Aspirin does not potentiate effect of suboptimal dose of the thrombin inhibitor inogatran during coronary thrombolysis.
OBJECTIVE
Coronary artery often reoccludes after thrombolytic therapy with recombinant tissue-plasminogen activator (rt-PA). This reocclusion is thought to be due to in situ platelet activation mediated by thromboxane (Tx) A2 and thrombin; hence, aspirin and thrombin inhibitors are often used in patients with acute myocardial infarction. This study was designed to examine the modulation of coronary artery reocclusion by a novel low molecular weight direct thrombin inhibitor inogatran with or without aspirin.


METHODS
22 dogs with electrically-induced occlusive intracoronary thrombus were treated with saline (n = 7, group A), or high dose inogatran (0.25 mg/kg bolus followed by 0.6 mg/kg per h for 2 h, n = 5, group B), or low dose inogatran (0.125 mg/kg bolus followed by 0.3 mg/kg per h for 2 h, n = 5, group C), or aspirin+low dose inogatran (n = 5, Group D). Recombinant tissue-plasminogen activator (rt-PA) was infused for 20 min starting 2 min after the bolus in all dogs. Coronary artery blood flow was monitored for 120 min after rt-PA administration.


RESULTS
Reperfusion rates were similar in all groups, but the time to reperfusion was shortest in group B dogs (18 +/- 2 min vs. 32 +/- 7 min in group A dogs, P < 0.05). Reocclusion rates were 80%, 0%, 50%, and 60% in groups A, B, C, and D dogs, respectively. The restored blood flow persisted for 19 +/- 10, > 120 min, 71 +/- 30 and 54 +/- 26 min in groups A, B, C, and D dogs, respectively. At the end of rt-PA infusion, prothrombin time (PT) and activated partial thromboplastin time (APTT) were increased 1.3-2 times the control value, and the changes in PT and APTT were similar in all groups. Thrombin generation and activity, assessed by rise in thrombin-antithrombin complex and fibrinopeptide A levels, and decrease in fibrinogen levels were most marked in group A dogs, and less so in group B, C and D dogs.


CONCLUSIONS
These data show that high dose of direct thrombin inhibitor inogatran shortens time to reflow and abolishes coronary artery reocclusion. However, aspirin does not potentiate the effect of suboptimal doses of inogatran.
Chen
L Y
LY
Department of Medicine, University of Florida College of Medicine, Gainesville, USA.
Nichols
W W
WW
Mattsson
C
C
Teger-Nilson
A C
AC
Wallin
R
R
Saldeen
T G
TG
Mehta
J L
JL
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D011994:Recombinant Proteins; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D001241:Aspirin