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European Heart Journal Advance Access originally published online on November 30, 2007
European Heart Journal 2008 29(1):21-30; doi:10.1093/eurheartj/ehm545
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please e-mail: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

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

Lars Wallentin1,*, Christoph Varenhorst1, Stefan James1, David Erlinge2, Oscar Ö Braun2, Joseph A. Jakubowski3, Atsuhiro Sugidachi4, Kenneth J. Winters3 and Agneta Siegbahn5

1 Department of Medical Sciences and Cardiology, Uppsala Clinical Research Center, University Hospital, 751 85 Uppsala, Sweden
2 Department of Cardiology, Lund University, Sweden
3 Lilly Research Laboratories, IN, USA
4 Daiichi Sankyo Co., Ltd., Tokyo, Japan
5 Coagulation Laboratory, Department Medical Sciences, Uppsala, Sweden

Received 17 September 2007; revised 26 October 2007; accepted 29 October 2007; online publish-ahead-of-print 30 November 2007.

* Corresponding author. Tel: +46 18 611 95 07, Fax: +46 18 50 66 38, Email: lars.wallentin{at}ucr.uu.se

Aims: P2Y12 receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease.

Methods and results: 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 µM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y12 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 P2Y12 inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; µM·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.

Conclusion: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y12 receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.

Key Words: Trials • Platelets • Coronary artery disease • Clopidogrel • Prasugrel


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