VKORC1, CYP2C9 AND CYP4F2 GENETIC BASED ALGORITHM FOR WARFARIN DOSING. PRELIMINARY RESULTS OF A PROSPECTIVE ITALIAN STUDY

Background. We have previously developed a pharmacogenetic algorithm (PG) for warfarin dosing based on VKORC1, CYP2C9 and CYP4F2 gene polymorphisms, Body Surface Area and age. We verified in a prospective randomized study whether our algorithm (PG arm) has any clinical advantage over standard warfarin dosing (STD arm). Methods. 38 patients (age >18y; atrial fibrillation; target INR2-3) were enrolled from October 2009. Randomization: 17 STD arm, 16 PG arm, 5 drop out. VKORC1 (-1639G>A SNP), CYP2C9 (*1,*2,*3 alleles) (INFINITITM Analyzer, Medical System) and CYP4F2 (*1,*3 alleles)(Taqman chemistry) polymorphisms were analysed within 24 hrs from enrolment. INR was monitored on days 0,5,7,9,12,15 and 19 of treatment. Results. INR findings over 3.5 were higher in the STD (7/102) than in the PG arm (1/96)(p=0.039). This difference was confirmed in patients under low maintenance dose <=20 mg/week (p=0.05), not in the other cases. Their relative risk of an INR finding >3.5 was lower in PG than STD arm (OR=0.828; 95% CI 0.68-1.00). To estimate in which arm INR results were closer to the target values, we applied the 6-sigma formula. After 12 treatment days higher 6-sigma values were always recorded among PG than STD arm (2.8 and 1.1 at day 15; 2.3 and 1.9 at day 19). Conclusions. These preliminary findings suggest that the application of the PG algorithm might significantly reduce the risk of bleeding especially in patients requiring very low warfarin dosing and it could also allow INR to better fit within the defined range