Pharmacogenetic testing to identify patients at risk of an inadequate response to the standard clopidogrel regimen so that alternate treatment strategies can be initiated, with the goal of preventing adverse cardiovascular events such as stent thromboses, recurrent ischemic events, and death.
Genetic polymorphisms in several genes (e.g., CYP1A2
, and CYP3A5
) have been studied for an association with antiplatelet response and clinical outcomes in those taking clopidogrel. However, despite the many enzymes known to be involved in the metabolism of clopidogrel, only genetic variation in CYP2C19
has been consistently and significantly associated with clopidogrel response in multiple populations ,,
The numerous commercial pharmacogenetic tests that are available genotype variants in CYP2C19
for the purpose of predicting response to clopidogrel (see Table 1). These tests differ in genotyping methodology, sample type required, and availability (direct-to-consumer or physician-ordered). However, all tests include, at a minimum, the most common alleles (*1, and loss-of-function alleles *2 and *3), which have been shown to account for most of the variability in response to clopidogrel ,
. Some tests also include other identified reduced-function variants (named *4, *5, *6, *7, *8, *9, and *10). A newer allele, CYP2C19*17
, has been described that is associated with increased enzymatic activity and ultra-rapid drug metabolism ,
, which in turn is predicted to result in higher levels of the active metabolite of clopidogrel.
Each test includes:
- Analysis of multiple single nucleotide polymorphisms in CYP2C19.
- Genotype-based prediction of CYP2C19 enzymatic activity to categorize patients as:
- Extensive metabolizers [carrying two "normal" alleles (i.e., *1/*1)].
- Intermediate metabolizers [carrying one reduced-function allele (e.g., *1/*2)].
- Poor metabolizers [carrying two reduced-function alleles (e.g., *2/*2 or *2/*3)].
- Ultra-rapid metabolizers [carrying one or two increased-function alleles (i.e., *1/*17 or *17/*17), though it is not clear whether *1/*17 carriers have a different phenotype than *1/*1 carriers].
Table 1. Pharmacogenetic Tests for Clopidogrel Response
Note: These tests were found through Google searches combining terms such as “clopidogrel”, “genetic test” and “CYP2C19” and by searching individual websites of known commercial genetics companies (such as Pathway Genomics). Attempts were made to make this table comprehensive. However, there are tests that genotype variants in CYP2C19 that either do not specify that the test is for pharmacogenetic purposes, or do not specifically mention that the test can be used in determining response to clopidogrel. Such tests have not been included in this table.
Inclusion of tests in this table does not constitute an endorsement of any test by the Centers for Disease Control and Prevention (CDC) nor the Department of Health and Human Services (DHHS) of the U.S. government. No endorsement should be inferred.