title: 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.
abstract: 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/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 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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. rgiugliano@rics.bwh.harvard.edu
authors.forename: R P
authors.initials: RP
authors.lastname: Giugliano
authors.forename: C H
authors.initials: CH
authors.lastname: McCabe
authors.forename: R F
authors.initials: RF
authors.lastname: Sequeira
authors.forename: M J
authors.initials: MJ
authors.lastname: Frey
authors.forename: T D
authors.initials: TD
authors.lastname: Henry
authors.forename: R N
authors.initials: RN
authors.lastname: Piana
authors.forename: J F
authors.initials: JF
authors.lastname: Tamby
authors.forename: B K
authors.initials: BK
authors.lastname: Jensen
authors.forename: S B
authors.initials: SB
authors.lastname: Nicolas
authors.forename: L K
authors.initials: LK
authors.lastname: Jennings
authors.forename: R J
authors.initials: RJ
authors.lastname: Wise
authors.forename: E
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011336:Probability; D012016:Reference Values; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D010455:Peptides; D010975:Platelet Aggregation Inhibitors