Division of Cardiac Surgery, Key Laboratory on Assisted Circulation, Ministry of Health, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Ann Thorac Surg. 2018 Dec;106(6):1774-1781. doi: 10.1016/j.athoracsur.2018.07.026. Epub 2018 Sep 8.
The clinical utility of genotype-guided warfarin dosing remains controversial. The objective of this trial was to evaluate the efficacy and safety of genotype-guided warfarin dosing in East Asians.
A double-blind, randomized control trial was performed to compare a genotype-guided dosing algorithm (CYP2C9, VKORC1, and CYP4F2) with a clinical-guided one in the initiation treatment for patients with mechanical heart valves. The primary outcomes included the time to reach a stable dose and the percentage of time in the therapeutic range (TTR).
Two hundred one patients were randomly assigned to treatment, 101 to control and 100 to study. The major bleeding and thromboembolic event-free rate in the study group was 97.0% (95% confidence interval: 90.9% to 99.2%). Compared with the control group, the study group shortened the time to reach a stable dose (mean: 42.09 ± 23.655 days versus 33.52 ± 20.044 days, p = 0.009). The TTRs were 47.257% and 47.461% in the control and study group (p = 0.941), respectively. Patients with the CYP2C9 *1/*3 genotype had higher international normalized ratio (INR) variability than patients with the CYP2C9 *1/*1 genotype (p = 0.024). Compared with normal and sensitive responders, the highly sensitive responders were at increased risk of an INR of 4.0 or greater (p < 0.05).
The genotype-guided warfarin dosing was safe and might be more efficient for the time to reach a stable dose. Pharmacogenomic testing might be beneficial to identify the patients with the CYP2C9 *1/*3 genotype and the highly sensitive responders, who were in the high-risk subgroup of patients with mechanical heart valves. An appropriately powered study is needed to further confirm these findings.
基因指导的华法林剂量仍然存在争议。本试验的目的是评估基因指导的华法林剂量在东亚人群中的疗效和安全性。
进行了一项双盲、随机对照试验，比较了机械心脏瓣膜患者起始治疗中基因指导剂量算法（CYP2C9、VKORC1 和 CYP4F2）与临床指导剂量算法。主要结局包括达到稳定剂量的时间和治疗范围内时间（TTR）的百分比。
201 例患者被随机分配到治疗组、对照组和研究组，每组 101 例和 100 例。研究组大出血和血栓栓塞事件无事件生存率为 97.0%（95%置信区间：90.9%至 99.2%）。与对照组相比，研究组达到稳定剂量的时间更短（平均：42.09 ± 23.655 天 vs. 33.52 ± 20.044 天，p=0.009）。对照组和研究组的 TTR 分别为 47.257%和 47.461%（p=0.941）。CYP2C9*1/3 基因型患者的国际标准化比值（INR）变异性高于 CYP2C91/*1 基因型患者（p=0.024）。与正常和敏感反应者相比，高敏感反应者 INR 为 4.0 或更高的风险增加（p<0.05）。
基因指导的华法林剂量是安全的，可能更有效地达到稳定剂量的时间。药物基因组学检测可能有助于识别 CYP2C9*1/*3 基因型和高敏感反应者，他们是机械心脏瓣膜患者高危亚组。需要进行一项适当的大型研究来进一步证实这些发现。
