Document Detail


The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study.
MedLine Citation:
PMID:  22450429     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: 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.
CONCLUSION: 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.
CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817.
Authors:
Deepak L Bhatt; Guillaume Paré; John W Eikelboom; Katy L Simonsen; Eileen S Emison; Keith A A Fox; Ph Gabriel Steg; Gilles Montalescot; Nihar Bhakta; Werner Hacke; Marcus D Flather; Koon-Hou Mak; Patrice Cacoub; Mark A Creager; Peter B Berger; Steven R Steinhubl; Gurunathan Murugesan; Shamir R Mehta; Kandice Kottke-Marchant; A Michael Lincoff; Eric J Topol;
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Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-03-26
Journal Detail:
Title:  European heart journal     Volume:  33     ISSN:  1522-9645     ISO Abbreviation:  Eur. Heart J.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-03     Completed Date:  2012-12-31     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  8006263     Medline TA:  Eur Heart J     Country:  England    
Other Details:
Languages:  eng     Pagination:  2143-50     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00050817
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MeSH Terms
Descriptor/Qualifier:
Aryl Hydrocarbon Hydroxylases / genetics*
Atherosclerosis / drug therapy,  genetics*
Female
Genotype
Hemorrhage / genetics*
Heterozygote
Humans
Ischemia / drug therapy,  genetics*
Kaplan-Meier Estimate
Male
Middle Aged
Myocardial Infarction / genetics
Platelet Aggregation Inhibitors / metabolism,  therapeutic use
Polymorphism, Genetic / genetics*
Stroke / genetics
Thrombosis / drug therapy,  genetics*
Ticlopidine / analogs & derivatives,  metabolism,  therapeutic use
Chemical
Reg. No./Substance:
0/Platelet Aggregation Inhibitors; A74586SNO7/clopidogrel; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C19 protein, human; OM90ZUW7M1/Ticlopidine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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