CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-Analysis

Study Questions:

What is the evidence on the association of CYP2C19 genotype and clopidogrel response?

Methods:

Studies that reported clopidogrel metabolism, platelet reactivity, or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included. The investigators extracted information on study design, genotyping, and disease outcomes, and investigated sources of bias. They estimated absolute risk differences between genotype categories based on the control group event rate from the CURE (acute coronary syndrome) and CHARISMA (stable coronary heart disease) trials and the trim-and-fill summary relative risk (RR) (to minimize small-study bias), comparing carriers of any loss-of-function CYP2C19 allele versus the reference category, and assuming consistency of RRs across a range of baseline absolute risks of cardiovascular and bleeding events.

Results:

The authors retrieved 32 studies of 42,016 patients reporting 3,545 CVD events, 579 stent thromboses, and 1,413 bleeding events. Six studies were randomized trials ("effect-modification" design) and the remaining 26 reported individuals exposed to clopidogrel ("treatment-only" design). In treatment-only analysis, individuals with one or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (RR, 0.84; 95% confidence interval [CI], 0.75-0.94; absolute risk reduction of 5-8 events per 1,000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1,000 individuals). However, there was evidence of small-study bias (Harbord test p = 0.001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD endpoints or bleeding (p > 0.05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes.

Conclusions:

The authors concluded that although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with CV events.

Perspective:

This systematic review and meta-analysis does not demonstrate a clinically important association of CYP2C19 genotype with CV outcomes with the possible exception of stent thrombosis. A large randomized controlled trial is needed to adequately test the clopidogrel pharmacogenomic hypothesis and its clinical significance. Pending such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with appropriate caution.

Clinical Topics: Acute Coronary Syndromes, ACS and Cardiac Biomarkers

Keywords: Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Biological Markers, Platelet Function Tests, Thrombosis, Genotype


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