ABSTRACT NUMBER: ESOC2026A945 CLOPIDOGREL HIGH ON-TREATMENT PLATELET REACTIVITY (HTPR) AND PHARMACOGENETICS PROFILING IN TIA/ISCHAEMIC STROKE PATIENTS: SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and aims Clopidogrel, a ‘pro-drug’, requires conversion by the cytochrome P450 enzyme system to its active metabolite. NICE(UK) 2024 guidelines recommend genotyping alone, especially for CYP2C19*2/*3 Loss of Function (LOF) Single Nucleotide Polymorphisms (SNPs), in TIA/ischaemic stroke patients, without assessment of Clopidogrel-High on-Treatment Platelet Reactivity (HTPR) status. Methods A Systematic Review and Meta-Analysis was performed to analyse subgroup data from 12 eligible prospective studies in cerebrovascular disease (CVD) patients on clopidogrel monotherapy/combination therapy, which included clopidogrel-HTPR status and CYP2C19 genotyping. Primary composite outcome: Subsequent ischaemic stroke/TIA/myocardial infarction/vascular death. Outcomes were pooled using a restricted maximum likelihood random-effects model with inverse-variance weighting to calculate Risk Ratios (RR) with 95% confidence intervals (CI). Results Clopidogrel-HTPR status predicted outcomes in 6 studies, Pharmacogenetics profiling alone predicted outcomes in 1 study, both Clopidogrel-HTPR and Pharmacogenetics status predicted outcomes in 1 study, and 4 studies showed that neither Clopidogrel-HTPR or Pharmacogenetics profiling predicted outcomes. All were conducted in China or Japan, and were small-medium in size (N=131-501). Meta-analyses showed a statistically-significant increase in the risk of the primary outcome in CVD patients with vs. without Clopidogrel-HTPR on clopidogrel monotherapy or combination therapy (RR ≥ 1.93; 95%CI: 1.58-2.36), with no statistically-significant increase in risk in patients with vs. those without CYP2C19-LOF SNPs (RR ≥1.36; 95%CI: 0.94-1.98). Conclusions The weight of current evidence supports conducting well-designed prospective studies to formally assess the strategy of combining data from platelet reactivity testing with CYP2C19 genotyping to guide precision-based secondary preventive therapy in CVD patients. Conflict of interest No conflict of interest. Our research work is supported by grant funding from several charities and organisations, including the Meath Foundation; The Adelaide Health Foundation; an Enterprise Ireland Innovation Partnership Programme grant with Acquis BI Technology, Ltd.; the VNRF; and in-kind contributions from Werfen, Spain; Sysmex Ireland-UK; Sinnowa, China; Genomadix Inc., Canada and Acquis BI Technology Ltd.