Therapeutic advances in neurological disorders · 2026
Paradoxical myocardial infarction risk with dual antiplatelet therapy in East Asian ischaemic stroke: a nationwide real-world cohort study and pharmacogenomic risk prediction model.
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Yang Chien-Tung, Lin Jung-Ju, Chen Paul J, Hsu Wei-Lin, Chen Der-Cherng, Lin Yu-Hsiang, Chen Chao-Hsuan, Lin Cheng-Li, Huang Hsiang-Ming, Chen XianXiu
Аннотация
BACKGROUND: Antithrombotic guidelines for secondary stroke prevention are derived predominantly from Western populations, yet East Asian patients exhibit markedly higher cytochrome P450 2C19 (CYP2C19) loss-of-function allele prevalence (50%-60% vs ~25% in Europeans) - polymorphisms essential for clopidogrel bioactivation - potentially generating population-specific cardiovascular risks not captured in Western-derived recommendations.
OBJECTIVES: To characterise the 100-day cardiovascular safety and effectiveness of antithrombotic regimens in East Asian ischaemic stroke patients and to develop a pharmacogenomically informed clinical risk prediction model.
DESIGN: Nationwide retrospective cohort study.
METHODS: We analysed 5746 adults from Taiwan's National Health Insurance Research Database (2011-2020) stratified by antithrombotic regimen initiated within 48 h of confirmatory neuroimaging. Primary outcomes - recurrent ischaemic stroke, haemorrhagic stroke, acute myocardial infarction, heart failure and all-cause mortality - were assessed over 100 days. Multivariable Cox regression, propensity score matching, inverse probability weighting, Fine-Gray competing risks models, E-value bias quantification and negative control outcome analysis were applied. The East Asian Post-Stroke Antithrombotic Risk (EPSAR) score was developed incorporating age, sex, comorbidities and treatment regimen.
RESULTS: Dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) was associated with a 17.2-fold increased acute myocardial infarction risk versus aspirin monotherapy (95% confidence interval (CI) 5.61-52.7; number needed to harm 14). This signal was robust across all analytical approaches (propensity-matched hazard ratio (HR) 11.8; inverse probability of treatment weighting HR 13.4; competing-risks subdistribution HR 14.8) and yielded an E-value of 33.4, substantially exceeding the strength of known clinical confounders. Warfarin-containing regimens conferred markedly elevated haemorrhagic stroke risk (HR 7.11-8.77). Aspirin monotherapy demonstrated a 94% all-cause mortality reduction versus no treatment. Negative control outcomes showed no systematic bias (joint test p = 0.98). The EPSAR model achieved a C-statistic of 0.78 (95%CI 0.72-0.84).
CONCLUSION: DAPT is associated with unexpected myocardial infarction risk in East Asian stroke patients, consistent with CYP2C19-mediated pharmacogenomic vulnerability. These findings challenge the universal applicability of Western-derived guidelines and support integration of pharmacogenomic risk stratification into antithrombotic prescribing for East Asian populations.
CLINICAL TRIAL REGISTRATION: Not applicable (observational study).
OBJECTIVES: To characterise the 100-day cardiovascular safety and effectiveness of antithrombotic regimens in East Asian ischaemic stroke patients and to develop a pharmacogenomically informed clinical risk prediction model.
DESIGN: Nationwide retrospective cohort study.
METHODS: We analysed 5746 adults from Taiwan's National Health Insurance Research Database (2011-2020) stratified by antithrombotic regimen initiated within 48 h of confirmatory neuroimaging. Primary outcomes - recurrent ischaemic stroke, haemorrhagic stroke, acute myocardial infarction, heart failure and all-cause mortality - were assessed over 100 days. Multivariable Cox regression, propensity score matching, inverse probability weighting, Fine-Gray competing risks models, E-value bias quantification and negative control outcome analysis were applied. The East Asian Post-Stroke Antithrombotic Risk (EPSAR) score was developed incorporating age, sex, comorbidities and treatment regimen.
RESULTS: Dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) was associated with a 17.2-fold increased acute myocardial infarction risk versus aspirin monotherapy (95% confidence interval (CI) 5.61-52.7; number needed to harm 14). This signal was robust across all analytical approaches (propensity-matched hazard ratio (HR) 11.8; inverse probability of treatment weighting HR 13.4; competing-risks subdistribution HR 14.8) and yielded an E-value of 33.4, substantially exceeding the strength of known clinical confounders. Warfarin-containing regimens conferred markedly elevated haemorrhagic stroke risk (HR 7.11-8.77). Aspirin monotherapy demonstrated a 94% all-cause mortality reduction versus no treatment. Negative control outcomes showed no systematic bias (joint test p = 0.98). The EPSAR model achieved a C-statistic of 0.78 (95%CI 0.72-0.84).
CONCLUSION: DAPT is associated with unexpected myocardial infarction risk in East Asian stroke patients, consistent with CYP2C19-mediated pharmacogenomic vulnerability. These findings challenge the universal applicability of Western-derived guidelines and support integration of pharmacogenomic risk stratification into antithrombotic prescribing for East Asian populations.
CLINICAL TRIAL REGISTRATION: Not applicable (observational study).