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1. Eur Heart J. 2012 Mar 26. [Epub ahead of print]

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

Bhatt DL, Paré G, Eikelboom JW, Simonsen KL, Emison ES, Fox KA, Steg PG,
Montalescot G, Bhakta N, Hacke W, Flather MD, Mak KH, Cacoub P, Creager MA,
Berger PB, Steinhubl SR, Murugesan G, Mehta SR, Kottke-Marchant K, Lincoff AM,
Topol EJ; on behalf of the CHARISMA Investigators.

VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical
School, 1400 VFW Parkway, Boston, MA 02132, USA.

AimsClinical 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 resultsA 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.ConclusionNo 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.

PMID: 22450429 [PubMed - as supplied by publisher]