Patients undergoing major lower-extremity
orthopedic surgery such as
total hip replacement (THR) and
total knee replacement (TKR) are at an increased risk of
venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of
deep vein thrombosis (DVT), which may progress to potentially fatal
pulmonary embolism and secondary complications such as
postthrombotic syndrome, recurrent DVT, and chronic
pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves
anticoagulant treatment with either
low-molecular-weight heparin (
LMWH) or
warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as
obesity,
cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter
hospital stays, making practicality of treatment an important consideration.
LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting.
Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new
anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved
anticoagulant,
fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with
LMWH, but this agent requires parenteral administration and does not overcome the convenience issue.
Ximelagatran is the oral form of the
direct thrombin inhibitor melagatran, which is available for subcutaneous administration.
Ximelagatran has a consistent
anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of
melagatran/
ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard
LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with
warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of
melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of
melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of
bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative
melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy/safety data provided by the METHRO III study have led to approval of
melagatran/
ximelagatran in 2004 in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery.
Ximelagatran has the potential to maximize the use of anticoagulation in patients discharged following major lower-extremity
orthopedic surgery.