Monitoring IIbIIIa Receptor Antagonists

GpIIb/IIIa antagonists prevent thrombus formation in proportion to their blockade of the approx 80,000 GpIIb/IIIa receptors present on the platelet surface (41). The most widely used method to monitor GpIIb/IIIa-receptor antagonists (RA) is turbidimetric aggrego-metry. Early studies found that inhibition of 50% of the GpIIb/IIIa receptors was needed to detect significant inhibition of ADP-induced platelet aggregation, whereas blockade of ©80% of the receptors completely abolished ADP-induced platelet aggregation, suggesting a steep dose-response curve.

Many factors may influence platelet aggregation measurements, including the number ofreceptors on platelets at the time ofblood sampling. A significant example is the citrate anticoagulation that reduces the ionized calcium concentration normally found in blood. It has been found to enhance artificially the apparent activity of eptifibatide in ex vivo measurements (42). It has been suggested that this phenomenon led to underdosing with eptifibatide in the IMPACT II trial (43), which was subsequently corrected with the higher

I Inhibition of Platelet Function ;

Fig. 6. Results of GOLD study showing clinical outcomes as function of platelet function inhibition with RPFA assay (26). MACE, major adverse coronary events.

dose chosen in the PURSUIT trial (44). Because of these variables in platelet aggregometry measurements, it is unclear which combination of conditions best reflects the effects of inhibitors in vivo.

Measurement of the degree of receptor occupancy by various agents of the GpIIb/IIIa inhibitor class has been proposed to be an alternate surrogate (45). Although dose-response curves for GpIIb/IIIa antagonist inhibition of platelet aggregation reach a plateau at "80% receptor occupancy," a value achieved in many clinical trials, it is not yet known whether the 80% receptor occupancy level optimizes the antithrombotic efficacy of this class of drugs. Indeed, the GpIIb/IIIa receptor blockade necessary to produce an antithrombotic effect depends on the thrombotic challenge, which is difficult to predict (46).

Because ofthe technical constraints of receptor-binding assays and standard turbidimet-ric platelet aggregometry, these studies were limited to only a small number of patients. The development of a rapid, whole-blood, point-of-care (POC) platelet function assay, the Ultegra RPFA (Accumetrics), with results that correlate well with turbidimetric aggregometry and receptor-binding assays (24), led to studies on a larger population, thus allowing correlation with clinical outcomes. In the GOLD study, those patients in the lowest quartile of platelet function inhibition (<95%) at 10 min after the Gp IIb/IIIa antagonist bolus had a significantly higher incidence of major coronary events compared with the others (Fig. 6) (46). At 8 h after the bolus dose, patients with <70% platelet function inhibition experienced three times the event rate of those with >70% inhibition (25 vs 8.1%; p < 0.009). By multivariate logistic modeling, when evaluated individually, the levels of inhibition achieved at 10 min and at 8 h after the Gp IIb/IIIa inhibitor bolus were found to correlate with clinical outcomes. The prospective TEAM study showed that 50% of the patients were undertreated when receiving the recommended dose of IIb/IIIa-RA and needed an additional bolus to reach 90% inhibition of platelet receptors (Fig. 7) (47).

GpIIb/IIIa antagonists are expensive drugs that require iv bolus plus infusion delivery. Of interest is the PEACE study, which assessed platelet activation with flow cytometry in 32 non-ST-elevation myocardial infarction (NSTEMI) patients to establish whether

Fig. 7. Results ofTEAM study. Platelet receptor blockade was assessed 10 min after Ilb/IIIa-RA bolus infusion and before elective PCI. An additional bolus of IIb/IIIa-RA was given if 90% inhibition of platelet function was not obtained (47).

Eptifibatide

Fig. 7. Results ofTEAM study. Platelet receptor blockade was assessed 10 min after Ilb/IIIa-RA bolus infusion and before elective PCI. An additional bolus of IIb/IIIa-RA was given if 90% inhibition of platelet function was not obtained (47).

eptifibatide provided a significant antiplatelet effect above that of aspirin and clopidogrel (48). Following ex vivo stimulation, activated GpIIb/IIIa receptor expression and fibrin-ogen binding were reduced following clopidogrel and markedly further reduced with epti-fibatide (all p < 0.0001). Total GpIIb/IIIa and P-selectin expression were also significantly reduced following clopidogrel, indicating that eptifibatide provides potent antiplatelet activity above that of aspirin and clopidogrel.

The RPFA, a bedside measure of platelet function, is effective and reliable and correlates with clinical outcomes. This convenient technology represents a significant advance compared with the prior "gold standard" of cumbersome platelet aggregometry for monitoring GpIIb/IIIa-RA and allows immediate dose adjustment ofthese expensive therapies. Whether the RPFA should be implemented in routine care warrants additional randomized studies. Indeed, whether titrating therapy to a specific level of inhibition will decrease risk remains unknown.

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