Pharmacodynamic and clinical trials of glycoprotein IIb/IIIa inhibitors and potential relationship of results to dosing.

ABSTRACT

Glycoprotein IIb/IIIa inhibitors have become the standard of care for patients undergoing percutaneous coronary intervention (PCI) and for those presenting with non-ST-segment elevation myocardial infarction (NSTE-ACS). Clinical effects of GP IIb/IIIa inhibitors in PCI and NSTE-ACS strongly correlate with potency, consistency, and durability of platelet aggregation inhibition. Under standardized conditions [light transmission aggregometry (LTA), 20 micromol adenosine diphosphate (ADP) as an agonist, and D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone (PPACK) as an anticoagulant], we demand consistent platelet aggregation inhibition >80% during the time of PCI (initial balloon inflation), and during the entire duration of therapy in NSTE-ACS. The benefit of abciximab (bolus 0.25 mg/kg plus infusion 10 microg/kg/min) correlates with >80% inhibition of platelet aggregation during the intervention (PCI) and immediately thereafter (<6 hours). The absence of a benefit with abciximab in NSTE-ACS is most likely due to <80% inhibition during the major part of the infusion period (>6 hours). Tirofiban does not achieve >80% inhibition at the time of PCI at a dose of 10 microg/kg bolus plus 0.15 microg/kg/min infusion, and at a dose of 0.4 lg/kg/min loading infusion for 30 minutes plus 0.1 microg/kg/min maintenance infusion, the target value is only reached after 18 h. Eptifibatide (double-bolus 180 microg/kg 10 min apart, followed immediately by a 2.0 microg/kg/min infusion) provided an instant, consistent, and durable antiplatelet effect for the entire duration of infusion, and a significant clinical benefit in both PCI (non-ACS patients) and medically managed NSTE-ACS patients.