Healthcare burden associated with the post-thrombotic syndrome and potential impact of the new oral anticoagulants

Deep-vein thrombosis (DVT) can have a significant impact on a patient's life. In particular, the development of post-thrombotic syndrome as a long-term complication of DVT can have devastating consequences for the individual and impose a substantial economic burden on healthcare systems. Anticoagulants are the mainstay of DVT treatment; however, the current standard of care, a parenteral anticoagulant followed by a vitamin K antagonist, is associated with complex patient management, often resulting in suboptimal therapy. New, oral anticoagulants have been developed, and a direct thrombin inhibitor--dabigatran etexilate--and two direct Factor Xa inhibitors--rivaroxaban and apixaban--have completed and/or have ongoing phase III trials in the treatment of venous thromboembolism. These agents do not have the drawbacks of the vitamin K antagonists and hold promise for more effective treatment of DVT, possibly resulting in a reduction in the incidence of post-thrombotic syndrome.     

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。     

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。     

Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants

Background

Non–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.

Objectives

This study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.

Methods

We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).

Results

We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R² = 0.92 to 0.99) and ecarin-based assays (R² = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R² = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.

Conclusions

Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.     

Inhibition of staphylothrombin by dabigatran reduces Staphylococcus aureus virulence

Summary. Background: Staphylocoagulase and von Willebrand binding protein (VWbp) bind to prothrombin to form the staphylothrombin complex that converts fibrinogen into fibrin. Objectives: To study the role of staphylothrombin and its inhibition by dabigatran on Staphylococcus aureus virulence. Methods: We studied the effect of staphylothrombin inhibition on bacterial attachment to polystyrene surfaces, leukocyte activation and bactericidal activity for S. aureus ATCC 25923, S. aureus Newman, and staphylocoagulase‐ and VWbp‐negative S. aureus Newman mutants in the presence or absence of prothrombin and fibrinogen. We measured the abscess size after subcutaneous (s.c.) injection of S. aureus ATCC 25923 and S. aureus Newman, as well as an S. aureus Newman mutant strain lacking staphylocoagulase and VWbp, in mice treated with either dabigatran or placebo. Results: Staphylothrombin‐mediated fibrin increased the association of S. aureus to polystyrene surfaces and reduced the bactericidal activity of leukocytes. The absence or inhibition of staphylothrombin decreased the bacterial association, enhanced leukocyte activation and reduced bacterial survival in vitro. Abscess size was smaller in mice treated with dabigatran or infected with a coagulase‐negative mutant. Conclusion: Inhibition or the absence of staphylothrombin reduced S. aureus virulence in in vitro and in vivo models.     

Changing anticoagulant paradigms for atrial fibrillation: dabigatran,apixaban and rivaroxaban

Introduction: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.

Areas covered: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.

Expert opinion: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.     

Protocol in managing oral surgical patients taking dabigatran

New anticoagulants are being introduced into the market. These drugs are orally administered, have predictable pharmacokinetics and dose response, do not require monitoring and have an acceptable safety profile when used appropriately, and so avoid many of the disadvantages and possible complications of warfarin and heparin. Dabigatran is the most widely used, and has been approved by the Therapeutic Goods Administration. The use of dabigatran will likely increase in the coming years, and so it is important for dentists to be aware of its mechanism of action, the possible complications, and how to reverse the bleeding if it occurs. This review discusses dabigatran and reports on our experience of five cases, and provides practical clinical advice on how to manage patients on dabigatran who require dental treatment, particularly extractions.