Background: Warfarin, which requires coagulation monitoring, is
associated with relatively high rates of thromboembolism despite providing
adequate prophylaxis. This study compared an oral direct thrombin inhibitor,
ximelagatran, with warfarin in order to evaluate the safety and efficacy of
the medication for the prevention of venous thromboembolism in patients
undergoing total knee arthroplasty.
Methods: Following surgery, patients were randomly assigned to
fixed-dose oral ximelagatran (36 mg twice daily) or warfarin (target
international normalized ratio, 2.5), both administered for seven to twelve
days in a double-blind, double-dummy design. Warfarin was initiated on the
evening of the day of surgery, and ximelagatran, on the morning after surgery.
The primary efficacy end point was the incidence of asymptomatic deep-vein
thrombosis determined by bilateral venography, objectively confirmed
symptomatic deep-vein thrombosis or pulmonary embolism, and death from all
causes during treatment.
Results: Adequate venograms or confirmed symptomatic events
(efficacy population) were obtained for 1949 patients. Venous thromboembolism
and death from all causes occurred in 22.5% (221) of 982 ximelagatran-treated
patients and in 31.9% (308) of 967 warfarin-treated patients (p < 0.001).
Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1%
(thirty) and 0.2%, respectively, of the patients in the ximelagatran group and
in 3.4% (thirty-three) and 0.4%, respectively, of the patients in the warfarin
group. The six deaths from all causes included 0.3% (four) of the
ximelagatran-treated patients and 0.2% (two) of the warfarin-treated patients.
Major bleeding was noted in 1% (twelve) of the ximelagatran-treated patients
and in 0.4% (five) of the warfarin-treated patients (p = 0.09).
Conclusions: Oral ximelagatran (36 mg twice daily), administered
without coagulation monitoring or dose adjustment and started the day after
total knee arthroplasty, demonstrates superior efficacy compared with warfarin
prophylaxis, with no wound complications and no significant difference with
respect to bleeding events, although the rate of major bleeding events was
greater with ximelagatran than with warfarin.
Level of Evidence: Therapeutic Level I. See Instructions
to Authors for a complete description of levels of evidence.