ANTITHROMBOTIC ACTIVITY OF INOGATRAN, A NEW LOW-MOLECULAR-WEIGHT INHIBITOR OF THROMBIN, IN A CLOSED-CHEST PORCINE MODEL OF CORONARY-ARTERY THROMBOSIS

Objective: To characterize the antithrombotic activity of inogatran pe t se in a porcine model of copper-coil-induced coronary artery thrombo sis and to compare its effect with that of heparin and ASA, Methods: F orty-eight pigs were assigned to one of the following groups: (1) sali ne; (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) A SA 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 reper fusion. Results: Cumulative time in which coronary arteries were paten t expressed as a percentage of the treatment time (i.e., 90 min) in he parin- and ASA-treated pigs, was 8 +/- 6 and 14 +/- 7%, respectively. This is not significantly different from placebo-treated pies. Inogatr an-treated pigs showed a dose-dependent antithrombotic effect, and the average patency rates were 34 +/- 39, 54 +/- 37 and 80 +/- 32% in gro ups 6, 7 and 8, respectively, Combined treatment with inogatran and AS A did not significantly improve the antithrombotic effect. A partial a ntithrombotic effect of inogatran was maintained for, on average, at l east 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, respec tively. Conclusion: Inogatran inhibits tile formation of arterial thro mbosis more effectively than heparin or ASA. inhibition of clot-bound thrombin and thrombin-induced platelet activation may be the mechanism s behind this effect. Our findings also suggest that a thrombus formed in the presence of inogatran is more susceptible to spontaneous endog enous fibrinolysis.