Comparative Antithrombotic and Antihemostatic Effects of the Direct Factor Xa Inhibitors, Apixaban and Rivaroxaban, and the Direct Thrombin Inhibitors, Dabigatran and Lepirudin, in Rabbit Models of Venous Thrombosis and Bleeding Time

Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of venous thromboembolism, stroke prevention in patients with atrial fibrillation, and secondary prevention in patients with acute coronary syndrome. The objective of this study was to assess the antithrombotic and antihemostatic effects of apixaban in rabbits, compared to the direct FXa inhibitor, rivaroxaban, and thrombin inhibitors, dabigatran and lepirudin.

Methods: We induced the formation of non-occlusive thrombus in venous thrombosis (VT) models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban, dabigatran and lepirudin were given as a bolus injection and supplemented with a constant IV infusion to achieve a stable plasma level.

Results: Control thrombus weight in the prevention VT model ranged from 65±3 to 88±5 mg, and in the VT treatment model ranged from 76±5 to 90±5 mg. Control bleeding time (BT) ranged from 163±5 s to 173±8 s (n=6 per group). In the prevention VT model, apixaban, rivaroxaban, dabigatran and lepirudin (infusion started at 30 min before VT initiation) exhibited dose-related efficacy in preventing VT with ED₅₀s (doses for 50% reduction of control thrombus weight; mg/kg) of 0.17±0.003, 0.15±0.03, 0.37±0.04 and 0.24±0.07 mg/kg, respectively. Apixaban, rivaroxaban and dabigatran, at doses for 80% reduction of control thrombus weight, prolonged BT by 13±2, 91±9*, 343±38* and 505±12%*, respectively (*P<0.05, vs. apixaban, n=6 per group). In the treatment VT model, these inhibitors (infusion started at 30 min after VT initiation) were equally effective in preventing growth of a preformed thrombus. Clot regression was observed following administration of apixaban, rivaroxaban and dabigatran at 2.7 mg/kg, and lepirudin at 3.5 mg/kg. The preformed thrombus decreased from an initial weight of 38±2 mg to 26±4*, 17±2*, 20±3* and 25±1* mg, respectively (*P<0.05, vs. control, n=6 per group).

Conclusion: In summary, apixaban was as efficacious as rivaroxaban, dabigatran and lepirudin in the prevention and treatment VT models in rabbits. At equivalent antithrombotic doses, apixaban preserved hemostasis better than the other three agents in the rabbit cuticle BT model. Clinical studies will be required to assess the therapeutic windows in humans.