How to use warfarin assays in patient management: analysis of 437 warfarin measurements in a clinical setting.

Abstract

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.