ORIGINAL ARTICLE Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis F Sofi 1,2 , B Giusti 1 , R Marcucci 1 , AM Gori 1,2 , R Abbate 1 and GF Gensini 1,2 1 Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy and 2 Don Carlo Gnocchi Foundation, Centro S Maria agli Ulivi, Onlus IRCCS, Florence; Azienda Ospedaliero- Universitaria Careggi, Florence, Italy Correspondence: Dr F Sofi, Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence. Viale Morgagni 85, 50134 Florence, Italy. E-mail: francescosofi@gmail.com Received 30 July 2009; revised 20 January 2010; accepted 15 February 2010; published online 30 March 2010 Several polymorphisms in genes that encode platelet components (receptors or enzymes), or cytochrome P450 enzyme isoforms, involved in clopidogrel metabolism, have been proposed as possible mechanisms for nonrespon- siveness to clopidogrel. Among them, a great deal of attention has been focused on the loss-of-function CYP2C19*2 (or 681 G4A) polymorphism. We performed a meta-analysis of all the prospective studies that have been published, which analyze the role of such a polymorphism in recurrent cardiovascular events in patients with coronary artery disease (CAD) being treated with clopidogrel. Studies were searched in MedLine, Embase, Web of Science, The Cochrane Systematic Review Database, Google Scholar and bibliographies of retrieved articles up to January 2010. The principal underlying hypothesis was that the presence of the *2 variant allele of the polymorphism would be associated with an increased risk of clinical recurrence. Data were available for a total of 8043 patients from seven cohort prospective studies, who were followed for a period of time ranging from 6 months to 8.3 years. The summary risk ratios (RRs) for the prospective cohort studies included showed a significant association between the CYP2C19*2 polymorphism and an increased risk of major adverse cardio- vascular events in the follow-up (RR: 1.96 (1.14–3.37); P ¼ 0.02). When studies evaluating stent thrombosis (n ¼ 4) for a total of 4975 patients were considered, the presence of the variant allele was associated with an increased risk of stent thrombosis (RR: 3.82 (2.23–6.54); P ¼ 0.0001). The current meta-analysis, carried out on nearly 8000 patients with CAD undergoing clopidogrel treatment, shows that the CYP2C19*2 polymor- phism is associated with an increased risk of major adverse cardiovascular events and stent thrombosis. The Pharmacogenomics Journal (2011) 11, 199–206; doi:10.1038/tpj.2010.21; published online 30 March 2010 Keywords: clopidogrel; cytochrome P450; major adverse cardiovascular events; meta-analysis; CYP2C19*2 polymorphism; stent thrombosis Introduction Large clinical trials have shown that dual antiplatelet therapy (aspirin plus clopidogrel) reduces the risk of recurrent cardiovascular events in patients with coronary artery disease (CAD). 1 Recently, however, studies have reported that the response to clopidogrel varies between individuals. Resulting in an ineffective response in a consistent proportion of patients. 2–4 In addition, it has been shown The Pharmacogenomics Journal (2011) 11, 199–206 & 2011 Macmillan Publishers Limited. All rights reserved 1470-269X/11 www.nature.com/tpj