Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations

Abstract

SummaryThe oral direct thrombin inhibitor ximelagatran shows great promise for prevention of venous thromboembolic events following major elective orthopaedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In orthopaedic surgery clinical trials, ximelagatran was effective and well tolerated compared with standard therapy, with dose and timing relative to surgery important factors in determining its optimal profile. In European trials, an initial 3-mg postoperative dose of subcutaneous melagatran, the active form of ximelagatran, followed by oral ximelagatran 24 mg twice daily achieved similar efficacy and safety to enoxaparin. Although the risk of spinal haematoma following neuraxial anaesthesia is rare, it is increased by the concomitant use of anticoagulants. In orthopaedic surgery trials with ximelagatran to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of ximelagatran suggests that concurrent use with neuraxial anaesthesia should require no further precautions than those currently necessary with low-molecular-weight heparin.

Anaesthesia and new antithrombotic drugs

“…However, based on the elimination half-life of 3-5 h, epidural and/or spinal needle/catheter insertion or catheter removal should only be performed when (xi)melagatran is no longer active: at least 8-10 h after last dose of these drugs and 2-4 h prior to the next administration [54 ].…”

“…Specific (xi)melagatran antagonists are not available, but both recombinant factor VIIa and activated prothrombin complex concentrate could be an option in case of bleeding [53]. Controlled clinical trials have shown promising results in the prophylaxis of deep-venous thrombosis following orthopaedic surgery [54 ], the treatment of symptomatic deep-venous thrombosis [55,56] and the prevention of thrombotic events in patients with atrial fibrillation or after myocardial infarction [57 ,58,59 ]. Recently some concerns have grown over the occurrence of liverfunction abnormalities when ximelagatran was administrated for longer than a month [58,59 ].…”

Direct Thrombin Inhibitors

“…31 However, a recent review article addressed this issue with respect to the melagatran/ximelagatran drugs. 32 Ximelagatran is converted rapidly to its active form melagatran after oral administration. Because of the better pharmacologic profile compared with LMWH and warfarin, ximelagatran can be administered using a fixed-dose regimen across a wide range of patient population with no need for monitoring in the outpatient setting.…”

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials

“…To date, low molecular weight heparin (LMWH) has been most frequently used to prevent VTE following orthopaedic surgery [3], but this therapy is administered subcutaneously. To optimize patient care, research into new anticoagulants has concentrated on oral therapies.…”