Routine genotyping of patients on clopidogrel: Why the resistance?

Clopidogrel is a pro-drug which requires conversion by several hepatic cytochromeP450 (CYP) isoenzymes to its active metabolite, which then irreversibly binds to platelet P2Y12 receptors and inhibits platelet activation. There is considerable variability in the response to clopidogrel in clinical practice. Some genetic polymorphisms in the CYP enzymes, particularly CYP2C19, have consistently been shown to be associated with higher residual platelet reactivity and ischemic cardiovascular events while on treatment with clopidogrel. As prasugrel and ticagrelol are not metabolized by these enzymes, these polymorphisms have little effect on platelet reactivity and ischemic events with these agents. Given that the lossof-function CYP2C19*2 allele (the variant most reproducibly associated with a reduced response to clopidogrel) is highly prevalent in the general population, it is reasonable to ask why genomic testing should not be used routinely to guide the choice of antiplatelet therapy, as Rath and colleagues report in this issue of the Journal. The answer to this question is not as simple as it appears at first glance. There are several issues to consider when evaluating the utility of a diagnostic test. First and foremost is the ability of the test to discriminate reliably between people who have the condition of interest and those who don't. Second, the detected condition should be reasonably common so as to make testing for it worthwhile. Third, a “positive” test should consistently be associated with the relevant clinical outcome. Finally, knowledge of the test result should help in improving clinical outcomes through appropriate treatment. Genotyping for the isoenzymes involved in clopidogrel metabolism easily