Visser Loes E, van Schaik Ron H N, van Vliet Martin, Trienekens Paul H, De Smet Peter A G M, Vulto Arnold G, Hofman Albert, van Duijn Cornelia M, Stricker Bruno H Ch
Department of Internal Medicine, Erasmus MC, 3000 DR Rotterdam, The Netherlands.
Thromb Haemost. 2004 Jul;92(1):61-6. doi: 10.1160/TH03-12-0741.
The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C92 and CYP2C93, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.
香豆素代谢过程中涉及的主要酶是CYP2C9。CYP2C9的等位基因变体CYP2C92和CYP2C93编码活性降低的酶。尽管越来越多的证据表明，携带这些基因变体的患者需要较低的抗凝治疗维持剂量，但关于出血风险与CYP2C9基因多态性的研究结果并不一致。因此，我们的目标是研究CYP2C9基因多态性在香豆素抗凝治疗起始和维持阶段对出血并发症的影响。本研究采用基于人群的队列研究设计，样本来自鹿特丹研究，该研究共有7983名受试者。纳入了在1991年1月1日至1998年12月31日研究期间开始使用醋硝香豆素或苯丙香豆素治疗且有国际标准化比值（INR）数据的所有患者。对患者进行随访，直至出现出血并发症、治疗结束、死亡或研究期结束。采用比例风险回归分析，在调整了年龄、性别、目标INR水平、INR、INR测量间隔时间和阿司匹林使用等几个潜在混杂因素后，估计与CYP2C9基因型相关的出血并发症风险。在开始使用香豆素治疗后的90天起始阶段，分别检查了变异基因型对出血风险的影响。996例有可分析数据的患者平均随访时间为481天（1.3年）；311例（31.2%）至少有1个CYP2C9变异等位基因，685例（68.8%）为野生型基因型。对于野生型基因型的患者，轻微出血、严重出血和致命出血的发生率分别为每100治疗年15.9例、3.4例和0.2例。对于变异基因型的患者，轻微、严重和致命出血的发生率分别为每100治疗年14.6例、5.4例和0.5例。使用醋硝香豆素的变异基因型患者发生严重出血事件的风险显著增加（风险比1.83，95%置信区间：1.01 - 3.32）。在治疗起始阶段，我们未发现变异基因型对出血风险有影响。在本项针对使用醋硝香豆素或苯丙香豆素的抗凝门诊门诊患者的研究中，携带CYP2C9变异等位基因与使用醋硝香豆素的患者发生严重出血事件的风险增加相关，但与使用苯丙香豆素的患者无关。尽管在开始使用醋硝香豆素治疗前，可能会考虑评估患者的CYP2C9基因型以进行剂量调整，但一项前瞻性随机试验应证明这是否会降低严重出血事件增加的风险。
