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 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.


CONCLUSIONS
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.
Uriuda
Y
Y
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
Wang
Q D
QD
Grip
L
L
Rydén
L
L
Sjöquist
P O
PO
Mattsson
C
C
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors*
D010880:Piperidines; C099871:inogatran; D006493:Heparin; D013917:Thrombin; D001241:Aspirin; D005998:Glycine