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in Canada, and the data from the pharmacogenomic study will help support regula-
tory fi lings for the combined use of the test with Plavix.
INFINITI CYP2C19 Assay (AutoGenomics) is approved by the FDA to clini-
cians in determining therapeutic strategy for drugs that are metabolized by the
CYP450 2C19 gene product. Although several studies have shown that carriers of
CYP2C19 alleles do not respond to Plavix as well as non-carriers, the FDA has
updated the drug’s label to notify physicians of the role of these alleles in Plavix
metabolism, the assay’s label specifi cally notes that “the INFINITI CYP2C19 Assay
is not intended to be used to predict drug response or non-response”.
The 17 variant CYP2C19 gene mutation adds more complexity to the evalua-
tion of clopidogrel therapy because it results in an enzyme that is classifi ed as gain-
of- function, and the patient is considered an ultra-rapid metabolizer (Sibbing et al.
2010 ). In patients undergoing coronary stent placement, a single 17 gene variant
resulted in about a twofold increase in the incidence in bleeding within 30 days fol-
lowing stent placement. The incidence of bleeding was 2.5 % in patients without
17, but 4 % in patients with a single 17 variant. Patients with the double 17/17
genotype exhibited a dose-response fourfold increase in bleeding (8 %). The most
striking fi nding was that among the patients tested, 35 % had the single 17 variant
and another 5 % had the 17/17 genotype.
Clopidogrel GenoSTAT test (Iverson Genetics) identifi es the genetic (CYP2C19)
cause of an individual’s resistance to the drug, detects mutation of the P450-2C19
genotypes (2, 3, 4, 5, 6, 7, 8 & 17) and determines if a patient should be
prescribed clopidogrel as a therapy. The test offers eight different variants.
According to the recommendation from the American College of Cardiology on
genotyping for clopidogrel, genotyping may be considered for identifying poor
metabolizers in “moderate to high risk patients” as alternate therapies are available
(Holmes et al. 2010 ). In agreement with these recommendations, another publica-
tion pointed out that with stent thrombosis rates in carriers of CYP2C19 as high as
11 %, mortality associated with such events close to 50 %, and a near twofold
increase in the risk of bleeding in CYP2C1917 carriers, it makes clinical sense to
implement all potential interventions to help prevent the catastrophic outcomes of
stent thrombosis and death, rather than wait years for results from future prospective
trials to be initiated (The Case for Routine Genotyping in Dual-Antiplatelet Therapy
(Damani and Topol 2010 )).
Although the FDA recommended that CYP2C19 genotyping be considered prior
to prescribing clopidogrel, researchers from the UK have published a systematic
review and meta-analysis that casts doubt on the effectiveness of such testing
(Holmes et al. 2011 ). They showed that although there was an association between
the CYP2C19 genotype and clopidogrel responsiveness, there was no signifi cant
association of genotype with cardiovascular events. In response to this publication,
cardiologists from Scripps Health as well as colleagues from Vanderbilt University
and Hôpital Pitié-Salpetrière in Paris pointed out what they see as fl aws in the
review analysis. They especially take issue with a metaanalysis of stent thrombosis
associated with CYP2C19 loss-of-function alleles, in which the UK researchers
concluded “an absolute increase of 14 stent thromboses per 1,000 individuals”.
4 Pharmacogenetics