Variable inhibition of high-shear–induced platelet plug formation by eptifibatide and tirofiban under conditions of platelet activation and high von willebrand release: a randomized, placebo-controlled, clinical trial

Background Glycoprotein (GP) IIb/IIIa antagonists have become a mainstay for the treatment of acute coronary syndromes. Yet, they have rarely been evaluated under relevant pathophysiologic conditions, for example, high shear rates in the presence of physiologic calcium concentrations. We compared the efficacy of eptifibatide and tirofiban versus placebo on high shear–induced platelet plug formation in a model in which healthy subjects exhibit von Willebrand factor concentrations and platelet activation comparable to patients with acute coronary syndromes. Methods Thirty male volunteers received 2 ng/kg endotoxin and standard doses of eptifibatide, tirofiban, or placebo over a period of 5 hours in a randomized, double-blinded, placebo-controlled, double-dummy parallel-group trial. Platelet inhibition was measured with the Platelet Function Analyzer-100 (PFA-100) and the Ultegra method. Results Although bolus infusion of both GPIIb/IIIa antagonists inhibited high shear–induced platelet plug formation, continuous infusion of eptifibatide prolonged closure times more effectively than did tirofiban (P < .008). Interestingly, tirofiban had only placebo-like effects on platelet plug formation after 2 hours. However, when additional drug was exogenously added, closure time values were maximally prolonged in all cases. Conclusions Standard doses, particularly of tirofiban, have limited impact on high shear–induced platelet plug formation at physiologic Ca2+ concentrations.