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Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo.

Erlinge, David LU ; Varenhorst, Christoph; Braun, Oscar LU ; James, Stefan; Winters, Kenneth J; Jakubowski, Joseph A; Brandt, John T; Sugidachi, Atsuhiro; Siegbahn, Agneta and Wallentin, Lars (2008) In Journal of the American College of Cardiology 52(24). p.1968-1977
Abstract
OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with... (More)
OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. RESULTS: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. CONCLUSIONS: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the American College of Cardiology
volume
52
issue
24
pages
1968 - 1977
publisher
Elsevier USA
external identifiers
  • wos:000261324000003
  • pmid:19055987
  • scopus:56849130022
ISSN
0735-1097
DOI
10.1016/j.jacc.2008.07.068
language
English
LU publication?
yes
id
a063ef11-330a-4c7c-a7fe-d256c969182c (old id 1276453)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19055987?dopt=Abstract
date added to LUP
2009-01-09 09:13:39
date last changed
2017-06-25 04:35:43
@article{a063ef11-330a-4c7c-a7fe-d256c969182c,
  abstract     = {OBJECTIVES: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. METHODS: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. RESULTS: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. CONCLUSIONS: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.},
  author       = {Erlinge, David and Varenhorst, Christoph and Braun, Oscar and James, Stefan and Winters, Kenneth J and Jakubowski, Joseph A and Brandt, John T and Sugidachi, Atsuhiro and Siegbahn, Agneta and Wallentin, Lars},
  issn         = {0735-1097},
  language     = {eng},
  number       = {24},
  pages        = {1968--1977},
  publisher    = {Elsevier USA},
  series       = {Journal of the American College of Cardiology},
  title        = {Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo.},
  url          = {http://dx.doi.org/10.1016/j.jacc.2008.07.068},
  volume       = {52},
  year         = {2008},
}