ELEVATE TIMI 56: One New Piece of the Clopidogrel Puzzle Reply

Jessica Mega

Tripling the maintenance dose of clopidogrel in most but not all patients with a common genetic variation will lower platelet reactivity to levels achieved in patients without the variation, according to results of the ELEVATE TIMI 56 trial. The finding helps solve one piece of the clopidogrel puzzle, but does not provide a path to a major change in clinical practice. Results of the trial were presented by Jessica Mega at the AHA and published simultaneously in JAMA.

The TIMI investigators randomized 333 patients already taking clopidogrel. After genetic screening, 86 carriers of the CYP2C19*2 loss-of-function allele received clopidogrel doses of 75, 150, 225, or 300 mg daily. 247 patients without the allele received 75 or 150 mg daily. After 14 days platelet function testing was performed.

The results show that tripling the maintenance dose to 225 mg daily achieved normal levels of platelet reactivity for the 80 heterozygotes with one loss-of-function allele. For the 6 homozygotes with two copies of the allele, however, the highest dose of 300 mg was  insufficient to achieve satisfactory platelet inhibition.

At an AHA news conference Mega said that the study offered some assistance to physicians if they are aware of a patient’s genotype. Carriers of one allele should be treated with higher dose clopidogrel while carriers of two alleles may be better served by prasugrel or ticagrelor. Mega acknowledged, however, that the trial offered no practical advice about when or how to perform genetic testing, a topic that is the subject of considerable uncertainty and controversy.

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