Dubey Ashish Kant, Kalita Jayantee, Nizami Mohammad Firoz, Kumar Surendra, Misra Usha Kant
Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
Department of Neurology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India.
Ann Indian Acad Neurol. 2024 May 1;27(3):274-281. doi: 10.4103/aian.aian_886_23. Epub 2024 Jun 22.
Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 ( CYP2C9*2/*3 ) and vitamin K epoxide reductase subunit 1 ( VKORC1 ) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST.
The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1 , CYP2C92 , and CYP2C93 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis.
INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23-13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13-0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06-0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05-0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19-26.06, P = 0.02).
Variant genotypes of VKORC1 , CYP2C92 , and CYP2C93 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention.
药物基因组学在药物代谢中发挥着重要作用。稳定的抗凝治疗对于心源性栓塞性卒中及脑静脉窦血栓形成（CVST）的一级和二级预防至关重要。我们报告了细胞色素P450（CYP2C9*2/*3）和维生素K环氧化物还原酶亚基1（VKORC1）基因型以及后天因素在使用醋硝香豆素后维持心源性栓塞性卒中和CVST患者抗凝稳定性中的作用。
该研究纳入了157例正在接受醋硝香豆素治疗的心源性栓塞性卒中和CVST患者。记录了他们的合并症、合并用药情况和饮食习惯。在随访期间测量凝血酶原时间和国际标准化比值（INR），并将凝血状态分为稳定（治疗范围内的时间>50%）和不稳定（治疗范围以下和以上的时间>50%）。通过聚合酶链反应-限制性片段长度多态性对VKORC1、CYP2C92和CYP2C93进行基因分型。记录出血和栓塞并发症。使用多变量分析评估INR不稳定的预测因素。
47.8%的患者INR稳定，52.2%的患者INR不稳定。携带突变基因型的患者需要较低剂量的醋硝香豆素。INR不稳定的预测因素包括金属瓣膜（比值比[OR]4.07，95%置信区间[CI]1.23 - 13.49，P = 0.02）、使用地高辛（OR 0.031，95% CI 0.13 - 0.74，P = 0.09）、质子泵抑制剂（OR 0.23，95% CI 0.06 - 0.91，P = 0.037）、丙戊酸钠（OR 0.22，95% CI 0.05 - 0.85，P = 0.029）以及CYP2C9*2基因型（OR 5.57，95% CI 1.19 - 26.06，P = 0.02）。
VKORC1、CYP2C92和CYP2C93的变异基因型需要较低剂量的醋硝香豆素，且CYP2C9*2与INR不稳定相关。合并用药是一个需要关注的可改变的危险因素。
