Uloga genskog polimorfizma CYP2C9 i VKORC1 u individualizaciji terapije varfarinom kod pacijenata sa akutnim moždanim udarom [The role of genetic polymorphism of CYP2C9 and VKORC1 in the individualization of warfarin therapy in patients with acute stroke]

Šupe, Svjetlana (2011) Uloga genskog polimorfizma CYP2C9 i VKORC1 u individualizaciji terapije varfarinom kod pacijenata sa akutnim moždanim udarom [The role of genetic polymorphism of CYP2C9 and VKORC1 in the individualization of warfarin therapy in patients with acute stroke]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Patients with cardioembolic stroke and stroke due to dissection of extracranial artery or cerebral sinus thrombosis require urgent anticoagulant therapy initiation.This high risk group of patients are at risk of 5-7% of embolic stroke recurrence within the first week or at the risk of bleeding into the infarct zone with worsening of neurologic deficits. Many reports confirmed that CYP2C9 and VKORC1 genetic polymorphisms have strong influence on interindividual warfarin sensitivity, variability of anticoagulant effects and dose requirement.Therefore, in patients with ischemic stroke it is important to select initial doses of warfarin based on individual genotype.The aim of individualisation is to achieve earlier anticoagulant effect and stable maintenance dose in order to reduce the risk of developing warfarin therapy side effects in early initiation of therapy due to hypo or overanticoagulation, particularly among carriers of multiple allelic variants. At the Department of neurology University hospital Centre Zagreb we conducted a prospective case-control study during 6 months among patients hospitalized for acute ischemic stroke with indications for anticoagulant therapy. The hypothesis was that by using the algorithm for pharmacogenetic polymorphism of CYP2C9 gene (wt, * 2, * 3 ) and VKORC1 1173C> T in these patients before initiating warfarin therapy, one can achieve an erlier anticoagulant effect and a stable maintenance dose in comparasion to the introduction of a standard fixed dose. The consented stroke patients (n=106) admitted at Referral centre for intensive neurologic care were pharmacogenetic tested for CYP2C9 and VKORC1 polymorphism before the initial dose of warfarin was predicted. The control group (n=104) were consented acute stroke patients hospitalized at other subunits of Department of neurology with the drug induction using the standard fixed dose, without pharmacogenetic prediction. Among both groups of patients we recorded initial International normalised ratio (INR), INR after 48 hours, 72 hours, on day 5., 7.,14. and 21. of warfarin therapy induction and studied time to reach first target INR value, time to reach stable maintance dose, percent of time spent in therapeutic INR range and appearance of eventual complications. The main goal of this research is to achieve the first target INR erlier, to have larger proportion of time spent in therapeutic INR range and to reach earlier achievement of a stable maintenance dose. Mentioned goals were achieved and confirmed by this study among patients with initial dose introduction after pharmacogenetic algorithm (FG) in comparasion with the group to which standard fixed dose was given. Time spent in over therpeutic INR >3,1 was shorter in genotype guided group, compared to standard fixed dose initiating group. Application of pharmacogenetic algorithm enabled the correct assessment of warfarin dose in 81,5% of 62% of patients who required a higher or lower dose of warfarin. We found no reduction in the development of complications in the FG group compared to group with standard fixed dose application, but we have proved the difference between clinical outcome in this group patients with complications had better clinical outcome due to the occurrence of mild bleeding in the FG group, in comparison with severe bleeding in patients using a standard fixed dose.We've shown a better clinical outcome with mild neurological deficits in relation to neurological deficit on admission among patients with pharmacogenetic prediction of doses in comparasion to the group of patients with standard fixed doses. Our findings highlight the importance of selection of initial warfarin dose based on individual genotype to therapy instead of a fixed dose for safer therapeutic intervention in high risk patients with acute stroke.

Abstract in Croatian

Pacijenti sa ishemičkim moždanim udarom (IMU) kardioembolijskog porijekla uz specifične uzroke IMU zbog disekcije ekstrakranijskih arterija ili tromboze venskih sinusa, iziskuju hitno uvođenje antikoagulantne terapije. To je visokorizična skupina bolesnika sa vjerojatnošću od 5-7% za recidiv embolijskog IMU unutar prvog tjedna ili sa visokim rizikom krvarenja u infarktnu zonu i pogoršanjem neurološkog deficita. Poznato je da polimorfizam gena CYP2C9 i VKORC1 značajno utječe na interindividualnu osjetljivost, varijabilnost antikoagulantnog učinka i potrebnu dozu varfarina. Stoga je u bolesnika sa IMU važna selekcija inicijalne doze varfarina bazirana na individualnom genotipu sa ciljem ranijeg postizanja antikoagulantnog učinka i stabilne terapijske doze uz smanjenje rizika razvoja komplikacija u ranoj fazi uvođenja terapije, posebno među nosiocima multiplih alelnih varijanti. Na Klinici za neurologiju KBC Zagreb smo proveli prospektivno „case-control“ istraživanje tijekom 6 mjeseci među hospitaliziranim bolesnicima sa akutnim IMU, kojima je indicirana antikoagulantna terapija sa hipotezom da je primjenom inicijalne doze prema farmakogenetičkom algoritmu za polimorfizam gena CYP2C9 (wt,*2,*3) i VKORC1 1173 C>T u takvih pacijenata prije započinjanja terapije varfarinom moguće ranije postići antikoagulantni učinak i stabilnu dozu održavanja u odnosu na standardno uvođenje fiksnom dozom. U studiju je uključeno 106 bolesnika sa IMU kojima je prije uvođenja varfarina provedeno farmakogenetičko testiranje u procjeni inicijalne doze uvođenja (FG skupina). Kontrolnu skupinu je sačinjavalo 104 bolesnika sa akutnim IMU kojima je lijek uvođen standarnom fiksnom primjenom doze. U svih se ispitanika pratio INR pri uvođenju terapije, INR nakon 48 h, 72h, 5. dan, 7., l4. i 21. dan, vrijeme potrebno za postizanje prvog ciljnog INR, postotak vremena provedenog u terapijskom rasponu INR, vrijeme potrebno da se postigne stabilna doza održavanja te pojava komplikacija. Osnovni cilj primjene farmakogenetičkog algoritma je bilo ranije postizanje prvog ciljnog INR, veća proporcija vremena provedena u terapijskom rasponu INR i ranije postizanje stabilne doze održavanja, što se u skupini bolesnika s inicijalnom dozom varfarina uvedenom po farmakogenetičkom algoritmu uspjelo i postići. FG skupina bolesnika je manje vremena provela u iznadterapijskom INR >3,1 u odnosu na grupu sa fiksnom primjenom doze. Primjenom farmakogenetičkog algoritma korektno je procijenjena potrebna doza za 81,5% od ukupno 62% bolesnika koji su iziskivali višu ili nižu dozu varfarina od uobičajene. Nismo našli smanjenje razvoja komplikacija u FG skupini u odnosu na fiksnu primjenu doze, ali smo dokazali razliku između kliničkog ishoda i pojave komplikacija sa boljim kliničkim ishodom zbog pojave blažih krvarenja u FG skupini u odnosu teža krvarenja u bolesnika sa fiksnom primjenom doze. Dokazali smo bolji klinički ishod sa blažim neurološkim deficitom u odnosu na neurološki deficit pri prijemu među bolesnicima sa farmakogenetičkom predikcijom doze u odnosu na bolesnike sa fiksnom primjenom doze. Rezultati našeg istraživanja ukazuju na važnost selekcije inicijalne doze varfarina bazirane na individualnom genotipu umjesto započinjanja terapije fiksnom dozom za sigurniju terapijsku intervenciju u viskorizičnih bolesnika sa moždanim udarom.

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