This question arrived last week in the American Society for Clinical Laboratory Science Consumer Forum: “I would like to know the differences between platelet aggregation testing and pharmacogenetic testing of CYP2C19 for clopidogrel. In 2010, the FDA issued a black box warning for clopidogrel in persons who are CYP2C19 poor metabolizers. I am very interested in what the results for both tests reveal and when these tests would be appropriate. Thank you.”
Here is the answer I provided: Clopidogrel (Plavix) is a “prodrug,” which means it is converted by the CYP2C19 enzyme pathway to its active form. The function of the active form is to suppress platelet activity, helping to control and reduce thrombosis. Clopidogrel suppresses a different platelet activation pathway than aspirin, so the two are usually prescribed together. Clopidogrel and aspirin are widely used to prevent a second adverse event in someone who has experienced an acute myocardial infarction.
About 15% of us have a polymorphism that causes us to metabolize clopidogrel more slowly than the rest, and the FDA black box encourages but doesn’t absolutely require physicians to order lab assays to detect the slow metabolizers and raise the clopidogrel dosage from 75 to 150 mg/day or switch to prasugrel (Effient) which is administered in its active form. The pharmacogenetic assay directly identifies the slow metabolizer polymorphism through molecular diagnostic techniques, mostly performed at reference laboratories using patient DNA, whereas platelet aggregometry (platelet clumping and secretion) is available in most larger, tertiary care institutions and is performed on fresh whole blood. The assay most commonly used is the Accumetrics VerifyNow test, which is popular because it is available as a point of care test and is FDA-cleared. The molecular assay may subsequently ordered as a confirmatory assay when the VerifyNow indicates slower clopidogrel response.
In theory, everyone who starts on clopidogrel could be screened for metabolic rate, however the requirement went “up for grabs” this fall when two large clinical trials reported at the American Heart Association annual meeting concluded that clopidogrel monitoring and dose change (or medication change) had no effect on long-term outcomes. Notably, one of the studies showed that monitoring and dosage change actually raised the risk of death/acute myocardial infarction/stent thrombosis/stroke/and need for urgent revascularization, an unexpected finding that has dampened everyone’s enthusiasm for monitoring. Tthese findings have triggered additional research, and you will be reading more in the future.
I’d like to hear from our participants about their experience with monitoring clopidogrel efficacy, and will forward your comments to the inquirer. Geo.