Reply: Subclassification of CYP2C19 Genotyping for Better-Adjusted Thienopyridine Treatment

Drs. Cha and Lim implicitly raise the question of a possible interethnic difference in the influence of CYP2C19 genetic variants and consequently in genotype-guided adjustment of antiplatelet therapies. The GIANT (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment) prospective, multicenter, observational study (1) mainly enrolled white Caucasians, and our results might not apply to other ethnic groups, notably East Asians as investigated in the study of Joo et al.. The results of the GIANT study are consistent with other studies conducted in Caucasians but might indeed differ from studies conducted in other ethnic groups. As compared with Caucasians, Asian population are reported to have a greater prevalence of CYP2C19 loss-of-function (LOF) alleles (with an incidence of at least 1 LOF allele estimated in Asians of 54 %, compared with 28 % in Caucasian).
Similarly, east Asian patients have a lower ischemic rate and a higher bleeding rates after percutaneous coronary intervention despite a higher level of platelet reactivity during dual antiplatelet therapy, as well as different pharmacological responses to antiplatelet agents. We thus agree that our conclusions should not be exported to non-Caucasian populations.
Drs. Cha and Lim rightfully pointed out that we provided to the clinician the genotype and a recommendation based on the predicted CYP2C19 metabolic status, in line with current guidelines. The adjustment of antiplatelet therapy was thus not made on subclassification of CYP2C19 genotypes. This pragmatic strategy was intentionally selected to facilitate the implementation of CYP2C19 genotyping into practice, a strategy that was further tested with success in the GIANT trial. We performed a series of additional analyses and found that our results were consistent across the different classes of CYP2C19 metabolic status or according to CYP2C19∗2 or ∗17 genetic variants (i.e., the most frequent variants in our patients). We agree that detailed subclassification of CYP2C19 genotyping could further help in adjusting thienopyridine treatments. In the GIANT trial, which included 1,500 patients, we tested for 6 different CYP2C19 genetic variants, with the identification of 13 genetic combinations, among which 6 were found in <1% of patients. Therefore, future studies would have to include a larger number of patients in order to identify those with rare (<1% frequency) CYP2C19 genotypes and provide evidence for appropriate genotype-guided drug adjustments in those patients.