Ethnicity, trial era, and timing: reappraising heterogeneity in the clopidogrel vs aspirin meta-analysis for chronic coronary syndromes

This commentary refers to ‘Aspirin vs clopidogrel in chronic coronary syndromes: a meta-analysis of ethnic differences’, by C. Laudani et al., https://doi.org/10.1093/eurheartj/ehag351 and the discussion piece ‘Rethinking Antiplatelet Evidence Through the Lens of Ethnicity’, by C. Laudani and M. Galli, https://doi.org/10.1093/eurheartj/ehag527 We read with great interest the systematic review and meta-analysis by Laudani et al.,1 which challenges the long-standing role of aspirin for secondary prevention in chronic coronary syndromes (CCS) by suggesting clopidogrel may offer superior ischaemic protection, particularly in East Asian populations. We commend the authors for their rigorous approach and for highlighting the critical issue of ethnicity in antiplatelet therapy. However, we wish to highlight several points that may be worth considering alongside the main conclusions. First, the non-East Asian trials, CAPRIE (enrolling patients with myocardial infarction onset ≤35 days prior to randomization), CADET (comparing clopidogrel 75 mg/day vs aspirin 75 mg/day over a 6-month period in patients with acute myocardial infarction occurring 3–7 days before enrolment, with exclusion of those scheduled for coronary artery bypass grafting or major surgery), and ASCET (patients with angiographically documented stable chronic coronary syndrome on long-term aspirin therapy), were conducted between 1996 and 2012. These trials enrolled few, if any, percutaneous coronary intervention (PCI)-treated patients and involved nearly no stent implantation. In contrast, the East Asian trials (HOST-EXAM, STOPDAPT-2, and SMART-CHOICE 3) are all contemporary, and all enrolled stabilized patients after PCI with drug-eluting stent (DES) implantation.2–4 The observed interaction by ethnicity may therefore largely reflect differences in background medical therapy, completeness of revascularization, and timing of randomization, not ethnicity alone. A sensitivity analysis grouping trials by era (older vs contemporary) might yield similar effect modification, suggesting the findings are not uniquely attributable to East Asian ethnicity but rather to contemporary CCS management.