© 1996 by European Society of Cardiology
Copyright © 1996, European Society of Cardiology
Antithrombotic activity of inogatran, a new low-molecular-weight inhibitor of thrombin, in a closed-chest porcine model of coronary artery thrombosis
aDepartment of Cardiology, Karolinska Hospital, S-I71 76Stockholm, Sweden
bAstra Hässle Preclinical R and D, Mölndal, Sweden
* Corresponding author. Tel.: (+46-8) 729 2171; fax: (+46-8) 311 044.
Objective: To characterize the antithrombotic activitiy of inogatran per se in a porcine model of copper-coil-induced coronary artery thrombosis and to compare its effect with that of heparin and ASA. Methods: Forty-eight pigs were assigned to one of the following groups: (1) saline; (2) heparin, (a) 75 and (b) 150 IU/kg/h; (3) acetylsalicylic acid (ASA), 12.5 mg/kg; (4) ASA 12.5 mg/kg + inogatran, 0.06 mg/kg/h; (5) ASA 12.5 mg/kg + inogatran, 0.30 mg/kg/h; (6) inogatran, 0.30 mg/kg/h; (7) inogatran, 0.60 mg/kg/h; (8) inogatran, 1.5 mg/kg/h. Computerized vectorcardiography was applied to monitor coronary occlusion and reperfusion. Results: Cumulative time in which coronary arteries were patent, expressed as a percentage of the treatment time (i.e., 90 min) in heparin- and ASA-treated pigs, was 8 ± 6 and 14 ± 7%, respectively. This is not significantly different from placebo-treated pigs. Inogatran-treated pigs showed a dose-dependent antithrombotic effect, and the average patency rates were 34 ± 39, 54 ± 37 and 80 ± 32%, in groups 6, 7 and 8, respectively. Combined treatment with inogatran and ASA did not significantly improve the antithrombotic effect. A partial antithrombotic effect of inogatran was maintained for, on average, at least 150 min after the end of treatment, as evidenced by patency rates of 31 ± 43, 52 ± 48 and 62% ± 44, in groups 6, 7, and 8, respectively. Conclusion: Inogatran inhibits the formation of arterial thrombosis more effectively than heparin or ASA. Inhibition of clot-bound thrombin and thrombin-induced platelet activation may be the mechanisms behind this effect. Our findings also suggest that a thrombus formed in the presence of inogatran is more susceptible to spontaneous endogenous fibrinolysis.
KEYWORDS Thrombosis; Thrombin inhibitors; Myocardial ischemia; Reperfusion; Pig, anesthetized
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