The anti-platelet agent clopidogrel bisulfate (sold under the trade name Plavix in the United States) is a widely prescribed medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant.
The drug’s oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 (CYP2C19). Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.
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 , CYP3A4 , 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:
- 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
|Test||Company||CYP2C19Variants Included||Sample Type||Available Direct-to-consumer (DTC)|
|AccuType™ CP testing for Clopidogrel CYP2C19 Genotype (*1, *2, *3, *4, *5)||Quest Diagnostics||*1, *2, *3, *4, *5||Whole blood or saliva||No|
|Clopidogrel P450 Genotype||Quest Diagnostics||*1, *2, *3 (also includes 26 variants in CYP2D6 )||Whole blood||No|
|Plavitest for Clopidogrel Resistance (CYP 2C19)||Genelex Corporation||*1, *2, *3, *4, *5, *6, *7, *8||Whole blood or buccal (cheek) swab||No|
|Comprehensive DNA Drug Sensitivity Test||Genelex Corporation||Unspecified||Whole blood or buccal (cheek) swab||No|
|Medications Panel [part of the “Health Compass”]||Navigenics, Inc.||“Two of the most common genetic variants in CYP2C19 ”||Saliva||No|
|Clopidogrel Efficacy [part of the “Health Edition” test]||23andMe||*1, *2, *3, *4, *8, and *17||Saliva||Yes|
|Drug Response (Medication) [part of the “Total Health Insight” test]||Pathway Genomics||Unspecified||Saliva||Yes, except in New York state|
|Clopidogrel Activation||Matrix Genomics||*1, *2, *3, *4, *5, *6, *7, *8, *9, *10, *17||Buccal (cheek) swab||Yes|
|Cytochrome P450 2C19 (CYP2C19) 7 Mutations||ARUP Laboratories||*1, *2, *3, *4, *5, *6, *7, *8||Whole blood||No|
|CYP450 2C19 Gene Test / Genetic Physician Consult||MyMedLab, Inc.||Unspecified||Buccal (cheek) swab||Yes, though orders must be approved by a MyMedLab physician|
|Clopidogrel Genetic Test||TheranostiCs Lab||Unspecified||Buccal (cheek) swab||Yes|
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.
Public Health Importance
An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death  . Approximately 9% of patients taking clopidogrel have a major adverse cardiovascular event such as myocardial infarction, stroke, or cardiovascular death  . Alternately, an enhanced response to clopidogrel may cause major bleeding  , which typically occurs in ˜1.5% of patients (though much higher rates have been reported)  .
Sizeable proportions of some populations possess at least one loss-of-function CYP2C19 allele (typically *2 or *3) that could affect clopidogrel response: ˜ 30-50% of Asians, 11-16% of Caucasians, and 14-25% of African-Americans  . It is estimated that the CYP2C19 “poor metabolizer” phenotype is exhibited by 10-25% of Asians, 2-3% of Caucasians, and 4% of African-Americans  . CYP2C19*2 and *3 account for more than 95% of cases of the “poor metabolizer” phenotype  . The allele frequency of CYP2C19*17 is estimated as 18-27% among Caucasians, 17-18% among Africans/African-Americans, and 0.5 – 4% among Asians 
Published Reviews, Recommendations and Guidelines
Systematic evidence reviews
Recommendations by independent group
Guidelines by professional groups
In July 2010, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) published a Clinical Alert in response to the FDA’s black box warning on clopidogrel  . The report stated that:
The U.S. Food and Drug Administration (FDA) determined in 2009 that the available data have “provided compelling evidence that genetic variation in CYP2C19 is a significant and independent predictor of clopidogrel pharmacokinetics, pharmacodynamics and clinical response”, which prompted the FDA to change clopidogrel’s prescribing information  . More recently (March 12, 2010), the FDA issued a black box warning for clopidogrel  due to the reduced effectiveness of the drug in poor metabolizers. The FDA recommended that health professionals be aware that some patients may be poor metabolizers of clopidogrel because of low CYP2C19 activity and to also “be aware that tests are available to determine patients’ CYP2C19 status”  . The FDA neither mandated nor explicitly recommended CYP2C19 genetic testing in patients prescribed clopidogrel , and the agency did not offer any specific guidance on drug dosing in CYP2C19 variant allele carriers  . The November 2009 label update did recommend that doctors avoid use of clopidogrel “in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity”  , while the more recent warning no longer specifically advises against use of clopidogrel in CYP2C19 poor metabolizers  .
Analytic Validity : Test accuracy and reliability in identifying CYP2C19 genotypes (analytic sensitivity and specificity).
Clinical Validity : Test accuracy and reliability in predicting response to clopidogrel (predictive value).
- HuGE Navigator : query “clopidogrel and CYP2C19″
Clinical Utility : Net benefit of test in improving health outcomes.
- The response to clopidogrel is unclear for some CYP2C19 genotypes, such as reduced-function alleles in the presence of *17. The only study to directly assess the combined effect of *17 and reduced-function alleles (in this case, *2) found a gradient of effect on pharmacodynamic response to clopidogrel  .
- Genotyping only for CYP2C19 alleles does not capture all of the genetic variability in pharmacodynamic, pharmacokinetic, or clinical responses to clopidogrel. Variants in the ABCB1 gene also seem to be potentially important to the interindividual variability in these phenotypes  .
- Currently, there are no standardized clinical guidelines to manage patients with an inadequate response to clopidogrel. Typically, one or more alternatives are tried: higher loading or maintenance doses of clopidogrel, dual therapy with aspirin if this has not already been initiated, or treatment with another antiplatelet medication  .
Last updated: September 16, 2010
I would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics for comments and guidance.
This work was supported by the Office of Public Health Genomics, Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention.
The author declares that no competing interests exist.
The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we suggest that you discuss them with your health care provider.
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