Uticaj CYP2C19*2 varijante gena na terapijski odgovor u toku primene klopidogrela kod bolesnika sa stenozom karotidnih arterija

Abstract

Aterosklerotske promene karotidnih arterija su najčešći uzrok moždane ishemije. Karotidna endarterektomija (KE) predstavlja efektivan tretman stenoze karotidnih arterija i danas je najčešći operativni zahvat za prevenciju moždanog udara. Još uvek se kod 2%-5% bolesnika razvija tromboza karotidnih arterija u perioperativnom periodu i dvojna antitrombocitna terapija (aspirin i klopidogrel) značajno smanjuje rizik od razvoja moždanog udara posle KE. Međutim, i pored dokazane kliničke efikasnosti ovih lekova, značajan broj bolesnika nema dobar terapijski odgovor na aspirin i/ili klopidogrel. U literaturi, prevalenca rezistencije na klopidogrel varira od 5% do 44% i najveća je kod bolesnika sa moždanim udarom. CYP2C19 enzim je uključen u oba oksidaciona procesa metabolizma klopidogrela. Nekoliko farmakogenetičkih studija je pokazalo da osobe koje su nosioci CYP2C19*2 alela imaju smanjeno stvaranje aktivnog metabolita klopidogrela i visoku reaktivnost trombocita, što dovodi do povećanja rizika od razvoja neželjenih kardiovaskularnih događaja. Međutim, postoje studije koje nisu ukazale na uticaj CYP2C19 genotipa na klinički efekat klopidogrela niti na prediktivnu vrednost CYP2C19*2 varijantne gena.Glavni cilj ove studije je bio da se ispita povezanost terapijskog odgovora na antitrombocitni lek klopidogrel, koji je praćen laboratorijskim ispitivanjem agregacije trombocita, i prisustva CYP2C19*2 varijante gena i da se utvrdi uticaj genetskih i negenetskih faktora na reaktivnost trombocita kod bolesnika sa stenozom karotidnih arterija kod kojih je izvršena karotidna endarterektomija.U istraživanju efekat antiagregacijskog leka klopidogrela praćen je ADP-indukovanom agregacijom trombocita. Vrednosti testa očekivano su opadale tokom prvih mesec dana tretmana i pokazana je statistički značajna razlika između vrednosti ADP-indukovane agregacije trombocita dobijene pre hirurške intervencije, dvadeset četiri časanakon uzimanja prve doze klopidogrela (75 mg), sedmog i tridesetog dana od uvođenja terapije (P<0,001)...

Carotid artery atherosclerosis is one of the many causes of acute ischemic stroke. Carotid endarterectomy (KE) is the standard treatment for carotid stenosis and is the most frequently performed operation to prevent stroke. Perioperative carotid thrombosis remains a significant problem in 2%-5% of patients and dual antiplatelet therapy, including aspirin and clopidogrel, has a potential role in reducing the risk of stroke after KE. Despite their proven clinical effect, a considerable number of patients don’t have an adequate response to aspirin, clopidogrel or both. According to published data, the prevalence of clopidogrel resistance varies from 5% and may be as high as 44% in patients with acute ischemic stroke. The CYP2C19 enzyme is involved in both oxidative steps of clopidogrel metabolism. Several pharmacogenomic studies have demonstrated that individuals who are carriers of CYP2C19*2 allele have a reduced conversion of clopidogrel into its active metabolite and higher platelet reactivity, which increases the risk of adverse cardiovascular events. However, there are contrasting conclusions in the literature regarding the predictive value of the CYP2C19*2 variant alleleThe aim of this study was to determine the prevalence of low responsiveness to clopidogrel and to identify risk factors, both genetic (CYP2C19*2) and non-genetic, for low responsiveness based on platelet function testing in patients with carotid artery stenosis undergoing KE.ADP-induced platelet aggregation was used to analyze the effect of clopidogrel. ADP-induced platelet aggregation showed a tendency of decline during the first month of treatment and the values of platelet aggregation obtained before the KE. Twenty four hours after the first dose of the clopidogrel, 7 and 30 days of taking the drug were statistical significantly different (P<0,001). In the study group, the number of patients with highplatelet reactivity declined from 79.5% after 24 h to about a quarter of the patients after 30 days of clopidogrel treatment...