Vitamin K antagonists

维生素 K 拮抗剂
  • 文章类型: Journal Article
    BrianMacGrory及其同事最近的一项研究调查了在入院前7天内使用维生素K拮抗剂(VKAs)的患者中血管内血栓切除术(EVT)的安全性。通过这次回顾,观察性队列研究,他们发现之前使用VKA并没有增加症状性颅内出血(sICH)的总体风险.然而,近期使用VKA的国际标准化比值(INR)>1.7与sICH风险显著增加相关.未来应开展大规模随机对照试验,进一步明确EVT治疗缺血性脑卒中患者抗凝治疗的效果和可行性。
    A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within 7 days prior to hospital admission. Through this retrospective, observational cohort study, they found prior VKA use did not increase the risk of symptomatic intracranial hemorrhage (sICH) overall. However, recent VKA use with a presenting international normalized ratio (INR) > 1.7 was associated with a significantly increased risk of sICH. Future large-scale randomized controlled trials should be conducted to further clarify the effects and feasibility of EVT therapy in ischemic stroke patients under anticoagulation.
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  • 文章类型: Journal Article
    直接口服抗凝剂(DOAC)与其他药物(如维生素K拮抗剂或低分子量肝素)相比,具有良好的优势,已成为治疗静脉血栓栓塞的首选选择。然而,随机对照试验的结果表明,在某些临床情况下,DOAC的使用存在疗效和/或安全性问题.本综述将总结DOAC已证明疗效和安全性的适应症,他们做不到的情况,与其他静脉血栓栓塞治疗相比,不确定性仍然存在的情况。
    Direct oral anticoagulants (DOACs) have become the preferred option for treatment of venous thromboembolism due to their favorable profile compared with other agents such as vitamin K antagonists or low-molecular-weight heparin. However, findings from randomized controlled trials suggest efficacy and/or safety concerns with DOAC use in some clinical contexts. This illustrated review will summarize indications where DOACs have proven efficacy and safety, situations where they fall short, and situations where uncertainty remains compared with other treatments for venous thromboembolism.
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  • 文章类型: Journal Article
    最近的指南建议,在经导管主动脉瓣置换术(TAVR)后没有长期口服抗凝(OAC)适应症的患者中,抗血小板治疗(APT)是治疗的标准。一种方法优于另一种方法仍然存在争议。
    几个数据库,包括MEDLINE,谷歌学者,和EMBASE,电子搜索。主要终点是全因死亡率(ACM)。次要终点包括心血管死亡,心肌梗死(MI),中风/TIA,出血性中风,出血事件,全身性栓塞,接受APT和口服抗凝剂(OAC)的TAVR后患者的瓣膜血栓形成。使用ReviewManager版本5.4生成森林地块,p值小于0.05,表明有统计学意义。进行亚组分析以探索异质性的潜在来源。
    选择了12项研究。APT和OAC组ACM无显著差异[风险比(RR):0.67;95%CI:0.45-1.01;P=0.05],心血管死亡[RR:0.91;95%CI:0.73-1.14;P=0.42],MI[RR:1.69;95%CI:0.43-6.72;P=0.46],卒中/TIA[RR:0.79;95%CI:0.58-1.06;P=0.12],缺血性卒中[RR:0.83;95%CI:0.50-1.37;P=0.47],出血性卒中[RR:1.08;95%CI:0.23-5.15;P=0.92],大出血[RR:0.79;95%CI:0.51-1.21;P=0.28],轻微出血[RR:1.09;95%CI:0.80-1.47;P=0.58],危及生命的出血[RR:0.85;95%CI:0.55-1.30;P=0.45],任何出血[RR:0.98;95%CI:0.83-1.15;P=0.78],和全身性栓塞[RR:0.87;95%CI:0.44-1.70;P=0.68]。接受APT的患者发生瓣膜血栓形成的风险高于接受OAC的患者[RR:2.61;95%CI:1.56-4.36;P=0.0002]。
    尽管接受APT的患者瓣膜血栓形成的风险增加,两组的其他终点风险相当.
    UNASSIGNED: Recent guidelines suggest that antiplatelet therapy (APT) is the standard of care in the absence of long-term oral anticoagulation (OAC) indications in patients post-transcatheter aortic valve replacement (TAVR). The superiority of one method over the other remains controversial.
    UNASSIGNED: Several databases, including MEDLINE, Google Scholar, and EMBASE, were electronically searched. The primary endpoint was the all-cause mortality (ACM) rate. Secondary endpoints included cardiovascular death, myocardial infarction (MI), stroke/TIA, haemorrhagic stroke, bleeding events, systemic embolism, and valve thrombosis in post-TAVR patients receiving APT and oral anticoagulants (OACs). Forest plots were generated using Review Manager version 5.4, with a p value less than 0.05 indicating statistical significance. Subgroup analysis was performed to explore potential sources of heterogeneity.
    UNASSIGNED: Twelve studies were selected. No significant differences were observed in APT and OAC group for ACM [risk ratio (RR): 0.67; 95% CI:0.45-1.01; P=0.05], cardiovascular death [RR:0.91; 95% CI:0.73-1.14; P=0.42], MI [RR:1.69; 95% CI:0.43-6.72; P=0.46], Stroke/TIA [RR:0.79; 95% CI:0.58-1.06; P=0.12], ischaemic stroke [RR:0.83; 95% CI:0.50-1.37; P=0.47], haemorrhagic stroke [RR:1.08; 95% CI: 0.23-5.15; P=0.92], major bleeding [RR:0.79; 95% CI:0.51-1.21; P=0.28], minor bleeding [RR:1.09; 95% CI: 0.80-1.47; P=0.58], life-threatening bleeding [RR:0.85; 95% CI:0.55-1.30; P=0.45], any bleeding [RR:0.98; 95% CI:0.83-1.15; P=0.78], and systemic embolism [RR:0.87; 95% CI:0.44-1.70; P=0.68]. The risk of valve thrombosis was higher in patients receiving APT than in those receiving OAC [RR:2.61; 95% CI:1.56-4.36; P =0.0002].
    UNASSIGNED: Although the risk of valve thrombosis increased in patients receiving APT, the risk of other endpoints was comparable between the two groups.
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  • 文章类型: Journal Article
    维生素K拮抗剂(VKA)是撒哈拉以南非洲大多数地区的主要抗凝剂。了解非洲大陆抗凝服务的质量对于优化预期的益处至关重要。这项研究评估了9个SSA国家接受VKA治疗的患者的抗凝质量和相关因素。我们进行了一项回顾性队列研究,对来自博茨瓦纳20个诊所的随机选择的抗凝患者,刚果民主共和国,埃塞俄比亚,冈比亚,加纳,莫桑比克,尼日利亚,坦桑尼亚,和南非。符合条件的参与者是那些在VKAs上至少三个月并且在2019-2021年至少有四个国际标准化比率(INR)结果的参与者。我们报告了INR值在治疗范围内的比例,使用Rosendaal方法的治疗时间范围(TTR),以及TTR≥65%(最佳抗凝)的患者比例。平均年龄为51.1(16.1)岁,64.2%为女性。VKA最常见的适应症包括静脉血栓栓塞(29.6%),人工瓣膜(26.7%)和心房颤动/扑动(30.1%)。我们分析了1011名参与者的6743项INR测试,其中,48.5%为亚治疗,34.1%治疗,相对于疾病特异性参考范围,17.4%是超治疗性的。使用4927INR测量值计算660名患者的TTR。中位数(四分位数间距[IQR])TTR为35.8(15.9,57.2)%。最佳抗凝控制在19.2%的参与者中明显,从坦桑尼亚的2.7%到埃塞俄比亚的23.1%不等。TTR≥65%的患者比例为15,4%用于人工心脏瓣膜,21.1%用于静脉血栓栓塞,23.7%用于心房颤动或扑动。全民健康覆盖的国家获得最佳抗凝控制的几率较高(调整比值比(aOR)1.79,95%置信区间[CI],1.15-2.81,p=0.01)。在SSA中接受不同治疗适应症的VKAs患者的TTR不理想。全民健康覆盖使实现TTR的几率增加了79%。证据要求在SSA中采用更密集的华法林管理策略,包括提供VKA服务而无需自付费用。
    Vitamin K antagonists (VKA) is the primary anticoagulant in most settings of Sub-Saharan Africa. Understanding the quality of anticoagulation services in the continent is vital in optimising the intended benefits. This study assessed the quality of anticoagulation and associated factors among VKA-treated patients in nine SSA countries. We conducted a retrospective cohort study of randomly selected patients on anticoagulation from 20 clinics in Botswana, the Democratic Republic of Congo, Ethiopia, Gambia, Ghana, Mozambique, Nigeria, Tanzania, and South Africa. Eligible participants were those on VKAs for at least three months and with at least four international normalised ratios (INR) results in 2019-2021. We report the proportion of INR values in the therapeutic range, time-in-therapeutic range (TTR) using the Rosendaal method, and the proportion of patients with TTR ≥ 65% (optimal anticoagulation). The mean age was 51.1(16.1) years, and 64.2% were women. The most common indications for VKA included venous thromboembolism (29.6%), prosthetic valves (26.7%) and atrial fibrillation/flutter (30.1%). We analysed 6743 INR tests from 1011 participants, and of these, 48.5% were sub-therapeutic, 34.1% therapeutic, and 17.4% were supratherapeutic relative to disease-specific reference ranges. TTR was calculated for 660 patients using 4927 INR measurements. The median (interquartile range [IQR]) TTR was 35.8(15.9,57.2) %. Optimal anticoagulation control was evident in 19.2% of participants, varying from 2.7% in Tanzania to 23.1% in Ethiopia. The proportion of patients with TTR ≥ 65% was 15,4% for prosthetic heart valves, 21.1% for venous thromboembolism and 23.7% for atrial fibrillation or flutter. Countries with universal health coverage had higher odds of optimal anticoagulation control (adjusted odds ratio (aOR) 1.79, 95% confidence interval [CI], 1.15- 2.81, p = 0.01). Patients on VKAs for different therapeutic indications in SSA had suboptimal TTR. Universal health coverage increased the odds of achieving TTR by 79%. The evidence calls for more intensive warfarin management strategies in SSA, including providing VKA services without out-of-pocket payments.
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  • 文章类型: Journal Article
    口服抗凝剂广泛用于治疗或预防全世界数百万患者的心血管疾病。它们是非瓣膜性心房颤动和人工心脏瓣膜患者预防中风和全身性栓塞的首选药物,以及静脉血栓栓塞的治疗/预防。口服抗凝剂包括维生素K拮抗剂(VKAs)和直接口服抗凝剂(DOAC)。止血实验室在治疗患者的管理中起着至关重要的作用,从基于适用于VKAs的实验室测试的剂量调整到适用于DOAC的特殊情况下的药物浓度测量。本文旨在概述止血实验室如何帮助临床医生管理口服抗凝剂的患者。特别感兴趣的是国际标准化比率,用于管理患者的VKAs和DOAC浓度的测量,实验室的作用还没有很好的定义,DOAC对一些最常见的止血参数的大多数干扰并未得到广泛重视。
    Oral anticoagulants are widely used to treat or prevent cardiovascular diseases in millions of patients worldwide. They are the drugs of choice for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation and prosthetic heart valves, as well as for treatment/prevention of venous thromboembolism. Oral anticoagulants include vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). The hemostasis laboratory plays a crucial role in the management of treated patients, spanning from dose adjustment based on laboratory testing that applies to VKAs to the measurement of drug concentrations in special situations that apply to DOACs. This article aims to overview how the hemostasis laboratory can help clinicians manage patients on oral anticoagulants. Special interest is devoted to the international normalized ratio, used to manage patients on VKAs and to the measurement of DOAC concentrations, for which the role of the laboratory is still not very well defined, and most interferences of DOACs with some of the most common hemostatic parameters are not widely appreciated.
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  • 文章类型: Journal Article
    心房颤动(AF)是成人最常见的心律失常。广泛建议使用口服抗凝剂(OAC)预防缺血风险,目前的临床指南推荐直接口服抗凝药(DOACs)作为卒中预防的优先选择疗法.然而,目前尚无专门针对和适应中美洲和加勒比地区背景的房颤患者OAC最佳管理的临床实践指南或推荐文件.这项类似Delphi的研究的目的是应对该地理区域非瓣膜性AF患者的OAC管理中可能出现的疑问。在对文献进行系统回顾的基础上进行了共识项目,推荐的类似于ADOLOPMENT的方法,和两轮德尔菲调查的应用。在第一轮中,评估了31项建议,达成了30项共识,其中,10一致同意该研究评估了各种情境建议中的专家意见,以优化非瓣膜性心房颤动(NVAF)患者的DOAC管理。在与抗凝适应症相关的临床实践指南(CPG)声明上存在广泛共识,患者随访,抗凝治疗并发症,COVID-19的管理和预防,和心脏干预。
    Atrial fibrillation (AF) is the most common arrhythmia in adults. Prevention of the ischaemic risk with oral anticoagulants (OACs) is widely recommended, and current clinical guidelines recommend direct oral anticoagulants (DOACs) as preference therapy for stroke prevention. However, there are currently no clinical practice guidelines or recommendation documents on the optimal management of OACs in patients with AF that specifically address and adapt to the Central American and Caribbean context. The aim of this Delphi-like study is to respond to doubts that may arise in the management of OACs in patients with non-valvular AF in this geographical area. A consensus project was performed on the basis of a systematic review of the literature, a recommended ADOLOPMENT-like approach, and the application of a two-round Delphi survey. In the first round, 31 recommendations were evaluated and 30 reached consensus, of which, 10 unanimously agreed. The study assessed expert opinions in a wide variety of contextualized recommendations for the optimal management of DOACs in patients with non-valvular atrial fibrillation (NVAF). There is a broad consensus on the clinical practice guideline (CPG) statements used related to anticoagulation indication, patient follow-up, anticoagulation therapy complications, COVID-19 management and prevention, and cardiac interventions.
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  • 文章类型: Journal Article
    (1)背景:需要紧急手术的直接口服抗凝剂(DOAC)或维生素K拮抗剂(VKA)治疗的抗凝患者的临床管理具有挑战性。(2)方法:前瞻性德国RADOA注册研究了入院后24小时内需要进行急诊手术的DOAC或VKA治疗的患者的治疗策略。通过包括大出血在内的临床终点分析有效性。主要观察终点是入院后30天之前的住院死亡率。(3)结果:共纳入78例患者(DOAC:44;VKA:34)。中位年龄为76岁。总的来说,43%的DOAC患者和79%的VKA患者用凝血酶原复合物浓缩物(PCC)治疗(p=0.002)。在DOAC患者中,30%的VKA患者没有接受止血治疗,而3%(1/34)的VKA患者(p=0.002),7%的DOAC患者和21%的VKA患者在手术部位发生了严重或临床相关的非严重出血(p=0.093)。住院死亡率为13%,两个治疗组之间没有显着差异(DOAC:11%,VKA:15%;p>0.20)。(4)结论:两组患者的30天住院死亡率具有可比性。在围手术期和术后手术期,VKA患者比DOAC患者需要更多的止血剂。
    (1) Background: The clinical management of anticoagulated patients treated with direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA) needing emergency surgery is challenging. (2) Methods: The prospective German RADOA registry investigated treatment strategies in DOAC- or VKA-treated patients needing emergency surgery within 24 h after admission. Effectiveness was analysed by clinical endpoints including major bleeding. Primary observation endpoint was in hospital mortality until 30 days after admission. (3) Results: A total of 78 patients were included (DOAC: 44; VKA: 34). Median age was 76 years. Overall, 43% of the DOAC patients and 79% of the VKA patients were treated with prothrombin complex concentrates (PCC) (p = 0.002). Out of the DOAC patients, 30% received no hemostatic treatment compared to 3% (1/34) of the VKA patients (p = 0.002), and 7% of the DOAC patients and 21% of the VKA patients developed major or clinically relevant non-major bleeding at the surgical site (p = 0.093). In-hospital mortality was 13% with no significant difference between the two treatment groups (DOAC: 11%, VKA: 15%; p > 0.20). (4) Conclusions: The 30-day in-hospital mortality rate was comparable between both patient groups. VKA patients required significantly more hemostatic agents than DOAC patients in the peri- and postoperative surgery period.
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  • 文章类型: Journal Article
    在亚洲,尤其是越南,房颤是一种常见的心律失常,与中风和全身性栓塞的高风险有关。用于预防房颤患者中风的抗凝治疗可导致出血并发症。为了有效地管理AF,采用适当的抗凝药物和解决可改变的危险因素至关重要.越南临床医生对非维生素K拮抗剂口服抗凝剂(NOAC)特别感兴趣,房颤治疗的最新进展。然而,缺乏比较NOAC的头对头试验使得选择特定NOAC具有挑战性.这篇综述旨在全面概述NOAC在房颤中预防卒中的现有临床证据,以帮助临床医生做出明智的决定并改善房颤患者的治疗结果。本综述的第一部分将介绍越南AF的现状,重点关注房颤患病率并突出临床实践中的差距。此外,本部分广泛讨论了房颤患者卒中一级和二级预防的抗凝策略.
    In Asia, especially Vietnam, AF is a common arrhythmia and is linked to a higher risk of stroke and systemic embolism. Anticoagulation therapy for stroke prevention in AF patients can result in bleeding complications. To effectively manage AF, adopting appropriate anticoagulation and addressing modifiable risk factors are crucial. Vietnamese clinicians are particularly interested in non-vitamin K antagonist oral anticoagulants (NOACs), a recent development in AF treatment. However, the lack of head-to-head trials comparing NOACs makes selecting a specific NOAC challenging. This review aims to provide a comprehensive overview of the available clinical evidence on NOACs for stroke prevention in AF to assist clinicians in making informed decisions and improving treatment outcomes in patients with AF. The first part of this review will present the current landscape of AF in Vietnam, focusing on AF prevalence and highlighting gaps in clinical practice. Furthermore, this part extensively discusses the anticoagulation strategy for both primary and secondary stroke prevention in AF.
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  • 文章类型: Journal Article
    背景:在肥厚型心肌病(HCM)和心房颤动(AF)患者中,直接口服抗凝药(DOAC)治疗的获益-风险特征尚未完全确定。本研究旨在评估DOAC与维生素K拮抗剂(VKA)在HCM和AF患者中的疗效和安全性。
    方法:PubMed,EMBASE,Cochrane图书馆,和clinicaltrials.gov进行搜索,以确定在HCM和AF患者中比较DOAC和VKA的研究。主要终点为血栓栓塞事件。使用通用逆方差方法通过随机效应模型汇集相对风险和标准误差。
    结果:本荟萃分析包括7项观察性研究,涉及9395例患者。与VKA组相比,DOAC组显示出相似的血栓栓塞事件风险[RR(95CI):0.93(0.73-1.20),p=0.59]和缺血性卒中[RR(95CI):0.65(0.33-1.28),p=0.22]。两组大出血的发生率相当[RR(95CI):0.75(0.49-1.15),p=0.19]。同时,DOAC治疗在降低全因死亡发生率方面优于VKA治疗[RR(95CI):0.44(0.35-0.55),p<0.001],心血管死亡[RR(95CI):0.41(0.22-0.75),p=0.004],和颅内出血[RR(95CI):0.42(0.24-0.74),p=0.003]。
    结论:在HCM和AF患者中,DOAC治疗与VKA治疗在降低血栓栓塞事件风险方面相似。不会增加出血风险。此外,与VKA组相比,DOAC组在降低死亡率和颅内出血方面显示出显著优势.需要进一步的随机对照试验为该人群的DOAC治疗提供更多证据。
    BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) has not been well established yet. This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF.
    METHODS: PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. The primary endpoint was thromboembolic events. The relative risks and standard errors were pooled by random-effect models using the generic inverse variance method.
    RESULTS: Seven observational studies involving 9395 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a similar risk of thromboembolic events [RR (95%CI): 0.93 (0.73-1.20), p = 0.59] and ischemic stroke [RR (95%CI): 0.65 (0.33-1.28), p = 0.22]. The incidence of major bleeding was comparable between the two groups [RR (95%CI): 0.75 (0.49-1.15), p = 0.19]. Meanwhile, DOAC therapy was superior to VKA therapy in reducing the incidences of all-cause death [RR (95%CI): 0.44 (0.35-0.55), p < 0.001], cardiovascular death [RR (95%CI): 0.41 (0.22-0.75), p = 0.004], and intracranial hemorrhage [RR (95%CI): 0.42 (0.24-0.74), p = 0.003].
    CONCLUSIONS: In patients with HCM and AF, DOAC therapy was similar to VKA therapy in reducing the risk of thromboembolic events, without increasing bleeding risk. In addition, the DOAC group displayed significant advantages in reducing mortality and intracranial hemorrhage compared with the VKA group. Further randomized controlled trials are needed to provide more evidence for DOAC therapy in this population.
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  • 文章类型: Journal Article
    目前的观察性研究比较了依度沙班与其他口服抗凝药在房颤患者中的有效性和安全性,但是结果仍然存在争议。本荟萃分析旨在比较依度沙班对房颤患者的疗效。
    我们从PubMed进行了系统研究,EMBASE,和Cochrane图书馆数据库,直到2022年11月才能获得相关的观察性研究。通过随机效应模型收集并汇总结果的调整风险比(RR)和95%置信区间(CI)。本研究在PROSPERO(CRD42022314222)中进行了前瞻性注册。
    本荟萃分析共纳入17项观察性研究。与维生素K拮抗剂相比,依度沙班与卒中或全身性栓塞的风险较低相关(RR=0.67,95%CI:0.61-0.74),大出血(RR=0.54,95%CI:0.44-0.67),和颅内出血(RR=0.51,95%CI:0.29-0.90)。与达比加群或利伐沙班相比,依度沙班与卒中或全身性栓塞风险降低相关(达比加群[RR=0.76,95%CI:0.66-0.87];利伐沙班[RR=0.81,95%CI:0.70-0.94])和大出血(达比加群[RR=0.82,95%CI:0.69-0.98];利伐沙班[RR=0.81-94%]:0.70.与阿哌沙班相比,依度沙班与卒中或全身性栓塞的风险降低相关(RR=0.87,95%CI:0.79-0.97),但有类似的出血事件风险.
    我们目前的证据表明,依度沙班可能比维生素K拮抗剂具有更好的有效性和/或安全性结果,达比加群,利伐沙班,和阿哌沙班用于预防房颤患者的卒中。
    UNASSIGNED: Current observational studies have compared the effectiveness and safety of edoxaban with other oral anticoagulants in patients with AF, but the results are still disputed. This meta-analysis was conducted to compare the effect of edoxaban in patients with AF.
    UNASSIGNED: We performed systematic research from the PubMed, EMBASE, and Cochrane Library databases until November 2022 to obtain relevant observational studies. Adjusted risk ratios (RRs) and 95 % confidence intervals (CIs) of the outcomes were collected and pooled by a random-effects model. This study was prospectively registered in PROSPERO (CRD42022314222).
    UNASSIGNED: A total of 17 observational studies were included in this meta-analysis. Compared with vitamin K antagonists, edoxaban was associated with lower risks of stroke or systemic embolism (RR = 0.67, 95 % CI:0.61-0.74), major bleeding (RR = 0.54, 95 % CI:0.44-0.67), and intracranial hemorrhage (RR = 0.51, 95 % CI:0.29-0.90). Compared with dabigatran or rivaroxaban, edoxaban was associated with reduced risks of stroke or systemic embolism (dabigatran [RR = 0.76, 95 % CI:0.66-0.87]; rivaroxaban [RR = 0.81, 95 % CI:0.70-0.94]) and major bleeding (dabigatran [RR = 0.82, 95 % CI:0.69-0.98]; rivaroxaban [RR = 0.81, 95 % CI:0.70-0.94]). Compared with apixaban, edoxaban was associated with a reduced risk of stroke or systemic embolism (RR = 0.87, 95 % CI:0.79-0.97), but had similar risks of bleeding events.
    UNASSIGNED: Our current evidence suggested that edoxaban might have superior effectiveness and/or safety outcomes than vitamin K antagonists, dabigatran, rivaroxaban, and apixaban for stroke prevention in patients with AF.
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