Clopidogrel is an inhibitor of the platelet P2Y12 receptor that requires activation by specific cytochrome P-450 (CYP) enzymes. Specifically, reduced responsiveness has been associated with specific alleles of the CYP2C19 and CYP3A4 genes.
In one study, from France, it was found that patients carrying any two CYP2C19 loss of function alleles had higher event rates after acute MI when treated with clopidogrel than those who did not carry such alleles. In the other study, from Boston, carriers of at least one CYP2C19 loss of function allele who were treated with clopidogrel had higher risk of stent thrombosis, death from MI and stroke as compared to non-carriers.
(Prasugrel, another P2Y12 inhibitor not yet on the U.S. market, appears to be unaffected by CYP2C19 variability. Recently, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to approve prasugrel for the treatment of patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Prasugrel is accompanied by an increased risk of serious bleeding events compared to clopidogrel.)
As the accompanying NEJM editorial noted, it is not yet clear whether routine genetic testing should be performed when considering drug treatment with clopidogrel.
Here is a link to the editorial: http://content.nejm.org/cgi/
Here are the links to the articles:
One more caveat: The CYP2C19 enzyme referred to above is not the same as the CYP2C9 enzyme involved in the metabolism of warfarin, single nucleotide polymorphisms of which have been implicated in the variability of dosing that some people require when being treated with warfarin.
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