From the Cardiovascular Division, Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston, Mass (C.P.C.,
C.H.M., E.B.); Henry Ford Hospital, Detroit, Mich (S.B.); Hennepin County
Medical Center, Minneapolis, Minn (T.D.H.); University of Vermont, Burlington
(M.D.T.); Montefiore Medical Center, Bronx, NY (H.S.M.); Munroe Regional
Medical Center/Mediquest, Ocala, Fla (R.F.); Robert Wood Johnson Medical
School, New Brunswick, NJ (S.T.P.); Maine Medical Research Institute, South
Portland (K.A.); and Genentech Inc, South San Francisco, Calif (S.A.H.,
J.M.R., W.F.N.).
Background—Inhibitors of
the platelet glycoprotein IIb/IIIa receptor given
intravenously have been shown to be effective in reducing
ischemic complications after coronary angioplasty and
in unstable angina, making this a promising new class of agents for the
treatment and prevention of ischemic events in patients with
acute coronary syndromes. Sibrafiban (Ro 48–3657) is an oral,
peptidomimetic, selective antagonist of the
glycoprotein IIb/IIIa receptor.
Methods and Results—The Thrombolysis in Myocardial
Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging
trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics
(PD), safety, and tolerability of sibrafiban in 329 patients after
acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106
patients were randomized to receive one of seven dosing regimens 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 four dose
regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once
daily) or aspirin for 28 days. High levels of platelet inhibition
were achieved: mean peak values ranged from 47% to 97% inhibition of
20 µmol/L ADP-induced platelet aggregation on day 28 across
the seven doses. Twice-daily dosing provided more sustained
platelet inhibition (mean inhibition, 36% to 86% on day 28),
whereas platelet inhibition returned to baseline levels by 24 hours
with once-daily dosing. Major hemorrhage occurred in 1.5% of
patients treated with sibrafiban and in 1.9% of patients treated with
aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous,
occurred in 0% to 32% of patients in the 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 presentation with unstable
angina (P<.01).
Conclusions—The oral glycoprotein IIb/IIIa
antagonist sibrafiban achieved effective, long-term
platelet inhibition with a clear dose-response but at the expense
of a relatively high incidence of minor bleeding. Oral IIb/IIIa
inhibition deserves further study as a new treatment strategy in
patients after acute coronary syndromes.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome
Results of the TIMI 12 Trial
Key Words: platelet aggregation inhibitors • aspirin • myocardial infarction • angina
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