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Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel
  1. Michel Zabalza1,
  2. Isaac Subirana2,3,
  3. Joan Sala1,4,
  4. Carla Lluis-Ganella3,
  5. Gavin Lucas3,
  6. Marta Tomás3,
  7. Rafel Masiá1,
  8. Jaume Marrugat3,
  9. Ramon Brugada1,4,5,
  10. Roberto Elosua2,3
  1. 1Cardiology Department, Hospital Universitari Josep Trueta, Girona, Spain
  2. 2CIBER Epidemiology and Public Health, Barcelona, Spain
  3. 3Cardiovascular Epidemiology and Genetics, IMIM (Institut de Recerca Hospital del Mar), Barcelona, Spain
  4. 4School of Medicine, Girona University, Girona, Spain
  5. 5Cardiovascular Genetics Center, Girona, Spain
  1. Correspondence to Roberto Elosua, Cardiovascular Epidemiology and Genetics, IMIM, Dr Aiguader 88, Barcelona 08003, Catalonia, Spain; relosua{at}


Aims To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies.

Methods A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity.

Results Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR =1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I2 =35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size <500 patients (HR =3.55; 95% CI 1.66 to 7.56) and lower among studies with a sample size ≥500 (HR =1.06; 95% CI 0.89 to 1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR =2.24; 95% CI 1.52 to 3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR =0.75; 95% CI 0.66 to 0.87) and a higher risk of major bleeding (HR =1.26; 95% CI 1.05 to 1.50).

Conclusions Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding.

  • CYP2C19
  • clopidogrel
  • pharmacogenomics
  • coronary intervention
  • genetics
  • acute coronary syndrome
  • antiplatelet treatment

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  • Funding This work was supported by Spain's Ministry of Science and Innovation through the Carlos III Health Institute - European Regional Development Fund (ERDF) (FIS PI09/90506, CIBER Epidemiologia y Salud Pública, Red HERACLES RD06/0009) and by the Government of Catalonia through the Catalan Research and Technology Innovation Interdepartmental Commission (SGR 1195). GL was funded by the Juan de la Cierva Program, Ministerio de Educación. MT was funded by the Beatriu de Pinos Grant.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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