Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis - ORBIT

Description:

ORBIT was a multicenter, placebo-controlled, randomized clinical trial to investigate the efficacy and safety of the oral glycoprotein IIb/IIIa antagonist Xemilofiban administered after percutaneous coronary intervention (PCI).

Hypothesis:

Compared to placebo, Xemilofiban therapy administered for four weeks after PCI would be associated with a sustained inhibition of platelet aggregation over the course of therapy.

Study Design

Patients Enrolled: 549
Mean Follow Up: 90 days
Mean Patient Age: Mean 59 years
Female: 28

Patient Populations:

Age 21-80, stable or unstable angina or recent myocardial infarction (>24 hours before enrollment), target lesion stenosis of ≥70%, and successful completion of PCI with an FDA-approved device

Exclusions:

Not listed

Primary Endpoints:

Inhibition of platelet aggregation (in 230 patients with ex vivo assays).

Secondary Endpoints:

Clinical cardiac events (including death, myocardial infarction, urgent revascularization, nonhemorrhagic stroke); and bleeding events (severe or life-threatening, moderate, mild, insignificant)

Drug/Procedures Used:

No periprocedural abciximab:

  1. Xemilofiban 15 mg three times a day (tid) for two weeks followed by twice a day (bid) dosing for two weeks
  2. Xemilofiban 20 mg tid for two weeks followed by bid dosing for two weeks
  3. Placebo
Periprocedural abciximab:
  1. Xemilofiban 10 mg tid for two weeks followed by 15 mg bid for two weeks
  2. Xemilofiban 10 mg tid for two weeks followed by 20 mg bid for two weeks
  3. Placebo

Concomitant Medications:

Aspirin 325 mg for all patients and ticlopidine 250 mg bid for stented patients receiving placebo. All patients underwent PCI with heparin (with additional abciximab per operator preference).

Principal Findings:

A total of 549 patients were enrolled from 31 clinical sites. Baseline characteristics were similar in study groups. Abciximab was administered in 29% of patients, and stents were used in 50% of patients. The time to peak plasma concentration of the active form of Xemilofiban was four hours after the first dose and two hours after steady-state dosing.

Dose-dependent inhibition of platelet aggregation in response to both ADP and collagen was observed after incremental doses of Xemilofiban, and the level of inhibition of platelet aggregation correlated with plasma levels of Xemilofiban. Inhibition of platelet aggregation was maintained over the four weeks of therapy. Mild epistaxis occurred more frequently in the Xemilofiban arm (20 mg dosing) and correlated with the inhibition of platelet aggregation on day 1.

Although the study was not adequately powered to detect differences in clinical outcomes, there was a trend toward less cardiovascular events among patients not receiving abciximab and treated with Xemilofiban.

Interpretation:

This randomized, multicenter study of the short-acting oral glycoprotein IIb/IIIa antagonist Xemilofiban following PCI demonstrates that Xemilofiban was generally well-tolerated and produced sustained inhibition of platelet aggregation.

Although this study was not powered to detect differences in clinical cardiac events, the results of the larger EXCITE trial of Xemilofiban demonstrated no significant clinical benefit in a similar patient population. Moreover several other oral glycoprotein IIb/IIIa trials as well as a meta-analysis of these trials have demonstrated no significant benefits (and even potential harm) with these agents.

References:

Kereiakes DJ, Kleiman NS, Ferguson JJ, et al. 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. Circulation 1998;98:1268-78.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention

Keywords: Myocardial Infarction, Platelet Aggregation Inhibitors, Coronary Disease, Immunoglobulin Fab Fragments, Constriction, Pathologic, Epistaxis, Benzamidines, Percutaneous Coronary Intervention, Stents, Collagen, Platelet Glycoprotein GPIIb-IIIa Complex


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