Teichert M, van Schaik R H N, Hofman A, Uitterlinden A G, de Smet P A G M, Stricker B H C H, Visser L E
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Clin Pharmacol Ther. 2009 Apr;85(4):379-86. doi: 10.1038/clpt.2008.294. Epub 2009 Feb 18.
The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.
本研究的目的是调查与维生素K环氧化物还原酶复合体亚单位1（VKORC1）和细胞色素P450 2C9（CYP2C9）活性降低相关的基因型在治疗的前6周内对醋硝香豆素抗凝作用的影响。在鹿特丹研究中开始接受醋硝香豆素抗凝治疗的1525例患者中，确定了VKORC1 1173C>T以及CYP2C9 2和3等位基因变异的存在情况。比较了不同基因型之间初始标准剂量后的首个国际标准化比值（INR）、抗凝过度风险以及起始期结束时的平均剂量。每多存在一个VKORC1 T等位基因，初始标准剂量会使严重抗凝过度风险显著增加85%。在起始期结束时，每存在一个VKORC1 T等位基因会使所需的醋硝香豆素剂量每周减少5.1 mg，而每存在一个CYP2C9变异等位基因会使所需剂量每周减少1.8 mg。我们的结论是，醋硝香豆素初始标准给药方案会增加VKORC1和CYP2C9基因变异等位基因患者严重抗凝过度的风险。
