylaxis after total knee replacement, according to a new study.

Warfarin is the most commonly used pharmacologic prophylaxis after total knee replacement in North America. However, warfarin has a delayed onset of action, requires monitoring of coagulation and dose adjustment, and has multiple interactions with food and drugs.

Alternatively, initial studies have shown ximelagatran, an orally administered direct thrombin inhibitor, to have good efficacy and safety in the prevention of venous thromboembolism after total knee or total hip replacement. Unlike warfarin, ximelagatran is rapidly absorbed and converted to active form, and appears to have no clinically relevant interactions with food or drugs.

Previous studies suggest that ximelagatran is safe in a wide dose range, and is comparable in efficacy to warfarin at a dose of 24 mg twice daily. To determine whether a higher dose of ximelagatran is superior to warfarin, Charles W. Francis, MD, of the University of Rochester, New York, United States, and colleagues performed a comparative study in 1851 patients undergoing total knee replacement.

Patients were randomised to receive a 7 to 12 day postoperative regimen of oral ximelagatran, 24 mg or 36 mg twice daily, or warfarin therapy, with a target international normalised ratio of 2.5.

Analysis showed that with respect to the primary composite end point of venous thromboembolism and death from all causes, oral ximelagatran at a dose of 36 mg twice daily (20.3%) was superior in efficacy to warfarin (27.6 %).

Rates of hemorrhagic complications with the 2 drugs were similar, with no significant differences observed with respect to major bleeding, perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death.

"The results of our study indicate that fixed-dose ximelagatran, administered without coagulation monitoring, was significantly more effective than warfarin and had similar safety," say the researchers. "It could therefore be considered as an alternative to other available thromboprophylactic agents."

The research was supported by AstraZeneca, maker of Exanta (ximelagatran).


N Engl J Med 2003 Oct 30;349:18:1703-12. "Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement"

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