Ximelagatran/Melagatran

Abstract

Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time. The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients. Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.