Salah Abohelaika1, Hilary Wynne2, Peter Avery3, Emmanouela Kampouraki1, Farhad Kamali4. 1. Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, NE1 7RU, UK. 2. Department of Older People's Medicine, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, UK. 3. School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. 4. Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, NE1 7RU, UK. Electronic address: farhad.kamali@ncl.ac.uk.
Abstract
INTRODUCTION: Warfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal. MATERIALS AND METHODS: 131 patients completing a course of warfarin provided blood samples over 9 days for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations. RESULTS: S-warfarin clearance was significantly lower in patients with either CYP2C9 single (*2 or *3) or double (*2*2 or *2*3) variant alleles compared to those with wild-type genotype (P < 0.001). Regression analysis revealed that patient age (P = 0.037) and CYP2C9 *2*2 & *2*3 genotype (P = 0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5). CONCLUSIONS: The inter-individual variability in the time needed for normal coagulation to resume following warfarin withdrawal is influenced, in the main, by variance in S-warfarin clearance, which in turn is affected by CYP2C9 polymorphism and age. Cost-effectiveness of pharmacogenetics-based algorithms incorporating CYP2C9 genotype and patient age could be increased if used not only to guide dosing decisions but also estimation of the correct length of time needed for individual patients to stop taking warfarin prior to surgery.
INTRODUCTION:Warfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal. MATERIALS AND METHODS: 131 patients completing a course of warfarin provided blood samples over 9 days for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations. RESULTS: S-warfarin clearance was significantly lower in patients with either CYP2C9 single (*2 or *3) or double (*2*2 or *2*3) variant alleles compared to those with wild-type genotype (P < 0.001). Regression analysis revealed that patient age (P = 0.037) and CYP2C9 *2*2 & *2*3 genotype (P = 0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5). CONCLUSIONS: The inter-individual variability in the time needed for normal coagulation to resume following warfarin withdrawal is influenced, in the main, by variance in S-warfarin clearance, which in turn is affected by CYP2C9 polymorphism and age. Cost-effectiveness of pharmacogenetics-based algorithms incorporating CYP2C9 genotype and patient age could be increased if used not only to guide dosing decisions but also estimation of the correct length of time needed for individual patients to stop taking warfarin prior to surgery.