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Ximelagatran Superior to Warfarin for Prevention of Venous Thromboembolism Following Total Knee Replacement Surgery

Oral ximelagatran prevented venous thromboembolism after total knee replacement surgery, at rates that were superior to those from warfarin therapy. A previous study showed a lower-dose ximelagatran regimen was similar to warfarin therapy for post-total-knee-replacement prevention of venous thromboembolism.

Charles W. Francis, MD, of the University of Rochester Medical Center, New York, United States, and fellow investigators with the Exanta Used to Lessen Thrombosis A (EXANTA) Study Group conducted a prospective, randomised, double-blind trial comparing 7 to 12 days of 24 mg or 36 mg ximelagatran with warfarin for the prevention of venous thromboembolism in 2301 patients who had undergone total knee replacement surgery at 116 centres in the United States, Canada, Israel, Mexico, and Brazil.

Patients in the twice daily ximelagatran groups started therapy the morning after surgery. Patients the warfarin group started therapy the evening of the day of surgery and continued each subsequent evening at a dose adjusted to achieve an international normalized ratio (INR) of 2.5. Baseline characteristics of the study population were similar, and 92% of the patients who underwent randomisation completed the study.

The investigators report that 20.3% and 24.9% of the 36 mg and 24 mg ximelagatran groups, respectively, compared with 27.6% of patients in the warfarin group experienced a composite of venous thromboembolism and death from all causes among the 1851 patients included in the efficacy analysis.

A total of 80.7% of the patients had venography adequate for evaluation. These analyses revealed total deep-vein thrombosis in 19.8% of the 36 mg ximelagatran group, 24.7% of the 24 mg ximelagatran group, and in 27.4% of the warfarin group, with the majority of these events due to distal deep-vein thrombosis. The rates of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism were low in all treatment groups and did not differ significantly between the 36 mg ximelagatran group and the warfarin group.

Of the patients receiving ximelagatran, 6 in each dosage group experienced major bleeding during treatment, compared with 5 patients receiving warfarin. One patient in the 36 mg ximelagatran group died after developing gastric-ulcer bleeding. The investigators report the most common post-operative complication was anaemia, which occurred in 8% to 10% of the patients in each of the 3 groups, and report no appreciable differences between the 3 treatment groups with respect to other adverse events. Also, there were no significant differences between treatment groups in bleeding, appearance, or treatment complications of the patients" wounds.

The authors conclude, "fixed-dose ximelagatran, administered without coagulation monitoring, was significantly more effective than warfarin," in this patient population.

N Engl J Med 2003;349:1703-12.

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