新型口服抗凝药物用于房颤患者抗凝治疗的研究进展

房颤是临床常见且严重的心律失常之一,脑卒中是房颤最常见和危险的并发症,口服抗凝药物是防治并发症的关键手段。新型口服抗凝药的研发克服了华法林治疗窗窄、需要长期监测INR的弊端,但也有许多临床试验在证明新型口服抗凝药疗效的同时,验证和发现了出血、肝损伤等不良反应。现将新型口服抗凝药物用于房颤患者抗凝治疗的研究进展做一综述。     

国内上市新型口服抗凝药预防非瓣膜性房颤卒中药物经济学研究系统评价

目的 系统评价国内上市新型口服抗凝药（NOAC）预防非瓣膜性房颤（NVAF）卒中的经济性。方法 计算机检索PubMed,Embase,The Cochrane Library数据库,以及中国知网（CNKI）、万方（WanFang）数据库、维普（VIP）数据库,收集使用国内上市的NOAC（利伐沙班、阿哌沙班、达比加群）和华法林预防NVAF卒中的经济学评价研究,检索时限为各数据库自建库起至2021年11月30日。由2名研究者根据标准独立筛选文献,并分别采用卫生经济评估报告综合标准（CHEERS）评估纳入文献的质量;描述性方法总结纳入文献的基本特征,归纳其经济学评价结果。结果 共纳入10项研究,均为中国环境下的成本-效果或成本-效用研究、并经质量评价均有一定参考价值（得分> 75%）。2014年至2019年的7项研究结果均显示,NOAC与华法林比较无成本-效果优势,而2021年的2项研究结果则显示NOAC比华法林更具有成本-效果优势。其中1项对比研究结果显示达比加群的成本-效果优于利伐沙班,更具有经济学优势。结论 NOAC预防NVAF卒中可能比华法林更具有成本-效果优势。     

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。     

新型口服抗凝药和华法林对<75岁和≥75岁房颤患者的有效性和安全性的meta分析

目的 系统评价新型口服抗凝药（new oral anticoagulants,NOACs）和华法林对<75岁和≥75岁房颤患者的有效性和安全性。方法 系统检索PubMed、Embase、the Cochrane Library、CNKI、万方数据库等数据库,检索时限均为从建库至2020年6月。由2名研究者独立筛选文献、提取资料并评价纳入研究的方法学质量,使用RevMan 5.3软件进行meta分析。结果 共纳入12篇研究,其中7篇随机对照研究（randomized controlled trial,RCT）和5篇观察性研究,包括572 968例患者。<75岁房颤患者meta分析结果显示：①在RCT中,与华法林相比,NOACs可以降低卒中/全身性栓塞（systemic embolism,SSE）、大出血、颅内出血风险和全因死亡的发生,不降低胃肠道出血风险的发生;②在观察性研究中,与华法林相比,NOACs可以降低卒中/SSE、大出血和颅内出血风险的发生,不降低胃肠道出血和全因死亡风险的发生。≥75岁房颤患者meta分析结果显示,①在RCT中,与华法林相比,NOACs可以降低卒中/SSE和颅内出血风险的发生,不降低大出血和全因死亡风险的发生,且会增加胃肠道出血风险的发生;②在观察性研究中,与华法林相比,NOACs可以降低卒中/SSE、大出血、颅内出血和全因死亡风险的发生;增加胃肠道出血风险的发生。结论 对于<75岁房颤患者,NOACs的有效性和安全性优于华法林。对于≥75岁房颤患者,NOACs在卒中/SSE和颅内出血方面优于华法林,但胃肠道出血方面劣于华法林。对于老年房颤患者应用NOACs,需根据具体情况慎重选择抗凝药物。     

新型抗凝药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新型抗凝药预防卒中的成本效果,为中国房颤患者抗凝治疗药物的合理选用提供理论依据。方法:基于全球性临床试验ARISTOTLE、RE-LY及ROCKET-AF的研究数据及我国目前医疗成本,建立一年期决策树及长期外推Markov模型的方法,通过分别计算3种新型口服抗凝药物阿哌沙班(5 mg bid)、达比加群(150 mg bid、110 mg bid)、利伐沙班(20 mg qd)和华法林的调整质量生命年(QLAYs)及治疗成本,对新型抗凝药物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:NOACs治疗的总成本为163586~582710元,使用NOACs患者可获得的质量调整生命年为6.812~7.010。以华法林为参考的增效成本效果分析显示,成本效果比(ICER)为177271~739480元/QLAY,ICER_利伐沙班> ICER_阿哌沙班> ICER_{达比加群150 mg}> ICER_{达比加群110 mg}。3种抗凝药物与华法林比较的ICER均大于我国人均国民生产总值(GDP)的3倍,但小于部分城市人均GDP的3倍。一维敏感度分析显示该成本效果分析结果稳定可靠。结论:目前在我国,与华法林相比,使用新型抗凝药物预防非瓣膜性房颤患者卒中不具备成本效果优势。目前仅在我国经济发达的某些城市,可推荐阿哌沙班或达比加群用于房颤卒中的治疗。     

直接口服抗凝药与华法林在有大出血史房颤患者中有效性和安全性的meta分析

目的 系统评价直接口服抗凝药（DOACs）与华法林治疗有大出血史的房颤患者有效性和安全性,为临床合理用药提供循证证据。方法 计算机检索PubMed、Cochrane Library、Embase、中国知网、万方数据库、维普数据库,检索时限从建库至2022年3月。收集其中已公开发表的关于DOACs（利伐沙班、达比加群、阿哌沙班、艾多沙班）与华法林在大出血史的房颤患者比较的文献。由2名研究员按照纳排标准独立筛选文献,提取资料并进行文献质量评价,采用Revman 5.3软件进行meta分析。结果 共纳入9项研究,共53 877例患者。Meta分析结果显示：在有效性方面,DOACs组比华法林组较少发生脑卒中或系统性栓塞的风险（OR=0.68,95%CI:0.48～0.96,P=0.03）,且差异有统计学意义;在安全性方面,DOACs组比华法林组较少发生大出血的风险（OR=0.56,95%CI:0.41～0.78,P=0.0005）和全因死亡率（OR=0.54,95%CI:0.38～0.77,P=0.0007）,且差异有统计学意义。进一步分析显示：DOACs组比华法林组较少发生脑卒中或系统性栓塞...     

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 探索抗凝门诊非瓣膜性房颤（non-valvular atrial fibrillation,NVAF）患者使用口服抗凝药物（oral anticoagulants,OAC）的情况,为真实世界研究指导临床实践提供数据支持。方法 对于2014—2019年抗凝门诊接受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,符合口服OAC适应证（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;使用新型口服抗凝药物（new oral anticoagulants,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 d导致短暂性脑缺血发作。结论 临床指南推荐NVAF患者优先选择NOACs,但真实世界使用华法林者占绝大多数,而NOACs较多用于高龄或既往卒中的患者,可能由于医师对于华法林的使用经验更为丰富和NOACs的价格较高等原因导致;药师对于不同抗凝药物之间转换的监护以及改善患者服药依从性是提高抗凝质量的重要举措。     

Direct oral anticoagulants and cardiovascular prevention in patients with nonvalvular atrial fibrillation

Introduction: Patients with atrial fibrillation have an increased risk for stroke, systemic embolism and cardiovascular events, including myocardial infarction and cardiovascular death. However, the majority of studies that have analyzed the efficacy of anticoagulants have been focused only on their effects on the risk of stroke.

Areas covered: The available evidence about the association between atrial fibrillation and cardiovascular disease as well as the effects of oral anticoagulation on cardiovascular death and myocardial infarction, with a particular focus on direct oral anticoagulants, was updated in this review.

Expert opinion: The management of patients with atrial fibrillation should not be limited to the prevention of stroke, but should also include the prevention of cardiovascular events. Despite treatment with vitamin K antagonists, many patients with atrial fibrillation still develop cardiovascular complications, particularly individuals whose anticoagulation is difficult to control. Direct oral anticoagulants overcome the majority of limitations of vitamin K antagonists and compared with warfarin, they lead to a greater reduction in the risk of stroke or systemic embolism, all-cause mortality, and intracranial hemorrhage. Although these drugs can only be compared indirectly, it seems that not all direct oral anticoagulants are equal with regard to the prevention of myocardial infarction.     

新型口服抗凝药与心房颤动的抗凝治疗

心房颤动(房颤)是临床最常见的心律失常,增加脑卒中的发病率和死亡率。抗凝治疗是预防房颤合并脑卒中的有效手段。目前能够长期服用的口服抗凝药物只有华法林,但华法林存在个体差异、复杂的药物和药物及药物和食物之间的相互作用,需要定期抗凝监测和频繁调整剂量,具有局限性。研发新型口服抗凝药成为新的热点,活化凝血因子X抑制剂和凝血酶抑制剂在房颤抗凝领域的研究进展迅速,已经取得了明确的循证医学证据。现将这一领域的研究进展做一综述。     

Consensus in cardiology on non-vitamin-K oral anticoagulants for patients with atrial fibrillation

Introduction: Non-vitamin-K oral anticoagulants (NOACs) are known to have advantages over vitamin K antagonists (VKAs) for patients with atrial fibrillation (AF). However, more than half of patients are still treated with VKAs. The absence of direct comparisons amongst NOACs and the insufficient evidence in some clinical situations could explain, at least in part, this predominance of VKAs. The aims of our study were: 1) to analyze the opinion of an expert panel on the role of NOACs in different clinical scenarios; 2) to elaborate specific consensus recommendations for the management of NOACs for each one of these situations.

Patients and methods: An online survey was created covering distinct aspects of the use of oral anticoagulants in various clinical settings. A two-round modified Delphi approach was used.

Results: Forty-eight experts responded to the survey. Consensus was reached on 58% (48/83) of the items. The panelists concluded that the term non-valvular AF should be avoided. In most clinical settings NOACs were preferred over VKAs. Once daily NOACs were preferred in elderly patients to improve therapeutic compliance and, in those over the age of 85, edoxaban could be the best choice. Edoxaban and apixaban were the favorites for patients with AF and moderate chronic kidney disease (CKD). In the case of patients on triple antithrombotic therapy due to AF and acute coronary syndrome (ACS) the lowest effective NOAC dose should be used.

Conclusion: Our study emphasizes that there are several clinical circumstances in patients with AF requiring complex decisions about anticoagulation treatment and offers some recommendations based on the consensus reached by an expert panel.     

Guidelines for stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is most commonly associated with nonvalvular cardiovascular disease and is especially frequent among the elderly. The annual risk for stroke in patients with AF is approximately 5% with a wide range depending on the presence of additional risk factors. For patients who cannot successfully be converted and maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective method for preventing stroke. The 2 drugs which are indicated for stroke prophylaxis in patients with AF are warfarin and aspirin. For primary prevention, warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less effective, resulting in a 20 to 30% risk reduction. Combination therapy with aspirin and low intensity warfarin adjusted to an International Normalised Ratio (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history of stroke or transient ischaemic attack (TIA), the absolute risk reduction with warfarin is even greater because of the high risk of stroke in this population. In contrast, aspirin has not been shown to significantly reduce the risk of stroke in patients with AF when used for secondary prevention. When appropriately managed, warfarin is associated with a low risk of major bleeding. In controlled trials of highly selected patients, the annual rate of intracranial haemorrhage (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty anticoagulation clinics can achieve similar low rates of major bleeding. However, these results cannot be extrapolated to the general population. Factors which have been identified as predictors of bleeding include advanced age, number of medications and most importantly, the intensity of anticoagulation. INR values above 4.0 have been associated with an increased risk of major bleeding while values below 2.0 have been associated with thrombosis. Slow careful dosage titration, regular laboratory monitoring and patient education can substantially reduce the risk of complications. In patients with AF, antithrombotic therapy has been shown to be cost effective. For high risk patients, warfarin is the most cost-effective therapy, provided the risks for bleeding are minimised. In contrast, aspirin is the most cost-effective agent for low risk patients. Current practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5: range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75 years of age or younger patients with additional risk factors. Aspirin should be reserved for low risk patients or those unable to take warfarin. Although these recommendations are strongly supported by the clinical trial evidence, studies show that many patients are not receiving appropriate antithrombotic therapy. In particular, warfarin is underutilised in high risk elderly patients. Additional studies are needed to identify barriers that prevent implementation of the clinical trial findings into clinical practice.     

达比加群酯的临床药理及其预防心房颤动患者卒中的研究进展

达比加群酯是近几年上市的一种新型口服抗凝药物,最初用于预防关节置换术后血栓的形成。美国FDA于2010年10月批准达比加群酯用于预防心房颤动患者的脑卒中。本文对其药理作用、药代动力学、临床疗效评价及不良反应等做一综述。     

Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly

Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food–drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older–elderly patients; additional research and post-marketing analysis in older–elderly patients are needed.     

新型口服抗凝药在非瓣膜性房颤中的应用进展

目的:对新型口服抗凝药(NOACs)在非瓣膜性房颤抗凝治疗中的临床应用和发展进行探讨。方法:收集最新发表的相关文章,对新型口服抗凝药的药理学特性、临床试验结果和临床应用进行分析总结。结果与结论:房颤是临床中最常见的心律失常,对于CHA_2DS_2-VASc评分≥2或既往曾有一过性脑缺血发作(TIA)或有卒中史的患者,应该使用抗凝药物。新型口服抗凝药,与维生素K拮抗剂(VKA)相比,有相似甚至更好的抗凝效果、安全性和便利性。它们具有快速起效,更多可预测的药动学特征,与其他药物相互作用少,饮食对其无明显影响,比华法林导致颅内出血的风险更低。