PERSISTENT INHIBITION OF ARTERIAL THROMBOSIS BY A 1-HOUR INTRAVENOUS-INFUSION OF ARGATROBAN, A SELECTIVE THROMBIN INHIBITOR

Background: Thrombin plays a pivotal role in early platelet-mediated arterial thrombosis. Methods: The efficacy of a 1-hour infusion of the competitive synthetic thrombin inhibitor, argatroban, (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinoline-sulfonyl)-L-arginyl]-2-piperidine-carboxylic acid monohydrate, relative to that of heparin, for the prevention of delayed (24 hours postinfusion) arterial thrombosis was studied. Results: Intravenous infusion of 50 U/kg heparin over 60 minutes was associated with arterial graft patency in only one of 11 animals after 24 hours. Heparin in combination with intravenous aspirin (17 mg/kg) maintained everted arterial graft patency at 24 hours in two of six rabbits, (P=0.51 vs heparin alone). Infusion of 100-mu-g/kg/min argatroban for 60 minutes prevented arterial graft occlusion in seven of 10 animals after 24 hours (P=0.008 vs heparin). The combination of argatroban and aspirin prevented occlusion within 24 hours in six of eight rabbits (P=0.28 vs heparin and aspirin). Pathologic examination of the grafts at 24 hours revealed that graft segment thrombosis was significantly less extensive in the group receiving argatroban alone than in the group receiving heparin alone (P=0.013). Conclusions: These findings indicate that a 1-hour intravenous infusion of the selective thrombin inhibitor, argatroban, reduces delayed (24 hours) arterial eversion graft thrombosis much more efficiently than heparin.