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.

Test Description

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 [1][2][3] .

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 [1][2] . 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 [4][5] , 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.

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.

Disclaimer:

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.

Clopidogrel is the second highest top-selling drug in the world [6] ; approximately 29 million prescriptions were dispensed in 2008 in the United States alone [7] .

Estimates of the prevalence of laboratory-defined clopidogrel non-responsiveness vary widely, but have been estimated at 21-26% overall [8][9][10] .

An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death [8][9][10] . Approximately 9% of patients taking clopidogrel have a major adverse cardiovascular event such as myocardial infarction, stroke, or cardiovascular death [11][12] . Alternately, an enhanced response to clopidogrel may cause major bleeding [13] , which typically occurs in ˜1.5% of patients (though much higher rates have been reported) [11][12][13][14] .

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 [1][15][16] . 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 [1][15][16] . CYP2C19*2 and *3 account for more than 95% of cases of the "poor metabolizer" phenotype [1] . 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 [4]

Recently, the U.S. Food and Drug Administration (FDA) issued a black box warning for clopidogrel due to the reduced effectiveness of the drug in poor metabolizers [17][18] .

Systematic evidence reviews

None.

Recommendations by independent group

None.

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 [19] . The report stated that:

The evidence base is insufficient to recommend routine genetic testing at the present time.

Other guidelines

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 [3][20][21] . More recently (March 12, 2010), the FDA issued a black box warning for clopidogrel [17][18] 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" [17] . 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 [17] . 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" [21] , while the more recent warning no longer specifically advises against use of clopidogrel in CYP2C19 poor metabolizers [17] .

Analytic Validity : Test accuracy and reliability in identifying CYP2C19 genotypes (analytic sensitivity and specificity).

When reported, accuracy of the various genotyping methods/platforms used in commercial tests is noted as = 99% [22][23][24][25][26][27] . However, no information on analytic sensitivity or specificity can be found for the tests offered by Pathway Genomics [28] , Matrix Genomics [29] , or MyMedLab [30] , or for some tests offered by Quest Diagnostics [31] or Genelex Corporation [32] .

Clinical Validity : Test accuracy and reliability in predicting response to clopidogrel (predictive value).

Numerous published studies have examined the relationship of CYP2C19alleles to clopidogrel response [33].

HuGE Navigator : query "clopidogrel and CYP2C19"

Clinical Utility : Net benefit of test in improving health outcomes.

A recent meta-analysis of seven prospective cohort studies was published that examined the CYP2C19*2 variant and cardiovascular recurrences in 8,043 coronary artery disease patients taking clopidogrel. The authors found a statistically significant increased risk of major adverse cardiovascular events in CYP2C19*2 carriers (RR = 1.96) and an even greater risk when stent thrombosis was analyzed separately using four studies that included 4,975 patients (RR = 3.82) [56] .

Human Cytochrome P450 (CYP) Allele Nomenclature Committee, CYP2C19 allele nomenclature ( https://www.cypalleles.ki.se/cyp2c19.htm ), last accessed: March 17, 2010.

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.