中国患者华法林抗凝治疗剂量的药物基因组学相关性及药物基因组学方程的比较分析

目的药物基因组学方程对华法林剂量的预测作用的重要性日益受到重视。但是,其准确性仍受到种族和包括华法林剂量在内的多种临床因素的影响。本文旨在接受低剂量华法林抗凝治疗的中国患者中,验证遗传因素对华法林治疗剂量的影响,并分析药物基因组学方程对华法林不同剂量范围的预测效果。方法在接受低强度华法林抗凝治疗（目标INR为1．6～2．5）的中国患者队列（n=282）人群中,检测CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性与华法林稳定治疗剂量的关系。根据华法林剂量将患者分为低剂量组（≤1．5mg／d）,中间剂量组（1．5～4．5mg／d）和高剂量组（≥4．5mg／d）,分别评估8个药物基因组学方程在各组患者中的预测效果。预测效果评估指标包括,剂量预测值位于实际值20％界限内的患者比例（20％内患者比例）,预测值与实际值之间绝对误差的平均值（MAE）。结果华法林的稳定治疗剂量在各个基因的变异基因型携带者和野生基因型携带者之间均存在显著差异（CYP2C9-3：P〈0．00l;VKORC1-1639A／G：P〈0．001;CYP4F2＊3：P=0．025）。来自白种人群和混合人群的药物基因组学方程在华法林高剂量组中预测效果最好,而来自亚洲人群的方程在中间剂量组中的预测效果更好。所有方程对低剂量患者的剂量预测效果均不佳。结论CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性均与中国人群华法林稳定治疗剂量相关。已有的药物基因组学方程尚不能有效的预测华法林各个剂量组患者的稳定治疗剂量。     

药物基因组学方程对中国患者低强度华法林抗凝治疗剂量的预测效果分析

目的在接受低强度华法林抗凝治疗的中国患者人群中,验证华法林药物基因组学剂量预测方程的效果。方法在接受低强度华法林抗凝治疗（目标国际标准化比值INR为1．6至2．5）的226例中国患者人群中,分别比较已公开发表并符合本研究入选标准的药物基因组学方程的效果。效果评估指标包括剂量预测值位于实际值20％界限内的患者比例（20％界限内的患者比例）以及剂量预测值与实际值之间绝对误差的平均值（MAE）。结果8个入选的药物基因组学方程的平均MAE为（0．87±0．17）mg／d[（0．73-1．17）mg／d],平均20％界限内的患者比例为（43．8％±8．1％）（29．1％-52．1％）。配对比较显示,来自亚洲人群的方程的预测效果明显优于来自高加索人群的方程（OR：1．61-3．36,P≤0．02）;加入INR值或CYP4F2＊3的方程较未加入的方程预测效果更好[加入INR的OR：1．71（1．08-2．72）,P=0．029;加入CYP4F2＊3的OR：2．67（1．41-5．05）,P=0．004]。结论来自亚洲人群,或者整合3个基因变异型和INR反应性的药物基因组学方程能更好地预测接受低强度抗凝治疗的中国患者人群的华法林剂量。     

华法林与血管钙化

华法林是临床用于预防血栓栓塞的首选长效抗凝药物。然而长期低剂量或短期大剂量服用华法林会诱导冠状动脉和周围的脉管系统血管钙化,加重心房颤动患者及慢性肾病患者血管钙化程度,影响心血管功能,加重高血压等基础疾病。有研究显示槲皮素、骨保护素可以通过干预Wnt/β-catenin、TG2/β-catenin、BMP2及EPA/MMP-9等信号通路减轻华法林诱导的血管钙化,但具体作用机理尚不明确。因此,如何在保证华法林发挥抗凝效果的同时,有效降低其诱导的血管钙化是临床迫切需要解决的问题。为了进一步开展华法林发挥抗凝效果的同时降低其诱导的血管钙化的相关研究,本文从华法林诱导血管钙化的临床现象、分子机制及潜在预防华法林诱导血管钙化的药物等方面进行综述,为合理使用华法林抗凝,降低其诱导血管钙化提供参考。     

142例心房颤动住院患者华法林使用情况的回顾性分析

目的回顾分析心房颤动住院患者华法林抗凝情况,初步探讨基层医院心房颤动患者的华法林治疗现状。方法选择2006年—2007年住院的心房颤动患者142例,全面收集患者血栓栓塞的高危因素、抗凝禁忌症,华法林的用法、用量,以及未用华法林的原因等。结果房颤患者总体接受抗栓治疗（华法林或阿司匹林）者85.28%,其中华法林治疗61.97%,〈65岁组华法林治疗66.19%,65岁～75岁组华法林治疗71.69%,〈75岁组华法林治疗仅16.67%;高危组华法林治疗71.3%,中危组华法林治疗46.7%,低危组华法林治疗为零。结论住院以房颤动患者总体接受华法林抗凝治疗的情况较好,但〉75岁高、中危的老年房颤患者抗凝治疗不足,加强医生对华法林抗凝的认识以及采用更方便安全有效的抗凝新药可能会进一步提高老年患者的抗凝治疗。     

华法林抗凝治疗中出血和血栓栓塞性不良反应及相关因素探讨

目的 研究华法林抗凝治疗过程中出血和血栓栓塞性不良反应并识别相关危险因素。方法 观察北京大学人民医院2001-04～2003-11抗栓门诊华法林使用大于4周患者的出血和血栓栓塞事件，事件分为小事件、严重事件和威胁生命或致命性事件，应用多种统计方法分析出血和血栓栓塞事件发生情况及相关危险因素。结果 128例服用华法林患者，平均年龄67岁（25—83岁），34例（占26．6％）共发生41次出血事件，严重和致命性的血栓栓塞事件5例（占3．9％）。年龄、肝硬化与出血事件显著相关（P=0．040，P=0．014）。结论 出血是华法林抗凝治疗最主要的不良反应，而年龄、肝硬化是出血事件的重要危险因素。     

华法林在心房颤动抗凝治疗中的应用

心房颤动(AF)是最常见的持续性心律失常,其主要可能致命的危险就是血栓形成。华法林抗凝治疗可显著减少2/3卒中风险,对瓣膜病和非瓣膜病AF均有效,但存在监测较麻烦、治疗窗窄、有潜在出血危险等不利之处。本文比较了华法林临床应用与其他口服凝血酶抑制剂和Xa因子拮抗剂及抗血小板药物治疗的现状。     

老年心房颤动患者的华法林抗凝治疗

脑卒中是严重威胁我国老年人群健康的主要疾病之一,规范的抗凝治疗可以显著减少与心房颤动(房颤)相关的心源性脑卒中的发生率。现对老年房颤患者的华法林抗凝治疗的有关问题作一阐述。1老年房颤的流行病学房颤是最常见的心律失常。在美国,约有230万房颤患者,每年因房颤住院的患     

华法林在心房颤动抗凝治疗中的应用

心房颤动(AF)是最常见的持续性心律失常,其主要可能致命的危险就是血栓形成.华法林抗凝治疗可显著减少2/3卒中风险,对瓣膜病和非瓣膜病AF均有效,但存在监测较麻烦、治疗窗窄、有潜在出血危险等不利之处.本文比较了华法林临床应用与其他口服凝血酶抑制剂和Xa因子拮抗剂及抗血小板药物治疗的现状.     

老年房颤患者华法林抗凝治疗的临床观察

<正>心房颤动(房颤)的最常见致命性并发症是血栓塞事件,血栓事件一旦发生将危及老年患者的命。在2010年ESC房颤治疗指南推荐中除低危患(孤立性房颤、年龄<65岁)或存在抗凝治疗的禁忌证患者,所有房颤患者均应接受抗凝治疗[1]。本文对     

Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients

Abstract. Objective. The aim of the study was to compare the incidence of bleeding complications in patients receiving warfarin alone and those receiving warfarin in combination with acetylsalicylic acid. Subjects and methods. This retrospective study comprises all outpatients in our hospital receiving warfarin (n = 3166) in the period 1 January 1986 to 31 December 1990. Of these, 2026 patients received warfarin alone, aiming at an international normalized ratio level of 4.2-2.5, whereas the combination of warfarin and acetylsalicylic acid (150 mg daily) was given to 1140 patients, aiming at an international normalized ratio level of 2.8-2.2. Total observation time represents 4420 treatment years. Results. A total of 175 bleeding episodes was observed, 18 of which were fatal, and 96 were serious (requiring hospitalization). The incidence of minor bleedings was significantly higher in the combined therapy group than in the group receiving warfarin alone, 2.9% and 1.4% respectively (P < 0.003). However, there was no difference in the therapy groups regarding the incidence of serious and fatal bleedings. The overall incidence of gastrointestinal bleedings was equal in the two groups. Conclusions. The combination of warfarin and aspirin 150 mg daily aiming at a less intense level of anticoagulation than in warfarin therapy alone does not increase the risk of major or fatal haemorrhage.     

Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin

A cohort of patients with an INR >7.0 were identified prospectively and compared with a group of patients with stable anticoagulant control. During the study 15 100 INR measurements were recorded and 31 (0.2%) were >7.0. Odds ratios of patient characteristics were calculated as an estimate of relative risk for the development of a high INR. The highest risk factor was a target INR of 3.5 (OR 7.3, 95% CI 2.6–20.2). The second highest risk factor was antibiotic therapy in the 4 weeks preceding the high INR (OR 6.2, 95% CI 1.4–27.7). Bleeding was reported more frequently in the high INR group (OR 5.4, 95% CI 2.1–13.9). Five major bleeds occurred in this group compared to none in the stable group. This analysis identifies risk factors for over-anticoagulation and hence when to intensify monitoring and when to consider pre-emptive warfarin dose reductions.     

Warfarin Dose Adjustments Based on CYP2C9 Genetic Polymorphisms

Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0–3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.     

Bleeding complications to long-term oral anticoagulant therapy

Objective: To evaluate the incidence of bleeding complications in recent randomized trials on oral anticoagulant treatment for prevention of arterial thromboembolism.Data sources: International publications on studies of prevention of arterial thromboembolism by oral anticoagulant therapy.Study selection and data extraction: Randomized trials on oral anticoagulant therapy in patients with atrial fibrillation, recent myocardial infarction, and prosthetic heart valves were selected. For comparison older nonrandomized studies were studied.Background: Oral anticoagulant drugs are recommended for primary prevention of thromboembolic events in patients with chronic atrial fibrillation, recent myocardial infarction, and prosthetic heart valves. Still many physicians hesitate to prescribe anticoagulant drugs, presumably for fear of bleeding complications.Results: In six recent trials of warfarin in patients with atrial fibrillation, the highest annual incidence of fatal and major bleeding was 0.8% and 2.0%, respectively. In patients treated with warfarin after a recent myocardial infarction, the incidence of fatal and major bleeding was 0.2% and 0.5% per year, respectively. The annual incidence of fatal and major bleeding in patients with prosthetic heart valves on warfarin treatment was found to be 1.4% and 5.2%, respectively. The mean incidence of fatal and major bleeding in patients on warfarin in these eight trials was 0.5% and 1.7% per year, respectively. The mean incidence of fatal and major bleeds in patients on placebo was 0.1% and 0.7% per year, respectively. In three randomized trials evaluating aspirin versus warfarin, the respective mean incidences of fatal and major bleeding during aspirin treatment were 0.2% and 0.8% per year. A remarkable decrease in the incidence of major bleeding complications to oral anticoagulant therapy is revealed by these trials as compared to previous studies. Reasons for this decline may be less intensive anticoagulant regimes, better control of anticoagulant therapy due to the introduction of the international normalized ratio, and careful pretreatment evaluation of risk factors for bleeding. In all prospective trials of oral anticoagulation, the risk of bleeding was more than over-weighed by the beneficial effect on the incidence of stroke and peripheral thromboemboli.