Aims: To investigate the efficacy and safety of a new dosage regimen of the oral direct thrombin inhibitor ximelagatran, and its subcutaneous (sc) form melagatran, started in close proximity to surgery. Methods: In a randomised, double-blind, parallel-group study, duration 8–11 days, patients undergoing total hip or knee replacement (THR, n= 1856; TKR, n= 908) received either sc melagatran 2 mg immediately before surgery followed by sc 3 mg in the evening after surgery, and then by oral ximelagatran 24 mg bid as a fixed dose (the ximelagatran group), or sc enoxaparin 40 mg od, started the evening before surgery. Bilateral venography was performed on the final day of treatment. Results: The rate of proximal deep vein thrombosis plus pulmonary embolism was 2.3% in the ximelagatran group vs. 6.3% in the enoxaparin group (p< 0.000002; RRR 63.2%). The total rates of venous thromboembolism (VTE) were 20.3% vs. 26.6%, respectively (p< 0.0003; RRR 23.6%). Cases with symptomatic VTE were rare: 8 in the ximelagatran group and 12 in the enoxaparin group. Bleeding events were more common in the ximelagatran group compared with the enoxaparin group (3.3% vs. 1.2%) as were the transfusion rates (66.8% vs. 61.7%). Importantly, there were no differences in fatal bleeding, critical organ bleeding or bleeding requiring re-operation. Conclusion: Pre-operatively initiated sc melagatran followed by oral ximelagatran was superior in efficacy to enoxaparin in preventing VTE in patients undergoing THR or TKR.

Ximelagatran is an oral direct thrombin inhibitor intended for the prophylaxis and treatment of thrombo-embolic complications. Purpose: The efficacy and safety of ximelagatran, and its subcutaneous (sc) form melagatran, were evaluated in patients undergoing total hip or knee replacement (THR, TKR). Study 1 was a randomised, double-blind, controlled, dose–response study in which patients received 2-6 doses of sc melagatran (1, 1.5, 2.25, or 3 mg bid) followed by oral ximelagatran (8, 12, 18, or 24 mg bid), or sc dalteparin (5000 IU od). Melagatran treatment was initiated immediately before surgery. Study 2 was a randomized, double-blind, controlled study in which patients received 1–5 doses of sc melagatran (3 mg bid) initiated 4–12 h after surgery followed by oral ximelagatran (24 mg bid), or sc enoxaparin (40 mg od). In both studies, low-molecular-weight heparin (LMWH) was started the evening before surgery, and all treatment regimens were continued for 8–11 days. Bilateral venography was performed on the final day of treatment.

Results: In Study 1, 1876 patients underwent THR (n=1270) or TKR (n=606). A significant dose-dependent reduction in venous thromboembolism (VTE) was seen with melagatran + ximelagatran for both THR (P< 0.0001) and TKR (P=0.0014). The rate of VTE was significantly lower with the highest dose of melagatran + ximelagatran (15.1%) when compared with dalteparin (28.2%) (P< 0.0001). In Study 2, 2788 patients underwent THR (n=1923) or TKR (n=865). The VTE rate was 31% in the melagatran + ximelagatran group and 27% in the enoxaparin group (P=0.053). Total bleeding volume was not significantly different between treatment groups. Conclusion: Fixed-dose sc melagatran followed by oral ximelagatran are efficacious and well tolerated for the prophylaxis of VTE following THR or TKR.