Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysisBMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d4588 (Published 04 August 2011) Cite this as: BMJ 2011;343:d4588
- Tim Bauer, research associate1,
- Heleen J Bouman, research associate23,
- Jochem W van Werkum, group leader23,
- Neville F Ford, director45,
- Jurriën M ten Berg, director3,
- Dirk Taubert, group leader1
- 1Department of Pharmacology, University Hospital of Cologne, D-50931 Cologne, Germany
- 2Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, Maastricht, Netherlands
- 3Department of Cardiology, St Antonius Hospital Nieuwegein, Nieuwegein, Netherlands
- 4UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- 5Woodfield Clinical Consulting LLC, Green Valley, AZ, USA
- Correspondence to: D Taubert
- Accepted 13 June 2011
Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel.
Design Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria.
Data sources Medline, Embase, the Cochrane Library, online databases, contents pages and bibliographies of general medical, cardiovascular, pharmacological, and genetic journals.
Eligibility criteria for selecting studies Original full length reports assessing the cumulative incidence of major adverse cardiovascular events or stent thrombosis over a follow-up period of at least a month in association with carrier status for the loss of function or gain of function CYP2C19 allele in adult patients with coronary artery disease and a clinical presentation of acute coronary syndrome or stable angina pectoris who were taking clopidogrel.
Results 15 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P<0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P=0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non-carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P=0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P=0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments.
Conclusions Accumulated information from genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel. The current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype.
Contributors: DT (principal investigator and guarantor) designed the study. TB and DT, with help from HJB, NFF, and JWvW, carried out literature searches, data entry, and data extraction. HJB, TB, and DT developed and wrote analysis scripts. All authors carried out the analyses. TB and DT wrote the manuscript, with contributions from HJB, NFF, and JWvW.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; JWvW has specified relationships with Accumetrics, Siemens, and The Medicines Company, and JMtB has specified relationships with Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Sanofi-Aventis, and Schering-Plough, that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data are available.
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