药物基因组学模型对机械瓣膜置换术后华法林低强度抗凝治疗剂量预测效果的评价

Evaluation of pharmacogenetic algorithms in dose prediction under low dose warfarin anticoagulation in mechanical cardiac valve replacement patients

目的评价华法林药物基因组学模型对机械瓣膜置换术后华法林低强度抗凝治疗剂量预测效果。方法按照设定的标准选取皖南医学院弋矶山医院2012年1月-2013年10月行心脏机械瓣膜置换术后接受华法林低强度抗凝治疗(目标国际标准化比值INR为1.6~2.5)患者107例,采用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP)和测序技术对CYP2C9和VKORC1基因进行检测。依据INR监测结果调整华法林至稳定剂量,并根据华法林实际稳定剂量将患者分为低剂量组(≤1.5 mg/d)、中剂量组(1.5~4.5 mg/d)和高剂量组(≥4.5 mg/d)。利用国际华法林药物基因组联合会(IWPC)模型计算华法林预测剂量,比较华法林预测剂量与实际稳定剂量的平均绝对误差(MAE),计算预测剂量位于理想剂量(实际稳定剂量20%界限)、高估和低估剂量患者比例,并以华法林预测剂量和实际稳定剂量拟合相关回归曲线R^2评价该模型预测剂量的准确性。结果华法林预测剂量与实际稳定剂量MAE为(0.89±0.62)mg/d,相关回归系数R^2为0.325,预测剂量在理想剂量范围内的比例为42.06%,其中高剂量组位于理想剂量范围内比例为50.00%,高于中剂量组(43.75%)和低剂量组(11.11%)。结论 IWPC模型对中国汉族人群华法林剂量预测的效果有限,适合于中国汉族人华法林低强度抗凝治疗药物的基因组学模型仍需进一步大规模临床研究和验证。

Objective Our aim is to assess the performance of warfarin pharmacogenetic algorithms in patients post me- chanical cardiac valve replacement under low dose warfarin anticoagulation. Methods Based on the specified standard, from January 2012 to October 2013, 107 patients of Yijishan Hospital of Wannan Medical College were enrolled in the study. The target international normalized ratio （INR） ranging from 1.6 to 2.5 post surgery of mechanical cardiac valve replacement were set under low dose warfarin anticoagulation. All the patients＇ CYP2C9 and VKORC1 genetic polymorphisms were detected by PCR-RELP and sequencing technology, and their doses of warfarin were adjusted by the results of INR. The patients were stratified into 3 groups according to the dose range：lower dose group （≤1.5 mg/d）, intermediate dose group （1.5 ～ 4.5 rag/d） and higher dose group （≥4.5 mg/d）. Then the predictive warfarin doses were calculated by international warfarin pharmaeo- genetics consortium （IWPC） algorithm, the performance of the algorithm was evaluated by the mean absolute error （MAE） be- tween warfarin predicted doses and actual stable doses,and the percentage of patients whose predicted doses within ideal doses （20% of their actual stable doses）,over doses and under doses were compared. As well,the predicted warfarin doses were also regressed on stable doses,from which we obtain R2 values. Results MAE between warfarin predicted doses and stable doses was （0.89 ±0.62） mg/d with R2 = 0. 325. The percentage of warfarin predicted doses within ideal doses was 42.06 %, and the percentage within ideal doses in higher group was 50.00%, which was higher than in intermediate dose group （43.75%） and lower dose group （11.11%）. Conclusion The performance of IWPC algorithm used in warfarin anticoagulation dose assess- ment in Chinese Han population is infinite, the pharmacogenetic algorithms suitable for the Chinese Han population with low dose warfarin anticoagulation need to be further studied and verified clinically.