BACKGROUND: There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab')2] with both heparin and the novel tripeptide arginal antithrombin efegatran (LY294468) in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg . kg-1. h-1), heparin (80 U/kg, single injection, plus 30 U . kg-1. h-1), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (P < .05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin-treated groups, respectively). Bleeding times were increased (P < .05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation. CONCLUSIONS: The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.
BACKGROUND: There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab')2] with both heparin and the novel tripeptide arginal antithrombin efegatran (LY294468) in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg . kg-1. h-1), heparin (80 U/kg, single injection, plus 30 U . kg-1. h-1), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (P < .05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin-treated groups, respectively). Bleeding times were increased (P < .05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation. CONCLUSIONS: The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.