A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)

Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena’s Simple Simon? PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type.

Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10?µL end-to-end capillary used to add the citrated plasma sample to 200?µL of prothrombin time (PT) reagent by either a 20?µL or a 5?µL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons.

Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20?µL variant showed markedly higher PT results than the 5?µL. The effects were even more pronounced at room temperature than at +37?°C. In plasmas from patients treated with NOACs (n?=?30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20?µL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1–2.1 for dabigatran and apixaban, and INR 1.1–5.0 for rivaroxaban. Using an INR ratio between the 20?µL and 5?µL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80?µg/L for apixaban, 60?µg/L for dabigatran, and 20?µg/L for rivaroxaban.

Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.     

基因多态性与新型口服抗凝药个体化用药概述

摘 要新型口服抗凝药(NOACs)由于治疗窗宽、无需常规凝血监测等优势逐渐被广泛使用。近年来,NOACs的药物反应出现个体差异,有报道发现,遗传变异是导致NOACs个体间差异的重要因素,因此研究基因多态性对NOACs药物反应的影响十分必要。通过综述近年来的相关研究探讨基因多态性对新型口服抗凝药的药动学和药效学的影响,指导NOACs个体化用药,提高疗效和安全性,减少不良事件的发生。     

达比加群酯抗凝治疗合理性和安全性评价

目的：调查住院患者接受达比加群酯治疗情况,了解该药的应用现状和不良反应并分析其危险因素,为临床更好的使用达比加群酯提供参考依据。方法：收集中日友好医院2017年4月1日至2018年3月31日住院期间使用达比加群的患者信息,进行回顾性分析。通过分析患者适应证、肝肾情况、凝血指标、不良反应、药物转换及合并用药情况,评价达比加群酯使用的合理性和安全性。结果：共收集患者247例,其中男139例（56.28%）,女108例（43.72%）。年龄29~91岁,平均（72.11±29.26）岁。使用达比加群的患者中老年人有207例（83.80%）,因房颤及房扑入院的患者有184例（74.49%）,占比最大。患者因CrCL<30 mL·min^-1禁忌使用达比加群的情况下仍使用的有10例（4.05%）。19例（7.69%）患者住院期间使用达比加群出现不良反应,出血有14例（73.68%）。服用达比加群期间进行药物转换的患者32例（12.96%）。由华法林向达比加群转换22例（68.75%）,使用错误率为36.36%。由达比加群向华法林转换6例（18.75%）,使用错误率为100%。合用药物中联合使用抗血小板药37例（14.98%）,联合使用胺碘酮16例（6.48%）,临床使用期间应该加强监测。结论：达比加群临床常用于老年非瓣膜性房颤患者,使用前应注意肝肾功能监测,常见不良反应为出血,合并使用抗血小板药和胺碘酮时多注意监护。达比加群与华法林药物转换时错误较多,是药学监护的重点。     

房颤合并肝硬化患者的口服抗凝药物选择及抗栓策略研究

目的 探讨房颤合并肝硬化患者临床治疗中口服抗凝药物的选择及安全性。方法 在1例房颤合并乙型肝炎肝硬化患者房间隔修补术后抗栓方案的制定中,通过查阅指南和文献,总结、分析房颤合并肝硬化患者口服抗凝药物的疗效及安全性评价现状。结果 通过综合评估患者情况,停用华法林,予达比加群酯110 mg,bid,联合氯吡格雷75 mg,qd抗栓6个月,之后达比加群酯110 mg,bid长期抗凝治疗。结论 房颤合并肝硬化患者抗栓治疗,应充分评估血栓及出血风险,制定个体化的抗栓策略。房颤合并Child-Pugh A级肝硬化,新型口服抗凝药均可使用;合并Child-Pugh C级肝硬化,口服抗凝剂均不建议使用;合并Child-Pugh B级肝硬化,出血风险高的患者长期抗凝治疗中可选用小剂量达比加群酯。     

Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review

The use of direct-acting oral anticoagulants (DOACs) has increased secondary to the mounting evidence for comparable efficacy and potentially superior safety to vitamin K antagonists (VKAs) in the general population. However, insufficient data regarding DOAC use in solid organ transplant (SOT) recipients and numerous pharmacokinetic and pharmacodynamic considerations limit their use in this highly selected patient population. A systematic review of recent clinical evidence on the safety and efficacy of DOACs compared to VKAs in SOT recipients was conducted. Additional considerations including transplant-specific strategies for DOAC reversal and common pharmacokinetic/pharmacodynamic concerns were also reviewed. Although current evidence is limited to single-center retrospective analyses, DOACs, especially apixaban, appear to be a safe and effective alternative to VKAs for SOT recipients with stable graft function and without drug-drug interactions. Reliable data on DOAC reversal at the time of transplant surgery are lacking, and clinicians should consider idarucizumab, andexanet alfa, and other non-specific reversal agents on an individual patient basis. There is no evidence supporting deviations from the Food and Drug Administration labeling recommendations for DOAC dosing in the setting of drug-drug interactions, obesity, and renal function, especially in patients on hemodialysis.     

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治疗效果

目的 探讨在治疗老年心房颤动合并不稳定型心绞痛时使用达比加群酯联合替格瑞洛对其凝血功能及临床疗效的影响.方法 120例老年心房颤动合并不稳定型心绞痛患者,按照入院的先后顺序分成观察组和对照组,每组60例.对照组在常规治疗的基础上口服华法林、替格瑞洛进行治疗,观察组在常规治疗的基础上加用达比加群酯联合替格瑞洛进行治疗.比...     

达比加群酯联合阿司匹林在非瓣膜性房颤治疗中的应用效果及安全性评价

目的 分析非瓣膜性心房颤动(房颤)患者使用达比加群酯联合阿司匹林进行治疗的临床疗效及安全性.方法 120例非瓣膜性房颤患者,根据随机数字表法分为对照组和实验组,各60例.对照组患者采用常规抗凝治疗,实验组患者采用达比加群酯联合阿司匹林治疗.对比两组患者的治疗效果及不良反应发生情况.结果 实验组患者的治疗总有效率为93....     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸与3-(吡啶-2-基氨基)丙酸乙酯在羰基二咪唑的作用下反应形成3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,经锌粉还原得到3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,随后与N-(4-氰基苯基)甘氨酸在羰基二咪唑以及醋酸作用下一锅制得3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯,再进行成脒化反应以及酰化反应后即可制得达比加群酯,总收率约48％.     

New therapeutic option for thromboembolism – dabigatran etexilate

Background: Thrombin plays a key role in blood coagulation and haemostasis; thus its inhibition has been identified as a reasonable target to block the coagulation cascade. Direct thrombin inhibitors are potential prophylactic agents for venous thromboembolism and arterial thrombosis, which often accompany operative procedures and cardiac disease, especially orthopedic surgery and atrial fibrillation, respectively. New orally available anticoagulant agents with a wide therapeutic window are keenly anticipated because warfarin and heparins have some disadvantages, and recent progress in pharmaceutical techniques has led to the development of orally administered direct thrombin inhibitors. Objectives: In this review, we discuss the usefulness of dabigatran etexilate as a new therapeutic option for preventing thromboembolism, including chemistry, pharmacokinetics, and pharmacodynamics, from the results of recent clinical studies. Methods: We systematically focused on relevant published studies, as data from recent clinical studies were difficult to obtain owing to their ongoing status. Conclusions: Dabigatran etexilate is a promising new oral anticoagulant that offers greatly expanded therapeutic options for both patients and physicians.     

Risk of gastrointestinal bleeding during anticoagulant treatment

Introduction: Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009.

Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, focusing on randomized controlled trials, meta-analyses, and post-marketing observational studies. Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily increase the risk of GIB compared to warfarin. The risk increase with edoxaban is dose-dependent, while apixaban shows apparently, no increased risk. We summarize what is known about GIB risk factors for individual anticoagulants, the location of GIB in patients taking these compounds, and prevention strategies that lower the risk of GIB.

Expert opinion: Recently there has been an important shift in the clinical presentation of GIB. Specifically, upper GIB has decreased with the decreased incidence of peptic ulcers due to the broad use of proton pump inhibitors and the decreased prevalence of H. pylori infections. In contrast, the incidence of lower GIB has increased, due in part to colonic diverticular bleeding and angiodysplasia in the elderly. In this population, the addition of oral anticoagulation therapy, especially DOACs, seems to increase the risk of lower GIB.