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。     

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。     

Periprocedural management of anticoagulation in patients on extended warfarin therapy

Patients receiving chronic anticoagulation therapy pose a clinical challenge when therapy needs to be interrupted for surgical or invasive procedures. Maintaining anticoagulation places them at risk of serious bleeding complications, whereas discontinuing anticoagulation puts them at risk of thromboembolic complications. The main patient groups that may require a periprocedural alternative to oral anticoagulation include patients with prosthetic heart valves, atrial fibrillation, and hypercoagulable states and those with chronic venous thrombosis undergoing surgery. Currently, there is little consensus on appropriate perioperative management of patients on long-term warfarin therapy. This article is an attempt to bring together all the available data on periprocedural bridging to assess the available options for patients undergoing surgical procedures and to provide a rationale for using low-molecular-weight heparins (LMWHs) while individualizing the risks versus benefits in a given patient population.     

老年心脏机械瓣置换术后华法林低强度抗凝疗效观察

目的 探讨老年心脏机械瓣置换术后华法林低强度抗凝标准及安全性。方法 回顾性分析2004年1月~2014年6月在我院心血管外科接受心脏机械瓣置换术后进行低强度抗凝治疗、资料完整患者356例,其中男性203例,女性153例,年龄60~73(64.3±5.1)岁。根据其手术方式分组:主动脉瓣置换术(AVR)组101例、二尖瓣置换术(MVR)组164例、主动脉瓣联合二尖瓣置换术(DVR)组91例。再根据其国际标准化比值(INR)进一步分为低水平组(INR1.6)19例、目标组(1.6≤INR≤2.5)299例、高水平组(INR2.5)38例。连续随访,记录其INR、血栓及出血等不良事件发生率。结果 本组患者发生血栓5例(1.4%),出血49例(13.8%),目标INR 1.6~2.5。AVR组、MVR组和DVR组患者术后出血比例比较无统计学差异,低水平组、目标组和高水平组患者术后出血比例比较有统计学差异。结论 老年人心脏机械瓣置换术后,口服华法林维持INR在1.6~2.5,抗凝效果理想。     

135例乙型肝炎病毒感染者基因分型及其临床分布

目的研究乙型肝炎病毒（HBV）感染者中HBV基因分型及其临床分布情况。方法应用基因型和亚型特异性引物聚合酶链反应（PCR）法,对鲁西地区135例HBV感染者血清进行HBV基因型及亚型分型。结果未分型11例,已分型124例。其中C型111例（C2基因亚型87例、非C1／C2亚型24例）;B型11例,其中Ba型8例、Bj型3例;B／C混合型2例均为BaC2亚型混和感染。在肝硬化和重度慢性乙型肝炎中C型所占比例较高,分别为100％、88％;无症状携带者中B型所占比例较高为8．51％;HBV基因型分型与性别无关。结论鲁西地区HBV感染者以C基因型为主,其中C2亚型占优势。     

Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia

OBJECTIVES: Venous limb gangrene has been reported to occur after high warfarin doses in heparin-induced thrombocytopenia (HIT), and this observation has been used to exclude warfarin management in this condition. The outcome of patients receiving modest doses of warfarin was studied. DESIGN: Retrospective study of 114 consecutive HIT patients who received diagnoses by platelet aggregometry; 51 of the 114 patients received warfarin. SETTING: Tertiary-care medical center. RESULTS: Thirty-five patients received warfarin for non-HIT indications, and 16 received warfarin for heparin-associated thrombosis. Warfarin was given to 23 patients (47%) 2.4 +/- 0.4 days prior to the onset of HIT, in 19 while receiving IV heparin for an overlap of 2.7 +/- 0.4 days. Twenty-eight patients (53%) received warfarin 2.8 +/- 1.0 days after the diagnosis of HIT. Patients received 11 +/- 1 doses of warfarin over 16 +/- 2 days, with a mean daily dose of 3.5 +/- 0.5 and a maximum dose of 9 +/- 0.5 mg. Prothrombin time at discharge was 17.3 +/- 0.4 s with a maximum of 22.8 +/- 0.8. The final international normalized ratio was 2.9 +/- 0. 3, and the maximum was 7.5 +/- 1.4. The minimum therapeutic range was reached in 59% of determinations. When compared to the 63 patients who did not receive warfarin, warfarin patients received more IV heparin (86% vs 41%; p < 0.001), open heart surgery (78% vs 43%; p < 0.001), and had a lower mortality (8% vs 43%; p < 0.001), but had no differences in thrombosis. CONCLUSIONS: Modest doses of warfarin were not associated with a worse outcome in patients with HIT.     

低强度华法林抗凝治疗高出血风险房颤患者的有效性及安全性临床研究

目的：应用2010年欧洲心脏病学协会（ESC）房颤新指南提出的新的评分系统卒中危险评分（CHA2DS2-VASc）和首次推出的出血风险评分法（HAS-BLED）,观察CHA2DS2-VASc积分≥1分且HAS-BLED出血风险积分≥3分时,低强度华法林抗凝治疗高出血风险房颤患者的抗栓疗效和安全性。方法2011年1月至2012年1月我院非瓣膜性房颤患者99例,其CHA2DS2-VASc卒中危险评分≥1分且HAS-BLED出血风险积分≥3分。全部病例分成两组,标准强度华法林治疗组[2.0＜国际标准化比值（INR）≤3.0]和低强度华法林治疗组（1.6≤INR≤2.0）。观察两组患者的血栓栓塞率及出血发生率。结果卡方检验结果显示,两组患者的血栓栓塞率差异无统计学意义（P＞0.05）;标准强度华法林治疗组的出血发生率高于低强度华法林治疗组患者,差异有统计学意义（P＜0.05）。结论 CHA2DS2-VASc卒中危险评分≥1分且HAS-BLED出血风险积分≥3分的高出血风险的房颤患者可以采用低强度华法林抗凝,能有效减少血栓栓塞事件的发生,同时不增加严重出血事件,使用安全可靠。     

Gains and losses of warfarin therapy as performed in an anticoagulation clinic

BACKGROUND: Knowledge of the net benefit of warfarin therapy in routine care is needed to define realistic management recommendations, but lack of randomized controls precludes conventional risk-benefit analysis. OBJECTIVE: Assess risk and benefit of routine warfarin therapy in an anticoagulation clinic. DESIGN: Retrospective observational analysis. PATIENTS: A total of 1435 outpatients on warfarin for a total of 1613 patient years, treated to prevent the target events recurrent venous thromboembolism (VTE) or myocardial infarction (MI), and stroke in patients with atrial fibrillation (AF) or mechanical heart valves. MEASUREMENTS: Major bleeding and thromboembolic (TE) events and all deaths. CALCULATIONS: Expected annual target event rates without warfarin were from published data. Differences between combined major events observed with warfarin, and expected without warfarin were calculated. RESULTS: In the total material, annual rates were 3.0% major TE events, 1.1% major bleeding events, 0.12% fatal bleeding, and a benefit/risk ratio of 3.8. The net gain, expressed in reduced combined bleeding and target TE annual event rate, was 9.9% in secondary prophylaxis in AF, 4.4% in VTE patients, 2.7% in post-MI patients, 2.4% in primary prophylaxis in AF and 0.6 in patients with mechanical heart valves. The apparent benefit/risk ratio was 3.9 in VTE patients, 5.8 in AF patients and 1.1 in patients with mechanical heart valves. CONCLUSION: Net effects of prolonged warfarin therapy in patients with VTE and AF performed in an anticoagulation clinic have an acceptable risk/benefit ratio, comparable with what has been obtained in elective clinical trials.     

不同抗凝强度华法林对80岁及以上心房颤动患者的安全性研究

目的 探讨80岁及以上非瓣膜性心房颤动(房颤)患者使用不同抗凝强度华法林的安全性.方法 130例老年持续性或永久性房颤患者被随机抽签分为3组:(1)低强度抗凝组国际标准化比率(INR)1.5～2.0;(2)中等强度抗凝组INR 2.1～2.5;(3)阿司匹林组.观察3组的出血事件情况及对肾功能的影响.结果 低强度抗凝组(35例)无致命性出血及严重出血,轻微出血2例(5.7%);中等强度抗凝组(32例)致命性出血及严重出血各1例(3.1%),轻微出血4例(12.5%);阿司匹林组(63例)致命性出血3例(4.8%),严重出血3例(4.8%),轻微出血7例(11.1%).3组总出血率比较,差异有统计学意义(χ2=5.13,P＜0.05).低强度抗凝组与中等强度抗凝组对肾功能的影响差异无统计学意义(P＞0.05),但两组明显优于阿司匹林组(P＜0.05).结论 80岁及以上房颤患者中,华法林抗凝INR值维持在1.5～2.0安全性好,对肾功能影响较阿司匹林轻.

Abstract：

Objective To investigate the safety of different intensity anticoagulation therapy of warfarin in preventing thromboembolism in octogenarian patients with nonvalvular atrial fibrillation (NVAF). Methods The 130 patients with persistent or permanent NVAF were randomly divided into three groups: low-intensity warfarin group (35 cases, international normalized ratio, INR (1.5-2.0), moderate-intensity warfarin group (32 cases, INR 2.1-2.5) and aspirin control group (63 cases). The rate of hemorrhagic events and the effect on renal function were observed. Results The incidence of hemorrhage was the lowest in low-intensity warfarin group compared to the other groups with slight bleeding in one case. life-threatening bleeding in one case, severe bleeding in one case and slight bleeding in four cases occurred in moderate-intensity warfarin group. Life-threatening bleeding in three cases, severe bleeding in two cases and slight bleeding in six cases occurred in aspirin control group. There were significant differences in bleeding incidence among the three groups (χ2=5.13,P＜0.05). The low-intensity warfarin group and moderate-intensity warfarin group were superior to the aspirin control group in the effect on renal function (P＜0.05). Conclusions It is safe that the dose of warfarin is maintained at low anticoagulation intensity between INR 1.5 and 2.0 in octogenarians with NVAF.     

Risks and benefits of combined use of bucolome and warfarin in anticoagulation therapy

Although bucolome has been used empirically to enhance and stabilize warfarin action in some institutes, the clinical risks and benefits of this combination are unclear. In the present study, warfarin monotherapy (WM) and bucolome combination (BC) therapy were compared in anticoagulation therapy.One hundred and ninety-five patients indicated for anticoagulation therapy were randomly assigned to WM (n = 98) or BC (bucolome 300 mg/day, n = 97). The dosage of warfarin was optimized in each patient to maintain the international normalized ratio (INR) level in the appropriate zone, ie, 1.6-2.6 for lower risk and 2.0-3.0 for higher risk patients. The clinical characteristics, clinical events, and time in therapeutic range (TTR) were evaluated and compared between the two groups. TTR was calculated using Rosendaal's linear interpolation method.The optimal dosage of warfarin was 3.3 ± 1.0 mg/day in WM and 1.4 ± 0.5 mg/day in BC (P < 0.001). During the observation period of 18 ± 6 months, no serious complication was observed and INR was measured 11 ± 3 times in each case. TTR was 0.61 ± 0.13 in WM and 0.62 ± 0.14 in BC (NS), but TTR in the WM subgroup with warfarin > 3 mg (0.58 ± 0.13) was lower than in the WM subgroup with warfarin ≤ 3 mg (0.64 ± 0.13, P = 0.026) and BC (P = 0.042).BC reduced the optimal dosage of warfarin without increasing clinical events. There was no significant difference in TTR between WM and BC, but BC may have benefits in selected cases, such as warfarin resistance.     

老年急性肺栓塞患者华法林抗凝治疗最佳起始剂量探究

目的探讨老年急性肺栓塞患者华法林抗凝治疗最佳起始剂量临床应用价值。方法入选住我院确诊为急性肺栓塞的老年患者181例,分为2组,老年组(60~79岁)151例,高龄组(≥80岁)30例,给予华法林抗凝治疗后,观察2组华法林起始剂量、达标剂量、达标时间及出血发生情况;另将老年组根据初始服用华法林剂量又分为3个亚组,2.5mg组(31例)、3.75mg组(89例)和5.0mg组(31例),以确定华法林的最佳起始剂量。结果老年组患者华法林起始剂量和达标剂量均高于高龄组[(3.75±0.80)mg vs(3.18±0.83)mg,(4.97±1.59)mg vs(3.96±1.11)mg,P0.01];2组达标时间比较无显著差异(P0.05)。老年组3个亚组之间比较,随着起始剂量增加,达标剂量也增加(P0.05)。与2.5mg组和3.75mg组比较,5.0mg组达标剂量显著增高(P0.05),与2.5mg组比较,3.75mg组和5.0mg组达标时间显著降低(P0.05)。老年组3个亚组出血10例(6.6%),高龄组出血4例(13.3%)。结论老年急性肺栓塞患者,华法林抗凝治疗推荐起始剂量应该高于高龄患者,并注意密切监测。     

高龄稳定性冠心病合并心房颤动患者不同强度华法林抗凝治疗研究

目的观察不同强度华法林抗凝治疗对高龄稳定性冠心病合并非瓣膜性心房颤动患者的疗效和安全性。方法选择高龄稳定性冠心病合并非瓣膜性心房颤动患者91例,随机分为低强度组45例,华法林初始量为1.25mg/d,如国际标准化比值(INR)1.4,3~5d加0.5~1.0mg/d,INR维持1.4~2.0;中强度组46例,INR维持2.0~2.6。平均随访2年,比较2组主要终点(缺血性脑卒中、体循环栓塞)和次要终点(非致命性心肌梗死、全因死亡联合终点)及安全性终点(致命性出血、严重出血和轻度出血)。结果与中强度组比较,低强度组INR明显降低(1.70±0.36 vs 2.35±0.37,P=0.034),华法林用量明显减少[(2.70±0.30)mg/d vs(3.50±0.35)mg/d,P=0.040]。中强度组安全性终点中的总出血事件比例明显高于低强度组(17.4%vs 4.4%,P=0.040)。结论高龄稳定性冠心病合并非瓣膜性心房颤动患者,华法林低强度与中强度抗凝治疗比较,预防缺血性心脑血管事件终点相似,但安全性甚好。     

Generic warfarin: implications for clinical practice and perceptions of anticoagulation providers

For more than 50 years, Coumadin was the dominant warfarin sodium product available in the United States. The approval of generic formulations of warfarin sodium has generated much debate over the therapeutic equivalency and the appropriateness of therapeutic substitution for the innovator product. Despite an AB rating by the Food and Drug Administration (FDA) and recent studies documenting successful switch programs from brand name to generic, much controversy remains concerning the approval process for generic formulations and whether substitution for the innovator product is appropriate. The healthcare professionals affected most by these questions are those working in specialized anticoagulation clinics. We conducted a survey to determine the current practice, experience, and views of healthcare professionals practicing in anticoagulation clinics regarding the substitution of generic products. In addition, the survey sought to identify factors important to healthcare professionals when deciding to use generic or brand name warfarin. Many of these healthcare professionals, primarily pharmacists and nurses, are resistant to generic warfarin substitution and prefer to use the innovator product. These perceptions may change over time as additional data showing comparative therapeutic outcomes between generic and brand name formulations are published.     

Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy

Bleeding is the most important complication of oral anticoagulation (OAC) with vitamin K-antagonists. Whilst bleeding is unavoidably related to OAC, it may have a great impact on the prognosis of treated subjects by leading to discontinuation of treatment, permanent disability or death. The yearly incidence of bleeding during OAC is 2%-5% for major bleeding, 0.5%-1% for fatal bleeding, and 0.2%-0.4% for intracranial bleeding. While OAC interruption and/or antagonism, as well as administration of coagulation factors, represent the necessary measures for the management of bleeding, proper stratification of the individual risk of bleeding prior to start OAC is of paramount importance. Several factors, including advanced age, female gender, poor control and higher intensity of OAC, associated diseases and medications, as well as genetic factors, have been proven to be associated with an increased risk of bleeding. Most of these factors have been included in the development of bleeding prediction scores, which should now be used by clinicians when prescribing and monitoring OAC. Owing to the many limitations of OAC, including a narrow therapeutic window, cumber-some management, and wide interand intra-individual variability, novel oral anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, have been recently developed. These agents can be given in f ixed doses, have little interaction with foods and drugs, and do not require regular monitoring of anticoagulation. While the novel oral anticoagulants show promise for effective thromboprophylaxis in atrial f ibrillation and venous thromboembolism, def initive data on their safety and eff icacy are awaited.     

Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance

Background

Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine/6-mercaptopurine (6-MP). Mutations in the enzyme lead to generation of excess thioguanine, which causes suppression of various cell lineages, especially neutrophils. Data on the prevalence of TPMT polymorphism are available from Western and some Asian countries; such data from India are sparse.

Aims

The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodulator therapy and its relation to the development of neutropenia on azathioprine therapy.

Methods

In this retrospective study, data of all patients who underwent TPMT genotyping by PCR-RFLP and allele-specific PCR prior to immunomodulator therapy were analyzed. The frequency of on-treatment development of neutropenia (total neutrophil count <1,500 per cubic millimeters) was noted.

Results

Data were available on 126 patients (mean age, 42 [SD 13.6] years; 73 men and 53 women). The disease indications included ulcerative colitis (61), Crohn's disease (43), indeterminate colitis (1), autoimmune hepatitis (16), and others (5). TPMT genotype was wild in 120 patients (95.23 %) and heterozygous in 6 patients (4.77 %); no patient had homozygous mutation. Seven of 87 patients (6.8 %) who received azathioprine developed neutropenia; blood counts normalized on cessation of the drug in all. The incidence of neutropenia in patients with wild type was 6/84 (7.14 %) and with heterozygous type 1/3 (33 %) (p?=?0.5764).

Conclusion

Nearly 5 % of this population of patients requiring immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation.     

Safety of joint and soft tissue injections in patients on warfarin anticoagulation

Performance of joint and soft tissue injections in patients receiving anticoagulation is subject to different protocols, some of which suggest continuing treatment within the therapeutic range, while others recommend stopping the treatment prior to procedures. The aim of this study was to evaluate the safety of two approaches to the management of patients prescribed warfarin requiring joint or soft tissue injection. A systematic literature review on this subject was undertaken. Our departmental protocol was changed from one where anticoagulation treatment was temporarily stopped prior to joint/soft tissue injection to one where treatment was continued in the context of a therapeutic international normalised ratio (INR) level within 24 h of the procedure. In patients in whom warfarin was withheld, 32 procedures were performed in 18 patients (13 rheumatoid arthritis, 11 osteoarthritis, 5 spondyloarthritis and 1 each of adhesive capsulitis, rotator cuff tendinopathy and trochanteric bursitis). Of these, 30 were joint injections and 2 were soft tissue injections. In patients who continued warfarin, 32 procedures were performed in 21 patients (11 rheumatoid arthritis, 7 osteoarthritis, 6 crystal arthritis, 4 rotator cuff tendinopathy, 2 spondyloarthritis and 1 each of adhesive capsulitis and carpal tunnel syndrome). Of these, 27 were joint injections and 5 were soft tissue injections. There were no clinical hemarthroses or complications in either group. Joint and soft tissue injections appear to be safe in patients receiving warfarin anticoagulation with an INR <3. Continuation of anticoagulants reduces staff workload and patient inconvenience with no evidence of increased risk of complications.     

The initial phase of oral anticoagulation with warfarin in outpatients with deep venous thrombosis.

Patients with deep venous thrombosis (DVT) treated out of hospital usually start warfarin with the recommended 5 mg loading dose and have their International Normalized Ratio (INR) test performed every 2-3 days. Thus, achievement of the therapeutic range may be more difficult than for inpatients, possibly resulting in extended duration of low molecular weight heparin (LMWH) treatment. We retrospectively examined the charts of 55 DVT outpatients (mean age, 61.4 years; 30 males) to assess the actual duration of LMWH treatment and to identify predictors of a slow achievement of the INR range. Thirty patients (54.4%) reached the therapeutic INR range and stopped LMWH within 7 days, and 25 patients (45.6%) had to continue for an average of 10.5 days. The latter group was significantly younger than the former (57 and 65 years, respectively; P = 0.039). Patients younger than 60 years old had an odds ratio for an extended treatment of 4.92 (P = 0.0057). Algorithms with different loading doses of warfarin according to age should be proposed for outpatient treatment of DVT.