BACKGROUND & AIMS: :Thromboembolism is a commonly observed condition in geriatrics that is caused by vascular endothelial injury, platelet activation, physiological coagulation processes, reduction of anticoagulant activity, decreased fibrinolytic activity and abnormal flow in the heart chamber, artery or vein. The protein C anticoagulant system serves a crucial role in anticoagulant therapy for the treatment of thromboembolism. Previous findings have suggested that edoxaban is an efficient oral anticoagulant in the acute treatment of venous thromboembolism. In the present study, the efficacy of edoxaban on thromboembolism induced by atrial fibrillation was investigated in a mouse model. Inflammatory factors interleukin (IL)-1, -4, -8 and tumor necrosis factor (TNF)-α were analyzed in the sera of mice with fibrillation induced by thromboembolism. Expression and activity of thymic stromal lymphopoietin (TSLP) and activated protein C resistance were investigated in platelets and vascular endothelial cells (VECs). TSLP-induced platelet viability, Wnt-β phosphorylation and integrin expression were analyzed in platelets. Furthermore, Wnt-β expression and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in VECs were analyzed. Results demonstrated that the expression levels of IL-1, -4, -8 and TNF-α were significantly downregulated in the sera of mice with fibrillation and thromboembolism following treatment with edoxaban (P<0.01). Furthermore, the expression levels of prostacyclin (PGI2), prostaglandin (PG)E2, PGD2 and PGF2α were significantly increased in the sera of experimental mice that received edoxaban therapy (P<0.01). Results also indicated that edoxaban significantly stimulated the protein expression of TSLP and activated Wnt-β phosphorylation and integrin expression in platelets (P<0.01). In addition, edoxaban therapy significantly upregulated the expression levels of PI3K and AKT, and subsequently increased the activity of protein C and S in VECs (P<0.01). Notably, edoxaban treatment improved atrial fibrillation and thromboembolism, as determined by pathological analysis. In conclusion, these results suggested that edoxaban elicited beneficial effects for mice with atrial fibrillation induced by thromboembolism through the regulation of the Wnt-β-induced PI3K/ATK-activated protein C system.

背景与目标： 血栓栓塞是老年病中常见的疾病，由血管内皮损伤，血小板活化，生理性凝血过程，抗凝活性降低，纤溶活性降低以及心腔，动脉或静脉血流异常引起。 C蛋白抗凝剂系统在抗凝剂治疗血栓栓塞的治疗中起着至关重要的作用。先前的研究结果表明，依多沙班在静脉血栓栓塞的急性治疗中是一种有效的口服抗凝剂。在本研究中，在小鼠模型中研究了依多沙班对房颤诱发的血栓栓塞的疗效。在血栓栓塞引起的原发性小鼠血清中分析了炎症因子白介素（IL）-1，-4，-8和肿瘤坏死因子（TNF）-α。胸腺基质淋巴细胞生成素（TSLP）的表达和活性以及活化的蛋白C抗性在血小板和血管内皮细胞（VEC）中进行了研究。分析了TSLP诱导的血小板生存力，Wnt-β磷酸化和整联蛋白表达。此外，分析了VEC中的Wnt-β表达和磷酸肌醇3-激酶（PI3K）/蛋白激酶B（AKT）信号传导途径。结果表明，在用依多沙班治疗后，患有纤颤和血栓栓塞的小鼠血清中IL-1，-4，-8和TNF-α的表达水平显着下调（P <0.01）。此外，在接受edoxaban治疗的实验小鼠的血清中，前列环素（PGI2），前列腺素（PG）E2，PGD2和PGF2α的表达水平显着升高（P <0.01）。结果还表明，依多沙班显着刺激了血小板中TSLP的蛋白表达，并激活了Wnt-β磷酸化和整联蛋白的表达（P <0.01）。此外，edoxaban治疗显着上调了PI3K和AKT的表达水平，并随后增加了VEC中C和S蛋白的活性（P <0.01）。值得注意的是，根据病理分析确定，依多沙班治疗改善了心房纤颤和血栓栓塞。总之，这些结果表明，edoxaban通过调节Wnt-β诱导的PI3K / ATK激活的蛋白C系统，对血栓栓塞引起的房颤小鼠产生了有益的作用。

BACKGROUND & AIMS: :Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options.

背景与目标： ：Edoxaban是每日一次的口服抗凝剂，以浓度依赖的方式快速选择性地抑制Xa因子。这篇综述描述了edoxaban的广泛临床开发计划，包括针对非瓣膜性房颤（NVAF）和有症状的静脉血栓栓塞（VTE）的患者的III期研究。 ENGAGE AF-TIMI 48研究（N = 21,105；平均CHADS2评分2.8）将依多沙班60 mg每天一次（大剂量方案）和依多沙班30 mg每天一次（低剂量方案）与剂量调整的华法林比较[国际标准化比例（INR）2.0-3.0]，发现这两种方案在NVAF患者预防中风和全身性栓塞方面均不逊于华法林。两种edoxaban方案还大大降低了出血性中风，心血管疾病死亡率，大出血和颅内出血的风险。 Hokusai-VTE研究（N = 8,292）对有症状VTE的患者进行了3到12个月的灵活治疗，发现最初的肝素治疗后，每天一次60 mg edoxaban不逊于剂量调整后的华法林（INR 2.0- 3.0）可预防复发性VTE，并且出血事件的风险也显着降低。两项研究均将血栓栓塞事件的中至高风险患者随机分组，并进一步设计为尽可能模拟常规临床实践，随机或在研究期间使用依多沙班减量剂量（减半剂量），经常监测并良好控制的华法林组，在研究结束时监测良好的过渡期，在北斋VTE中采用灵活的治疗时间。鉴于已获得III期结果，每天一次的edoxaban可能很快成为抗血栓治疗方案范围的关键补充。

BACKGROUND & AIMS: BACKGROUND:Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF-TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. METHODS AND RESULTS:Twenty-one thousand one-hundred and five patients enrolled in the ENGAGE AF-TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (Ptrend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66-1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70-0.99]). The absolute risk difference in major bleeding (-82 events/10 000 pt-yrs) and in intracranial hemorrhage (-73 events/10 000 pt-yrs) both favored edoxaban over warfarin in older patients. CONCLUSIONS:Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

背景与目标： 背景：与年轻患者相比，老年房颤患者发生缺血和出血事件的风险更高。在ENGAGE AF-TIMI 48试验的预先分析中，我们根据年龄评估了依多沙班与华法林的临床结局。
方法和结果：参与ENGAGE AF-TIMI 48试验的21,05例患者分为3个预先设定的年龄组：<65（n = 5497），65至74（n = 7134）和≥ 75（n = 8474）年。年龄较大的患者更可能是女性，体重减轻且肌酐清除率降低，从而导致埃多沙班减量率更高（3个年龄组分别为10％，18％和41％，P <0.001）。华法林的卒中或全身性栓塞事件（1.1％，1.8％和2.3％）和大出血（1.8％，3.3％和4.8％）的发生率在各个年龄段均有所增加（两者的Ptrend <0.001）。在主要疗效和安全性结果方面，年龄组和随机治疗之间没有相互作用。在老年人（≥75岁）中，中风/全身性栓塞事件的发生率与edoxaban和warfarin相似（危险比0.83 [0.66-1.04]），而edoxaban显着减少了大出血（危险比0.83 [0.70-0.99） ]）。在老年患者中，大出血（-82事件/ 10 000 pt-yrs）和颅内出血（-73事件/ 10 000 pt-yrs）的绝对风险差异均偏重于依法沙班优于华法林。
结论：在房颤患者中，年龄对严重出血的影响大于血栓栓塞风险。鉴于随着年龄的增长出血和死亡的发生率更高，相比于年轻患者，与依法沙班和华法林治疗相比，与依法沙班相比，依多沙班治疗老年患者的安全性事件绝对值甚至更高。
临床试验注册：URL：https://www.clinicaltrials.gov/。唯一标识符：NCT00781391。

BACKGROUND & AIMS: BACKGROUND:We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti-Xa agent edoxaban in patients with atrial fibrillation (AF). METHODS AND RESULTS:ENGAGE AF-TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high-dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower-dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HRadj]=1.46; 95% CI, 1.27-1.67, P<0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HRadj for HDER)=0.94; (95% CI: 0.77-1.15) with SAPT, HRadj=0.70 (95% CI: 0.50-0.98), P interaction (Pint)=0.14. (HRadj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99-1.43) With SAPT, 1.03 (95% CI, 0.76-1.39) Pint=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HRadj for HDER=0.80 (95% CI, 0.68-0.95), and with SAPT, HRadj=0.82 (95% CI, 0.65-1.03; Pint=0.91). For LDER without SAPT (HRadj=0.56 [95% CI 0.46-0.67]) and with SAPT (HRadj=0.51 [95% CI 0.39-0.66]). CONCLUSIONS:Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

背景与目标： 背景：我们研究了单一抗血小板治疗（SAPT）在抗Xa药物edoxaban对房颤（AF）患者的疗效和安全性中的同时使用。
方法和结果：参与AF-TIMI 48是一项随机试验，比较了edoxaban与华法林的两种剂量方案。我们研究了批准的大剂量edoxaban方案（HDER；预期药物暴露量增加的患者每天60 mg减少一半），以及低剂量的edoxaban方案（LDER；每天30 mg，也减少一半）预期药物治疗增加的患者）。 SAPT（阿司匹林占92.5％）由主治医师酌情服用。在治疗为协变量的情况下，进行了3​​个月SAPT分层的Cox比例风险回归分析。与未接受SAPT的14 977例患者相比，接受SAPT的4912例患者更为男性，有冠心病和糖尿病病史，并且CHADS2Vasc和HAS BLED评分更高。与未接受SAPT的患者相比，接受SAPT的患者发生大出血的几率更高； （调整后的危险比[HRadj] = 1.46； 95％CI，1.27-1.67，P <0.001）。与华法林相比，SAPT在预防中风或全身性栓塞事件（SEEs）中没有改变edoxaban的相对疗效：edoxaban与没有SAPT的华法林相比，危险比（HDER的HRadj）= 0.94； （95％CI：0.77-1.15）和SAPT，HRadj = 0.70（95％CI：0.50-0.98），P相互作用（Pint）= 0.14。 （对于LDER的HRadj与未使用SAPT的华法林相比，华法林= 1.19（95％CI 0.99-1.43）在使用SAPT时，1.03（95％CI，0.76-1.39）Pint = 0.42。 = 0.80（95％CI，0.68-0.95）和使用SAPT时，HRadj = 0.82（95％CI，0.65-1.03; Pint = 0.91）。对于不使用SAPT的LDER（HRadj = 0.56 [95％CI 0.46-0.67]）并使用SAPT（HRadj = 0.51 [95％CI 0.39-0.66]）。
结论：除抗凝剂外，由医生选择接受房颤治疗的房颤患者与未接受房颤治疗的患者相比，发生中风/ SEE的风险和出血率更高。与华法林相比，在有或没有SAPT的情况下，依多沙班表现出相似的相对疗效并减少了出血。
临床试验注册：URL：http://www.clinicaltrials.gov/。唯一标识符：NCT00781391。

BACKGROUND & AIMS: :We conducted a randomized clinical trial to compare the effectiveness of the A-V Impulse System foot pump for reducing the incidence of deep-vein thrombosis (DVT) after total knee arthroplasty (TKA) in patients under edoxaban thromboprophylaxis. Patients undergoing primary TKA at our institution between September 2013 and March 2015 were enrolled after obtaining informed consent. The patients were randomized to use the foot pump (n = 58) and not to use the foot pump (n = 62). Both groups were given prophylactic edoxaban. Primary outcomes were any DVT as detected by bilateral ultrasonography up to postoperative day 10 (POD10) and pulmonary embolism (PE) up to POD28. The safety outcomes were bleeding and death of any cause up to POD28. Plasma D-dimer levels were measured before TKA and on POD10 after TKA. Immunoglobulin G (IgG)-class anti-PF4/heparin antibodies were measured using an IgG-specific enzyme-linked immunosorbent assay. The incidences of any DVT up to POD28 were 31.0% and 17.7% in patients with or without the foot pump, respectively. The incidences of major bleeding up to POD28 were 5.1% and 4.8% in patients with or without the foot pump, respectively. Foot pump use did not significantly reduce the incidence of DVTs in patients undergoing TKA under edoxaban thromboprophylaxis. Although seroconversion of anti-PF4/heparin antibodies was confirmed in one-fourth of patients, the seroconversion rates did not differ between patients with (20.7%) or without (25.8%) foot pump use. This study shows that the A-V Impulse system foot pump did not affect the incidence of DVT under edoxaban thromboprophylaxis in patients undergoing TKA. Seroconversion of anti-PF4/heparin antibodies was detected in a significant number of patients who underwent TKA under antithrombotic prophylaxis using edoxaban.

背景与目标： ：我们进行了一项随机临床试验，以比较A-V脉冲系统脚踏泵在接受edoxaban血栓预防性治疗的患者中，降低全膝关节置换术（TKA）后深静脉血栓形成（DVT）的发生率。在获得知情同意后，于2013年9月至2015年3月在我们机构接受原发性TKA的患者入选。患者被随机分配使用脚踏泵（n = 58），而不使用脚踏泵（n = 62）。两组均给予预防性依多沙班治疗。主要结局是术后10天（POD10）通过双侧超声检查发现的任何DVT，以及POD28之前通过肺栓塞（PE）进行的检查。安全结果是出血和任何原因致死，直至POD28。在TKA之前和TKA之后在POD10上测量血浆D-二聚体水平。使用IgG特异性酶联免疫吸附测定法测量了免疫球蛋白G（IgG）类抗PF4 /肝素抗体。有或没有脚踏泵的患者中，直至POD28的任何DVT的发生率分别为31.0％和17.7％。有或没有脚踏泵的患者中，直至POD28的大出血发生率分别为5.1％和4.8％。在使用依多沙班预防血栓形成的TKA患者中，脚踏泵的使用并没有显着降低DVT的发生率。尽管在四分之一的患者中证实了抗PF4 /肝素抗体的血清转化，但在使用（20.7％）或不使用（25.8％）脚踏泵的患者之间，血清转化率没有差异。这项研究表明，接受TKA的患者在依多沙班血栓预防措施下，A-V脉冲系统脚踏泵不会影响DVT的发生率。在使用依多沙班进行抗血栓预防的TKA患者中，有大量患者检测到抗PF4 /肝素抗体的血清转化。

BACKGROUND & AIMS: BACKGROUND:Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS:With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 ml/min, weight ≤60 kg, and/or use of strong p‑glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS:Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION:There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION:NCT02944019; Date of registration 24 October 2016.

背景与目标： 背景：未经选择的房颤（AF）患者使用非维生素K拮抗剂口服抗凝剂的研究表明，每个地区的临床特征和给药方法不同，但缺乏关于edoxaban的数据。
方法：根据一项大型前瞻性观察研究的欧洲房颤患者常规临床实践中的Edoxaban治疗数据（ETNA-AF-Europe），我们比较了临床特征（包括edoxaban的剂量降低标准：肌酐清除率15-50ml / min，体重≤60kg和/或使用比利时和荷兰（BeNe）以及其他欧洲国家（OEC）的患者。
结果：在欧洲ETNA-AF地区的全部13,639名患者中，有2579名来自BeNe。 BeNe患者比OEC患者年轻（平均年龄：72.3 vs 73.9岁），且CHA2DS2-VASc（平均：2.8 vs 3.2）和HAS-BLED分数较低（平均：2.4 vs.2.6）。与来自OEC的患者相比，来自BeNe的患者患高血压的比例更低（分别为61.6％和80.4％）和/或糖尿病（分别为17.3％和23.1％）。此外，相对于OEC（25.4％），服用BeNe减少剂量的30mg edoxaban（14.8％）的患者相对较少。总体而言，依多沙班按标签服用的剂量占83.1％的患者的剂量。然而，在没有任何降低剂量标准的情况下，BeNe的30mg使用者中有36.9％（占所有患者的5.5％）开具了edoxaban处方，而在OEC中为35.5％（占所有患者的9.0％）。
结论：BeNe和OEC在处方依多沙班患者的临床特征和给药方式方面存在显着差异，这与局部实施剂量评估和优化有关。
试用注册：NCT02944019;注册日期2016年10月24日。

BACKGROUND & AIMS: :Optically active 3-cyclohexene-1-carboxylic acid (CHCA) derivatives are important pharmaceutical intermediates. Due to the special rotatable structure, enantioselective preparation of chiral CHCA is hard to achieve. To identify efficient and enantioselective hydrolases for the biosynthesis of CHCA from methyl 3-cyclohexene-1-carboxylate (CHCM), target-oriented screening from soil samples and gene mining from genome database were explored. All putative hydrolases attempted displayed low enantioselectivity. A hydrolase-producing strain JNU9335 was successfully identified with relatively high enantioselectivity, and was designated as a strain of Acinetobacter sp. according to 16S rDNA sequence and phylogenetic analysis. After optimization, strain JNU9335 could produce 233 U·L‒1 hydrolase with E value of 21. Isooctane/aqueous biphasic system is favorable for the enzymatic resolution of CHCM, the E value of JNU9335 could further be increased to 36. The newly identified JNU9335 could tolerate as high as 1.0 M CHCM, producing (S)-CHCM with ees of 99.6% and isolation yield of 34.7%. This study provides an efficient biocatalyst for the preparation of chiral 3-cyclohexene-1-carboxylic acid derivatives.

背景与目标： ：旋光性3-环己烯-1-羧酸（CHCA）衍生物是重要的药物中间体。由于其特殊的可旋转结构，很难实现手性CHCA的对映选择性制备。为了鉴定3-环己烯-1-甲酸甲酯（CHCM）生物合成CHCA的高效和对映选择性水解酶，探索了从土壤样品中进行靶向筛选并从基因组数据库中进行基因挖掘的方法。尝试的所有推定水解酶均显示出低对映选择性。以相对高的对映选择性成功鉴定了产生水解酶的菌株JNU9335，并将其命名为不动杆菌属的菌株。根据16S rDNA序列和系统发育分析。经过优化，菌株JNU9335可以产生233 U·L‒1水解酶，E值为21。能够耐受高达1.0 M CHCM，产生（S）-CHCM的ee为99.6％，分离产率为34.7％。该研究为制备手性3-环己烯-1-羧酸衍生物提供了一种有效的生物催化剂。

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。