Elsevier

American Heart Journal

Volume 153, Issue 1, January 2007, Pages 66.e9-66.e16
American Heart Journal

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

https://doi.org/10.1016/j.ahj.2006.10.010Get rights and content

Background

The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel 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 P2Y12 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 clopidogrel 300 mg. Platelet aggregation response to 5 and 20 μmol/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 μmol/L ADP) and from 30 minutes through 24 hours (20 μmol/L ADP). For 20 μmol/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 clopidogrel for 5 μmol/L ADP and 78.8% ± 9.2% versus 35.0% ± 24.5%, respectively, for 20 μmol/L ADP (P < .001). Response to prasugrel was more consistent compared to clopidogrel (P < .01). The lower IPA response to clopidogrel 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 clopidogrel 300 mg LD. Lower IPA responses to clopidogrel were associated with lower concentrations of its active metabolite.

Section snippets

Study design and subjects

This was a phase 1 randomized, 2-way crossover, open-label study in healthy subjects conducted at a single center from September to November 2003. The study was approved by the local investigational review board, and subjects provided written informed consent before enrolling in the study. Sixty-eight subjects were randomly allocated to receive either prasugrel 60 mg (15 mg as the HCl salt, 4 tablets, Eli Lilly and Co, Indianapolis, IN) or clopidogrel 300 mg (75 mg, 4 tablets, Plavix,

Results

Sixty-eight healthy subjects were enrolled in this study. The majority of the subjects were men (n = 48, 71%) and the mean ± SD age was 42 ± 17 years. Their average weight was 76.3 ± 11.6 kg, and their average body mass index was 24.7 ± 3.7 kg/m2.

Two subjects randomly allocated to receive prasugrel during the first dosing period were withdrawn from the study before the second dosing period; 1 for taking medications not permitted by the study protocol and the other for personal reasons. Two

Discussion

Studies in animals have demonstrated that prasugrel has a more rapid onset and is a more potent inhibitor of platelet P2Y12 function than clopidogrel or ticlopidine.8, 23 The results from the present study extend these findings to healthy human subjects. Prasugrel 60 mg LD was associated with more rapid, more consistent, and significantly greater inhibition of platelet aggregation than was clopidogrel 300-mg LD. The faster onset of platelet inhibition after prasugrel was evident in a number of

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  • Cited by (0)

    This study was funded by Eli Lilly and Company and Sankyo Co, Ltd., Tokyo, Japan.

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