Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease

TLDR

The study randomized 110 aspirin‑treated stable coronary artery disease patients to receive either clopidogrel (600 mg loading, 75 mg maintenance) or prasugrel (60 mg loading, 10 mg maintenance) and measured platelet aggregation (maximal platelet aggregation) and P2Y12 function (platelet reactivity index) via light transmission aggregometry and vasodilator‑stimulated phosphoprotein assay, including pharmacokinetic assessment of active metabolites and ex vivo addition of clopidogrel’s active metabolite. Prasugrel produced a faster and greater reduction in platelet aggregation and P2Y12 activity—mean maximal platelet aggregation fell to 31 % versus 55 % and platelet reactivity index to 8.3 % versus 55.9 % at 2 h post‑loading, with higher active‑metabolite concentrations and earlier peak inhibition—compared with clopidogrel, confirming superior platelet inhibition in aspirin‑treated coronary artery disease patients.

Abstract

P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease.One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited.In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.