Introduction: AVE5026 is a new extractive heparinoid, with predominantly anti-Xa activity (anti-Xa/anti-IIa ratio >30). TREK (a multicenter, randomized, double-blind, double-dummy, parallel group, dose response study of subcutaneous AVE5026 with an enoxaparin calibrator arm in the prevention of venous thromboembolism in patients undergoing elective total knee replacement surgery) evaluated the efficacy and safety of AVE5026 for primary prophylaxis of venous thromboembolism (VTE)
Methods: TREK was a stratified (pre-operative injection/no pre-operative injection) dose-ranging study. Patients were randomized to receive subcutaneously and once daily AVE5026 (5, 10, 20, 40 or 60mg) or enoxaparin 40 mg for up to 10 days after surgery. Depending of the stratum, the first dose was administered 11-13h before or 7–9h after surgery. A mandatory bilateral venography was performed 5–11 days after surgery. The primary efficacy endpoint was the composite outcome of
any deep vein thrombosis (DVT) identified on mandatory venography;
symptomatic VTE and
VTE-related deaths. The primary safety endpoint was major bleeding.
Results: Of 678 treated patients, 464 were eligible for the primary efficacy analysis with evaluable venous thromboembolism (VTE) assessment. The primary efficacy endpoint rates were at 40.0%, 44.1%, 15.6%, 13.6% and 5.3% for the AVE5026 doses of 5, 10, 20, 40 and 60 mg, respectively demonstrating a highly significant dose response (p<0.0001). The rate in the enoxaparin calibrator arm was 35.8%. A significant dose response was also observed for proximal deep vein thrombosis (DVT) with rates decreasing from 7.7% to 0% (p=0.0002). A statistically significant dose response was found for major bleeding with rates increasing from 0% to 3.4% (p=0.02) and any bleeding ranging from 3.8% to 20.5% (p= 0.0003) for the AVE 5026 dosing arms, compared with 0% and 5.0%, respectively, in the enoxaparin group.
Conclusions: In TREK, AVE5026, a novel anticoagulant, showed a significant dose response in prevention of venous thromboembolic events and a reverse dose-response for bleeding. These data suggest that AVE5026 may be a valuable addition to the armamentarium of antithrombotic agents and support further clinical development.
Disclosure:Employment: Dr. DDestrée is an employee of the sanofi-aventis group. Consultancy: MRL, OED and PM have done consultancy for the sanofi-aventis Group.