European journal of clinical pharmacology · 2026
Recent research progress on the mechanisms of clopidogrel resistance.
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Wu Chunrong, Huang Xinyi, Zhu Guoliang, Cao Qing, Yang Yali, Li Hewei, Hu Yali, Lin Yapeng, Hao Junli, Chen Kejie, Wang Lingling, Li Jiangmin, Tan Quandan, Yang Jie
Аннотация
PURPOSE: To narratively review recent advances in clopidogrel resistance, including genetic determinants, epigenetic regulation, clinical modifiers, and methods of assessment. Particular attention is given to distinguishing laboratory-defined high on-treatment platelet reactivity (HTPR) from clinical treatment failure, with the aim of supporting risk assessment and individualized antiplatelet therapy.
METHODS: PubMed was searched from inception to August 23, 2026, using combinations of "clopidogrel resistance," "high on-treatment platelet reactivity," "CYP2C19," "pharmacogenetics," "epigenetics," "miRNA," "clinical risk factors," "drug interactions," "gut microbiota," and "platelet-function testing." Targeted searches of reference lists and publisher websites identified recent guidelines and online-ahead-of-print articles not yet indexed in PubMed. Peer-reviewed original human studies and relevant experimental studies, guidelines, and foundational reports were included when they addressed clopidogrel pharmacokinetics, pharmacodynamics, biomarkers, or clinical modifiers; duplicates, case reports, conference abstracts, and reports without direct relevance were excluded. As this was a narrative review, no formal risk-of-bias score was applied; evidence was appraised qualitatively by study design, sample size, confounding control, replication, and whether outcomes were laboratory or clinical.
RESULTS: CYP2C19 loss-of-function alleles remain the principal pharmacokinetic determinant of reduced clopidogrel responsiveness by impairing two-step bioactivation, although they explain only 12%-20% of interindividual variability. HTPR, defined as residual platelet reactivity above an assay- and study-specific threshold during treatment, has been reported in approximately 20%-45% of clopidogrel-treated patients; this range reflects heterogeneous platforms and cutoffs rather than a harmonized prevalence estimate. In this review, HTPR is treated as a laboratory pharmacodynamic surrogate, whereas clinical treatment failure denotes an adjudicated ischemic event during therapy. Competing CES1-mediated hydrolysis and transporter activity involving ABCB1 and ABCC2 may further modify exposure, whereas P2RY12 and platelet-signaling variants predominantly affect pharmacodynamic responsiveness. Epigenetic mechanisms, inflammation, metabolic comorbidity, concomitant medications, and food interactions may also influence active-metabolite formation or platelet reactivity.
CONCLUSION: Clopidogrel resistance is multifactorial and extends beyond CYP2C19 genotype. Laboratory-defined HTPR should not be equated with clinical treatment failure, because ischemic outcomes also depend on baseline risk, adherence, comorbidity, and concomitant therapy. Integrating validated genetic, laboratory, and clinical information may improve individualized antiplatelet strategies.
METHODS: PubMed was searched from inception to August 23, 2026, using combinations of "clopidogrel resistance," "high on-treatment platelet reactivity," "CYP2C19," "pharmacogenetics," "epigenetics," "miRNA," "clinical risk factors," "drug interactions," "gut microbiota," and "platelet-function testing." Targeted searches of reference lists and publisher websites identified recent guidelines and online-ahead-of-print articles not yet indexed in PubMed. Peer-reviewed original human studies and relevant experimental studies, guidelines, and foundational reports were included when they addressed clopidogrel pharmacokinetics, pharmacodynamics, biomarkers, or clinical modifiers; duplicates, case reports, conference abstracts, and reports without direct relevance were excluded. As this was a narrative review, no formal risk-of-bias score was applied; evidence was appraised qualitatively by study design, sample size, confounding control, replication, and whether outcomes were laboratory or clinical.
RESULTS: CYP2C19 loss-of-function alleles remain the principal pharmacokinetic determinant of reduced clopidogrel responsiveness by impairing two-step bioactivation, although they explain only 12%-20% of interindividual variability. HTPR, defined as residual platelet reactivity above an assay- and study-specific threshold during treatment, has been reported in approximately 20%-45% of clopidogrel-treated patients; this range reflects heterogeneous platforms and cutoffs rather than a harmonized prevalence estimate. In this review, HTPR is treated as a laboratory pharmacodynamic surrogate, whereas clinical treatment failure denotes an adjudicated ischemic event during therapy. Competing CES1-mediated hydrolysis and transporter activity involving ABCB1 and ABCC2 may further modify exposure, whereas P2RY12 and platelet-signaling variants predominantly affect pharmacodynamic responsiveness. Epigenetic mechanisms, inflammation, metabolic comorbidity, concomitant medications, and food interactions may also influence active-metabolite formation or platelet reactivity.
CONCLUSION: Clopidogrel resistance is multifactorial and extends beyond CYP2C19 genotype. Laboratory-defined HTPR should not be equated with clinical treatment failure, because ischemic outcomes also depend on baseline risk, adherence, comorbidity, and concomitant therapy. Integrating validated genetic, laboratory, and clinical information may improve individualized antiplatelet strategies.