Pharmacogenetic-guided Algorithm To Improve Warfarin Stable Dose In The Elderly Han-Chinese Population

Objective To 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.Methods According to the inclusion criteria,544 patients with non-valvular atrial fibrillation who were receiving warfarin anticoagulation therapy were enrolled.The data of the whole population,people under 65 years old and over 65 years old were respectively substituted into the IWPC algorithm to verify its accuracy.The basic data and clinical information of 360 elderly people were collected for statistical treatment.The genotypes of VKORC1-G1639A and CYP2C9 were detected by polymerase chain reaction(PCR).The new pharmacogenetics warfarin algorithm for the elderly Han-Chinese population is obtained by stepwise multiple linear regression.The root mean squared error(RMSE),determination coefficient(R2)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 our new algorithm.Results Among the three different age groups,the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the patients above 65-year-old.Among the 360 patients above 65 years,GG,GA and AA genotypes were detected in polymorphism of VKORCl,among which AA genotypes accounted for 83.06%(299/360)and GG genotypes only accounted for 0.83%(3/360).Three genotypes were detected in CYP2C9:*1/*1,*1/*3 and*1/*2.CYP2C9*1/*1 accounted for 92.78%(334/360)and*1/*3 for 6.94%(25/360).There was only one case of type*1/*2.Patients with CYP2C9*1/*1 required significantly higher stable dose than those with*1/*3 and*1/*2[(3.16±0.90)mg/d vs.(2.39±0.67)mg/d,P<0.001].The stable dose of patients with combined genotypes VKORC1(GA,GG)and CYP2C9(*1*2,*1*3)was 2.0(2.0,2.0)mg/d,which was significantly lower than that of patients with other combined genotypes(P<0.001).In this study,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 linear regression analysis,we established a new elder warfarin dosing algorithm(R2=0.3714)containing height,creatinine,amiodarone,CYP2C9(*1/*2 or*1/*3)and VKORC1(GA or GG)genotypes.The prediction accuracy of new algorithm was significantly better than IWPC algorithm verified by RMSE,R2 and(20%-p)methods.Conclusion Polymorphisms of VKORC1 and CYP2C9 obviously affected warfarin stable dose of the elder.Combination of pharmacogenetic data along with clinical factors would help to better improve warfarin dose in the elder Han-Chinese population.