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

PURPOSE: Clopidogrel is a cornerstone of antiplatelet therapy after lower-limb endovascular intervention in patients with peripheral arterial disease (PAD), yet interindividual variability in treatment response may influence clinical outcomes. To our knowledge, this is the first systematic review and meta-analysis to combine an updated quantitative synthesis of functional clopidogrel resistance with a dedicated qualitative appraisal of CYP2C19 genetic determinants, while explicitly separating analyses based on raw event data from exploratory analyses using published effect estimates and applying conservative small-sample sensitivity methods. We evaluated the association between functional clopidogrel resistance and clinically relevant limb outcomes-target lesion/target vessel revascularization (TLR/TVR) and major adverse limb events (MALE)-with all-cause mortality as a secondary exploratory outcome. METHODS: The review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD42026129845). MEDLINE (PubMed), EMBASE, Web of Science, and Google Scholar were searched from inception to May 17, 2026. Functional resistance was defined as high on-treatment platelet reactivity (HTPR) assessed by platelet function testing, and genetic determinants as CYP2C19 loss-of-function alleles or metabolizer status associated with impaired clopidogrel response. Random-effects meta-analyses using restricted maximum likelihood (REML) were performed, with Hartung-Knapp-Sidik-Jonkman (HKSJ) sensitivity analyses and prediction intervals to quantify statistical uncertainty in sparse data. Genetic studies were synthesized qualitatively. FINDINGS: Ten studies met the inclusion criteria; 6 functional studies contributed to the quantitative analyses. In the primary analysis based on 3 studies with raw event data, HTPR was associated with an approximately 3.7-fold increase in TLR/TVR risk (odd ratios [OR] 3.68; 95% confidence interval [CI] 1.56-8.68; P = 0.003; I² = 59%). An exploratory analysis of 5 studies with published effect estimates was directionally consistent (OR 4.46; 95% CI 1.09-18.31; I² = 87%). HKSJ sensitivity analyses preserved the direction of effect but produced substantially wider confidence intervals crossing the null, indicating increased statistical uncertainty. HTPR was not significantly associated with all-cause mortality (OR 1.49; 95% CI 0.92-2.42). IMPLICATIONS: Functional clopidogrel resistance may be associated with an approximately 3- to 4-fold higher risk of repeat revascularization after lower-limb endovascular intervention; however, the small number of studies, substantial heterogeneity, and conservative sensitivity analyses warrant cautious interpretation. Larger prospective studies and randomized trials are needed before platelet-function-guided or genotype-guided antiplatelet strategies can be recommended. PROSPERO REGISTRATION: CRD42026129845.