CYP2C19 defines clopidogrel response in patients undergoing percutaneous neurointervention procedure

Abstract

Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.[Introduction]: Clopidogrel is a widely prescribed thienopyridine prodrug which inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients who are given a stent implant in carotid, vertebral or cranial arteries. CYP2C19 is the most studied enzyme involved in clopidogrel metabolism. The most common CYP2C19 no function polymorphisms (*2 and *3) have been associated with hyporesponse to clopidogrel, showing lower levels of the active metabolite. On the contrary, the presence of the increased function allele (*17) has demonstrated enhanced platelet inhibition and clopidogrel hyperresponse.[Methods]: This observational retrospective study assessed antiplatelet response and clinical events after clopidogrel treatment in patients who underwent percutaneous neurointervention, related to CYP2C19 metabolizer status (normal (NM), intermediate/poor (IM-PM) and ultra-rapid (UM); inferred from *2, *3 and *17 allele determination by real-time PCR).[Results]: One hundred twenty-three patients were analysed, of which 83% had cardiovascular risk factors. The most common type of intervention was angioplasty with stent. According to the aggregation value, 58.7% of the patients were responders to clopidogrel; moreover, 4.1% required dose reduction and 12.2% change of treatment. CYP2C19 IM-PM had higher aggregation value (201.1 vs 137.6 NM, 149.4 UM, p<0.05) and lower response rate (37.5% vs. 69.8% NM, 61.1% UM), along with higher treatment change rate (25% vs. 5.7% NM, 10.5% UM). Moreover, 20% of the patients suffered from a subsequent clinical event. The highest ischemic events incidence occurred in NM (11.3% vs. 6.3% IM, 10.5% UM; p=0.358) and haemorrhagic events in UM (13.2% vs. 0% IM and 3.8% NM; p=0.041). No differences found regarding ischemic events’ onset time, while haemorrhagic events’ frequency in UM was higher with shorter onset time (p=0.047). Additionally, 53% of the patients were receiving concomitant treatment with proton-pump inhibitors (PPIs), which showed significantly higher aggregation value when compared to those not receiving PPI concomitant treatment (178.1 vs. 134.4; p=0.009).[Conclusion]: CYP2C19 no function and increased function alleles defined clopidogrel response. CYP2C19 genotyping and platelet reactivity quantification help to determine whether a patient could be at risk of ischemic or haemorrhagic event. CYP2C19 UM patients have increased bleeding risk after percutaneous neurointervention. Therapeutic recommendations should include an alternative therapeutic option in IM-PM or UM patients.M. Saiz-Rodriguez was co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo. D. Koller is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant.Peer reviewe