First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: Results of theTIMI 15A and 15B trials

Background RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhi bitor available in intravenous and oral formulations. Two phase II dose-ran ging studies were performed to investigate pharmacodynamics and safety in a cute coronary syndromes. Methods The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a ra ndomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind compar ison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) co mpared with placebo (n = 50). Results Intravenous RPR 109891 exhibited a dose-response inhibition of plat elet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inh ibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycopro tein IIb/IIIa receptor occupancy and platelet inhibition were highly correl ated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for i ncreased major hemorrhage (10% vs 6%, P = .57), thrombocytopenia <90,000 ce lls/mm(3) (13% vs 4%, P = .11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P = .33) with intravenous plus oral RPR 109891 compared with placeb o. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interr upted because of bypass surgery, and a precipitous fall in platelet count o ccurred after the first postoperative oral dose. Conclusions Intravenous RPR 109891 is a potent, predictable, dose-related p latelet inhibitor. Oral RPR 109891 (less than or equal to 600 mg/d) achieve s moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deser ves closer examination in future studies.