Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis

Abstract

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.

Fig 1 Selection of studies of association of CYP2C19 variant genes with cardiovascular events in patients treated with clopidogrel

Fig 2 Association between loss of function polymorphisms of CYP2C19 and major adverse cardiovascular events (MACE) or stent thrombosis in patients with coronary artery disease taking clopidogrel treatment. Odds ratios shown for individual studies for dominant model genotype contrasts (carriers of one or two loss of function alleles v non-carriers). Cumulative odds ratios shown for each additional information step obtained by stepwise inclusion of every new study into pooled estimate

Fig 3 Association between gain of function CYP2C19*17 polymorphisms with major adverse cardiovascular events (MACE) or stent thrombosis in patients with coronary artery disease receiving clopidogrel treatment. Odds ratios shown for individual studies for dominant model genotype contrasts (carriers of one or two gain of function alleles v non-carriers). Cumulative odds ratios shown for each additional information step obtained by stepwise inclusion of every new study into pooled estimate

Fig 4 Funnel plots for association studies of loss of function genotypes of CYP2C19 with major adverse cardiovascular events (MACE) or stent thrombosis and for association studies of the gain of function variant CYP2C19*17 with MACE. Solid vertical line represents summary effect estimate, derived by using fixed effects meta-analysis for displaying centre of plot in absence of bias. Red lines represent 95% confidence limits for expected distribution of studies in absence of heterogeneity between studies or of selection biases