BACKGROUND & AIMS: :Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use in the treatment of venous thromboembolism (VTE) in Latin America, following global approvals for this indication. Edoxaban features some particular characteristics when compared to the previously approved DOACs. This review summarizes the main properties of edoxaban, the outcomes results of its pivotal global clinical trials and the peculiar clinical features of this compound. This practical guide aims to help Latin America clinicians understand edoxaban, its proper indication and its use for the appropriate patients with VTE.

背景与目标： ：Edoxaban是一种直接因子Xa抑制剂（FXa），是全球公认的第四种直接口服抗凝剂（DOAC），在拉丁美洲已被批准用于临床治疗静脉血栓栓塞（VTE）。与先前批准的DOAC相比，Edoxaban具有一些特殊的特性。这篇综述总结了edoxaban的主要特性，其关键的全球临床试验的结果以及该化合物的特殊临床特征。本实用指南旨在帮助拉丁美洲临床医生了解依多沙班，依妥沙坦的适当适应症以及对适当的VTE患者的使用。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

背景与目标： ：直接口服抗凝剂对癌症患者的静脉血栓栓塞（VTE）可能是有效和安全的，但尚未与低分子量肝素（LMWH）（目前推荐用于这些患者）进行比较。 Hokusai VTE癌症研究是一项随机，开放标签的临床试验，旨在评估口服Xa因子抑制剂edoxaban是否不逊于LMWH治疗癌症患者的VTE。我们介绍了这项研究的基本原理和一些设计特征。这样的特征之一是在12个月的研究期间内，复发性VTE和主要出血的复合主要预后。这两种并发症在接受抗凝治疗的癌症患者中经常发生，并产生重大影响。超过六个月的评估将填补这些患者长期治疗的证据基础中的空白。基于观察到活动性癌症患者复发VTE的风险与有癌症史的患者相似，如果在过去两年内诊断出癌症，Hokusai VTE癌症研究将招募患者。此外，患有偶然性VTE的患者符合资格，因为其复发性VTE的风险与有症状疾病的患者相似。 Hokusai VTE癌症研究的独特设计特征应可招募可从口服抗凝治疗中受益的众多VTE癌症患者。

BACKGROUND & AIMS: :Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

背景与目标： ：Edoxaban是一种口服，直接，每日一次的Xa因子抑制剂，被开发用于房颤患者的中风预防以及急性症状性静脉血栓栓塞的复发性血栓栓塞的治疗和二级预防。在需要抗凝治疗的老年患者中，有些患者可能患有晚期肾病（ESRD）。进行了这项开放标签的1期随机，双向交叉研究，以评估edoxaban在10例血液透析患者中​​的药代动力学。符合条件的接受慢性血液透析的ESRD受试者在（透析前）或透析（非透析）之间2小时（小时）接受edoxaban 15 mg的单次口服剂量。与非透析患者的平均总暴露量（691.7 ng·h / ml）相比，血液透析导致平均总暴露量（AUC0-∞; 676.2 ng·h / ml）略有下降。平均最大观察血浆浓度（Cmax）值在透析和非透析治疗之间相当（分别为53.3 ng / ml和56.3 ng / ml）。在透析期和非透析期，平均总表观清除率（CL / F）分别为24.1和22.5 l / h。透析清除率为5.7 l / h，血液透析清除率为6.1 l / h。血液透析清除率仅为6.1 l / h，这表明这些透析清除率仅占总清除率的四分之一。 ESRD受试者可以很好地耐受15 mg的单次口服edoxaban。总之，基于这些单剂量PK数据，血液透析后可能不需要补充剂量的edoxaban。重要的是，血液透析不是从血液中去除依多沙班的有效机制。

BACKGROUND & AIMS: :The ENSURE-AF study (NCT 02072434) of anticoagulation for electrical cardioversion in nonvalvular atrial fibrillation (NVAF) showed comparable low rates of bleeding and thromboembolism between the edoxaban and the enoxaparin-warfarin treatment arms. This post hoc analysis investigated the relationship between renal function and clinical outcomes. METHODS:ENSURE-AF was a multicenter, PROBE evaluation trial of edoxaban 60 mg, or dose reduced to 30 mg/d for weight≤60 kg, creatinine clearance (CrCl; Cockcroft-Gault) ≤50 mL/min, or concomitant P-glycoprotein inhibitors compared with therapeutically monitored enoxaparin-warfarin in 2,199 NVAF patients undergoing electrical cardioversion. Efficacy and safety outcomes and time in therapeutic range in the warfarin arm were analyzed in relation to CrCl in prespecified ranges ≥15 and ≤30, >30 and ≤50, >50 and <80, and ≥80 mL/min, and an exploratory ≥95-mL/min analysis. RESULTS:A total of 1,095 subjects were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64.3±10 and 64.2±11 years. Mean time in therapeutic range was progressively lower with reducing CrCl strata, being 66.8% in those with CrCl >30 to ≤50 compared with 71.8% in those with CrCl ≥80. The odds ratios for the primary efficacy and safety end points were comparable for the different predefined renal function strata; given the small numbers, the 95% CI included 1.0. In the subset of those with CrCl ≥95, the odds ratios showed consistency with the other CrCl strata. When CrCl was assessed as a continuous variable, there was a nonsignificant trend toward higher major or clinically relevant nonmajor bleeding with reducing CrCl levels, with no significant differences between the 2 treatment arms. When we assessed CrCl at baseline compared with end of treatment, there were no significant differences in CrCl change between the edoxaban and enoxaparin-warfarin arms. The proportions with worsening of renal function (defined as a decrease of >20% from baseline) were similar in the 2 treatment arms. CONCLUSION:Given the small number of events in ENSURE-AF, no effect of renal (dys)function was demonstrated in comparing edoxaban to enoxaparin-warfarin for cardioversion; efficacy and safety of edoxaban remained consistent even in patients with normal or supranormal renal function.

背景与目标： ：ENSURE-AF研究（NCT 02072434）在非瓣膜性心房颤动（NVAF）中进行电凝抗凝抗凝研究显示，依多沙班和依诺肝素-华法林治疗组之间的出血和血栓栓塞发生率相当低。事后分析调查了肾功能与临床结局之间的关系。
方法：ENSURE-AF是一项多中心的PROBE评估试验，使用60 mg的埃多沙班，或当体重≤60 kg，肌酐清除率（CrCl； Cockcroft-Gault）≤50mL / min或伴随的P-剂量降低至30 mg / d时糖蛋白抑制剂与依诺肝素-华法林的治疗监测相比，在2199例行心脏电复律的NVAF患者中。分析了华法林组在预定范围≥15和≤30，> 30和≤50，> 50和<80，以及≥80mL / min中与CrCl有关的疗效和安全性结果以及在治疗范围内的时间≥95mL / min分析。
结果：总共1,095名受试者被随机分为依多沙班和1,104名依诺肝素-华法林。平均年龄为64.3±10岁和64.2±11岁。随着CrCl层的减少，治疗范围内的平均时间逐渐缩短，CrCl> 30至≤50的患者为66.8％，而CrCl≥80的患者为71.8％。对于不同的预定义肾功能层，主要疗效和安全终点的比值比是可比的；鉴于数量较少，95％CI包括1.0。在CrCl≥95的那些子集中，优势比显示出与其他CrCl层一致。当将CrCl评估为连续变量时，随着CrCl含量的降低，趋势不明显，即出现更高的主要或临床相关的非主要出血，两个治疗组之间无显着差异。当我们评估与治疗结束时相比基线时的CrCl时，依多沙班和依诺肝素-华法林组之间的CrCl变化没有显着差异。在两个治疗组中，肾功能恶化的比例（定义为比基线降低> 20％）相似。
结论：鉴于ENSURE-AF发生的事件较少，因此在比较依多沙班和依诺肝素-华法林进行心脏复律时，未显示肾脏（功能障碍）的影响；即使在肾功能正常或超正常的患者中，依多沙班的疗效和安全性也保持一致。

BACKGROUND & AIMS: Aims:The EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of atrial fibrillation (ENSURE-AF) (NCT02072434) study was a multicentre prospective, randomized, open-label, blinded-endpoint evaluation (PROBE) trial comparing edoxaban with enoxaparin/warfarin followed by warfarin alone in 2199 non-valvular atrial fibrillation patients undergoing electrical cardioversion and showed comparable rates of bleeding and thromboembolism between treatments. This prespecified ancillary analysis investigated the impact of edoxaban therapy on treatment satisfaction and utilization of healthcare services. Methods and results:The Perception of Anticoagulant Treatment Questionnaire (PACT-Q2) was completed by study patients on Day 28 post-cardioversion. Higher scores represent greater satisfaction. Healthcare resource utilizations were collected from randomization to Day 28 post-cardioversion. Data from patients who received at least one dose of study drugs were analysed. Patients treated with edoxaban were more satisfied than enoxaparin/warfarin in both PACT-Q treatment satisfaction and convenience scores (P < 0.001 for both). Differences in treatment satisfaction scores were greater in patients who underwent non-transoesophageal echocardiography (TOE)-guided cardioversion than in patients who underwent TOE-guided cardioversion. Edoxaban was associated with fewer clinic visits (4.75 visits vs. 7.60 visits; P < 0.001) and fewer hospital days (3.43 days vs. 5.41 days; P < 0.05). Rates of hospitalizations and emergency room visits were not significantly different. Overall, edoxaban therapy was estimated to reduce healthcare costs by €107.73, €437.92, €336.75, and $246.32 per patient in German, Spanish, Italian, and US settings, respectively. Conclusions:The convenience of edoxaban therapy over warfarin in patients undergoing cardioversion may provide greater treatment satisfaction and cost savings to the healthcare system.

背景与目标： 目的：EdoxabaN与华法林的研究对象心房颤动的持续进展（ENSURE-AF）（NCT02072434）研究是一项多中心前瞻性，随机，开放标签，盲点评估（PROBE）试验，将edoxaban与依诺肝素/ warfarin进行了比较，随后对其进行了比较在2199例接受心脏电复律的非瓣膜性心房颤动患者中，单独使用华法林治疗，并显示治疗之间的出血和血栓栓塞发生率相当。这项预先确定的辅助分析调查了依多沙班疗法对治疗满意度和医疗服​​务利用的影响。
方法和结果：研究患者在心脏复律后第28天完成了抗凝治疗问卷的感知（PACT-Q2）。分数越高表示满意度越高。从随机分配到心脏复律后第28天收集医疗资源利用率。分析了接受至少一剂研究药物的患者的数据。依多沙班治疗的患者在PACT-Q治疗满意度和便利性评分上均比依诺肝素/华法林满意（两者均P << 0.001）。非经食道超声心动图（TOE）指导的心脏复律患者的治疗满意度评分差异大于经TOE指导的心脏复律的患者治疗满意度得分的差异更大。 Edoxaban与更少的门诊就诊次数（4.75次比7.60次就诊； P <0.001）和更少的住院天数（3.43天对5.41天； P <0.05）相关。住院率和急诊室就诊率没有显着差异。总体而言，在德国，西班牙，意大利和美国，依多沙班疗法估计每位患者的医疗费用分别降低107.73欧元，437.92欧元，336.75欧元和246.32美元。
结论：在心脏复律患者中，edoxaban治疗优于warfarin治疗的方便性可为医疗体系带来更大的治疗满意度并节省成本。

BACKGROUND & AIMS: :A 45-year-old man complained of swelling of the left side of his neck and left upper limb. Ultrasonography and enhanced computed tomography (CT) revealed thrombosis of the left internal jugular, subclavian, and brachiocephalic vein. Based on various examinations, the patient was diagnosed with idiopathic venous thrombosis early in his clinical course. There were no findings to suggest malignancy or abnormal coagulability. However, two months after the start of treatment, the patient was diagnosed with gastric cancer. Despite the presence of Trousseau syndrome, treatment with edoxaban (an oral anticoagulant), reduced the swelling dramatically without any bleeding complications.

背景与目标： ：一个45岁的男人抱怨脖子左侧和左上肢肿胀。超声检查和增强型计算机断层扫描（CT）显示左颈内，锁骨下和头臂静脉的血栓形成。根据各种检查，该患者在其临床过程的早期就被诊断出患有特发性静脉血栓。没有发现提示恶性肿瘤或凝血功能异常。但是，在开始治疗两个月后，该患者被诊断出患有胃癌。尽管存在Trousseau综合征，但使用edoxaban（口服抗凝剂）治疗仍可显着减少肿胀，而无任何出血并发症。

BACKGROUND & AIMS: :There are concerns that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. We have shown that low-dose administration of a direct thrombin inhibitor, melagatran, significantly worsens the coagulation status induced by tissue factor injection in rats. We compared the effect of inhibition of thrombin and factor Xa for their potential to aggravate tissue factor-induced coagulation in rats. Hypercoagulation was induced by the injection of 2.8 U/kg tissue factor after administration of melagatran, heparin and edoxaban in rats. Blood samples were collected 10min after tissue factor injection. Platelet numbers, thrombin-antithrombin complex concentrations and plasma compound concentrations were measured. Though a high dose of melagatran (1mg/kg, i.v.) suppressed platelet consumption and thrombin-antithrombin complex generation induced by tissue factor, lower doses of melagatran (0.01, 0.03 and 0.1mg/kg, i.v.) significantly enhanced platelet consumption and thrombin-antithrombin complex generation. In addition, although melagatran (3mg/kg, i.v.) improved coagulation status when tissue factor was given 5min after the drug administration, and 2, 4 and 8h after melagatran dosing, it deteriorated coagulation status. These results were well explained by the plasma melagatran concentration. Low concentrations (15-234ng/ml) of melagatran aggravated coagulation status whereas it was mended by high concentrations (1190ng/ml or more) of the compound. In contrast, edoxaban and heparin did not show any exacerbation under these examination conditions. These results show that subtherapeutic concentrations of melagatran are associated with coagulation pathway activation, whereas factor Xa inhibition with edoxaban has a low risk of paradoxical hypercoagulation.

背景与目标： ：有人担心在某些情况下某些抗凝剂会反常增加血栓形成。我们已经显示，直接凝血酶抑制剂美拉加群的低剂量给药显着恶化了大鼠组织因子注射诱导的凝血状态。我们比较了凝血酶和凝血因子Xa抑制其加重组织因子诱导的大鼠凝血的作用的效果。在大鼠中施用美拉加群，肝素和依多沙班后，通过注射2.8 U / kg组织因子诱导高凝。组织因子注射后10分钟收集血样。测量血小板数，凝血酶-抗凝血酶复合物浓度和血浆化合物浓度。尽管高剂量的美拉加群（1mg / kg，iv）抑制了组织因子诱导的血小板消耗和凝血酶-抗凝血酶复合物的产生，但低剂量的美拉加群（0.01、0.03和0.1mg / kg，iv）显着增加了血小板的消耗和凝血酶-抗凝血酶复合物的产生。另外，尽管在药物给药后5分钟，给药后2、4和8小时给予组织因子，美拉加群（3mg / kg，i.v。）改善了凝血状态，但是其恶化了凝血状态。血浆三聚氰胺浓度很好地解释了这些结果。低浓度（15-234ng / ml）的美拉加群加剧了凝血状态，而高浓度（1190ng / ml或更高）的化合物改善了凝血状态。相反，依多沙班和肝素在这些检查条件下未显示出任何恶化。这些结果表明美拉加群的亚治疗浓度与凝血途径激活有关，而用edoxaban抑制因子Xa具有较低的矛盾性高凝风险。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Edoxaban-a non-vitamin K antagonist oral anticoagulant (NOAC)- 60-mg and 30-mg once-daily dose regimens are noninferior versus well-managed warfarin for the prevention of stroke or systemic embolic events (SEE) with less major bleeding in patients with nonvalvular atrial fibrillation (NVAF). There are no published data from phase 3 clinical trials specifically evaluating the use of NOACs in elderly NVAF patients, especially those considered ineligible for available oral anticoagulants. The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study that will compare the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy. A total of 800 patients (400 in each treatment group) are planned for randomization (1:1) to either edoxaban or placebo using a stratified randomization method with CHADS2 index score (2 points, ≥3 points) as a factor. The primary efficacy end point is the time to first onset of stroke or SEE. The net clinical outcome is the composite of stroke, SEE, major bleeding, and all-cause mortality. The primary safety end point is the incidence of major bleeding. The treatment period will continue until 65 patients with the primary efficacy events (ie, stroke or SEE) have been observed (2- to 2.5-year expected mean treatment period). The results of ELDERCARE-AF may provide clarity as to the efficacy and safety of edoxaban for the prevention of stroke or SEE in this high-risk population.

背景与目标： ：Edoxaban-一种非维生素K拮抗剂口服抗凝剂（NOAC）-60毫克和30毫克每日一次的剂量方案与良好管理的华法林相比，在预防中风或全身性栓塞事件（SEE）且大出血少的情况下效果不差非瓣膜性房颤（NVAF）的患者。没有3期临床试验的公开数据专门评估老年NVAF患者，尤其是那些认为不适合口服抗凝剂的NOAC的使用。 Edoxaban EldeR CARE AF患者低剂量（ELDERCARE-AF）研究是一项3期，随机，双盲，安慰剂对照，平行组，多中心研究，将比较每日一次edoxaban的安全性和有效性15在日本NVAF≥80岁的患者中，mg与安慰剂比较，被认为不符合标准口服抗凝治疗的条件。计划使用分层随机化方法，以CHADS2指数评分（2分，≥3分）为因子，将总共800名患者（每个治疗组400名）随机分配（1：1）到依多沙班或安慰剂中。主要功效终点是中风或SEE首次发作的时间。最终的临床结果是中风，SEE，大出血和全因死亡率的综合结果。主要安全终点是大出血的发生率。治疗期将持续到观察到65位具有主要疗效事件（即中风或SEE）的患者（预期平均治疗期为2至2.5年）。 ELDERCARE-AF的结果可能为埃德沙班预防高危人群中风或SEE的有效性和安全性提供了明确的依据。

BACKGROUND & AIMS: :Edoxaban is the most recently approved factor Xa inhibitor within the class of direct oral anticoagulants (DOACs). Like other DOACs, edoxaban was approved by the US Food and Drug Administration for treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Similar to other DOACs, edoxaban has fewer drug-drug interactions than warfarin and does not require routine laboratory monitoring. Unlike other DOACs, edoxaban has yet to be approved for secondary or postoperative venous thromboembolism thromboprophylaxis. Currently no antidote for edoxaban is available. To optimally prescribe agents in the DOAC class, it is critical that providers 1) understand how the agents compare; and 2) identify specific settings in which one agent may be preferred over another.

背景与目标： ：依多沙班（Edoxaban）是直接口服抗凝剂（DOAC）类别中最新批准的Xa因子抑制剂。像其他DOAC一样，edoxaban被美国食品和药物管理局批准用于治疗非瓣膜性房颤患者的静脉血栓栓塞和预防中风。与其他DOAC相似，edoxaban的药物相互作用比华法林少，并且不需要常规实验室监测。与其他DOAC不同，edoxaban尚未被批准用于继发性或术后静脉血栓栓塞的血栓预防。目前尚无可用于edoxaban的解毒剂。为了在DOAC类中最好地指定代理，至关重要的是提供者1）了解代理之间的比较；和2）确定特定设置，在该设置中，一个代理可能比另一个代理更受青睐。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.

背景与目标： ：直接口服抗凝剂edoxaban与维生素K拮抗剂在治疗静脉血栓栓塞（VTE）方面一样有效。但是，对VTE的治疗作用的潜在机制尚待确定。这项研究的目的是评估依多沙班对人血浆中纤溶酶原激活物（t-PA）诱导的血块溶解的影响，并确定纤溶酶和凝血酶可激活的纤溶抑制剂（TAFI）在依多沙班促纤溶作用中的作用。将合并的人类正常血浆或TAFI缺陷血浆（包含180ng / mL t-PA和0.1nM血栓调节素）与edoxaban或活化的TAFI抑制剂马铃薯块茎羧肽酶抑制剂（PCI）混合。通过添加组织因子和磷脂诱导凝集。测定凝块溶解时间和血浆纤溶酶-α2抗纤溶酶复合物（PAP）浓度。用扫描电子显微镜对凝块结构成像。在正常血浆中，临床相关浓度（75、150和300ng / mL）的edoxaban和PCI显着缩短了血凝块溶解时间。 PCI增加了PAP浓度，并观察到PAP浓度与凝块溶解百分比之间存在相关性。依多沙班也剂量依赖性地升高PAP浓度。在TAFI缺乏的血浆中，与正常血浆相比，edoxaban和PCI对血块溶解和PAP浓度的影响明显减弱。血纤蛋白纤维在edoxaban存在下形成的凝块中较细。总之，在临床上相关浓度的依多沙班通过增加人血浆中纤溶酶的产生来加速t-PA诱导的纤维蛋白溶解。 edoxaban的作用主要取决于TAFI。依多沙班的纤溶作用可能有助于治疗VTE。

BACKGROUND & AIMS: :Patients with atrial fibrillation and prior stroke or transient ischemic attack exhibit a very high risk of recurrence. Secondary prevention with oral anticoagulants is mandatory. Overall, clinical guidelines recommend the use of target-specific oral anticoagulants over vitamin K antagonists for secondary prevention of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation and previous stroke are not receiving the appropriate antithrombotic treatment, perhaps due to the perceived risks of anticoagulation including the risk of hemorrhagic transformation of an ischemic stroke. The ENGAGE AF-TIMI 48 trial showed that although edoxaban 60 mg and warfarin reduced the risk of stroke to a similar extent, edoxaban exhibited a lesser risk of bleeding, particularly intracranial hemorrhage. Importantly, these data were independent of the presence of prior stroke or transient ischemic attack. Therefore, edoxaban can be used in both primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. The aim of this review was to update the available evidence about edoxaban in the clinical management of secondary prevention in individuals with non-valvular atrial fibrillation.

背景与目标： ：患有房颤和先前中风或短暂性脑缺血发作的患者表现出很高的复发风险。口服抗凝剂的二级预防是强制性的。总体而言，临床指南建议使用特定于目标的口服抗凝剂，而不是维生素K拮抗剂，对房颤患者的卒中进行二级预防。但是，许多患有房颤和先前卒中的患者未接受适当的抗血栓治疗，可能是由于人们认为存在抗凝风险，包括缺血性卒中发生出血性转化的风险。 ENGAGE AF-TIMI 48试验显示，尽管60毫克edoxaban和华法林可降低中风的风险，但edoxaban出血的风险较小，尤其是颅内出血。重要的是，这些数据与既往中风或短暂性脑缺血发作的存在无关。因此，edoxaban可用于非瓣膜性房颤患者的一级和二级卒中预防。这篇综述的目的是在非瓣膜性房颤患者的二级预防的临床管理中，更新有关依多沙班的现有证据。

BACKGROUND & AIMS: AIMS :To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS).

METHODS AND RESULTS :In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1-12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59-1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68-1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70-1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47-1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573).

CONCLUSIONS :In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation.

背景与目标： AIMS ：比较经皮冠状动脉介入治疗（PCI）并发急性冠状动脉综合征（ACS）或慢性冠脉综合征（ED）的患者经皮冠状动脉介入治疗（PCI）后依多沙班联合P2Y12抑制的安全性和有效性（ CCS）。

方法和结果：在ENTRUST-AF PCI试验的预先指定的亚分析中，参与者被以1：1的比例随机分配给edoxaban-或维生素K拮抗剂基于（VKA）的策略和随机化由ACS（edoxaban n == 388，VKA n == 389）与CCS（edoxaban n == 363，VKA = 366）进行分层。参加者每天一次接受edoxaban60μmg加P2Y12抑制剂治疗12个月，或VKA联合P2Y12抑制剂和阿司匹林100μmg（1-12个月）。 59例（15.2％）vs 79例（20.3％）ACS患者在12个月时的主要出血终点发生率为[危险比（HR）：0.73，95％置信区间（CI）：0.59-1.02，P = 0.063]，以及分别接受依多沙班和VKA治疗的69例（19.0％）vs 73例（19.9％）CCS患者（HR：0.94，95％CI：0.68-1.31，P = 0.708）[P相互作用（P-int ）= 0.2741]。 ACS患者的主要次要终点（心血管死亡，心肌梗塞，中风，全身性栓塞事件或明确的支架血栓形成的复合指标）分别为33（8.5％）和28（7.2％）（HR：1.16、95％CI：0.70 -1.92），相比之下，分别接受edoxaban和VKA疗法治疗的CCS患者分别为16（4.4％）和18（4.9％）（HR：0.91，95％CI：0.47-1.78）（P-int = 0.5573）。

结论：在接受PCI的房颤患者中，与基于VKA的方案相比，以依多沙班为基础的方案为房颤患者提供了一致的安全性和相似的疗效不论其临床表现如何。