How to Use Warfarin Assays in Patient Management: Analysis of 437 Warfarin Measurements in a Clinical Setting
Tóm tắt
Approximately 50 % of inter-individual variation in warfarin dose requirements is attributed to the polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genotypes. What contributes to the remaining 50 % of variation remains unclear. The aim of this study is to assess the clinical usefulness of monitoring plasma warfarin concentrations. We examined genotypic and clinical factors influencing high and low warfarin concentrations. We included 325 Korean patients who received warfarin therapy for more than 7 days whose plasma warfarin concentrations were measured and whose genotypes for VKORC1 and CYP2C9 were determined. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by high-performance liquid chromatography-tandem mass spectrometry. Using 437 warfarin measurements obtained from 325 patients, we found a correlation between plasma warfarin concentration and warfarin dose (r
2 = 0.356; P < 0.001) and a significant difference in the warfarin/7-hydroxywarfarin ratios of the CYP2C9*1/*1 and CYP2C9*1/*3 genotypes combined with drugs that inhibited warfarin (P = 0.003). Insufficient warfarin dose and patient noncompliance were the most common causes of low warfarin concentrations (<0.54 µg/mL, <5th percentile). Genetic factors that cause pharmacodynamic resistance (e.g., VKORC1 genotype) and thus require high warfarin doses were the most common causes of high warfarin concentrations (>1.85 µg/mL, >95th percentile). Monitoring warfarin concentrations along with the prothrombin time-international normalized ratio may be clinically useful for managing patients with long-term warfarin therapy and identifying factors contributing to inter- or intra-individual variability such as genetic polymorphisms, underlying diseases, drug interactions with warfarin, and patient compliance.
Tài liệu tham khảo
Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e44S–88S.
Johnson JA. Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation. 2012;125:1964–6.
Sconce EA, Khan TI, Wynne HA, 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;106:2329–33.
Lombardi R, Chantarangkul V, Cattaneo M, et al. Measurement of warfarin in plasma by high performance liquid chromatography (HPLC) and its correlation with the international normalized ratio. Thromb Res. 2003;111:281–4.
Cho HJ, Sohn KH, Park HM, et al. Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients. Pharmacogenomics. 2007;8:329–37.
Kwon MJ, Kim HJ, Kim JW, et al. Determination of plasma warfarin concentrations in Korean patients and its potential for clinical application. Korean J Lab Med. 2009;29:515–23.
Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore). 2004;83:107–13.
Linder MW, Bon Homme M, Reynolds KK et al. Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy. Clin Chem. 2009; 55:1861–1868.
Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095–106.
Byung Koo L, Ju Yeun L et al. Analysis of factors affecting nontherapeutic INRs in Korean outpatients with mechanical heart valves. Korean J Thorac Cardiovasc Surg. 2005; 38:746–760.
Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis. 2007;50:433–40.
Mozayani A, Raymon LP. Handbook of drug interactions: a clinical and forensic guide. Totowa: Humana Press; 2004. pp. x, 663.
Goldberg DM. The expanding role of microsomal enzyme induction, and its implications for clinical chemistry. Clin Chem. 1980;26:691–9.
Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90:625–9.
Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004;91:87–94.
Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics. 2006;16:101–10.
Gong IY, Schwarz UI, Crown N, et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PLoS One. 2011;6:e27808.
Harrington DJ, Gorska R, Wheeler R, et al. Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1. J Thromb Haemost. 2008;6:1663–70.
Linder MW, Looney S, Adams JE 3rd, et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J Thromb Thrombolysis. 2002;14:227–32.
Klein TE, Altman RB, Eriksson N, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753–64.
Fung E, Patsopoulos NA, Belknap SM, et al. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost. 2012;38:893–904.
Harrison J. Managing variability in warfarin dosing: drugs, diseases and diets. N Z Fam Phys. 2008;35:116–21.
Sattar A, Willman JE, Kolluri R. Possible warfarin resistance due to interaction with ascorbic acid: case report and literature review. Am J Health Syst Pharm. 2013;70:782–6.
Osinbowale O, Al Malki M, Schade A, et al. An algorithm for managing warfarin resistance. Cleve Clin J Med. 2009;76:724–730.
Orensky IA, Holdford DA. Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic. Pharmacotherapy. 2005;25:1801–8.