直接凝血酶抑制药——希美加群

希美加群（ximelagatran）具有独特的作用机制，通过直接抑制凝血酶来发挥抗凝作用。与华法令相比，其优点是：①抑制作用强；②剂量-效应曲线较平坦，治疗窗口较宽；③对凝血酶的抑制是一种可逆性的抑制；④对游离的和与血栓结合的凝血酶均有抑制作用；⑤抑制作用直接，起效较快。此外，它还有抗血小板作用。这是一种脂溶性药物，口服后吸收好，吸收率为40％-70％。吸收后快速转变为美拉加群而发挥作用。口服后达峰时间不到1h。终末半衰期为3．5—4h。故每日以口服2次为宜。此药主要通过肾小球滤过而排泄，肾功能减退者清除减慢。其主要用途是在心房颤动时用于抗凝治疗，可减少血栓栓塞的发生。此外还可用于下肢大手术后预防深静脉血栓形成。此药引起出血的不良反应少，用药时不需作实验监测。     

全球范围召回抗凝血药希美加群（Exanta）

经过上市几年的资料反馈,阿斯利康公司(AstraZeneca)已向全球召回其抗凝血药希美加群(ximelagatran,Exanta)。EXTEND临床研究显示,接受本品治疗的患者中出现了严重肝损害的不良反应。鉴于以上不良反应,美国FDA已发出不批准函,英国的新药申请已撤销,法国已经延期。两项正在进展中的试验已停止,所有待批准的申请均被撤销。希美加群已在12个国家上市销售,被批准用于预防髋、     

抗凝治疗在心血管疾病中的应用

抗凝治疗的现状、进展,以及在心血管疾病中的广泛应用。新指南在抗凝治疗方面的更新。     

抗血栓药希美加群(ximelagatran)

1商品名 Exanta 2开发与上市厂商 由阿斯利康（Astrazeneca）公司研发,2004年6月首次在德国上市,目前已在奥地利、芬兰、德国、冰岛、挪威、葡萄牙和瑞典上市.     

希美加群药品风险管理的案例简析

药品风险管理适用于药品从前体化合物筛选、新药审批、上市后监控以及药品撤出市场的整个过程。通过介绍阿斯利康公司生产的新一代抗凝血药物希美加群（Exanta。）从新药审批上市到撤出市场的风险管理相关事件,以期为我国抗凝药物的监测和安全管理工作提供借鉴,从而更好地规范我国的药品市场。     

新型口服凝血酶抑制剂希美加曲

新型口服凝血酶抑制剂希美加曲(ximelagatran)可被用于血管栓塞性疾病的预防及治疗.口服给药后迅速吸收,与食物及其他药物相互作用较小,迅速转化为有效的活性中间产物美加拉群(melagatran),通过抑制人α-凝血酶的活性产生抗凝作用.该药生物利用度高,治疗窗较宽,出血不良反应少,临床应用时无需监测凝血时间,抗凝效果与肝素及华法林相当.目前该药已进入Ⅲ期临床试验阶段.     

抗凝药物在心房颤动治疗中的应用

主要探讨抗凝药物在心房颤动治疗中的重要作用。心房颤动患者具有较高的血栓栓塞发生风险,通过应用抗凝药物治疗,能够明显地降低血栓栓塞,尤其是脑卒中的发生。降低致残率,提高生活质量。     

抗凝药Rivaroxaban获准用于降低心房颤动患者中风风险

继美国FDA于2011年7月批准抗凝药rivaro-xaban（商品名：Xarelto）用于降低膝、髋关节置换术后凝血、深静脉血栓和肺栓塞风险之后,该药又于近日获准用于降低心律失常（非瓣膜心房颤动）患者的中风风险。     

心房颤动患者抗凝治疗的体会

目的：探讨华法林在房颤患者抗凝治疗中的标准化比值（INR）,以减少华法林的不良反应。方法：回顾性分析2004年3月～2009年3月使用华法林抗凝治疗房颤患者106例的临床资料。结果：房颤患者使用华法林抗凝治疗后脑卒中的年发生率为1.61%、年出血并发症为0.49%,分别低于文献报道的4%及1%。结论：无抗凝禁忌证的房颤患者,均应使用华法林抗凝治疗,但应密切监测INR,确保华法林的安全使用。     

心房颤动并脑卒中抗凝治疗的临床评价

目的 评价心房纤颤并脑卒中患者抗凝治疗的效果。方法住院房颤患者312例，其中风湿性瓣膜病并发房颤74例，非风湿性瓣膜病并发房颤238例，房颤并脑卒中51例。分析合并的疾病及临床抗凝应用情况。结果房颤合并脑卒中发病率16．3％，且随年龄增长而增加；非风湿性瓣膜病并发房颤中以高血压、冠心病居多；均口服抗凝治疗，卒中前口服小剂量阿司匹林25～75mg／d159例，有36例脑卒中，口服阿司匹林100～300mg／d 82例，有9例脑卒中，口服华法林71例，有6例脑卒中。结论房颤患者的合理抗凝治疗可减少脑卒中的发生率，阿司匹林剂量应在100—300mg/d之间。     

Dabigatran etexilate,a new oral direct thrombin inhibitor,for stroke prevention in patients with atrial fibrillation

Importance of the field: Warfarin is the only oral anticoagulant recommended for the prevention of ischemic stroke in atrial fibrillation. A newer and safer anticoagulant is needed because of increased hemorrhagic risks with warfarin, difficult-to-maintain therapeutic levels, and higher drug to drug and food interactions.

Areas covered in this review: Dabigatran etexilate is a new, effective, reversible, rapid-acting, oral direct inhibitor of thrombin. This review focuses on the results of major Phase II and III trials conducted to evaluate the use of dabigatran in prevention of stroke in atrial fibrillation.

What the reader will gain: The objective of this paper is to discuss the use of dabigatran for prevention of stroke in patients with atrial fibrillation and to review its major advantages and disadvantages over warfarin.

Take home message: After the recent publication of Phase III trial RE-LY (randomized evaluation of long-term anticoagulation therapy), the use of dabigatran in atrial fibrillation is more clearly defined. A higher dose of dabigatran may be beneficial in patients who have recurrent ischemic events, despite therapeutic levels of warfarin. A lower dose is potentially safer than warfarin because of fewer hemorrhagic complications. Disadvantages include twice-daily dosing, dyspepsia and higher cost.     

Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects

Objective To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran.Methods In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing.Results The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (C_max) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, C_max, half-life (t_1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The C_max of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t_1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls.Conclusion The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.     

Novel uses for current and future direct thrombin inhibitors: focus on ximelagatran and bivalirudin

Ximelagatran and bivalirudin are direct thrombin inhibitors that have been studied for the prevention and treatment of thrombosis and have potential advantages over the traditional indirect thrombin inhibitors (i.e., warfarin, unfractionated heparin and low molecular-weight heparin). They are both reversible inhibitors of thrombin and block both circulating and fibrin-bound thrombin. Ximelagatran and bivalirudin possess favourable pharmacokinetic and pharmacodynamic profiles including wider therapeutic indices, faster onsets of action and less interpatient variability compared to indirect thrombin inhibitors. Ximelagatran has shown favourable clinical trial results in venous thromboembolism prophylaxis and atrial fibrillation. Similarly, bivalirudin has shown positive results in patients with acute coronary syndromes, however, further investigation is needed. Ximelagatran and bivalirudin have shown promising results in the management of thrombosis and the results of future studies confirming their use for the aforementioned indications are anticipated.     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.     

Stroke prevention in atrial fibrillation patients

Importance of the field: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic.

Areas covered in this review: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area.

What the reader will gain: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment.

Take home message: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it.     

直接凝血酶抑制剂比伐卢定的研究现状

比伐卢定在2000年经美国食品药品管理局批准上市,是直接的、特异的、可逆的凝血酶抑制剂,具有抗凝效果的可预测性、不诱导血小板减少及对纤维蛋白结合的凝血酶有效等优势,克服了肝素、水蛭素的局限性。本文对其药理学特点、药效学与药代动力学、药物相互作用、临床应用与不良反应等进行简要综述。     

心房颤动持续时间对左心房内径的影响

目的 探讨心房颤动(房颤)持续时间与左心房大小的关系及其临床意义.方法 选择78例阵发性房颤、48例持续性房颤、22例永久性房颤患者,利用入院后首次超声心动图检测其左心房收缩末内径及左心室射血分数.结果 阵发性房颤组患者左心房内径24～41(36.3±5.8)mm,增大2例(2.6%);持续性房颤组患者左心房内径29～49(43.7±6.8)mm,增大26例(54.2%);永久性房颤组左心房内径32～50(49.8:±5.6)mm,增大18例(81.8%).从阵发性房颤组、持续性房颤组到永久性房颤组左心房内径逐渐增大;持续性房颤组与阵发性房颤相比,及永久性与阵发性房颤相比,差异均有统计学意义(P＜0.05).阵发性房颤组、持续性房颤组及永久性房颤组左心室射血分数分别为(58±10)%、(54±25)%、(50±15)%,随房颤持续时间而逐渐下降.持续性房颤组、永久性房颤组分别与阵发性房颤组相比,差异均具有统计学意义(P＜0.05).结论 房颤是左心房扩大的原因之一,房颤持续时间越长,左心房扩大越显著.

Abstract：

Objective To compare the effect of three types of atrial fibrillation on left atrial size and to investigate the relationship between atrial fibrillation and left atrium. Methods Totally 78 patients of paroxysmal atrial fibrillation, 48 patients of persistent atrial fibrillation and 22 patients with permanent atrial fibrillation were analyzed by echocardiography. Left atrial end systolic diameter and Left ventricular ejection fraction were measured.Results Of the three groups of patients, the largest left atrial dimension was found in and the left atrial dimension in group of paroxysmal atrial fibrillation was the lowest ( P ＜ 0.05 ). Meanwhile the Left ventricular ejection fraction was the highest in the group of permanent atrial fibrillation(P ＜0.05). Conclusions Atrial fibrillation is one of the causes of left atrial enlargement. The longer the duration of atrial fibrillation is, the more significant enlargement left atrium showes.     

心房颤动患者左心耳封堵术后抗栓策略

心房颤动可引起血栓栓塞,甚至脑卒中.大多数房颤患者血栓主要形成于左心耳.左心耳封堵术(LAAO)通过对左心耳进行介入封堵,以替代长期口服抗凝药预防血栓栓塞,其安全性和有效性已在众多临床研究中得到证实.LAAO后抗栓治疗对患者的康复及减少不良反应的发生至关重要.目前LAAO后抗栓治疗策略主要有抗凝+抗血小板联合治疗、双联...     

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants

Objective:

Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are efficacious in reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF) with differences in the reduction of bleeding risks vs. warfarin. The objective of this study was to assess bleeding-related hospital readmissions among hospitalized NVAF patients treated with dabigatran, rivaroxaban, and apixaban in the US.

Research design and methods:

Patients (≥18 years) with a discharge diagnosis of NVAF who received apixaban, dabigatran, or rivaroxaban during hospitalization were identified from the Premier Hospital database (1 January 2012–31 March 2014) and the Cerner Health Facts hospital database (1 January 2012–31 August 2014). Patients identified from each database were analyzed separately and grouped into three cohorts depending on which DOAC was received. Patient characteristics, hospital resource use and costs, and frequency of readmissions within 1 month were evaluated.

Results:

Among study populations identified from the Premier database (N?=?74,730) and the Cerner database (N?=?14,201), patients who received apixaban were older, had greater comorbidity, and had higher stroke and bleeding risks. After controlling for patient characteristics, including comorbidity and stroke and bleeding risks, compared with patients who received apixaban during their index hospitalizations, the odds of bleeding-related hospital readmissions were significantly greater by 1.4-fold (p?<?0.01) for patients who received rivaroxaban and 1.2-fold (p?=?0.16) numerically greater for patients who received dabigatran among patients identified from the Premier Hospital database. Among patients in the Cerner Health Facts hospital database, bleeding-related hospital readmissions were significantly greater by 1.6-fold (p?=?0.04) for patients who received rivaroxaban and 1.3-fold (p?=?0.30) numerically greater for patients who received dabigatran compared to patients who received apixaban.

Limitations:

No causal relationship between treatment and outcomes can be concluded.

Conclusions:

NVAF patients using different DOACs had different characteristics, including stroke and bleeding risks. Use of rivaroxaban, compared to apixaban was associated with significantly greater risk of bleeding-related readmissions across two database claims analyses.     

辛伐他汀对心房颤动患者左房内径影响的研究

目的：探讨辛伐他汀对心房颤动患者左房内径（LAD）的影响。方法：选取确诊的房颤患者56例,随机分为辛伐他汀干预组（28例）和对照组（28例）。分别于入院时及随访6个月后测量LAD。结果：辛伐他汀干预组入院时（43.73±4.33）mm与随访后（40.86±3.80）mm的LAD比较,差异有统计学意义（P〈0.05）,而对照组二者差异无统计学意义（P〉0.05）;辛伐他汀干预组（40.86±3.80）mm和对照组（44.18±3.73）mm随访后的LAD比较,差异有统计学意义（P〈0.05）。结论：辛伐他汀可以有效防治心房颤动患者LAD增大,有望成为房颤治疗的新途径。