Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

• Published in: Journal of thrombosis and haemostasis 2008-10, Vol.6 (10), p.1736-1741
• Main Authors: WONG, P. C., WATSON, C. A., CRAIN, E. J.
• Format: Article
• Language: English
• Subjects: Animals; apixaban; arterial thrombosis; aspirin; Aspirin - therapeutic use; Bleeding Time; Carotid Artery Thrombosis - drug therapy; clopidogrel; direct factor Xa inhibitor; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; hemostasis; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyridones - pharmacology; Pyridones - therapeutic use; Rabbits; Ticlopidine - analogs & derivatives; Ticlopidine - therapeutic use; Treatment Outcome
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2008.03092.x

Background: Optimal treatment of arterial thrombosis may include a combination of antiplatelet and anticoagulant drugs. We evaluated apixaban, a direct and highly selective factor Xa inhibitor, in combination with clinically relevant doses of aspirin and/or clopidogrel for prevention of arterial thrombosis in rabbits. Methods: Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time (BT). Apixaban 0.04 and 0.3 mg kg−1 h−1 or aspirin 1 mg kg−1 h−1 was infused intravenous (i.v.) continuously from 1 h before artery injury or cuticle bleed until the end of the experiment. Clopidogrel at 3 mg kg−1 was dosed orally once daily for three days, with the last dose given 2 h before injury. Results: Control thrombus weight and BT averaged 8.6 ± 0.9 mg and 181 ± 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED20 and ED50) were 0.04 and 0.3 mg kg−1 h−1 i.v., respectively. Addition of aspirin to apixaban ED20 and ED50 significantly reduced the thrombus weight from 7.4 ± 0.5 to 5.3 ± 0.3 and 3.6 ± 0.3 mg, respectively, with no significant increases in BT (190 ± 7 s vs.181 ± 9 and 225 ± 11 s, respectively). Addition of aspirin and apixaban (ED20 dose) to clopidogrel produced a further significant reduction in thrombus weight from 5.3 ± 0.3 to 0.7 ± 0.1 mg. This combination of clopidogrel and aspirin with apixaban (ED20 dose) produced a significant but moderate BT increase of 2.1 times control. Conclusions: The combination of apixaban and aspirin or apixaban, aspirin and clopidogrel can reduce formation of occlusive arterial thrombosis without excessive increases in BT in rabbits.