Re: 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 appreciate thoughtful commentary on our systematic review and updated meta-analysis of CYP2C19 polymorphisms and the efficacy and safety of clopidogrel in patients with ischemic stroke or transient ischemic attack (TIA). 1 Their commentary raises important methodological and translational issues that are central to the safe implementation of pharmacogenomics in secondary stroke prevention, and we thank for the opportunity to respond.First, we fully agree that individual participant data (IPD) meta-analysis is the optimal approach to explore heterogeneity in vascular risk, renal function, stroke mechanism, antiplatelet regimen, follow-up duration and genetic variants such as CYP2C19 *17 alleles. 2 However, our analysis was constrained to aggregate data reported in the original publications, limiting our formally adjust for these effect modifiers.1,3 Consequently, we interpreted our results as average effects across heterogeneous real-world settings and diverse populations and explicitly framed the findings as a foundation evidence rather than a prescriptive algorithm.Therefore, as highlighted in our discussion, future well-designed randomized clinical trials or IPD meta-analyses are warranted.Second, we acknowledged that the category "Asian versus non-Asian" is an imperfect surrogate that may obscure underlying genetic and environmental diversity.However, it is important to note that our "Asian" cohort was predominantly East Asian.Among 22 studies included in the Asian category, 21 were performed in China, Korea, or Japan, with only one study from Saudi Arabia.Given that East Asian populations share a similarly high prevalence of CYP2C19 loss-of-function alleles compared to other Asian subgroup we believe our findings accurately reflect the pharmacogenomic association within specific East Asian context, although they should not be extrapolated to all Asian populations.4,5 To fully disentangle ancestry-related differences and avoid overgeneralization, consistent with our response to the first comment, we believe that IPD meta-analyses are warranted.Building an international consortium to harmonize genotypes, clinical characteristics, and outcomes across diverse regions would allow us to move much closer to a definitive conclusion.Third, we share the concern that bleeding outcomes in the available literature are limited and heterogeneous.As noted, only 14 of 28 studies in our meta-analysis reported hemorrhagic events, and the variability in definitions (e.g., Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries vs. trial-specific criteria) precludes a granular safety analysis.1 Consequently, we deliberately presented our safety conclusions with caution, acknowledging that the current evidence base is stronger efficacy than for safety.We fully agree that the therapeutic dilemma lies in balancing ischemic reduction against intracranial hem-