Comments on: “Association of Clopidogrel Genetic Polymorphism With Efficacy and Safety for Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Updated Meta-Analysis”

Dear Editor,We read with great interest the systematic review and meta-analysis by Park et al. 1 examining the relationship between cytochrome P450 2C19 (CYP2C19) loss-of-function alleles and clinical outcomes in patients with ischemic stroke or transient ischemic attack receiving clopidogrel.The authors deserve recognition for synthesizing 28 studies encompassing 11,401 participants, integrating both observational and randomized data, and using robust statistical techniques such as the Hartung-Knapp-Sidik-Jonkman estimator to mitigate heterogeneity.The inclusion of the large Korean PLATELET trial and application of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework markedly strengthened the evidentiary base.However, several interpretive and translational aspects merit further consideration.First, exclusive reliance on aggregate-level data obscures patient-level heterogeneity in vascular risk, concomitant antiplatelet use, and follow-up duration.These variables critically modify clopidogrel responsiveness and recurrent event risk, yet cannot be fully adjusted through conventional subgroup meta-analysis. 2 Without an individual participant data approach, effect modification by dual therapy, CYP2C19 *17 alleles, or renal function may remain confounded, limiting precision for genotype-guided treatment decisions.Clinically, this constraint may overstate the uniformity of the recurrence risk across secondary prevention subgroups.Second, the ethnic stratification presented as "Asian versus non-Asian" amalgamates genetically distinct populations with divergent CYP2C19 allele frequencies and environmental determinants of platelet reactivity.Combining Han Chinese, Japanese, and Korean cohorts may inflate the apparent ancestry signal and obscure intra-Asian pharmacogenomic variability.3,4 Clinicians applying these pooled estimates risk overgeneralizing genotyping thresholds and therapeutic substitution strategies across ethnically diverse Asian patients.Third, bleeding outcomes were evaluated in only half of the included studies, and the heterogeneity in the definitions of hemorrhagic events-ranging from the Global Use of Strategies to Open Occluded Arteries (GUSTO) to trial-specific criteria-precludes meaningful safety inferences.Because the therapeutic dilemma in stroke prophylaxis lies in balancing ischemic and intracranial bleeding risks, the absence of harmonized endpoints undermines the translational value of the efficacy-safety ratio reported here.5 Clinically, individualized risk prediction integrating both genetic and bleeding propensity markers would provide more actionable guidance.Finally, while the authors noted parallel associations for ABCB1, P2Y12, PON1, and CE-