新型口服抗凝药物拮抗剂的研究进展

心房颤动患者大多需要口服抗凝药物,传统抗凝药物华法林应用临床已逾60年,尽管其作用明确,但存在各种局限性。近年来新型口服抗凝药(new oral anticoagulant,NOAC)的问世弥补了华法林的不足,因具有更好的风险/获益比,成为心房颤动患者的新选择。虽然NOACs有着众多优点,然而缺少特异性的拮抗剂仍限制了其临床应用。不过,目前NOACs拮抗剂的研究已经取得了突破性的进展,2015年10月美国FDA通过加速审批程序批准idarucizumab作为达比加群酯的唯一拮抗剂。2018年5月Andexxa获FDA批准作为Xa抑制剂的首个及唯一特异性拮抗药物,另外,目前处于研究阶段的Ciraparantag也有望成为NOACs的特异性拮抗剂。该文将对上述药物的研究进展作简要的综述。     

新型口服抗凝药

心房颤动血栓栓塞的多项一级预防试验的荟萃分析显示,华法林可使脑卒中的相对危险降低68%,但华法林存在起效慢、治疗窗口窄,需经常化验检测国际标准化比值(INR)等,因此华法林临床应用率不高,INR达标率更加有限。目前包括Ⅱa因子     

口服抗凝药物治疗心房颤动的新进展

心房颤动(房颤)是一种常见的心律失常,老年人中尤甚。我国关于房颤的流行病学资料较少,其中一项重要研究为覆盖全国13个省、14个横断面的自然人群研究,其结果显示房颤的发生率为0.77%,年龄标化后发生率为0.61%[1]。房颤的长期危险性主要是脑栓塞、心力衰竭和死亡率增加,房颤导致栓塞事件的发生率在3%~8%[2],其中以脑栓塞最为常见,严重影响患者的生活质量,甚至危及患者生命。胡大一     

药物治疗

马里兰急诊医学必知(Maryland Emergency Medicine Pearls) 在急诊科使用万古霉素负荷会导致较高的最低有效治疗水平 Bryan Hayes 万古霉素的剂量应该根据体质量进行调整,而不是所有的患者都默认使用1 g.急诊室高负荷量真的可以带来更长时间的最低有效治疗水平? 一项新的随机对照研究,比较了急诊科患者使用30mg/kg和15 mg/kg的初始剂量.与接受15 mg/kg负荷剂量的患者比较,更多的接受30 mg/kg负荷剂量的患者,在12h到达了目标治疗有效最低水平(34％ vs.3％,P＜0.01).该研究没有使用最大剂量2 g.纳入的患者中包括体质量120 kg接受3.6g负荷量的患者.两组之间肾毒性的发生率没有区别.     

新型抗凝药物

近年来,随着血栓和止血研究的深入,各类新型抗凝药物不断涌现。本文就直接凝血酶抑制剂、FⅦa／TF复合物抑制剂和FXa抑制剂三类药物的作用机制、实验室监测、临床疗效以及毒副作用等作一综述。     

华法林在新型口服抗凝药物时代的地位

抗凝治疗是血栓栓塞性疾病,尤其是肺栓塞防治的重要措施。华法林作为经典的抗凝药物,从20世纪50年代起用于治疗血栓栓塞性疾病。相比华法林,新型口服抗凝药物(novel oral anticoagulants,NOACs)具有药代动力学稳定、可固定剂量使用、无须频繁监测凝血功能、与药物及食物相互作用少、药物安全性良好等突出优点。NOACs给临床医生带来更多用药选择的同时,也挑战了华法林在抗凝领域的地位。然而目前很多临床情况下,华法林的抗凝价值仍不可替代。     

新型口服抗凝药物相关性出血的处理策略现状

新型口服抗凝药物（NOACs）包括直接凝血酶抑制剂（达比加群）和直接Xa因子抑制剂（阿哌沙班、利伐沙班）,因其具有起效快、半衰期短、药物间相互作用少、药代动力学确切、个体差异小等优点而受到广泛关注。     

心房颤动患者应用新型口服抗凝药物的指南解读

脑卒中是心房颤动(房颤)最危险而严重的并发症,而抗凝治疗可显著降低房颤患者的卒中风险,改善患者预后,因而成为房颤治疗的核心策略之一。华法林于20世纪50年代开始应用于房颤抗凝,其疗效可靠,但治疗窗窄、起效慢、失效时间长、个体间的有效剂量差异大(部分与患者的基因分型有关)、药物和食物影响因素多,并需要定期监测抗凝强度以调整华法林的用量,故导致其在临床上的应用受到较多限制[1]。随着医疗技术的进展,近年来     

新型抗凝药物研究展望

对血液凝固的潜在分子机制的更多了解、重组DNA技术的进步、吸血生物中抗凝蛋白质的分离和鉴定,以及以结构为基础药物设计的进展,已经加速了新药发现的步伐.     

新的抗凝药物治疗心房颤动的评价

心房颤动（atrial fibrillation ,简称房颤）是最常见的持续性心律失常,其发病率随年龄增长逐年升高,是引起缺血性脑卒中的一个独立危险因素。房颤可使各年龄段脑卒中的危险增加4～5倍［1］。在我国部分地区房颤住院病例回归调查资料中,房颤患者脑卒中的患病率为17．5％。因此房颤的主要治疗目标之一就是减少脑卒中的发生率。维生素K拮抗剂-华法林是目前临床上最常用的治疗房颤的长效口服抗凝药物,虽然抗凝疗效确切,但该药剂量-效应多变,半衰期长［2］,治疗窗狭窄,药物间相互作用大,需要频繁监测凝血机制,且有出血事件发生的可能,给临床上应用带来种种明显的局限性,其在房颤患者中的利用率仅为65％左右［3］。因此替代华法林新的抗凝药物研究成为该领域最具期望的研究。     

New oral anticoagulants: An emergency department overview

As of September 2013, three new oral anticoagulants (NOACs) are now available for clinical use on the Pharmaceutical Benefits Scheme in Australia. All three are for stroke prevention in atrial fibrillation, and one will also be available for the treatment of deep venous thrombosis and pulmonary embolism. All have been evaluated in large, multicentre randomised clinical trials. These drugs show at least equivalent efficacy to the current standard of care, the vitamin K antagonist warfarin. Major bleeding rates are overall comparable with warfarin, but there is an important reduction in intracranial bleeding of approximately 50% with all NOAC agents. The NOACs are administered in a simple, fixed dose regimen. There are a few clinically important interactions with other medications or diet. Concerns exist about the potential for irreversible bleeding in the small number of patients in which that occurs. This short report will discuss the pharmacology of these agents, the indications for use, aspects of laboratory monitoring and the management of bleeding with these agents.     

Novel oral anticoagulants

Oral anticoagulants have been used widely for the treatment of venous thromboembolism and stroke prevention. The vitamin K antagonists (VKAs), such as warfarin, have been around for the last 65 years and its efficacy as thromboprophylaxis remained largely unchallenged, at least until recently. Nonetheless, the VKAs have significant limitations with marked inter‐ and intra‐individual variability, requiring regular monitoring and have important food and drug interactions. Thus, there is an unmet need, with the quest for alternative oral anticoagulants with stable pharmacokinetics and pharmacodynamics that do not need monitoring. The novel oral anticoagulants are in 2 broad drug classes – the oral direct thrombin inhibitors and oral factor Xa inihibitors. This review article provides an overview of the pharmacology and describes the most recent published data on clinical trials with the new oral anticoagulants, which are in the more advanced stages of clinical development.     

New oral anticoagulants in the ED setting: a review

Background

Emergency department (ED) clinicians are not typically involved in the long-term management of patients' anticoagulation therapy, but they are responsible for decision making for emergency conditions requiring anticoagulation, such as acute venous thromboembolism (VTE). In addition, emergency physicians are often faced with patients who present first to the ED with conditions that may prompt long-term anticoagulation upon hospital discharge, such as atrial fibrillation (AF), or who have acute or potential bleeding complications from anticoagulation.

Objective

In this review, clinical trials of new oral anticoagulants evaluated for treatment of VTE and stroke prophylaxis in AF, as well as practical management aspects, will be discussed. In addition, clinical trials evaluating the adjunctive use of the new oral anticoagulants with antiplatelet therapy in patients who have experienced acute coronary syndrome will be explored.

Discussion

Both dabigatran etexilate and rivaroxaban have successfully completed phase III trials for acute VTE treatment and are currently approved for the reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. In a recently completed phase III trial, apixaban also demonstrated promising efficacy and safety in that indication. Rivaroxaban represents the only new anticoagulant to date to have shown promising phase III results as an adjunct to antiplatelet therapy after acute coronary syndrome.

Conclusion

Knowledge of the appropriate clinical use and safety concerns of the new anticoagulants is imperative as they become more frequently prescribed, and their potential uses in the ED setting represent an important aspect of continuing education for emergency physicians.     

New oral anticoagulants: are coagulation units still required?

Chronic antithrombotic therapy involves the use of anticoagulants, antiplatelets given either as monotherapy or in combination for the prevention of thrombotic complications. The most feared and sometimes fatal complication with this therapy is bleeding. It should be considered a “golden rule” that a drug or combination of drugs that maximizes efficiency (decreased thromboembolic risk) will probably be less safe (increased risk of bleeding), and this holds true either for single therapy or during combined therapy. The chances of bleeding indicated by risk tables can be useful but show only a snapshot, and the biological, social, environmental, and drug changes and therapeutic adherence also determine changes in the risk of thrombosis and bleeding. Bleeding is an eventuality that occurs in places of “locus minoris resistentiae,” and the results of careful phase 3 studies thus cannot be completely predictive of outcomes when a medication is introduced on the pharmaceutical market. With the use of warfarin, the International Normalized Ratio (INR) that has been established to indicate adequately balanced therapy is between 2.0 and 3.0. With the new oral anticoagulants, the pharmaceutical companies emphasize that it is not necessary to monitor anticoagulant effects. In studies with different doses of new oral anticoagulants, however, incidence of clinically significant bleeding complications have been directly related to the doses. Therefore, therapeutic excesses can condition bleeding risk and therapeutic limitation can increase thrombotic risk, especially when short-acting drugs such as the new oral anticoagulants are used. Hence, it is imperative to establish an appropriate method for monitoring new oral anticoagulants, setting levels of safety and effectiveness through periodic dosage and monitoring of their anticoagulant effects. Therefore, we still recommend the use of anticoagulation units for monitoring during treatment with the new oral anticoagulants.     

New anticoagulants

This review updates the latest developments concerning new anticoagulants. It describes potential targets in the coagulation pathway: inhibition of the initiation of coagulation, factor Xa and thrombin inhibitors. The focus is laid on substances in late development that already passed the phase II trial for venous thromboembolism (VTE)-prevention as "proof of concept". In the group of factor Xa inhibitors, the indirect inhibitor Fondaparinux has got approval for the indications prevention and therapy of VTE and acute coronary syndromes (OASIS 5 and 6). Rivaroxaban is the first direct factor Xa inhibitor that was admitted for approval in the indication VTE-prevention. The first trial of the program RECORD 1-4 was finished, trials for the indications therapy of VTE (EINSTEIN) and stroke prevention in atrial fibrillation (ROCKET AF) are in phase III. The use in acute coronary symptoms is - like apixaban - evaluated in phase II. The ADOPT trial with apixaban for VTE-prevention, as well as the BOTTICELLI trial for atrial fibrillation, have reached phase III. After the withdrawal of Ximelagatran, Dabigatran is the most developed direct thrombin inhibitor, being extensively studied in the comprehensive phase- III-program REVOLUTION and in approval for the indication VTE-prevention.     

New anticoagulants

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.     

New oral anticoagulants to revolutionise venous thromboembolism (VTE) management

Warfarin, a vitamin K antagonist has been the mainstay of venous thromboembolism treatment for over 60 years. However, it has significant limitations in relation to achieving a safe and therapeutic efficacy. Evolution in the development of oral anticoagulants to offset the drawbacks of warfarin, has led to the introduction of two new oral anticoagulants, namely dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor. This paper examines the potential of the two new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. In seven randomized clinical trials, dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, The National Institute of Clinical Excellence (NICE) have now endorsed its clinical efficacy as a serious alternative to low molecular weight heparin and fondaparinux.Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopaedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban within its marketing authorisation was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.