Abstract
ObjectivesTo verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.MethodsAccording to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm.ResultsAmong the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R2=0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods.ConclusionsThe IWPC model may not be suitable for the elder Han-Chinese population. Polymorphism of CYP2C9 and VKORC1 obviously affected warfarin stable dose of the elder Han-Chinese. Combination of genetic data with demographic and clinical factors could help to better improve warfarin doses in the elder Han-Chinese population.
Highlights
Warfarin is the most commonly used anticoagulant for treatment and prophylaxis of thromboembolic diseases, such as pulmonary embolism and atrial fibrillation (Kimmel et al, 2013)
The results showed that the correlation coefficient (R2) of the predicted value and the true value was 0.1321, root mean squared error (RMSE) was 1.0137, and the proportion of the predicted value within the true value ±20% (20%-p) was 55.15% (Figure 1)
The results showed that R2 of the non-elderly group was 0.2293, RMSE was 0.9376 and (20%-p) was 61.75% (Figure 2)
Summary
Warfarin is the most commonly used anticoagulant for treatment and prophylaxis of thromboembolic diseases, such as pulmonary embolism and atrial fibrillation (Kimmel et al, 2013). The narrow therapeutic window and individual variation of warfarin dose make it difficult to achieve desired anticoagulation effect. Numerous studies displayed that gene polymorphisms could influence warfarin dose requirements (Johnson, 2012). More and more evidences suggested that genetic variants of the cytochrome P450 complex subunit 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) greatly affected effective warfarin dose (Bourgeois et al, 2016; Farzamikia et al, 2017; Liu et al, 2019). Observational studies demonstrated that age, body mass index, and polymorphism of CYP2C9 and VKORC1 accounted for nearly 50% of individual variations in warfarin stable dose (Bourgeois et al, 2016)
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