What is the role of ximelagatran in deep venous thrombosis (DVT) prophylaxis prior to orthopedic surgery?

Updated: Jul 25, 2019
  • Author: David A Forsh, MD; Chief Editor: Vinod K Panchbhavi, MD, FACS  more...
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Answer

Answer

Ximelagatran, a direct thrombin inhibitor consisting of an oral prodrug of melagatran, is rapidly absorbed through the GI tract, where it is converted to its active form, melagatran. It does not require monitoring, as it has a rapid onset of action, a predictable dose-response, and a therapeutic half-life. Also, like the other direct thrombin inhibitors, it does not affect the aPTT or PT.

The results reported by Francis et al in the New England Journal of Medicine showed that ximelagatran and warfarin did not differ significantly with respect to the incidence of major or minor bleeding. [62] The report also determined that ximelagatran was significantly more effective in preventing DVT after TKR than was warfarin.

In the United States, four studies showed that postoperatively initiated ximelagatran (24 mg twice daily) had efficacy similar to that of enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those of comparator anticoagulants. Some patients experienced transient elevations of liver enzyme levels, which returned to normal after cessation of treatment. [63]

The FDA Cardiovascular and Renal Drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program to propose the following three indications [64] :

  • Prevention of VTE in patients undergoing TKR
  • Prevention of stroke and other thromboembolic complications associated with atrial fibrillation
  • Secondary prevention of VTE after an episode of acute DVT

The committee reviewed data from 30,698 subjects and included five phase III studies, which led the CRAC to use the finding of ximelagatran hepatic toxicity as a key feature for an unfavorable benefit/risk ratio of ximelagatran for the three proposed indications. A report by Colwell and Mouret, however, indicated that melagatran/ximelagatran has been approved in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. [65] Boudes reported on the challenges and risk analysis to be learned from the ximelagatran FDA CRAC findings. [64]


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