title: Comparison of antithrombotic efficacy between edoxaban, a direct factor Xa inhibitor, and fondaparinux, an indirect factor Xa inhibitor under low and high shear rates.
abstract: Edoxaban is an oral, direct factor Xa (FXa) inhibitor under late-phase clinical development. This study compared the antithrombotic efficacy of edoxaban with that of an indirect FXa inhibitor, fondaparinux, in in vivo venous and arterial thrombosis models and in ex vivo perfusion chamber thrombosis model under low and high shear rates in rats. Venous and arterial thrombi were induced by platinum wire insertion into the inferior vena cava and by application of FeCl₃ to the carotid artery, respectively. The perfusion chamber thrombus was formed by blood perfusion into a collagen-coated capillary at 150 s⁻¹ (low shear rate) and 1,600 s⁻¹ (high shear rate). Effective doses of edoxaban that reduced thrombus formation by 50% (ED₅₀) in venous and arterial thrombosis models were 0.076 and 0.093 mg/kg/h, respectively. In contrast, ED₅₀ of fondaparinux in the arterial thrombosis model (>10 mg/kg/h) was markedly higher compared to ED₅₀ in the venous thrombosis model (0.021 mg/kg/h). In the perfusion chamber thrombosis model, the ratio of ED₅₀ under high shear rate (1.13 mg/kg/h) to that under low shear rate (0.63 mg/kg/h) for edoxaban was 1.9, whereas that for fondaparinux was more than 66. While the efficacy of fondaparinux markedly decreased in arterial thrombosis and in a high-shear state, edoxaban exerted consistent antithrombotic effects regardless of flow conditions. These results suggest that shear rate is a key factor in different antithrombotic effects between edoxaban and fondaparinux.
authors.affiliation: Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. fukuda.toshio.tx@daiichisankyo.co.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukuda
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsuji
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.forename: Chikako
authors.initials: C
authors.lastname: Kamisato
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shibano
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D000991:Antithrombins / Q000008:administration & dosage* / Q000009:adverse effects; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000473:pathology; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006801:Humans; D008297:Male; D011134:Polysaccharides / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014682:Vena Cava, Inferior / Q000473:pathology / Q000601:surgery
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D011134:Polysaccharides; D011725:Pyridines; D013844:Thiazoles; D000077425:Fondaparinux; C552171:edoxaban