Clinical Investigations: Acute Ischemic Heart Disease
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,☆☆,

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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/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.)

Section snippets

TIMI 15A

Ninety-three patients were enrolled over a 6-month period. Inclusion criteria were acute coronary syndrome ≤48 hours, age 18 to 75 years, creatinine clearance ≥50 mL/min, and ability to provide informed consent. Exclusion criteria were hemorrhagic risk, severe concomitant illness, active substance abuse, pregnancy/lactation, recent participation in another experimental protocol, current or prior thrombocytopenia, planned coronary artery bypass grafting (CABG) in ≤24 hours, low-molecular-weight

Patient population and treatments

Baseline characteristics are shown in Table I.

. Baseline characteristics

Empty CellTIMI 15ATIMI 15BAll patients
n91192283
Age(y, mean ± SD)55.4 ± 9.960.0 ± 10.858.5
Male767475
Prior MI393033
Prior CABG or PCI123226
Prior aspirin688378
Index event
 ST-elevation MI282625
 Non-ST-elevation MI252525
 Unstable angina without MI474948
Therapy of index event
 Fibrinolytic131514
 PCI within 24 hours191716
Received adjunctive heparin868887

Data are % of patients unless otherwise specified.

MI, Myocardial infarction; PCI, percutaneous

Discussion

In this first report of a single GP IIb/IIIa receptor inhibitor administered to patients in an intravenous followed by oral formulation, we observed a dose-dependent increase in plasma concentration, RO, and IPA with both intravenous and oral formulations of RPR 109891. Greater fluctuation and lower levels of IPA were seen with oral administration. Variability in the pharmacodynamic effect of short-acting oral GP IIb/IIIa inhibitors caused by a relatively low and variable bioavailability is

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Supported by a grant from Rhone-Poulenc Rorer, Collegeville.

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*Persons and institutions participating in TIMI 15A and 15B are listed in the Appendix.

Reprint requests: Robert P. Giugliano, MD, TIMI Study Office, 333 Longwood Ave, Suite 402, Boston, MA 02115.E-mail: [email protected]

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