Oral platelet glycoprotein IIb/IIIa receptor inhibitors—part I

Abstract

Summary:With the central importance of antiplatelet therapy in patients with coronary artery disease and the numerous positive trials with glycoprotein (GP) IIb/IIIa inhibitors given intravenously, it was hoped that one could extend the benefit of IIb/IIIa inhibition to long-term treatment. Although the hypothesis that prolonged oral IIb/IIIa inhibition was appealing, many issues have been identified in the initial Phase II trials that would limit the usefulness of these compounds. Variability of the level of platelet inhibition was one major culprit that distinguished the oral compounds from intravenous ones. The problems that arose were that increased bleeding has been seen when levels of platelet inhibition are high (e.g., > 90%) and that, conversely, efficacy would likely be limited when levels of platelet inhibition were low. If further development of this class of drugs is undertaken, formal dosing studies would have to establish an oral dosing strategy that achieves appropriately high (80-95% inhibition) and steady levels of inhibition.

Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

“…Blockade of glycoprotein (GP) IIb/IIIa represents a major advancement in the management of patients with acute vascular disease (for reviews, see Cannon 1 and Nurden et al 2 ). However, thrombocytopenia complicates the treatment and some cases have been severe (nadir Ͻ 20 000 platelets/L).…”

Complications of cutaneous surgery in patients taking clopidogrel-containing anticoagulation

“…Receptor inhibition interferes with activation of the glycoprotein IIb/IIIa complex, resulting in less platelet aggregation and, ultimately, in impaired thrombus formation. [7][8][9] Platelet inhibition by clopidogrel is irreversible and lasts the life of the platelet (on average, 7-10 days). 10 With regular platelet turnover, recovery of normal platelet function occurs 5 to 7 days after discontinuing clopidogrel.…”

Antiplatelet Agents

“…(Fig. 25) [391][392][393][394][395][396][397]. However, in the Phase-III clinical trials, these agents failed to reproduce the success of intravenous GP IIb/IIIa antagonists [398].…”