RANDOMIZED TRIAL OF AN ORAL PLATELET GLYCOPROTEIN IIB IIIA ANTAGONIST, SIBRAFIBAN, IN PATIENTS AFTER AN ACUTE CORONARY SYNDROME - RESULTS OF THE TIMI-12 TRIAL/

Background-Inhibitors of the platelet glycoprotein IIb/IIIa receptor g iven intravenously have been shown to be effective in reducing ischemi c complications after coronary angioplasty and in unstable angina, mak ing this a promising new class oi agents for the treatment and prevent ion of ischemic events in patients with acute coronary syndromes, Sibr afiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist o f the glycoprotein IIb/IIIa receptor. Methods and Results-The Thrombol ysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-b lind, dose-ranging trial designed to evaluate the pharmacokinetics (PK ), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 32 9 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regim ens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of fo ur dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibitio n were achieved: mean peak values ranged from 47% to 97% inhibition of 20 mu mol/L ADP-induced platelet aggregation on day 28 across the sev en doses. Twice-daily dosing provided more sustained platelet inhibiti on (mean inhibition, 36% to 86% on day 28), whereas platelet inhibitio n returned to baseline levels by 24 hours with once-daily dosing. Majo r hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined ''minor'' b leeding, usually mucocutaneous, occurred in 0% to 32% of patients in t he various sibrafiban groups and in none of the patients treated with aspirin, Minor bleeding was related to total daily dose (P=.002), once -versus twice-daily dosing (P<.0001), renal function (P<.0001), and pr esentation with unstable angina (P<.01). Conclusions-The oral glycopro tein IIb/IIIa antagonist sibrafiban achieved effective, long-term plat elet inhibition with a clear dose-response but at the expense of a rel atively high incidence of minor bleeding. Oral IIb/IIIa inhibition des erves further study as a new treatment strategy in patients after acut e coronary syndromes.