Comment on ‘comparative effectiveness of clopidogrel vs. potent P2Y12 inhibitors in CYP2C19 normal metabolizers following percutaneous coronary intervention: A real‐world cohort study’

We read with great interest the article titled ‘Comparative Effectiveness of Clopidogrel vs. Potent P2Y12 Inhibitors in CYP2C19 Normal Metabolizers Following Percutaneous Coronary Intervention: A Real-World Cohort Study’.1 We commend the authors for employing a pragmatic study design that is firmly anchored in real-world evidence. Notably, the study leverages Taiwan's largest genetic database and corroborates its findings through comprehensive sensitivity analyses, thereby enhancing the validity and robustness of the results. However, additional facets of the study warrant systematic evaluation to provide a more comprehensive understanding; residual confounding from unmeasured factors, such as adherence and socioeconomic status, could bias the results, which remain unaddressed beyond IPTW. The long recruitment window (2004–2020) spans multiple eras of stent technology, drug availability and procedural practice, which may confound treatment comparisons. Newer generation DES, evolving PCI techniques, changing DAPT guidelines and the staggered introduction of potent P2Y₁₂ inhibitors could each influence thrombotic and bleeding rates independent of antiplatelet choice. Moreover, the bleeding endpoint captured hospitalizations for intracranial and gastrointestinal bleeding, potentially underrepresenting clinically relevant nonhospitalized bleeding; if such events differ by treatment group, misclassification may further distort effect estimates. What is unclear is when pharmacogenomic testing is routinely done in Taiwan; was the use of clopidogrel or potent drugs based on this testing, or was the testing done later over the treatment course? The data for bleeding events with the potent drugs is consistently lower than that with clopidogrel, contrary to what is expected. Is this due to genetic factors unique to the East Asian population or an unidentified confounder? Although the authors emphasize genotype-guided de-escalation strategies, their findings indicate that CYP2C19 normal metabolizers achieved favourable ischemic outcomes without excess bleeding during the first year, thereby questioning the necessity of switching to clopidogrel. As the primary rationale for de-escalation is bleeding reduction, the absence of increased bleeding events renders the argument somewhat inconsistent, although it is appropriate to suggest the need for caution given the study limitations and the need to test this prospectively. We also note that the details regarding funding sources/potential conflicts of interest were not disclosed in the paper. Clarifying these issues will help in better understanding of the research findings and enhance its validity. M.R. and A.K. contributed to the study conception and interpretation. Both drafted and critically revised the manuscript, approved the final version, and accept responsibility for its accuracy and integrity. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.