The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: The CHARISMA genetics study

Bhatt, Deepak L., Pare, Guillaume, Eikelboom, John W., Simonsen, Katy L., Emison, Eileen S., Fox, Keith A. A., Steg, Ph. Gabriel, Montalescot, Gilles, Bhakta, Nihar, Hacke, Werner, Flather, Marcus D., Mak, Koon-Hou, Cacoub, Patrice, Creage, Mark A., Berger, Peter B., Steinhubl, Steven R., Murugesan, Gurunathan, Mehta, Shamir R., Kottke-Marchant, Kandice, Lincoff, A. Michael, Topol, Eric J., on behalf of CHARSMA Investigators and Walker, Philip (2012) The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: The CHARISMA genetics study. European Heart Journal, 33 17: 2143-2150. doi:10.1093/eurheartj/ehs059

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Author Bhatt, Deepak L.
Pare, Guillaume
Eikelboom, John W.
Simonsen, Katy L.
Emison, Eileen S.
Fox, Keith A. A.
Steg, Ph. Gabriel
Montalescot, Gilles
Bhakta, Nihar
Hacke, Werner
Flather, Marcus D.
Mak, Koon-Hou
Cacoub, Patrice
Creage, Mark A.
Berger, Peter B.
Steinhubl, Steven R.
Murugesan, Gurunathan
Mehta, Shamir R.
Kottke-Marchant, Kandice
Lincoff, A. Michael
Topol, Eric J.
on behalf of CHARSMA Investigators
Walker, Philip
Title The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: The CHARISMA genetics study
Journal name European Heart Journal   Check publisher's open access policy
ISSN 0195-668X
Publication date 2012
Year available 2012
Sub-type Article (original research)
DOI 10.1093/eurheartj/ehs059
Volume 33
Issue 17
Start page 2143
End page 2150
Total pages 8
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2013
Language eng
Formatted abstract
Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events.

Methods and results

A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69–0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints.

No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications.
Keyword Coronary disease
Peripheral vascular disease (PVD)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes First published online: 26 March 26 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 36 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 48 times in Scopus Article | Citations
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Created: Thu, 14 Jun 2012, 10:40:26 EST by Professor Philip Walker on behalf of Surgery - Royal Brisbane and Women's Hospital