Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation. We compared the efficiency of DAB formation from DABE when exposed sequentially to human intestinal and then human hepatic microsomes (mimicking the normal metabolic sequence) with the reverse metabolic sequence in which DABE is exposed to hepatic and then intestinal microsomes. The poor efficiency of DAB formation with reverse sequential hydrolysis indicates that CES2 activity is crucial for active metabolite formation. Thus, the decrease in DAB formation with normal sequential hydrolysis was more sensitive to CES2 inhibition by verapamil (CES2 IC50 = 3.4 μM) than CES1 inhibition by diltiazem (CES2 IC50 = 9.1 μM). These results show CES2 activity plays a crucial role in DAB formation and that variability in its activity is an important determinant of therapeutic response.     

达比加群酯联合替格瑞洛对老年心房颤动合并不稳定型心绞痛患者的有效性及安全性研究

目的　观察达比加群酯联合替格瑞洛对老年心房颤动合并不稳定型心绞痛患者的有效性及安全性。方法　选取2015年2月—2017年2月天津医科大学第四中心临床学院收治的100例老年心房颤动合并不稳定型心绞痛患者。将100例老年心房颤动合并不稳定型心绞痛患者随机分为达比加群酯组和华法林组,每组50例。华法林组：在常规治疗基础上加用华法林、替格瑞洛口服。调整华法林剂量维持国际标准化比值（INR）为2.0~3.0。达比加群酯组：在常规治疗基础上加用达比加群酯、替格瑞洛口服。达比加群酯110 mg,2次/d;替格瑞洛90 mg,2次/d。两组均随访1年。分别于治疗前、治疗1、3、12个月测定凝血指标,记录出血事件及心血管不良事件。结果　两组凝血酶原时间（PT）、INR、凝血酶时间（TT）、活化部分凝血活酶时间（APTT）、纤维蛋白原（Fib）、D-二聚体比较,差异有统计学意义（P<0.05）;不同时间点PT、INR、TT、APTT比较,差异有统计学意义（P<0.05）;不同时间点Fib、D-二聚体比较,差异无统计学意义（P>0.05）;组别和时间在PT、INR、TT上存在交互作用（P<0.05）。治疗前,两组PT、INR、TT、APTT、Fib、D-二聚体比较,差异无统计学意义（P>0.05）;治疗1、3、12个月时,达比加群酯组PT、INR、TT、APTT低于华法林组,Fib、D-二聚体高于华法林组,差异有统计学意义（P<0.05）。随访12个月两组患者心血管事件发生率比较,差异无统计学意义〔4.0%（2/50）比6.0%（3/50）;χ2<0.001,P=0.999〕。两组患者均未出现严重出血事件。达比加群酯组出血事件总发生率低于华法林组,差异有统计学意义（χ2=4.955,P=0.026）。结论　对于老年心房颤动合并不稳定型心绞痛患者应用达比加群酯联合替格瑞洛能有效预防血栓事件,且与华法林相比具有较低的出血发生率,表明其具有良好的安全性。     

Bleeding and clotting in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia(HHT) is arelatively common inherited vascular disorder that was first described in 1864, and is notable for epistaxis, telangiectasia, and arterial venous malformations. While genetic tests are available, the diagnosis remains clinical, and is based on the Curacao criteria. Patients with HHT are at increased risk for both bleeding and clotting events. Because of these competing complications, hematologists are often faced with difficult clinical decisions. While the majority of management decisions revolve around bleeding complications, it is not infrequent for these patients to require anticoagulation for thrombosis. Any anticoagulation recommendations must take into account the bleeding risks associated with HHT. Recent reviews have found that HHT patients can be safely anticoagulated, with the most frequent complication being worsened epistaxis. Large clinical trials have shown that factor Ⅱa and Ⅹa inhibitors have less intracranial bleeding than warfarin, and basic coagulation research has provided a possible mechanism. This article describes the anticoagulation dilemma posed when a 62-year-old female patient with a history of bleeding events associated with HHT was diagnosed with a pulmonary embolism. The subsequent discussion focuses on the approach to anticoagulation in the HHT patient, and addresses the role of the new oral anticoagulants.     

REVIEW: Atrial Fibrillation and Dabigatran: Has the Time Come To Use New Anticoagulants?

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance found in clinical practice, increasing in prevalence with age. AF is often associated with structural heart disease, although a significant proportion has no detectable heart disease. In the last 2 decades, there has been an increase of 66% in hospitalizations for AF, and it is an extremely costly public health problem. AF is associated with an increased long‐term risk of stroke, heart failure, and all‐cause mortality. In fact, the mortality rate in patients with AF is about double that of patients in normal sinus rhythm. Antithrombotic therapy is recommended for all patients with AF to prevent thromboembolism, except those with lone AF or contraindications. Selection of the antithrombotic agent should be based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient. However, despite oral anticoagulation with vitamin K antagonists (warfarin or acenocoumarol) some patients still have thromboembolic events. Furthermore, for the majority of patients, international normalized ratio (INR) monitoring may be an inconvenience. This is why new anticoagulants, such as the direct thrombin inhibitors, are being investigated. The results of the RE‐LY trial have recently been published. In this study, in a population of patients with AF, dabigatran at 110 mg b.i.d was associated with stroke and systemic embolism rates similar to those associated with warfarin, and with lower rates of major hemorrhage. However, when dabigatran was administered at a dose of 150 mg, lower rates of stroke and systemic embolism and similar rates of major hemorrhage were found compared with warfarin. The aim of this review is to update information on the prevention of thromboembolic events in patients with AF and how dabigatran may change daily clinical practice.     

In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves

Introduction

Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for ≈ 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.

Material and Methods

Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 μmol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.

Results

In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164 ± 55 mg, in the UFH group 159 ± 69 mg, and in the LMWH group 182 ± 82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.

Conclusisons

Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.     

Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans

AIM: To investigate the outcomes of trauma patients with traumatic brain injury(TBI) on Dabigatran Etexilate(DE). METHODS: Following IRB approval, all patients taking DE who were admitted to our level 1 trauma service were enrolled in the study. Injury complexity, length of stay(LOS), intensive care length of stay, operative intervention, therapeutic interventions and outcomes were analyzed retrospectively. RESULTS: Twenty-eight of 4310 admissions were taking DE. Eleven patients were excluded on concurrent antiplatelet therapy. Average age was 77.14 years(64-94 years), and average LOS was 4.7 d(1-35 d). Thirty-two percent were admitted with intracranial hemorrhage. Eighteen percent received factor Ⅶ, and 22% received dialysis in attempts to correct coagulopathy. Mortality was 21%.CONCLUSION: The low incidence, absence of reversal agents, and lack of practice guidelines makes managing patients with TBI taking DE frustrating and provider specific. Local practice guidelines may be helpful in managing such patients.     

达比加群酯治疗ACS心房颤动的研究进展

我国流行病学调查显示,35岁及以上人群心房颤动加权患病率为0.71％,随年龄增长患病率明显增高,房颤人群的脑卒中风险明显高于非房颤人群,房颤的疾病负担是一个重要的公共卫生问题,而抗凝治疗能够降低房颤患者的血栓栓塞风险.达比加群酯作为新型口服抗凝药目前在临床上得到了应用.其口服后经胃肠吸收,在体内转化为有抗凝活性的达比加...     

达比加群酯联合双联抗血小板药物对非瓣膜性房颤患者PCI术后凝血功能及终点事件发生率的影响

目的:研究达比加群酯联合双联抗血小板药物应用于非瓣膜性房颤患者经皮冠状动脉介入治疗(PCI)术后的效果。方法:选取2018年10月至2019年10月期间漯河市第六人民医院收治的非瓣膜性房颤患者86例,按照随机数字表法分为对照组、观察组,各43例。两组均行PCI术,并给予阿司匹林、氯吡格雷双联抗血小板治疗,对照组采用华法林治疗,观察组采用达比加群酯治疗。比较两组治疗前、治疗6个月后凝血功能[凝血酶时间(TT)、活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)]、血栓弹力图指标[凝血因子反应时间(R值)、Angle角、MA值]及终点事件发生率。结果:治疗6个月后观察组TT、APTT、PT长于对照组(P<0.05);治疗6个月后两组Angle角、MA值比较,差异无统计学意义(P>0.05);治疗6个月后观察组R值大于对照组(P<0.05);观察组终点事件发生率4.65%低于对照组20.93%(P<0.05)。结论:达比加群酯联合双联抗血小板药物应用于非瓣膜性房颤患者PCI术后能改善凝血功能,提高R值,降低终点事件发生率。     

利伐沙班与达比加群低剂量治疗非瓣膜性房颤患者有效性和安全性的Meta分析

目的:系统评价低剂量利伐沙班与达比加群在治疗非瓣膜性房颤患者中的有效性和安全性.方法:计算机检索中、英文数据库PubMed、EMBASE、Cochrane Library、MEDLINE、中国知网、万方、维普,收集低剂量利伐沙班与达比加群治疗非瓣膜性房颤有效性和安全性的队列研究,检索期限从建库至2021年8月.对符合纳入标准的研究进行资料提取和质量评价,采用Revman5.3软件进行统计学分析.结果:最终纳入了17篇研究.Meta分析结果显示:在有效性方面,利伐沙班与达比加群低剂量给药后卒中/全身性栓塞、心肌梗死发生率均无显著差异(P>0.05).在安全性方面,利伐沙班大出血、颅内出血、全因死亡风险均显著高于达比加群(P<0.05),而两组消化道出血风险无显著差异(P>0.05).亚组分析结果表明:欧洲和北美洲地区,两组卒中/全身性栓塞发生率无显著差异,利伐沙班大出血风险高于达比加群;亚洲地区,利伐沙班卒中/全身性栓塞发生率低于达比加群,但中国人群中两药无差异;两组大出血风险无显著差异.无论随访时间是否>1年,利伐沙班大出血风险均高于达比加群,且差异有统计学意义.结论:房颤患者超说明书低剂量给予达比加群的有效性与利伐沙班相似,而达比加群的安全性更高、死亡率更低;由于中国人群纳入的研究数过少,故该结论需谨慎对待.