Summary

It was the objective of this study to compare the antithromboticeffects and bleeding profiles of the oral direct thrombin inhibitorximelagatran, an anticoagulant, and the antiplatelet agent clopidogrelon top of steady-state acetylsalicylic acid (ASA) in ahuman arterial thrombosis model. Healthy male volunteers(n=62) receivedASA (160 mg once daily),plus either clopidogrelfor 6 days (loading dose 300 mg, then 75 mg once daily), or asingle dose of ximelagatran (36 or 72 mg) on Day 6. Changes intotal thrombus area (TTA) under low shear rate (LSR; 212 s –1)and high shear rate (HSR; 1690 s –1) conditions were measured,using the ex vivo Badimon perfusion chamber model pre-doseand 2 and 5 hours after dosing on Day 6, and capillary bleedingtimes (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASAalone. Ximelagatran plus ASA reduced TTA more than clopidogrelplus ASA under LSR after 2 hours (36 mg, P=0.0011; 72 mg,P<0.0001) and 5 hours (72 mg, P=0.0057), and under HSR after2 and 5 hours (72 mg, P<0.05). Compared with ASA alone, CBTwas markedly prolonged by clopidogrel plus ASA (ratio 6.4;P<0.0001) but only slightly by ximelagatran plus ASA (72 mgximelagatran,ratio 1.4;P=0.0010).Both drug combinations werewell tolerated. Oral ximelagatran plus ASA has a greater antithromboticeffect in this human ex vivo thrombosis model and aless prounounced prolongation of bleeding time than clopidogrelplus ASA.