阿哌沙班与华法林用于非瓣膜性房颤患者卒中防治的成本效果分析

目的 评估中国非瓣膜性房颤患者使用阿哌沙班或华法林预防卒中的成本效果。方法 基于全球性临床试验ARISTOTLE的研究数据及中国目前医疗成本,建立1年期决策树及长期外推Markov模型的方法,通过计算新型口服抗凝药物阿哌沙班(5 mg bid)及华法林(INR控制在2.0~3.0)的质量调整生命年(quality-adjusted life-years QALYs)及治疗成本,对阿哌沙班用于中国房颤患者卒中预防的成本效果进行了分析和研究。结果 阿哌沙班和华法林的总成本分别为271 826元和40 126元,阿哌沙班组患者可获得的QALYs为6.256,华法林组患者的QALYs为5.614。阿哌沙班较华法林的增量成本效果比(incremental cost-effectiveness ratio,ICER)为360 903元/QALY。ICER>3倍中国人均GDP,但<3倍部分城市人均GDP。敏感度分析显示该成本效果分析结果稳定可靠。结论 在中国目前整体经济形势下,与华法林相比,将阿哌沙班预防非瓣膜性房颤患者卒中预防不具备成本效果优势。目前仅在中国经济发达的某些城市,可推荐阿哌沙班替代华法林成为房颤卒中治疗药物。     

新型口服抗凝药在治疗非瓣膜性房颤中的研究进展

目的:为临床合理使用新型口服抗凝药(NOACs)治疗非瓣膜性房颤(NVAF)提供参考。方法:查阅近年来国内外相关文献,对NOACs在治疗NVAF中的研究进行归纳和分析。结果:凝血酶抑制剂达比加群酯和Ⅹa因子抑制剂利伐沙班、阿哌沙班、依度沙班和贝曲西班等NOACs相较于华法林在NVAF患者中,能显著降低卒中、颅内出血及死亡的发生率。NOACs服用方便、无需检测凝血指标、无需频繁调整剂量,在最新的房颤指南中得到推荐,但临床研究有限,价格昂贵,缺乏有效的拮抗药。结论:NOACs在治疗NVAF中有可观的临床发展前景。     

达比加群酯与利伐沙班、阿哌沙班和依度沙班用于非瓣膜病房颤患者预防卒中的有效性和安全性比较

目的根据临床相关研究文献,以华法林为共同对照组,间接比较达比加群酯与利伐沙班、阿哌沙班和依度沙班用于非瓣膜病房颤(NVAF)患者预防卒中的有效性与安全性差异。方法直接选用新型口服抗凝药(NOACs)与华法林比较的4项Ⅲ期临床试验研究,提取每项试验中卒中或体循环栓塞、主要出血等有效性和安全性终点事件的发生率,用Bucher法对4种NOACs的有效性和安全性进行间接比较。结果与达比加群酯(110 mg,bid)组相比,利伐沙班组卒中或体循环栓塞事件发生率无显著差异,主要出血事件发生率升高(HR 1.30,95%CI 1.06~1.60);达比加群酯(110 mg,bid)组卒中或体循环栓塞事件和主要出血事件发生率与阿哌沙班组和高剂量依度沙班组相当,但低剂量依度沙班组主要出血事件风险更低(HR 0.59,95%CI 0.48~0.72)。与达比加群酯(150 mg,bid)组相比,利伐沙班组卒中或体循环栓塞事件发生率较高(HR 1.33,95%CI 1.02~1.75),阿哌沙班组主要出血事件发生率较低(HR 0.74,95%CI 0.61~0.91),低剂量依度沙班组卒中或体循环栓塞发生率较高(HR 1.71,95%CI 1.30~2.25),主要出血发生率较低(HR 0.51,95%CI 0.41~0.62);高剂量依度沙班组卒中或体循环栓塞事件和主要出血事件发生率和达比加群酯(150 mg,bid)组相当。结论在有效性方面,达比加群酯(150 mg,bid)最优,阿哌沙班与之相当。在安全性方面,低剂量依度沙班最优,阿哌沙班和达比加群酯(110 mg,bid)次之,利伐沙班出血风险最高。     

艾多沙班用于非瓣膜性心房颤动抗凝治疗的研究进展

口服抗凝药物是非瓣膜性房颤患者降低血栓栓塞和卒中风险的有效治疗方法。既往临床长期应用的口服抗凝药为维生素K拮抗剂及肝素,近年来新型口服抗凝剂逐渐得到广泛应用,包括直接凝血酶抑制剂达比加群和Xa因子抑制剂如利伐沙班、阿哌沙班及艾多沙班,均可用于非瓣膜性心房颤动患者的卒中预防。艾多沙班作为新型口服抗凝剂,为房颤患者提供了更多的用药选择。本研究对艾多沙班在房颤患者抗凝预防和临床治疗中的作用进行综述。     

新型口服抗凝药物的安全性

新型抗凝药物主要包括直接凝血酶抑制剂和Xa因子抑制剂。其中,直接凝血酶抑制剂达比加群酯口服制剂、直接Xa因子抑制剂利伐沙班和阿哌沙班口服制剂已在我国上市;另外一种直接Xa因子抑制剂贝曲沙班口服制剂也正在进行Ⅲ期临床研究;而直接Xa因子抑制剂爱多沙班口服制剂已在日本上市。达比加群酯致颅内出血发生风险低于华法林,但该药可能增加急性冠状动脉综合征患者严重出血和具有临床意义轻度出血的发生率,以及心肌梗死或急性冠状动脉综合征的发生风险。利伐沙班在预防非瓣膜性心房颤动所致脑卒中和栓塞方面优于华法林,预防骨科术后血栓效果优于依诺肝素,大出血事件发生风险与两药相似,而颅内出血发生风险低于华法林。阿哌沙班在降低心房颤动患者脑卒中或全身性栓塞发生率及病死率方面优于华法林,颅内出血发生率低于华法林,大出血发生率与华法林相似或降低;阿哌沙班的安全性与用药剂量相关。爱多沙班的主要不良反应为出血,用于心房颤动患者的有效性及安全性均优于华法林。贝曲沙班用于全膝关节置换术后预防血栓效果与依诺肝素相似,出血发生率低于依诺肝素。     

达比加群酯在老年非瓣膜性房颤患者中的疗效及安全性分析

目的:比较新型口服抗凝药物达比加群酯和传统抗凝药物华法林在老年非瓣膜性房颤患者中的安全性。方法:收集2015年1月至2016年12月在北京大学第一医院老年科住院的接受达比加群酯或华法林抗凝治疗的老年非瓣膜性房颤患者109例,根据使用抗凝药物不同,分为达比加群酯组65例和华法林组44例,监测凝血功能指标,比较两组治疗后凝血功能的变化情况、血栓栓塞事件发生的情况。结果:老年非瓣膜性房颤患者存在危险因素多、伴随疾病多、需要联合使用抗血小板聚集药物比例高的特点。达比加群酯组血栓栓塞事件发生率3.06%,华法林组6.81%,两组比较无统计学差异(P0.05)。结论:新型口服抗凝药物达比加群酯与华法林抗栓效果相当,不良事件发生率更低。     

新型口服抗凝药治疗非瓣膜病房颤的成本-效用分析

摘要：目的:评价3种新型口服抗凝药物达比加群酯、阿哌沙班、利伐沙班治疗非瓣膜病房颤（NVAF）的成本-效用值,为合理用药及医保目录的评审、药品集中采购、价格谈判等提供决策依据。方法:构建Markov模型模拟NVAF发展过程,依据3种新型口服抗凝药物的国际多中心随机对照试验获得安全性和有效性数据,从文献中获取效用值,运行Treeage Pro 2011软件计算新型口服抗凝药物的成本-效用比,同时进行敏感性分析。结果:新型口服抗凝药治疗NVAF中达比加群酯110 mg成本-效用比18 155.17,达比加群酯150 mg成本-效用比23 034.72,阿哌沙班成本-效用比25 979.16,利伐沙班成本-效用比18 517.53。结论:达比加群酯110 mg在治疗NVAF过程中更具有经济优势,同时利伐沙班在治疗此类疾病相对于达比加群酯110 mg所增加的成本可以接受。     

真实世界非瓣膜性房颤患者口服抗凝药物的使用研究

目的：探索专门的抗凝门诊非瓣膜性房颤(Non-valvular atrial fibrillation,NVAF)患者口服抗凝药物的使用情况,为真实世界临床实践提供指导。方法：对于2014年至2018年抗凝门诊接受口服抗凝药物(Oral anticoagulants,OAC)治疗的NVAF患者的情况进行回顾性分析。结果：选择服用华法林者551人,达比加群酯者83人,利伐沙班者48人;服用3药物的NVAF患者中CHA2DS2-VASc评分男性≥1分、女性≥2分者分别占89.7%、94.0%和93.8%;卒中低危患者中约50%为复律或射频消融前3周或后4周抗凝治疗;使用NOACs患者的平均年龄和既往有卒中史的比例高于华法林的患者。由于NOACs使用的方便性,临床实践中华法林转换为NOACs最为常见;仍有相当多的抗凝药物不依从的情况,其中1例患者因自行停用达比加群酯3天导致短暂性脑缺血发作。结论：与目前临床指南的推荐不同,真实世界使用华法林者占绝大多数,NOACs较多用于高龄或既往卒中的患者,不同抗凝药物之间转换的监护以及改善服药的依从性是提高抗凝质量的重要举措。     

不同类型房颤患者使用新型口服抗凝药物和华法林预防卒中的疗效比较:Meta分析

目的比较新型口服抗凝药物(NOACs)与华法林预防不同类型心房颤动(房颤)患者卒中的有效性和安全性。方法应用计算机从PubMed、 Cochrane图书馆、 Elsevier、 Web of Science、中国知网、万方等电子数据库中检索自建库至2018年7月关于口服抗凝治疗预防房颤患者卒中的随机对照临床试验(RCTs)。获取数据资料后用RevMan 5.3和STATA软件进行荟萃及偏倚统计分析,比较口服抗凝治疗在阵发性房颤与持续性或永久性房颤患者卒中预防的有效性和安全性。结果通过筛选最终纳入了4项大型Ⅲ期RCTs,对其荟萃分析表明在阵发性房颤患者中,无论使用NOACs还是华法林,患者卒中和全身性栓塞发生率[NOACs组(2.58%, 197/7 642) vs.华法林组(3.25%, 193/5 929), RR=0.83, 95%CI:0.61～1.13, P=0.24, I2=57%]和大出血发生率[NOACs组(6.4%, 489/7 642) vs.华法林组(7.12%, 422/5 929),RR=0.88, 95%CI:0.78～1.00, P=0.06, I2=0%]无显著差异。在持续性或永久性房颤患者中,NOACs组卒中和全身性栓塞发生率显著低于华法林组[NOACs组(3.22%, 813/25 197) vs.华法林组(7.12%, 846/20 956), RR=0.82, 95%CI:0.75～0.90, P <0.000 1, I2=0%],同时大出血事件也显著降低[NOACs组(5.5%, 1 386/25 197) vs.华法林组(6.45%, 1 351/20 956), RR=0.85, 95%CI:0.73～0.99, P=0.03, I~2=77%]。结论阵发性房颤患者使用NOACs预防卒中的有效性和安全性与华法林相当,持续性或永久性房颤患者使用NOACs预防卒中的有效性和安全性较华法林好。     

吲哚布芬用于心房颤动的网状Meta及药物经济学评价

目的：评估吲哚布芬与抗凝药物用于非瓣膜性心房颤动患者的有效性、安全性及经济性。方法：系统检索吲哚布芬与抗凝药物治疗非瓣膜性心房颤的临床试验。采用网状Meta分析评价吲哚布芬与抗凝药物的疗效及安全性。从支付方角度,以成本-效果分析进行药物经济性评价。结果：本研究共纳入5篇研究,房颤患者72 599例。吲哚布芬与阿哌沙班（RR：0.97,95% CI：0.92,1.03）、达比加群酯110 mg（RR：1.03,95% CI：0.98;1.09）在临床净效益（卒中、系统性栓塞、出血事件及全因死亡率）事件发生数上无统计学差异。吲哚布芬与利伐沙班（RR：1.167,95% CI：1.10;1.23）、达比加群酯150 mg（RR：1.10,95% CI：1.04;1.16）、依度沙班（RR：1.07,95% CI：1.02;1.14）、华法林（RR：1.22,95% CI：1.15;1.29）相比,吲哚布芬可降低临床净效益事件发生数。原始研究中,在一年观察期内吲哚布芬组未观察到任何严重出血事件发生。吲哚布芬日成本27.8元,低于抗凝药物。结论：吲哚布芬可降低临床净效益事件发生数,降低临床相关非严重出血事件的发生率,在观察期内未出现严重出血事件。此外,吲哚布芬的日均成本低于抗凝药物,具有一定的成本优势。由于缺乏直接比较结果,未来仍需进一步开展多中心大样本的临床试验,为判断吲哚布芬治疗房颤疗效、安全性及经济性提供证据支持。     

Non-vitamin-K oral anticoagulants (NOACs) for the prevention of secondary stroke

ABSTRACT

Introduction: In patients with atrial fibrillation (AF), oral anticoagulation with vitamin K antagonists (VKA) (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention with a 60–70% relative reduction in stroke risk compared with placebo. Mortality is reduced by 26%. VKA have a number of well-documented shortcomings which were overcome by non-vitamin-K oral anticoagulants (NOACs).

Areas covered: Results of randomized trials for four NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) have been published (ARISTOTLE, RE-LY, ENGAGE, ROCKET-AF). In this review, the authors discuss the results in subgroups of patients with prior transient ischemic attacks or ischemic stroke. In aggregate, the NOACs are superior to warfarin for secondary prevention and result in a 50% reduction in intracerebral hemorrhage. Apixaban was superior to aspirin in the AVERROES trial and had a similar rate of major bleeding complications.

Expert opinion: NOACs add to the therapeutic options for secondary stroke prevention in patients with AF and offer advantages over warfarin including a favorable bleeding profile and convenience of use. Aspirin should no longer be used for secondary stroke prevention in patients with AF.     

心房颤动抗栓药物治疗进展

心房颤动(房颤)是导致卒中和外周栓塞的重要独立预测因素,华法林抗凝治疗可降低卒中率,但目前华法林临床应用不足。正在研究或已经上市的新型抗栓药物包括达比加群酯、利伐沙班和阿派沙班等可能革命性的改变这一现状。     

Novel Oral Anticoagulants for Stroke Prevention in the Geriatric Population

Prior to the availability of several newer anticoagulant medications, there had been no new advances in anticoagulation management for stroke prevention since the advent of warfarin in the 1950s. The availability of the novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban represent improvements over warfarin in many respects, including the elimination of the need for therapeutic drug monitoring, fewer drug and food interactions, and favorable efficacy; however, these agents are not without risk. Specifically, the use of the NOACs in the geriatric population, who are more likely to have an increased risk of stroke due to atrial fibrillation and other medical comorbidities, is not without risk. The objective of this review is to update the clinician on the use of the NOACs in the geriatric population and introduce the controversies and risks surrounding these newer therapies.     

不同抗凝用药方案对房颤合并心衰患者疗效与安全性的网状Meta分析

目的:系统评价不同抗凝用药方案对房颤合并心衰患者疗效与安全性的差异,为房颤合并心衰的临床用药提供循证参考.方法:计算机检索各大中英文文献数据库,搜集房颤合并心衰患者抗凝方案的随机对照试验(RTCs).筛选文献后,用Cochrane手册5.3推荐的偏倚风险评估工具评价纳入研究质量.提取数据,使用Stata15.1软件进行...     

Potential use of NOACs in developing countries: pros and cons

Purpose

Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries’ health care systems.

Methods

A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were “atrial fibrillation”, “oral anticoagulants”, “warfarin”, “NOACs”, “dabigatran”, “rivaroxaban”, “apixaban”, “edoxaban”, “time in therapeutic range”, “International Normalized Ratio” “cost-effectiveness”, “stroke”, “adverse-drug reactions” and “drug–drug interactions”, together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles.

Results

Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised.

Conclusion

The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice.     

Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation

This article provides an overview of the clinical profile of oral dabigatran etexilate (Pradaxa?, Pradax?) [hereafter referred to as dabigatran] when used for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), followed by a review of cost-utility analyses of dabigatran in this patient population. Dabigatran (110 or 150?mg twice daily) demonstrated noninferiority versus adjusted-dose warfarin with regard to the prevention of stroke and systemic embolism (primary endpoint) in patients with AF in the RE-LY trial, and the 150?mg twice-daily dosage was significantly more effective than warfarin for this endpoint, as well as most other efficacy endpoints. The incidence of major bleeding was generally similar in patients receiving dabigatran 150?mg twice daily or warfarin, but was lower in patients receiving dabigatran 110?mg twice daily. With regard to other bleeding endpoints, dabigatran was generally associated with lower rates than warfarin, except for gastrointestinal major bleeding. Dabigatran (both dosages) was associated with a higher incidence of dyspepsia than warfarin. Results of modelled cost-utility analyses from several countries from the perspective of a healthcare payer over a lifetime (or 20-year) time horizon and primarily based on data from the RE-LY trial were generally consistent. All but one analysis demonstrated that twice-daily dabigatran 150?mg (or age-adjusted, sequential dosing) was cost effective with regard to the incremental cost per QALY gained relative to adjusted-dose warfarin in the prevention of stroke and systemic embolism in AF patients, as the results were below generally accepted cost-effectiveness thresholds. In contrast, the incremental cost per QALY gained for dabigatran 110?mg twice daily versus warfarin exceeded cost-effectiveness thresholds in all studies except one. Sensitivity analyses suggested that the cost utility of dabigatran versus warfarin was generally robust to variations in the majority of parameters. However, the incremental cost per QALY gained for dabigatran versus warfarin improved when levels of international normalized ratio control in warfarin recipients decreased and when the baseline level of risk of stroke increased.     

Challenges and Treatment for Stroke Prophylaxis in Patients with Atrial Fibrillation in Mexico: A Review

Atrial fibrillation (AF) is associated with an increased risk of stroke. AF-related strokes cause greater disability and mortality than those in patients without AF, and are associated with a significant clinical and economic burden in Mexico. Antithrombotic therapy reduces stroke risk in patients with AF and is recommended for all patients except those classified as having a low stroke risk. However, its use is suboptimal all around the world; one study showed that only 4 % of Mexican patients with AF who presented with ischemic stroke were in the therapeutic range for anticoagulation. Vitamin K antagonists (VKAs) such as warfarin or acenocoumarin have long been the only oral anticoagulants for stroke prevention in AF. Although effective, VKAs have disadvantages, including the need for regular coagulation monitoring and dose adjustment. Interactions with numerous common medications and foods contribute to the risk of serious bleeding and thrombotic events in VKA-treated patients. Thus novel oral anticoagulants (NOACs), more properly called direct oral anticoagulants (DOACs), such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban (not available in Mexico), have been developed. These offer the convenience of fixed-dose treatment without the need for monitoring, and have few drug or food interactions. Pivotal phase III trials have demonstrated that these agents are at least as effective as warfarin in preventing stroke and are associated with a reduced risk of intracranial hemorrhage. With apixaban approved in Mexico in April 2013, clinicians now have the choice of three novel DOACs as alternatives to warfarin. However, it is yet to be established which of these agents should be the first choice, and treatment decisions are likely to depend on the individual patient’s characteristics.     

Antidotes to non-vitamin K oral anticoagulants: necessary or not?

In the last few years, a new category of anticoagulants have been developed, the non-vitamin K oral anticoagulants (NOACs). The NOACs are of two classes: the direct thrombin inhibitor, namely dabigatran etexilate; and the oral factor Xa inhibitors rivaroxaban, apixaban and edoxaban, which have been proven to be as effective and safe (and sometimes, superior) compared to warfarin in the treatment of both atrial fibrillation (AF) and venous thromboembolism (VTE). One major concern about their use has always been the lack of an effective antidote or reversal strategy. The objective of this editorial is to provide an overview of the characteristics of NOAC antidotes that are in development. Moreover, we review their likely place in the management of NOAC-related bleeding episodes.     

Insights from the dabigatran versus warfarin in patients with atrial fibrillation (RE-LY) trial

Oral anticoagulants such as warfarin have been used widely for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation (AF) patients. Warfarin has significant limitations and also requires frequent monitoring. Thus, there is an unmet need, with the quest for alternative oral anticoagulants with stable pharmacokinetics and pharmacodynamics that do not need monitoring. The paper under evaluation provides us with up-to-date information on the safety and efficacy of a new oral anticoagulant, dabigatran, compared with warfarin for stroke prevention in AF patients.