From the Carl and Edyth Lindner Center for Clinical Cardiovascular
Research, Health Alliance of Greater Cincinnati (D.J.K, L.C.A.), Cincinnati,
Ohio; Department of Cardiology and Internal Medicine (D.J.K., J.P.R.),
University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of
Cardiology (N.S.K), Baylor University College of Medicine, Houston, Tex; St
Luke's Episcopal Hospital (J.J.F), Texas Heart Institute, University of
Texas Health Sciences Center, Dallas, Tex; Millard Fillmore Hospital
(A.R.Z.M.), Buffalo, NY; Ohio Heart Health Center (D.J.K., T.M.B., C.W.A.
J.P.R), Cincinnati, Ohio; G.D. Searle & Co (R.J.A., R.J.D., G.L.H., B.B.),
Skokie, Ill; and Department of Cardiology, Cleveland Clinic Foundation
(E.J.T), Cleveland, Ohio.
Correspondence to Dean J. Kereiakes, MD, FACC, The Carl and Edyth Lindner Center for Clinical Cardiovascular Research, 2123 Auburn Ave, Suite 424, Cincinnati, OH 45219. E-mail lindner{at}healthall.com
Background—Parenteral
administration of platelet glycoprotein IIb/IIIa (GP
IIb/IIIa) receptor blockers can reduce ischemic complications
of coronary angioplasty. Orally active GP IIb/IIIa blockers may
allow more sustained receptor antagonism with the potential for
long-term secondary prevention. The pharmacodynamic efficacy, clinical
safety, and outcomes after prolonged receptor blockade with an orally
active GP IIb/IIIa antagonist are not known. The Oral
Glycoprotein IIb/IIIa Receptor Blockade to Inhibit
Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled,
randomized trial of xemilofiban, an oral platelet GP IIb/IIIa
blocking agent, administered to patients after
percutaneous coronary intervention.
Methods and Results—After successful elective
percutaneous coronary intervention, 549
patients were randomized to receive either placebo or xemilofiban in a
dose of 15 or 20 mg. Stented patients randomized to placebo also
received ticlopidine 250 mg orally BID for 4 weeks. Patients who
received abciximab during the coronary intervention and who
were randomized to receive xemilofiban were administered a reduced
dosage (10 mg TID for 2 weeks) followed by the randomized
maintenance dose of 15 or 20 mg BID for 2 more weeks. All
patients received 325 mg aspirin PO QD. Ex vivo platelet
aggregation in response to 20 µmol/L ADP and 4 µg/mL collagen
was measured over time after the initial dose of study drug and at days
14 and 28 of long-term therapy in 230 patients. All patients were
followed clinically for 90 days. Xemilofiban inhibited platelet
aggregation to both ADP and collagen with peak levels of inhibition
that were similar at 14 and 28 days of long-term oral therapy. Plasma
levels of xemilofiban correlated with the degree of platelet
inhibition. Peak platelet inhibition on day 1 correlated with the
subsequent occurrence of insignificant or mild bleeding events.
Although this study was not powered to evaluate differences in clinical
outcomes, a trend (P=0.04) was observed for reduction of
cardiovascular events at 3 months in patients not
treated with abciximab who received the highest dose (20 mg) of
xemilofiban studied.
Conclusions—Xemilofiban inhibited platelet aggregation and
was well tolerated during 28 days of long-term oral therapy. The
observed trend in reduction of cardiovascular events in
follow-up awaits confirmation in the larger-scale phase III study
(EXCITE trial) currently in progress.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Pharmacodynamic Efficacy, Clinical Safety, and Outcomes After Prolonged Platelet Glycoprotein IIb/IIIa Receptor Blockade With Oral Xemilofiban
Results of a Multicenter, Placebo-Controlled, Randomized Trial
Key Words: glycoproteins • xemilofiban • receptors • platelets • thrombosis
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