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

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. 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. 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. 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.