Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model

Kai Wang; Xiaorong Zhou; Yanming Huang; Mazen Khalil; Dominik Wiktor; J. J. J. van Giezen; Marc S. Penn

doi:10.1160/TH09-12-0823

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 104(03): 609-917
DOI: 10.1160/TH09-12-0823

Animal Models

Schattauer GmbH

Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model

Kai Wang

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

²Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, USA

,

Xiaorong Zhou

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

,

Yanming Huang

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

,

Mazen Khalil

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

,

Dominik Wiktor

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

,

J. J. J. van Giezen

³TA CV/GI, AstraZeneca R&D Mölndal, Mölndal, Sweden

,

Marc S. Penn

¹Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA

› Institutsangaben

Abstract

Summary

Reperfusion therapy for myocardial infarction is limited by significant re-occlusion rates and less-than-optimal myocardial tissue perfusion. It was the objective of this study to assess and compare the effect of ticagrelor, the first reversibly binding oral P2Y₁₂ receptor antagonist, with that of clopidogrel, in conjunction with thrombolytic therapy, on platelet aggregation, thrombus formation, and myocardial perfusion in a canine model. Thrombus formation was induced by electrolytic injury and blood flow was measured with a Doppler ultrasonic flowmeter. All animals received tissue plasminogen activator (tPA) (1 mg/kg over 20 min); 10 animals received clopidogrel (10 mg/kg IV bolus over 5 min), 10 animals received ticagrelor initiated with a 1-min bolus (75 μg/kg/ min), followed by continuous infusion (10 μg/kg/min) for 2 h, and 10 animals received IV saline. Re-occlusion rate and cyclic flow variation decreased with ticagrelor compared to saline groups (p<0.05). Adenosine phosphate (ADP)-induced platelet aggregation decreased with ticagrelor (1.9% ± 2.67) and clopidogrel (1.11% ± 2.0) vs. saline (26.3% ± 23.5, p<0.05) at the end of adjunctive therapy. Bleeding time increased in the clopidogrel compared to the ticagrelor group (p=0.01). Infarct size was reduced with ticagrelor compared to the clopidogrel and saline groups (p<0.05). Blood flow remained significantly below baseline values at 20 min after tPA administration in the saline and clopidogrel groups but not in the ticagrelor group. In conclusion, in a dog coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation; prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and cyclic flow variation; and significantly decreases infarct size and rapidly restores myocardial tissue perfusion.

Keywords

P2Y₁₂ receptor - thrombosis - myocardial tissue perfusion - myocardial contrast echocardiography - ticagrelor

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Referenzen

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