A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation

Background The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopiclogrel and to relate platelet inhibition to systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y(12) adenosine diphosphate (ADP) receptor. Methods This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopiclogrel 300 mg. Platelet aggregation response to 5 and 20 mu mol/L of ADP was measured by turbidometric aggregometry. Plasma concentrations of the active metabolites of prasugrel and clopidogrel were quantified by liquid chromatography with tandem mass spectrometry detection methods. Results Inhibition of platelet aggregation (IPA) after prasugrel was significantly higher (P <.01) than that after clopidogrel from 15 minutes through 24 hours (5 mu mol/L ADP) and from 30 minutes through 24 hours (20 mu mol/L ADP). For 20 mu mol/L ADP, the median time to reach >= 20% IPA was 30 minutes for prasugrel and 1.5 hours for clopidogrel (P <.001). The maximum IPA was 84.1% +/- 9.5% with prasugrel versus 48.9% +/- 27.0% with clopiclogrel for 5 mu mol/L ADP and 78.8% +/- 9.2% versus 35.0% +/- 24.5%, respectively, for 20 mu mol/L ADP (P <.001). Response to prasugrel was more consistent compared to clopiclogrel (P <.01). The lower IPA response to clopiclogrel was associated with lower plasma concentrations of its active metabolite (P <.001). Conclusions Prasugrel 60 mg LD results in more rapid, potent, and consistent inhibition of platelet function than clopiclogrel 300 mg LD. Lower IPA responses to clopiclogrel were associated with lower concentrations of its active metabolite.