Prevention of arterial thrombosis by edoxaban, an oral factor Xa inhibitor in rats: monotherapy and in combination with antiplatelet agents.
In addition to platelet aggregation, coagulation activation is considered to be involved in arterial thrombosis. In this study, we determined antithrombotic effects of edoxaban, an oral factor Xa (FXa) inhibitor, as both a monotherapy and in combination with antiplatelet agents in a rat model of arterial thrombosis. We further examined its effects on a procoagulant biomarker and bleeding. Arterial thrombosis was induced by topical application of 15% ferric chloride to rat abdominal aortas. Bleeding time was measured by a tail incision method. Edoxaban, clopidogrel, and aspirin were orally administered 30min, 4h, and 2h before thrombus or bleeding induction. As a biomarker of coagulation activation, plasma thrombin-antithrombin complex (TAT) was measured. Edoxaban dose-dependently prevented arterial thrombosis in a manner comparable to clopidogrel and aspirin. The combination of edoxaban plus clopidogrel or edoxaban plus aspirin significantly potentiated the antithrombotic effects compared with these drugs alone. The combination of edoxaban and clopidogrel was more potent than clopidogrel and aspirin. Plasma TAT concentration was elevated after thrombus induction and suppressed by edoxaban and clopidogrel, but not by aspirin, suggesting P2Y12 receptor-mediated platelet procoagulant activity. Bleeding time was prolonged by the coadministration of edoxaban and clopidogrel, but not by edoxaban and aspirin. In conclusion, the present study demonstrates that the monotherapy with edoxaban and combination therapy with edoxaban plus clopidogrel or edoxaban plus aspirin are promising options for the prevention of arterial thrombosis as effective as the standard antiplatelet agents; however, a combination of edoxaban and clopidogrel increased the risk of bleeding.
Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Yuko
Y
Honda
Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
Chikako
C
Kamisato
Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
Yoshiyuki
Y
Morishima
D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000097:blood; D001158:Arteries / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001760:Bleeding Time; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control*
D000991:Antithrombins; D015415:Biomarkers; D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D013844:Thiazoles; D013917:Thrombin; C552171:edoxaban
Antiplatelet agent; Arterial thrombosis; Aspirin (PubChem CID: 2244); Bleeding; Clopidogrel (PubChem CID: 115366); Direct factor Xa inhibitor; Edoxaban; Edoxaban (PubChem CID: 25022378); Platelet procoagulant activity