Clinical Impact of Pharmacogenomics of Clopidogrel in Stroke
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- outcome assessment (health care)
- platelet aggregation inhibitors
Article, see p 21
Despite progress in the diagnosis and treatment of stroke, it is estimated that >900 000 patients each year in the United States have a new stroke or transient ischemic attack (TIA) with an annual risk of 3% to 4% for recurrent events.1 The incidence of stroke or TIA is even higher in some countries such as China.2 Preventing stroke is therefore a major worldwide public health issue.
Clopidogrel, in addition to 3 weeks of aspirin therapy, has been effective in reducing the risk of recurrence at 3 months in Chinese patients with TIA or a minor acute ischemic stroke, mainly by reducing the risk of recurrent ischemic stroke.3 To become active, clopidogrel needs to be metabolized via a 2-step oxidation process involving several hepatic cytochrome P450 isoenzymes, notably CYP2C19, and irreversibly binds to P2Y12 receptors.4 Conversion of clopidogrel to its active metabolite depends on CYP2C19 genetic polymorphisms, with decreased platelet inhibition in carriers of 1 or 2 loss-of-function alleles (ie, intermediate or poor metabolizers).
Several studies have shown that in patients with acute coronary syndromes treated by clopidogrel, carriers of at least 1 CYP2C19 loss-of-function allele, notably CYP2C19*2, were at increased risk of major cardiovascular events and stent thrombosis, with a gene-dose relationship.5–8 Conversely, the CYP2C19*17 variant allele has been related to enhanced levels of active clopidogrel metabolites, greater inhibition of ADP-induced platelet aggregation, and increased risk of bleeding without an impact on ischemic events.9
The US Food and Drug Administration boxed warning in 2010 stated that CYP2C19 genotyping can be used as an aid in assessing the therapeutic safety and for considering alternative strategies to CYP2C19 poor metabolizers. From a clinical standpoint, however, the added value of assessing CYP2C19 polymorphisms depends on 3 factors: the …