Ximelagatran in Orthopaedic Surgery

Abstract

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.

Use and Misuse of Surrogate Outcomes in Arrhythmia Trials

“…Information provided relatively efficiently in this clinical setting can provide some guidance for the design of the megatrials required to demonstrate efficacy and safety for stroke prevention in atrial fibrillation. 4,5 Thus, surrogate outcomes are useful in numerous settings, but we must be wary of our assumptions and test them when possible.…”

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

“…Excessive bleeding as judged by the investigator was more frequent with melagatran/ximelagatran than enoxaparin. The EXPRESS study conclude that in patients undergoing total hip or knee replacement pre-operative melagatran/ximelagatran treatment was more effective in preventing VTE than preoperative enoxaparine [113][114][115][116][117].…”