Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
Department of Cardiovascular Surgery, The First Hospital of Lanzhou University, Lanzhou, China.
Eur J Clin Pharmacol. 2019 Dec;75(12):1685-1693. doi: 10.1007/s00228-019-02747-5. Epub 2019 Aug 23.
Factors influencing responsiveness to warfarin at treatment onset time were not well identified in Chinese patients undergoing heart valve replacement. We sought to select the most relevant factors that associated with patient response to warfarin early after heart valve surgery.
In this observational study, 289 patients starting warfarin therapy early after heart valve replacement surgery were enrolled. CYP2C9 *1, *2, *3, and *5; VKORC1-1639 G>A, CYP4F2 V433M, and GGCX rs11676382 genotypes; clinical characteristics, response to therapy, and bleeding and thrombosis events were collected. The primary outcomes were the time to the first INR equal to or more than lower limit of therapeutic range and the warfarin dose requirements. Stepwise multiple linear regression was performed to develop a dosing algorithm to predict the warfarin dose requirements.
The results of univariate analysis showed lone VKORC1-1639 G>A, CYP2C9 *1/*3, cefazolin, cefoperazone-sulbactam, increased BMI, Δhemoglobin, and white blood cell count could significantly affect patient responsiveness to warfarin in the initial period of anticoagulation. Multivariate analysis resulted in an equation: Accumulated warfarin doses (mg) = 17.068 VKORC1-1639 G>A - 4.261 hypertension + 0.593 BMI - 0.115 age - 4.852 CYP2C9 *1/*3 - 2.617 cefazolin - 4.902 cefoperazone-sulbactam - 4.537, which could explain 40.2% of the variability in warfarin dose needed to reach the first INR equal to or more than lower limit of therapeutic range.
Both genetic and clinical factors contributed to anticoagulation effect of warfarin in the initial period of treatment. Our findings could provide a basis for the personalized management of warfarin use in the early stage of anticoagulation in northern Chinese patients.
在中国行心脏瓣膜置换术的患者中，治疗起始时影响华法林反应性的因素尚不清楚。我们旨在选择与心脏瓣膜置换术后早期华法林治疗反应最相关的因素。
在这项观察性研究中，纳入了 289 例心脏瓣膜置换术后早期开始华法林治疗的患者。收集 CYP2C9*1、*2、3 和5；VKORC1-1639 G>A、CYP4F2 V433M 和 GGCX rs11676382 基因型；临床特征、治疗反应以及出血和血栓形成事件。主要结局为首次 INR 等于或大于治疗范围下限的时间和华法林剂量需求。采用逐步多元线性回归建立预测华法林剂量需求的剂量算法。
单因素分析结果显示，仅 VKORC1-1639 G>A、CYP2C9*1/3、头孢唑林、头孢哌酮-舒巴坦、BMI 增加、Δ血红蛋白和白细胞计数可显著影响抗凝初始期患者对华法林的反应性。多因素分析得出以下方程：累积华法林剂量（mg）=17.068 VKORC1-1639 G>A-4.261 高血压+0.593 BMI-0.115 年龄-4.852 CYP2C91/*3-2.617 头孢唑林-4.902 头孢哌酮-舒巴坦-4.537，该方程可解释华法林剂量达到首次 INR 等于或大于治疗范围下限的变异性的 40.2%。
遗传和临床因素均对华法林治疗初期的抗凝效果有影响。我们的研究结果可为中国北方地区患者抗凝治疗早期个体化华法林使用管理提供依据。
