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(Circulation. 1996;94:1719-1725.)
© 1996 American Heart Association, Inc.

Articles

Antithrombotic Assessment of the Effects of Combination Therapy With the Anticoagulants Efegatran and Heparin and the Glycoprotein IIb-IIIa Platelet Receptor Antagonist 7E3 in a Canine Model of Coronary Artery Thrombosis

Timothy J. Shetler, BS; V. Gail Crowe, BS; Blanche D. Bailey, AAS; Charles V. Jackson, PhD

the Cardiovascular Research Division, Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, Ind.

Correspondence to Charles V. Jackson, PhD, Research Scientist, Cardiovascular Research Division, Lilly Corporate Center, MC304, Indianapolis, IN 46285-0524.

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.

Key Words: thrombosis • 7E3 • efegatran • heparin • anticoagulants • arteries • platelet aggregation inhibitors