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

被引：76

作者：

Bhatt, Deepak L. ^{[1
,2
]}

Pare, Guillaume ^{[3
]}

Eikelboom, John W. ^{[3
]}

Simonsen, Katy L. ^{[4
,5
]}

Emison, Eileen S. ^{[6
]}

Fox, Keith A. A. ^{[7
,8
]}

Steg, Ph Gabriel ^{[9
,10
,11
]}

Montalescot, Gilles ^{[12
,13
]}

Bhakta, Nihar

Hacke, Werner ^{[14
]}

Flather, Marcus D. ^{[15
,16
]}

Mak, Koon-Hou ^{[17
]}

Cacoub, Patrice ^{[18
,19
]}

Creager, Mark A. ^{[20
]}

Berger, Peter B. ^{[21
]}

Steinhubl, Steven R. ^{[21
]}

Murugesan, Gurunathan ^{[22
]}

Mehta, Shamir R. ^{[3
]}

Kottke-Marchant, Kandice ^{[22
]}

Lincoff, A. Michael ^{[22
]}

Topol, Eric J. ^{[23
,24
]}

机构：

[1] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02132 USA

[2] Harvard Univ, Sch Med, Boston, MA 02132 USA

[3] McMaster Univ, Hamilton, ON, Canada

[4] Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA

[5] Bristol Myers Squibb Co, Global Biometr Sci, Princeton, NJ USA

[6] Bristol Myers Squibb Co, Clin Biomarkers, Pharmacogenet, Princeton, NJ USA

[7] Univ Edinburgh, Edinburgh, Midlothian, Scotland

[8] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland

[9] INSERM, U698, Paris, France

[10] Univ Paris 07, Paris, France

[11] Assistance Publ Hop Paris, Paris, France

[12] CHU Pitie Salpetriere, AP HP, Inst Cardiol, INSERM,U937, Paris, France

[13] Univ Paris 06, Paris, France

[14] Heidelberg Univ, Dept Neurol, Heidelberg, Germany

[15] Royal Brompton Hosp, Clin Trials & Evaluat Unit, London SW3 6LY, England

[16] Univ London Imperial Coll Sci Technol & Med, London, England

[17] Mak Heart Clin, Singapore, Singapore

[18] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Dept Internal Med, Paris, France

[19] Univ Paris 06, UPMC, CNRS, INSERM,UMR 7211,U959, Paris, France

[20] Brigham & Womens Hosp, Div Cardiovascular Med, Boston, MA 02132 USA

[21] Geisinger Med Ctr, Div Cardiol, Danville, PA 17822 USA

[22] Cleveland Clin, Cleveland, OH 44106 USA

[23] Scripps Clin, La Jolla, CA USA

[24] Scripps Translat Sci Inst, La Jolla, CA USA

来源：

EUROPEAN HEART JOURNAL | 2012年 / 33卷 / 17期

关键词：

Coronary disease; Genetics; Peripheral Vascular disease; Platelets; Thrombosis; PERCUTANEOUS CORONARY INTERVENTION; CLOPIDOGREL-TREATED PATIENTS; OF-FUNCTION POLYMORPHISM; ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; PLATELET-FUNCTION; STENT THROMBOSIS; CONTROLLED TRIAL; ASPIRIN;

D O I：

10.1093/eurheartj/ehs059

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2143 / 2150

页数：8

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