COMPARATIVE EFFECTS OF ASPIRIN, A SYNTHETIC THROMBIN INHIBITOR AND A MONOCLONAL ANTIPLATELET GLYCOPROTEIN-IIB/IIIA ANTIBODY ON CORONARY-ARTERY REPERFUSION, REOCCLUSION AND BLEEDING WITH RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR IN A CANINE PREPARATION

The comparative effects of intravenous aspirin, the synthetic thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (Argatroban) and F(ab′)2 fragments of monoclonal antibody 7E3 against platelet glycoprotein IIb/IIIa (7E3-F[ab′]2) on thrombolysis, reocclusion and bleeding associated with 0.45 mg/kg body weight bolus injections of recombinant tissue-type plasminogen activator (rt-PA) were studied in a canine coronary artery thrombosis model. Coronary patency was monitored for 2 h both by flow probe and by coronary angiography. Four groups were studied: Group I = pretreated with 17 mg/kg intravenous aspirin (n = 6), Group II = pretreated with 200 μg/kg per min intravenous Argatroban for 60 min (n = 5), Group III = pretreated with aspirin and Argatroban (n = 5) and Group IV = pretreated with 0.8 mg/kg intravenous 7E3-F(ab′)2 (n = 5). In Group I, reflow occurred in four of six dogs, but did not persist; reflow was induced in Group II in four of five dogs, persisting in one; in Group III, reflow occurred in all five dogs, persisting in four; in Group IV reflow was achieved in four of five dogs, persisting in two. The frequency of persistent reflow in Group III was significantly higher than in the combined Groups I and II (p = 0.012), whereas the time to reflow was significantly shorter in the groups receiving Argatroban than in the aspirin group (median 25 versus 55 min, p = 0.04). There were no significant differences between Groups III and IV. Bleeding times prolonged from 4.2 ± 1.2 min to 5 ± 3 min at 60 min in Group I, to 9.4 ± 11 min in Group II, to 12 ± 11 min in Group III and to 27 ± 8 min in Group IV. One hour after the end of infusion, the bleeding times were 5.0 ± 0.9, 5.2 ± 1.3, 14 ± 9.2 and 26 ± 9 min, respectively. These findings indicate that Argatroban accelerates coronary thrombolysis with rt-PA and that the combination of aspirin and Argatroban prevents coronary reocclusion. This is achieved in association with less pronounced prolongation of the bleeding time than observed with the potent antiplatelet glycoprotein IIb/IIIa receptor antibody. Inhibition of platelet activation with aspirin in combination with a short-lived synthetic thrombin inhibitor may constitute an alternative approach to improve coronary artery patency with thrombolytic therapy in patients with acute myocardial infarction. © 1990.