August 29th, 2010
Genetic Substudies of Large Trials Question Value of Clopidogrel Genotyping
Genetic substudies across a broad range of large clinical trials that used clopidogrel raise questions about the clinical utility of clopidogrel genotyping. The substudies come from large and important trials like PLATO, TRITON-TIMI 38, CURE, and ACTIVE A.
A genetic substudy of PLATO finds that ticagrelor is superior to clopidogrel irrespective of genetic subtype. Therefore, according to Lars Wallentin and colleagues in their presentation at the ESC in Stockholm and in a simultaneous publication in the Lancet, “use of ticagrelor instead of clopidogrel eliminates the need for presently recommended genetic testing before dual antiplatelet treatment.” Wallentin et al. analyzed the role of CYP2C19 and ABCB1 polymorphisms in more than 10,000 patients enrolled in PLATO. Among patients with any CYP2C19 variation, the primary endpoint occurred less often in those treated with ticagrelor than in those treated with clopidogrel (8.6% vs. 11.2%). A similar pattern occurred with ABCB1.
In a Lancet press release, Wallentin said that the “findings emphasise that ticagrelor will be a simple and reliable treatment to further improve survival and reduce the risk of recurrences in almost all patients with acute coronary syndrome without the need for any specific tests of its activity before or during routine treatment.”
In a second study appearing in the Lancet, Jessica Mega and colleagues genotyped ABCB1 in nearly 3000 patients enrolled in the TRITON-TIMI 38 trial comparing prasugrel with clopidogrel. They also examined the combined effect of ABCB1 variants and CYP2C19 variants and found that a majority of people have a genetic variation that may reduce the efficacy of clopidogrel. In sharp contrast to the PLATO investigators, they conclude that “as clinicians, professional societies, and patients integrate information about genetic factors affecting the response to thienopyridines, the roles of both ABCB1 and CYP2C19 should be considered.”
In an accompanying comment in the Lancet, Betti Giusti and Rosanna Abbate observe that both studies “confirmed the independent role of the CYP2C19 loss-of-function alleles as a determinant of major adverse cardiovascular events in these patients on clopidogrel… whereas they did not show any effects of CYP2C19 genetic variants in patients on prasugrel or ticagrelor.”
In a third paper, published online in the New England Journal of Medicine, Guillaume Paré and colleagues genotyped patients who had been enrolled in the CURE and ACTIVE A trials and found no reduction in the effect of clopidogrel among patients with a loss-of-function CYP2C19 genotype, although patients with a gain-of-function genotype received greater benefit from clopidogrel.