Functional Clopidogrel Resistance and CYP2C19 Genetic Determinants After Lower Limb Endovascular Intervention: A Systematic Review and Meta-analysis of Clinically Relevant Outcomes.

CYP2C19 loss-of-function alleles reduce clopidogrel bioactivation, resulting in high on-treatment platelet reactivity and an increased risk of repeat revascularization.

This systematic review and meta-analysis, conducted according to PRISMA 2020 and registered in PROSPERO (CRD42026129845), searched MEDLINE, EMBASE, Web of Science and Google Scholar from inception to May 17, 2026, to assess the link between functional clopidogrel resistance and limb outcomes after lower-limb endovascular intervention. Functional resistance was defined as high on-treatment platelet reactivity (HTPR) on platelet function testing, and genetic determinants as CYP2C19 loss-of-function alleles or associated metabolizer status. Ten studies were included, 6 functional studies contributing to the quantitative synthesis; in the primary analysis based on 3 studies with raw event data, HTPR was associated with a 3.68-fold risk of target lesion or target vessel revascularization (95% CI 1.56-8.68; P = 0.003; I² = 59%), directionally consistent with the exploratory analysis of 5 studies (OR 4.46; 95% CI 1.09-18.31; I² = 87%). Hartung-Knapp-Sidik-Jonkman sensitivity analyses preserved the direction of effect but yielded confidence intervals crossing the null, and HTPR was not associated with all-cause mortality (OR 1.49; 95% CI 0.92-2.42); genetic studies were synthesized qualitatively only.

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

The methodology is beyond reproach - registered protocol, explicit separation of raw event data from published effect estimates, conservative sensitivity analyses - and it is precisely that rigour which makes the result cautious: only three studies carry the primary analysis, and the confidence interval crosses the null as soon as HKSJ is applied. What holds me back is that the CYP2C19 side could not be meta-analysed and remains qualitative: the paper documents an association between platelet phenotype and revascularization, not a demonstrated utility of genotyping in peripheral arterial disease. Clinically, this does not yet justify extending to this setting the genotype-guided strategies validated in interventional cardiology.

Analysis by Dr Thibaut Benquey