Recent research progress on the mechanisms of clopidogrel resistance.

CYP2C19

Two-step clopidogrel bioactivation dependent on CYP2C19, modulated by hydrolysis via the carboxylesterase encoded by CES1, the ABCB1 and ABCC2 transporters, and P2RY12 variants.

This narrative review surveys the determinants of clopidogrel resistance, based on a PubMed search to 23 August 2026 supplemented by reference lists and publisher websites. CYP2C19 loss-of-function alleles remain the principal pharmacokinetic determinant but explain only 12% to 20% of interindividual variability. High on-treatment platelet reactivity is reported in roughly 20% to 45% of patients, a range that mostly reflects heterogeneous platforms and cut-offs rather than a harmonised prevalence. The authors stress the distinction between this laboratory surrogate and clinical treatment failure defined by an adjudicated ischaemic event, and recall the role of CES1, the ABCB1 and ABCC2 transporters, P2RY12 variants, inflammation, metabolic comorbidity, and drug and food interactions.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a narrative review, with no registered protocol and no count of included studies, so it carries no evidential weight of its own — yet it renders a precise clinical service by refusing to equate residual platelet reactivity with treatment failure, a confusion that still drives unjustified treatment switches. The reminder that CYP2C19 explains only 12% to 20% of variability is the useful counterpoint to enthusiasm for genotyping alone. For prescribers nothing changes in management: genotype remains one element among others, to be integrated with baseline risk, adherence and co-medications.

Analysis by Dr Thibaut Benquey