title: Antithrombotic effects of ximelagatran plus acetylsalicylic acid (ASA) and clopidogrel plus ASA in a human ex vivo arterial thrombosis model.
abstract: It was the objective of this study to compare the antithrombotic effects and bleeding profiles of the oral direct thrombin inhibitor ximelagatran, an anticoagulant, and the antiplatelet agent clopidogrel on top of steady-state acetylsalicylic acid (ASA) in a human arterial thrombosis model. Healthy male volunteers (n=62) received ASA (160 mg once daily), plus either clopidogrel for 6 days (loading dose 300 mg, then 75 mg once daily), or a single dose of ximelagatran (36 or 72 mg) on Day 6. Changes in total 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-dose and 2 and 5 hours after dosing on Day 6, and capillary bleeding times (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone. Ximelagatran plus ASA reduced TTA more than clopidogrel plus 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 after 2 and 5 hours (72 mg, P<0.05). Compared with ASA alone, CBT was markedly prolonged by clopidogrel plus ASA (ratio 6.4; P<0.0001) but only slightly by ximelagatran plus ASA (72 mg ximelagatran, ratio 1.4; P=0.0010). Both drug combinations were well tolerated. Oral ximelagatran plus ASA has a greater antithrombotic effect in this human ex vivo thrombosis model and a less pronounced prolongation of bleeding time than clopidogrel plus ASA.
authors.affiliation: AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. karin.wahlander@astrazeneca.com
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson-Lepkowska
authors.forename: Per
authors.initials: P
authors.lastname: Nyström
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
authors.forename: Inge
authors.initials: I
authors.lastname: Kalies
authors.forename: Margareta
authors.initials: M
authors.lastname: Elg
authors.forename: Anders
authors.initials: A
authors.lastname: Bylock
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects / Q000473:pathology; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001596:Benzylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000473:pathology / Q000517:prevention & control*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; C109573:melagatran; C426686:ximelagatran; D000077144:Clopidogrel; D013917:Thrombin; D013988:Ticlopidine; D001241:Aspirin