Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement - A phase 2 dose-finding study

Background: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular- weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of fre e and clot-bound thrombin. Methods: We performed a randomized, parallel, dose-finding study of 600 adu lts undergoing elective total knee replacement at 68 North American hospita ls to determine the optimum dose of ximelagatran to use as prophylaxis agai nst venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 1 8, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice da ily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venogr aphic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. Results: A total of 594 patients received at least I dose of the study drug ; 443 patients were evaluable for efficacy. Rates of overall venous thrombo embolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%) , 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thr omboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolis m (3.1%) for enoxaparin did not differ significantly compared with 24-mg xi melagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4 .2%; P=.3). There was no major bleeding with administration of 24 mg of xim elagatran twice daily. Conclusion: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against ven ous thromboembolism after total knee replacement.