An Expanding Arsenal for Therapeutic Options
for Venous Thromboembolism

By Stephanie L. Perry, M.D.

Oral vitamin K antagonists have been the standard of care for chronic anticoagulation in patients diagnosed with deep vein thrombosis (DVT). Because of the “narrow therapeutic window” and extensive list of food and drug interactions for these agents, patients and their physicians have been waiting for an alternative oral anticoagulation agent. Ximelagatran is a prodrug to an oral direct thrombin inhibitor, melagatran, that has a rapid onset of action, no known CYP450 food or drug interactions, and therefore predictable pharmacokinetics. In the Plenary Session given yesterday, the results of a noninferiority trial of ximelagatran versus enoxaparin/warfarin were presented. The speaker, Dr. Charles Francis, gave a clear overview of the methods and interpretation of the results in The Thrive Treatment Study (Abstract #4310).

The design of this international clinical trial was a randomized, double-blind, and doubledummy trial. Patients were randomized to receive either oral ximelagatran 36 mg twice a day for six months or enoxaparin 1mg/kg subcutaneous for at least five days followed by dose-adjusted warfarin for a target INR of 2.0 to 3.0 for six months. The investigators followed 2489 patients with DVT (37% with pulmonary embolus), 1240 patients in the ximelagatran arm, and 1249 patients in the enoxaparin/warfarin arm. The mean age of 57 years was similar, and an approximately equal representation of gender was present in each group.

To determine if ximelagatran is non-inferior to enoxaparin/warfarin in efficacy and safety, the endpoints of recurrent venous thromboembolism (primary endpoint), bleeding events, and mortalitity were evaluated. The results of all three endpoints, evaluated as intention-to-treat and on-treatment, as well as the composite endpoint of recurrent venous thromboembolism and/or major bleeding, were not statistically significantly different. The investigators concluded that ximelagatran was noninferior to enoxaparin/warfarin based on these clinical endpoints. It was pointed out that 9.6% of patients receiving ximelagatran compared to 2% of patients receiving enoxaparin/warfarin developed elevations in serum alanine aminotransferase greater than three times the upper limit of normal. The clinical importance of this adverse effect remains unknown.

Related topics were also presented yesterday in the Simultaneous Sessions on Anticoagulant Trials. In the EXULT B Trial (Abstract #3828; presenter: Dr. Clifford Clowell), ximelagatran was compared to warfarin to “confirm superior efficacy” and safety in the prevention of venous thromboembolism after total knee replacement. Anticoagulation was given for seven to 12 days after surgery, with oral ximelagatran initiated the morning after surgery at the fixed dose of 36 mg twice a day and warfarin initiated the evening after surgery with a target INR of 2.5. Although ximelagatran was found to have superior efficacy, the frequency of total venous thromboembolic events was high for both groups with 22.5% in the ximelagatran group and 31.9% in the warfarin group.

In a Phase II study to evaluate DVT prevention after total knee replacement, razaxaban (a new orally active inhibitor of factor Xa) was evaluated (Abstract #1069; presenter: Dr. Michael Lassen). In their dose-finding study, the investigators discovered that razaxaban 25 mg given twice daily beginning eight hours after surgery appeared to have increased efficacy with no significant difference in major bleeding when compared to enoxaparin 30 mg twice daily subcutaneous beginning 12 to 24 hours after surgery.