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

Background RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods The Thrombolysis In Myocardial Infarction...

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Published in:	The American heart journal Vol. 140; no. 1; pp. 81 - 92
Main Authors:	Giugliano, Robert P., McCabe, Carolyn H., Sequeira, Rafael F., Frey, Martin J., Henry, Timothy D., Piana, Robert N., Tamby, Jean-Francois, Jensen, Bradford K., Nicolas, Sylvain B., Jennings, Lisa K., Wise, Robert J., Braunwald, Eugene
Format:	Journal Article Conference Proceeding
Language:	English
Published:	New York, NY Mosby, Inc 01-07-2000 Elsevier
Subjects:	Administration, Oral Adolescent Adult Aged Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Dose-Response Relationship, Drug Double-Blind Method Female Follow-Up Studies Hemorrhage - chemically induced Hemorrhage - epidemiology Humans Infusions, Intravenous Male Medical sciences Middle Aged Myocardial Infarction - drug therapy Myocardial Infarction - mortality Peptides - administration & dosage Peptides - adverse effects Pharmacology. Drug treatments Platelet Aggregation Inhibitors - administration & dosage Platelet Aggregation Inhibitors - adverse effects Probability Reference Values Survival Rate Thrombocytopenia - chemically induced Thrombocytopenia - epidemiology Treatment Outcome Human Thrombocytopenia Glycoprotein IIbIIIa Intravenous administration Infarct Toxicity Treatment efficiency Oral administration Cardiovascular disease Hemopathy Coronary heart disease Myocardial disease Fibrinolysis Antiplatelet agent Chemotherapy Platelet Treatment Phase II trial Myocardium Antagonist Inhibition Comparative study Biological receptor
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Summary:	Background RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P =.57), thrombocytopenia <90,000 cells/mm3 (13% vs 4%, P =.11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P =.33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (≤600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies. (Am Heart J 2000;140:81-93.)
ISSN:	0002-8703 1097-6744
DOI:	10.1067/mhj.2000.107172