Cardiovascular Drugs and Therapy 17 129–132 2003 C  2003 Kluwer Academic Publishers. Manufactured in The Netherlands CLINICAL PHARMACOLOGY AND DRUG STUDIES Role of Oral Blockade of Platelet Glycoprotein IIb/IIIa on Neutrophil Activation in Patients with Acute Coronary Syndromes Carlos V. Serrano Jr. 1 , Jos´ e C. Nicolau 1 , Margareth Venturinelli 1 , Luciano M. Baracioli 1 , Robert J. Anders 3 , Christopher P. Cannon 2 , and Jos´ e A. F. Ramires 1 1 Heart Institute (InCor), University of S ˜ ao Paulo, Medical School, S ˜ ao Paulo, Brazil; 2 Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 3 Pharmacia Corporation Summary. Orboﬁban is a unique antiplatelet agent that in- hibits the binding of ﬁbrinogen to gycoprotein (GP) IIb/IIIa integrin receptors and thus prevents platelet aggregation induced by various agents. However, recent studies indi- cate that treatment with orboﬁban does not reduce the inci- dence of recurrent ischemic events. The mechanisms under- lying the lack of beneﬁt of orboﬁban in patients with acute coronary syndromes are not completely clear. The purpose of this study was to characterize the effects of orboﬁban on cellular activation (neutrophil superoxide generation) and surface expression of adhesion molecules of circulat- ing neutrophils (CD18, CD11b, and L-selectin) and platelets (P-selectin and GP IIb/IIIa) in patients with acute coro- nary syndromes. After 5–7 days, orbiﬁban (50 mg BID) did not reduce PMN adhesion molecule expression and ex vivo- stimulated PMN superoxide generation—as was observed in the placebo group, without orboﬁban. In contrast, orboﬁban induced marked reductions in GP IIb/IIIa and P-selectin ex- pressions after 5–7 days of treatment. The sustained neu- trophil activation observed with orboﬁban may have a role on the recurrent thrombotic events observed with orboﬁban treatment in the OPUS-TIMI 16 trial. Key Words. orboﬁban, oral platelet glycoprotein IIb/IIIa inhibitor, platelets, neutrophils, acute coronary syndromes Introduction The Orboﬁban in Patients with Unstable coronary Syndromes—Thrombolysis In Myocaridal Infarction (OPUS-TIMI 16) trial was based on the hypothesis that prolonged oral glycoprotein (GP) IIb/IIIa inhibition with orboﬁban, combined with aspirin, could prevent major cardiovascular events during long-term treat- ment in patients with acute coronary syndromes [1]. Orboﬁban is a novel antiplatelet agent that blocks the binding of ﬁbrinogen to GP IIb/IIIa integrin receptors and thus prevents platelet aggregation induced by var- ious agents [1]. However, the recent published results have shown that treatment with orboﬁban did not re- duce the incidence of recurrent events [1]. The mechanisms underlying the lack of beneﬁt of orboﬁban in patients with acute coronary syndromes are not completely clear. Potential explanations for the lack of beneﬁt were recently discussed by Cannon et al. [1]. To identify additional factors that might contribute to the lack of efﬁcacy, we studied the effect of orboﬁban on platelet-neutrophil (PMN) interactions. We believe that the elucidation of this issue will help determine future clinical strategies that include the use of oral GP IIb/IIIa inhibitors for preventing subsequent cardiac events. Therefore, the purpose of this substudy was to point out the effects of orboﬁban on cellular activation (PMN superoxide generation) and surface expression of adhe- sion molecules of circulating PMNs (CD18, CD11b, and L-selectin) and platelets (P-selectin and GP IIb/IIIa) in patients with acute coronary syndromes. Methods In the OPUS-TIMI 16 trial, investigators at 888 hospi- tals in 29 countries enrolled 10,288 patients with acute coronary syndromes. Patients included presented is- chemic discomfort at rest lasting ≥5 minutes with onset within 72 hours of randomization. All patients received aspirin and were randomized to receive, for the dura- tion of the trial, (1) 50 mg of orboﬁban twice daily (50/50 group), (2) 50 mg of orboﬁban twice daily for 30 days fol- lowed by 30 mg of orboﬁban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia re- quiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the Address for correspondence: Dr. Carlos V. Serrano Jr., Heart In- stitute (InCor HCFMUSP), Av. Eneas C. de Aguiar, 44, Building II, 2nd Floor, S˜ ao Paulo, SP 05403-000, Brazil. Tel.: (55-11) 3069- 5058; Fax: (55-11) 3088-3809; E-mail: dclserrano@incor.usp.br 129