Uloga polimorfizma gena CYP2C19 i određivanja reaktivnosti trombocita na klopidogrel u predviđanju kliničkoga ishoda i opravdanosti individualiziranoga antitrombocitnoga liječenja u bolesnika s akutnim koronarnim sindromom [Role of CYP2C19 polymorphism and determining platelet reactivity on clopidogrel in predicting clinical outcome and justification of individualized approach to antiplatelet treatment of patients with acute coronary syndrome]

Samardžić, Jure (2014) Uloga polimorfizma gena CYP2C19 i određivanja reaktivnosti trombocita na klopidogrel u predviđanju kliničkoga ishoda i opravdanosti individualiziranoga antitrombocitnoga liječenja u bolesnika s akutnim koronarnim sindromom [Role of CYP2C19 polymorphism and determining platelet reactivity on clopidogrel in predicting clinical outcome and justification of individualized approach to antiplatelet treatment of patients with acute coronary syndrome]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is the cornerstone of the treatment of acute coronary syndrome (ACS) during the following 12 months to prevent future atherothrombotic events. High on-treatment platelet reactivity (HTPR) on clopidogrel, most widely used P2Y12 inhibitor, is associated with a higher rate of adverse ischemic outcomes. Genetic polymorphism of CYP2C19 enzyme, highly involved in clopidogrel metabolism, influences the degree of platelet inhibition on clopidogrel and, therefore, clinical outcome as well. We performed a prospective, controlled, randomized study comparing the 12-month efficacy and safety of serial clopidogrel dose adjustment based on platelet function testing (PFT) using Multiplate® aggregometer with standard clopidogrel treatment in ACS patients treated with percutaneous coronary intervention (PCI) and verified HTPR. The study also sought to evaluate the effect of CYP2C19 polymorphism on platelet reactivity changes and clinical outcome. The results show that the interventional group had significantly fewer new total and composite ischemic events without increasing the risk for bleeding during the follow-up. We showed that HTPR could potentially be a modifiable risk factor and that maintaining proposed therapeutic window range of platelet reactivity with adjusted clopidogrel dosing throughout the 12 months of DAPT might achieve a clinical benefit. The effect of CYP2C19 genotype on platelet reactivity was overcome by the adjustment of the clopidogrel dose. As CYP2C19*2 carriers had more than three times higher risk for ischemic events in the total study population and since CYP2C19 genotyping has low negative predictive value for HTPR, we can conclude that CYP2C19 genotyping might be used for predicting ischemic risk but not for P2Y12 inhibitor dose adjustment. Antiplatelet therapy adjustment and further investigations should primarily be based on PFT and platelet reactivity phenotype. Routine use of PFT in guiding antiplatelet therapy might improve the treatment of patients with ACS, especially those initially presenting with HTPR phenotype.

Abstract in Croatian

Dvojna antitrombocitna terapija s acetilsalicilnom kiselinom (ASK) i inhibitorom P2Y12 receptora predstavlja temelj u liječenju bolesnika s akutnim koronarnim sindromom (ACS) kroz idućih 12 mjeseci kako bi se prevenirali budući aterotrombotski događaji. Povišena ostatna reaktivnost trombocita (HTPR) uz klopidogrel, najčešće korišteni inhibitor P2Y12 receptora, povezana je s višom stopom neželjenih ishemijskih događaja. Polimorfizam gena za enzim CYP2C19 koji ima značajnu ulogu u biotransformaciji klopidogrela, također utječe na stupanj inhibicije reaktivnosti trombocita (RT) uz terapiju klopidogrelom te tako i na klinički ishod bolesnika. U sklopu disertacije je provedeno prospektivno, kontrolirano i randomizirano istraživanje u kojem se uspoređivala učinkovitost i sigurnost serijskoga prilagođavanja doze klopidogrela prema agregometrijskim rezultatima uređaja Multiplate® s primjenom standardne doze klopidogrela u bolesnika s ACS liječenih s perkutanom koronarnom intervencijom (PCI) i verificiranim HTPR fenotipom. Analiziran je i utjecaj polimorfizma CYP2C19 na promjene RT i klinički ishod bolesnika. Rezultati su pokazali kako su bolesnici u ispitivanoj skupini imali značajno manju pojavnost novih sveukupnih neželjenih događaja, ali i manje ukupnih ishemijskih događaja bez porasta rizika krvarenja tijekom vremena praćenja. Pokazali smo kako je HTPR podesiv čimbenik rizika i da održavanje preporučenog terapijskog raspona RT prilagođavajući dozu klopidogrela tijekom svih 12 mjeseci primjene dvojne antitrombocitne terapije može biti klinički korisno. Utjecaj genotipa CYP2C19 na RT je prevladan prilagođavanjem doze klopidogrela. Kako su nositelji CYP2C19*2 alela imali više od tri puta veći rizik za ishemijski događaj u cijeloj populaciji ispitanika i kako genotip CYP2C19 ima slabu negativnu prediktivnu vrijednost za HTPR, smatramo da određivanje genotipa CYP2C19 može biti korisno u predviđanju ishemijskog rizika, ali da prilagođavanje antitrombocitne terapije i daljnja istraživanja treba ponajprije bazirati prema rezultatima testova reaktivnosti trombocita. Rutinska uporaba testova reaktivnosti trombocita u navođenju antitrombocitne terapije mogla bi poboljšati klinički ishod bolesnika s ACS, osobito onih koji se inicijalno prezentiraju s HTPR fenotipom.

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