Supe Svjetlana, Božina Nada, Matijević Vesna, Bazina Antonela, Mišmaš Antonija, Ljevak Josip, Alvir Domagoj, Habek Mario, Poljaković Zdravka
Department of Neurology, Intensive Care Unit, University Hospital Center Zagreb, Zagreb, Croatia.
Clinical Institute of Laboratory Diagnosis, Zagreb University Hospital Center, Department of Pharmacology, Zagreb, Croatia; University of Zagreb, School of Medicine, Croatia.
J Neurol Sci. 2014 Aug 15;343(1-2):30-5. doi: 10.1016/j.jns.2014.04.039. Epub 2014 May 5.
Data on the prevalence of CYP2C9 and VKORC1 genes and their influence on anticoagulant effect and warfarin dose in stroke patients are scarce. The aim of this study was to determine the occurrence and significance of these gene polymorphisms and to establish pharmacogenetic algorithm to estimate the dose of introduction. Also, the goal was to determine tailored safety and intensity of anticoagulation response depending on the allelic variants and their impact on the clinical outcome in acute stroke patients in Croatia.
A total of 106 consented acute stroke patients were tested for CYP2C9 2, 3 and VKORC1 1173C>T gene polymorphisms. We estimated the dose of introduction and monitored anticoagulant effect obtained by INR values, time to reach stable dose, stable maintenance dose, time spent within the therapeutic/supratherapeutic INR range, occurrence of dosage side effects and clinical outcome depending on genotypes.
We found that 83% of stroke patients in our study were carriers of multiple allelic variants. The predicted initial dose correlated with the stable warfarin maintenance dose (p=0.0311) and we correctly estimated the dose for 81.5% of 61.3% of study patients who required higher/lower doses than average. Warfarin dosage complications were slightly more frequent among the carriers of CYP2C9 2, 3 compared to the carriers of VKORC1 1173T alleles (68. 9% versus 62.5%), but their occurrence did not affect the final clinical outcome.
Our data indicated rapid and safe anticoagulation achieved by using pharmacogenetically-predicted warfarin dose in high-risk acute stroke patients without increasing the risk of warfarin dosage complications in an elderly population.
关于CYP2C9和VKORC1基因的流行率及其对中风患者抗凝效果和华法林剂量的影响的数据很少。本研究的目的是确定这些基因多态性的发生率和意义，并建立药物遗传学算法以估计起始剂量。此外，目标是根据等位基因变体及其对克罗地亚急性中风患者临床结局的影响，确定个体化的抗凝反应安全性和强度。
对106名同意参与研究的急性中风患者进行CYP2C9 2、3和VKORC1 1173C>T基因多态性检测。我们估计了起始剂量，并通过国际标准化比值（INR）值、达到稳定剂量的时间、稳定维持剂量、在治疗/超治疗INR范围内的时间、剂量副作用的发生率以及根据基因型的临床结局来监测抗凝效果。
我们发现本研究中83%的中风患者是多种等位基因变体的携带者。预测的初始剂量与稳定的华法林维持剂量相关（p = 0.0311），对于61.3%需要高于/低于平均剂量的研究患者，我们正确估计了81.5%患者的剂量。与VKORC1 1173T等位基因携带者相比，CYP2C9 2、3携带者的华法林剂量并发症略多（68.9%对62.5%），但其发生并未影响最终临床结局。
我们的数据表明，在高危急性中风患者中使用药物遗传学预测的华法林剂量可实现快速安全的抗凝，且不会增加老年人群华法林剂量并发症的风险。
