Five things you need to know about the CYP2C19*2 variant

As genetic testing and personalized medicine become increasingly important in guiding therapeutic decisions for various medical specialties, these approaches have also taken on a more prominent role in cardiology. In particular, testing for the CYP2C19*2 variant has been a topic of much scientific study and discussion.

Individuals with the CYP2C19*2 variant are less able to metabolize clopidogrel, which is currently a mainstay of antiplatelet therapy for patients with ACS and those undergoing stent placement. Because patients with the CYP2C19*2 variant have a reduced antiplatelet response to clopidogrel, the FDA in 2010 called for revision to the clopidogrel product label to clarify the role of genomics in the efficacy of the drug. Additionally, several studies have focused on evaluating the role of genetic testing for the variant, and the therapeutic decisions subsequently based on these test results.

However, study findings have yielded mixed results regarding the efficacy of testing for CYP2C19*2, and for the moment, the value of this approach is uncertain.

Cardiology Today has compiled a list of key facts and findings about this genetic polymorphism and its relevance to the cardiology field.

1. CYP2C1 9*2 polymorphism is an independent predictor of inadequate antiplatelet response to clopidogrel.

According to data from the EXCELSIOR trial, the CYP2C19*2 polymorphism, followed by age, diabetes, and BMI, was independently predictive of insufficient antiplatelet response to clopidogrel among 802 patients who underwent coronary stent placement.

However, the researchers wrote that these factors combined “can explain less than 12% of the variability in residual platelet aggregation.” Read more

2. Clopidogrel monitoring does not improve outcomes.

Results from the ARCTIC-GENE study indicated that in patients who exhibited a poor response to antiplatelet therapy, platelet function monitoring with drug adjustment does not achieve better outcomes from clopidogrel than conventional treatment strategies.

The researchers collected DNA samples from 1,420 patients and stratified them based on genotyping for CYP2C19 genes associated with platelet reactivity, and found that patients at least one CYP2C19*2 (loss-of-function) allele had similar risk for a composite primary endpoint of death, MI, stroke, stent thrombosis or urgent revascularization compared with those with at least one CYP2C19*17 (gain-of-function) allele. Read more

3. The use of platelet function testing appears to change antiplatelet prescribing habits, but not short-term outcomes.

Routine accessibility of platelet function testing appears to guide physician decision-making for patients treated with PCI after acute MI. Data from the TRANSLATE-POPS study, presented at TCT 2013, indicated that clinicians were more likely to adjust or switch their patients’ antiplatelet regimens when given free access to platelet function testing. However, the researchers also found that there was no difference between this group and a group receiving standard care in terms of bleeding complications or major cardiac events at 30 days. Read more

4. An adjusted clopidogrel loading dose may reduce platelet reactivity in carriers of the CYP2C19*2 variant.

According to a study of 411 patients with non-ST segment elevation ACS, patients who carry the CYP2C19*2 variant experienced a decrease in on-treatment platelet activity after receiving an adjusted dose of clopidogrel. After these patients showed high on-treatment platelet activity (HTPR) on an initial 600-mg loading dose of clopidogrel, they were given an adjustment of up to three additional loading doses, with the goal of a vasodilator-stimulated phosphoprotein index below 50% achieved by 88% of carriers. Read more

5. In patients with the CYP2C19*2 polymorphism, a switch from clopidogrel to prasugrel may reduce HRP.

Another possibility for patients who carry the CYP2C19*2 variant is a switch to a different antiplatelet agent. A follow-up analysis to the SWAP study indicated a link between switching from clopidogrel to prasugrel and a decreased incidence of high platelet reactivity. While this study did not determine CYP2C19 genotype among participants, the findings indicate that prasugrel may be effective for addressing high platelet reactivity related to impaired clopidogrel metabolism. Read more