THE ROLE OF GENETIC POLYMORPHISMS OF CYP2C9 AND VKORC1 IN THE INDIVIDUALIZATION OF WARFARIN THERAPY IN PATIENTS WITH ACUTE STROKE

N Bozina1, S Supe2, Z Poljakovic2, Z Riffer3, S Hajnsek2. 1University Hospital Center Zagreb, Department of Laboratory Diagnostics, Croatia, 2University Hospital Center Zagreb, Department of Neurology, Croatia, 3University of Zagreb, Faculty of Pharmacy and Biochemistry, Croatia

Introduction. Patients with cardioembolic stroke and stroke due to dissection of extracranial artery or cerebral sinus thrombosis require urgent anticoagulant therapy initiation. CYP2C9 and VKORC1 polymorphisms have strong influence on interindividual warfarin sensitivity. The aim of the study was to estimate the role of CYP2C9 and VKORC1 gene variants in the individualization of warfarin therapy in patients with acute ischemic stroke, to achieve earlier anticoagulant effect and stable maintenance dose and reduce the risk of developing side effects. We tested the differences in achieving desirable anticoagulant effects and stable maintenance dose of warfarin betwean two group of patient, with and withouth pharmacogenetic profile for CYP2C9 and VKORC1. Subjects and methods. We conducted a prospective case-control study during 6 months among patients hospitalized for acute ischemic stroke with indications for anticoagulant therapy. The consented stroke patients (n=106) admitted for intensive neurologic care were genotyped for CYP2C9*2,*3 and VKORC1 1173C>T polymorphisms, by Real-time PCR based methods, before the initial dose of warfarin was predicted (FG group) according to Sconce et al1. In control group (CG) (n=104) were included hospitalized consented acute stroke patients, to whom drug induction was started according standard fixed dose procedure, without pharmacogenetic data. In both groups 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 (2-3), time to reach stable maintanance dose, percent of time spent in therapeutic INR range and appearance of eventual complications. Results. The proportion of patients who reached target INR was higer in FG group, and was statisticaly different on day 3 (p=0.02), on day 5 (p=0.002), on day 7 (p=0.0005) and on day 14 (p=0.0001) comparing to CG. On the day 21st of warfarin therapy there were no differences among groups. FG group achieved first target INR erlier comparing to CG (5.63 vs. 7.15 days) (p=0.005); FG group had larger proportion of time spent in therapeutic INR range (p=0.005), and earlier reached stable maintenance dose (p=0.005). In FG group shortest time to reach target INR was observed in variant allele cariers comparing to wild type allele carriers (2.7 vs 5.5 days, p=0.01). Time spent in over-therpeutic INR >3.1, was shorter in FG group, compared to CG (p=0.0004). Application of algorithm with pharmacogenetic data enabled the correct prediction of warfarin dose in 81.5% of patients who required a higher or lower than standard dose of warfarin. Conclusion. Our findings highlight the importance of CYP2C9 and VKORC1 pharmacogenetics in selection of initial warfarin dose in high risk patients with acute stroke.

1Sconce et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106(7):2329-33.