Clinical experience of melagatran/ximelagatran in major orthopaedic surgery

Abstract

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.