Genetic and Non-Genetic Factors Impact on INR Normalization in Preprocedural Warfarin Management

Background: Annually, 10% of warfarin patients will likely need to stop warfarin prior to elective surgery to achieve a baseline international normalization ratio (INR) level (INR ≤ 1.2) at the time of the procedure. This study explores the influence of genetic and non-genetic factors on INR normalization in the Arab (major part of Near Eastern) population in preprocedural warfarin management. Methods: An observational prospective cohort study was designed to recruit Arab patients taking warfarin and scheduled for an elective procedure. Two INR readings were recorded. DNA extraction and genotyping of variants in CYP2C9*2, CYP2C9*3, CYP4F2*3, VKORC1*2 , and FII (rs5896) and FVII (rs3093229) genes using real-time polymerase chain reaction were performed. Results: Data from 116 patients were included in the analysis. CYP2C9 and VKORC1 genetic variants carriers required lower maintenance dose compared to non-carriers. The analysis showed that ciprofloxacin, antiplatelet medications, and INR index (INR at visit 1) are the only factors associated with the INR decline rate. Also, the proportion of CYP2C9*3 carriers with normal INR (≤ 1.2) on the day of surgery was significantly lower than those with wild-type genotype (28% vs 60%, p =0.013). In addition, heparin bridging, INR target, and Sudanese nationality are significant predictors of INR normalization (≤ 1.2) on the day of the procedure. Conclusion: Despite the confirmed effect of genetic factors on warfarin maintenance dose, the study was not able to find a significant effect of any genetic factor on the rate of INR normalization possibly due to the small sample size. Index INR and interacting medications showed to be significant predictors of INR decline rate. Keywords: INR, periprocedural, pharmacogenetics, pharmacogenomics, warfarin