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First chronic platelet glycoprotein IIb/IIIa integrin blockade. A randomized, placebo-controlled pilot study of
C Simpfendorfer1, K Kottke-Marchant, M Lowrie
1Department of Cardiology, Cleveland Clinic Foundation, Ohio 44195, USA.
Insights
Xemilofiban effectively inhibits platelet aggregation for up to 30 days in patients undergoing percutaneous coronary interventions. However, this oral glycoprotein IIb/IIIa inhibitor was associated with significant bleeding events.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Intravenous glycoprotein IIb/IIIa receptor antagonists are effective in percutaneous coronary revascularization.
- Prolonged blockade enhances efficacy, suggesting a need for oral agents for chronic therapy.
Purpose of the Study:
- To evaluate the efficacy and safety of orally active Xemilofiban, a glycoprotein IIb/IIIa receptor inhibitor, in patients with unstable angina undergoing percutaneous coronary interventions.
Main Methods:
- Thirty patients with unstable angina were randomized to receive placebo or Xemilofiban (35 mg orally initially, then 20-25 mg TID for 30 days).
- Assessed parameters included bleeding events, platelet aggregation, pharmacokinetics, and hematologic profiles.
Main Results:
- Xemilofiban demonstrated rapid, sustained, and marked inhibition of platelet aggregation compared to placebo.
- ADP-induced aggregation was reduced to 8-15% in the Xemilofiban group versus 68-80% in placebo.
- One death occurred due to bleeding complications after bypass surgery; 3 patients experienced major bleeding events.
Conclusions:
- Oral Xemilofiban effectively inhibits platelet aggregation for up to 30 days.
- The tested dose was associated with acute major bleeding and mucocutaneous bleeding during chronic administration.
Background:
Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy.
Methods And Results:
Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding.
Conclusions:
Xemilofiban, an orally active glycoprotein IIb/ IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.