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March 14, 2012

Clopidogrel Dosing Based on Genotype—Reply

Author Affiliations

Author Affiliations: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts (jmega@partners.org).

JAMA. 2012;307(10):1024-1025. doi:10.1001/jama.2012.282

In Reply: Drs Alexopoulos and Xanthopoulou ask about the timing of the intervention in ELEVATE-TIMI 56 relative to the patients' clinical course. The aim of ELEVATE-TIMI 56 was to evaluate whether higher maintenance doses of clopidogrel could improve the pharmacological response in the setting of loss-of-function CYP2C19 genotypes. Thus, by design, patients were in the maintenance phase of P2Y12 adenosine diphosphate (ADP) receptor blockade therapy and were enrolled between 4 weeks and 6 months following PCI or acute MI. Clinical circumstances such as PCI or acute MI can affect platelet reactivity. Therefore, the protocol specified that enrollment should occur at a time in which platelet reactivity should have stabilized to minimize the risk of these clinical circumstances influencing results with the different doses of clopidogrel, which were administered in various temporal sequences. The findings in ELEVATE-TIMI 56, which evaluated maintenance doses of clopidogrel, are consistent with the findings of the Clopidogrel and Response Variability Investigation Study 2 (CLOVIS-2), which evaluated loading doses of clopidogrel.1 Both trials demonstrated that on average a tripling of the clopidogrel dose in carriers of a CYP2C19 loss-of-function allele was required to achieve a degree of platelet inhibition comparable with what was observed in response to the standard clopidogrel doses in noncarriers.1