Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain.
Department of Dental Training, Ministry of Health, Manama, Kingdom of Bahrain.
J Clin Pharm Ther. 2021 Jun;46(3):640-648. doi: 10.1111/jcpt.13334. Epub 2020 Dec 21.
Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.
Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates.
Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype.
The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
在评估基于基因型的华法林剂量的随机临床试验 (RCT) 中观察到基因型的变化。我们进行了一项网络荟萃分析，以评估评估 CYP2C9 与 VKORC1、CYP2C9 单独和 CYP2C9、VKORC1、CYP4F2 给药策略的 RCT 之间是否存在任何临床显著差异。
电子记录中检索了比较基于基因型的华法林与传统剂量策略的 RCT。主要结局包括首次治疗性国际标准化比值 (INR) 的时间；达到稳定 INR 或华法林剂量的时间；治疗范围内的时间百分比 (TTR)；以及 INR 超过治疗范围的患者比例。加权均数差 (WMD) 和 95%置信区间 (95%CI) 的比值比 (OR) 是效应估计值。
纳入了 26 项研究 (7898 名患者)。CYP2C9 为基础的华法林给药与首次治疗性 INR 时间较短相关 (WMD: -2.73，95%CI: -3.41，-2.05) 和稳定的 INR/华法林剂量 (WMD: -8.1，95%CI: -12.54，-3.66)。CYP2C9 和 VKORC1 观察到首次治疗性 INR 时间较短 (WMD: -1.92，95%CI: -3.23，-0.61) 和稳定的 INR/华法林剂量 (WMD: -4.6，95%CI: -6.87，-2.34) 以及更长的 TTR (%) (WMD: 3.91，95%CI: 1.18，6.63)。CYP2C9、VKORC1 和 CYP4F2 观察到 INR 超过治疗范围的患者比例降低 (OR: 0.68，95%CI: 0.49，0.93)。试验序贯分析证实了 CYP2C9 与 VKORC1 基因型相比，基于基因型的华法林剂量更具优势。
目前的证据支持与传统策略相比，仅基于 CYP2C9 和 VKORC1 基因型来个性化华法林剂量。需要更多的 RCT 来阐明添加 CYP4F2 是否有任何益处，以便为汇总分析提供足够的效力。没有令人信服的证据支持 CYP2C9 单独的作用。
