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

Abstract

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% (ED(20) and ED(50)) were 0.04 and 0.3 mg kg(-1) h(-1) i.v., respectively. Addition of aspirin to apixaban ED(20) and ED(50) 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 (ED(20) 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 (ED(20) 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.