The Protective Dose of the Potent GPIIb/IIIa Antagonist SC-54701A Is Reduced When Used in Combination With Aspirin and Heparin in a Canine Model of Coronary Artery Thrombosis

Publisher Website
Google Scholar
Abstract
Background Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally active fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury. Methods and Results Sixty-six dogs were used (6 per treatment). SCa (15-minute loading dose followed by [//] infusion [μg/kg per minute]: (0.87//0.39=1×SCa; 0.52//0.23=0.6×SCa; and 0.425//0.20=0.5×SCa), ASA (2.8 mg/kg), heparin (200 U/kg plus 1000 U/h), or saline (0.1 mL/kg) was administered intravenously. Experimental time was 180 minutes of current. Time to occlusion was increased ( P <.05) by SCa (T=incidence of thrombosis) (1×SCa, >180 minutes [T=0]; 0.6×SCa, 158±15 minutes [T=2]; 0.5×SCa, 130±22 minutes [T=4]), heparin (114±16 minutes [T=5]), and ASA plus heparin (130±11 minutes [T=5]) relative to saline (58±7 minutes [T=6]). Time to occlusion for the SCa treatments was increased compared with ASA (64±7 minutes [T=6]). When 0.5×SCa was administered with ASA plus heparin, time to occlusion was >180 minutes [T=0]. SCa provided complete protection at ≥90% inhibition of ex vivo collagen-induced platelet aggregation. Cyclic flow variations were minimal with SCa or any treatment involving 0.5×SCa and ASA. Conclusions SCa has dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. SCa (0.5×) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.