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Modulation of mucus production by the human ecto- and endo-cervical epithelium by steroid hormones and associated interactions with commensal microbiome play a central role in the physiology and pathophysiology of the female reproductive tract. However, most of our knowledge about these interactions is based on results from animal studies orin vitromodels that fail to faithfully mimic the mucosal environment of the human cervix. Here we describe microfluidic organ-on-a-chip (Organ Chip) models of the human cervical mucosa that recreate the cervical epithelial-stromal interface with a functional epithelial barrier and produce abundant mucus that has compositional, biophysical, and hormone-responsive properties similar to the living cervix. Use of continuous fluid flow promoted ecto-cervical differentiation, whereas use of periodic flow including periods of stasis stimulated endo-cervical specialization. Similar results with minor differences were obtained using epithelial cells isolated from three donors each from a different ethnic background (African American, Hispanic, and Caucasian). When the endo-Cervix Chips were co-cultured with livingLactobacillus crispatusandGardnerella vaginalisbacterial communities to respectively mimic the effects of human host interactions with optimal (healthy) or non-optimal (dysbiotic) microbiome, significant differences in tissue innate immune responses, barrier function, cell viability, and mucus composition were detected reminiscent of those observedin vivo. Thus, human Cervix Chips provide a physiologically relevant experimentalin vitromodel to study cervical mucus physiology and its role in human host-microbiome interactions as well as a potential preclinical testbed for development of therapeutic interventions to enhance women’s health.

Introduction Limited data were published on the management of direct oral anticoagulants in the insertion of pacemaker and cardiac monitoring devices. This study describes the management and outcomes of edoxaban, a direct oral factor Xa inhibitor, in patients undergoing pacemaker or monitoring device implantation in routine clinical practice. Methods and results EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of peri-procedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from five days pre- until 30 days post-procedure. The primary outcomes were the incidences of acute thromboembolic events (ATE), ischemic events, and International Society on Thrombosis and Haemostasis defined Major Bleeding; secondary outcomes included incidence of Clinically Relevant Non-Major Bleeding (CRNMB) and perioperative edoxaban interruption times. Conformance with European Heart Rhythm Association (EHRA) Guidance on interruption of DOAC therapy was variable: of the cardiac monitoring device patients, where no interruption of therapy would be expected, nonetheless, 62.5% had interruption of treatment, whereas in pacemaker procedures, where interruption would be expected, 23.4% had no interruption. No ATE or ischemic events occurred. One case of CRNMB and two of minor bleeding occurred. All bleedings occurred more than three days after the procedure. Conclusion/relevance The periprocedural complication risk for edoxaban treated patients undergoing pacemaker or invasive cardiac monitoring implantation was low. This population of patients was well managed in routine practice. This article is protected by copyright. All rights reserved.

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

BACKGROUND: Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38-1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45-3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT. CONCLUSIONS: In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.

Background Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing. Methods We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing. Results A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) were prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the nonrecommended 60-mg dose. Compared with the recommended 60-mg group, the nonrecommended 30-mg group had a higher proportion of patients aged ≥75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group. Conclusion The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label.

BACKGROUND To compare the efficacy and safety of edoxaban vs. warfarin in high-risk subgroups. Methods ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial fibrillation (AF) within 12 months and CHADS2 score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin and followed for 2.8 years (median). The primary outcome for this analysis was the net clinical outcome (NCO), a composite of stroke/systemic embolism events, major bleeding, or death. Multivariable risk-stratification analysis was used to categorize patients by the number of high-risk features. RESULTS The annualized NCO rates in the warfarin arm were the highest in patients with malignancy (19.2%), increased fall risk (14.0%), and very-low body weight (13.5%). The NCO rates increased with numbers of high-risk factors in the warfarin arm: 4.5%, 7.2%, 9.9% and 14.6% in patients with 0-1, 2, 3, and >4 risk factors, respectively (Ptrend 4+), the absolute risk reductions favoring edoxaban over warfarin increased: 0.3%->2.0% for HDER; 0.4%->3.4% for LDER vs warfarin (P=0.065 and P

BACKGROUND: Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion. HYPOTHESIS: EMIT-AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice. METHODS: Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre- until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding, acute coronary syndrome, and acute thromboembolic events. RESULTS: Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non-major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred. CONCLUSIONS: The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban. ispartof: CLINICAL CARDIOLOGY vol:43 issue:7 pages:769-780 ispartof: location:United States status: published

Background New technologies developed to improve survival outcomes for glioblastoma (GBM) continue to have limited success. Recently, image-guided dose painting (DP) radiotherapy has emerged as a promising strategy to increase local control rates. In this study, we evaluate the practical application of a multiparametric MRI model of glioma infiltration for DP radiotherapy in GBM by measuring its conformity, feasibility, and expected clinical benefits against standard of care treatment. Methods Maps of tumor probability were generated from perfusion/diffusion MRI data from 17 GBM patients via a previously developed model of GBM infiltration. Prescriptions for DP were linearly derived from tumor probability maps and used to develop dose optimized treatment plans. Conformity of DP plans to dose prescriptions was measured via a quality factor. Feasibility of DP plans was evaluated by dose metrics to target volumes and critical brain structures. Expected clinical benefit of DP plans was assessed by tumor control probability. The DP plans were compared to standard radiotherapy plans. Results The conformity of the DP plans was >90%. Compared to the standard plans, DP (1) did not affect dose delivered to organs at risk; (2) increased mean and maximum dose and improved minimum dose coverage for the target volumes; (3) reduced minimum dose within the radiotherapy treatment margins; (4) improved local tumor control probability within the target volumes for all patients. Conclusions A multiparametric MRI model of GBM infiltration can enable conformal, feasible, and potentially beneficial dose painting radiotherapy plans.

Background/Introduction ETNA-AF (ETNA) is a multinational, prospective, observational study evaluating the experience with edoxaban in the clinical practice of patients with atrial fibrillation (AF). ENGAGE AF-TIMI 48 was a randomized double-blind trial that tested the clinical benefits of edoxaban versus warfarin. The recommended dose is 60 mg, dose-reduced to 30 mg daily in patients with at least 1 of 3 label-indicated criteria (renal impairment [creatinine clearance: 15–≤50 mL/min], weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors). Purpose We assessed whether the effectiveness and safety of edoxaban in clinical practice were consistent with findings from the pivotal randomized clinical trial. Methods We obtained patient-level data from ETNA and ENGAGE AF-TIMI 48. We initially extracted patients from similar geographic regions, and then used propensity-score matching (PSM) to adjust key baseline characteristic differences between studies. The primary effectiveness endpoint was all stroke or systemic embolism (SSE) and mortality; the safety endpoint was major bleeding (MB). We used Cox proportional hazards models to compare event rates for the clinical outcomes between ETNA and ENGAGE AF-TIMI 48. Results 8,615 AF patients with CHADS2 score ≥2 received the 60 mg edoxaban recommended dose (5,462 ETNA; 3,153 ENGAGE AF-TIMI 48). After PSM, key baseline characteristics were well-balanced between the studies: mean age 71.0 years (SD: 9.07); for both ETNA and ENGAGE AF-TIMI 48 median CHA2DS2-VASc score and median HAS-BLED score were 4 and 2. The annualized incidence rate of SSE was 1.65% in ETNA vs 1.53% in ENGAGE AF-TIMI 48 (HR 0.98; 95% CI 0.49, 1.93; p=0.94). ETNA had similar annualized mortality, 2.81%, compared with ENGAGE AF-TIMI 48, 2.34%, (HR 1.49; 95% CI 0.84, 2.63; p=0.17). MB was less frequent in ETNA vs ENGAGE AF-TIMI 48 (1.10% vs 3.56%; HR 0.25; 95% CI 0.14, 0.44; p Conclusions The effectiveness of edoxaban in clinical practice from a large registry was consistent with efficacy findings from the randomized controlled trial. We observed a lower rate of bleeding events in the ETNA observational study compared with the ENGAGE AF-TIMI 48 trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Age is a risk factor for ischemic stroke and bleeding in patients with atrial fibrillation (AF). The large dataset from the global prospective, noninterventional ETNA-AF program allows for analysis of the impact of age on clinical events in AF patients treated with edoxaban. Purpose Evaluate the safety and effectiveness of edoxaban by age subgroups and the impact of age on clinical events. Methods Baseline patient characteristics, thromboembolic and bleeding events, and mortality data were collected from patients with 2-year follow-up in ETNA-AF program and analyzed in defined age subgroups. Cox regression analysis was conducted using age as a continuous variable and clinical events as outcome variables. Results A total of 27,617 patients were categorized into four age subgroups: Conclusion Two-year follow-up data from the global ETNA-AF program support the use of edoxaban as a safe and effective treatment for AF patients across all age groups, including the very elderly, in routine clinical care. The impact of age on the risk of ICH was smaller than that of ischemic stroke and major bleeding.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background and Purpose The large global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program was designed to assess the safety and effectiveness of edoxaban, complementing randomized clinical trials. Methods ETNA collects data on patient characteristics and clinical events in unselected AF patients treated with edoxaban for stroke prevention, integrating data from prospective, noninterventional studies conducted in Europe, Japan, South Korea, and Taiwan. Results The 2-year follow-up analysis included 27,617 patients, the majority of whom (82.6%) received the recommended dose according to the local label. At baseline, the mean age was 73.6 ± 9.8 years and 58.1% were male. Half of the patients (50.5%) were 75 years or older. The CHA2DS2-VASc score was 3.3 ± 1.5, and the modified HAS-BLED score was 2.4 ± 1.1. The rate of ischemic stroke was 0.74%/yr, major bleeding 1.02%/yr, intracranial hemorrhage 0.29%/yr, and major gastrointestinal (GI) bleeding 0.51%/yr. All-cause mortality was 3.13%/yr, and cardiovascular (CV) mortality 1.45%/yr (see Table). Conclusion The rates of ischemic stroke and major bleeding events remained low globally and across regions during the two-year follow-up period in AF patients treated with edoxaban. Global(N = 27,617) Japan(N = 11,330) Korea/Taiwan(N = 2,870) Europe(N = 13,417) Age, mean (SD) 73.6 (9.8) 74.2 (10.1) 71.6 (9.5) 73.6 (9.5) Gender, male, % 58.1 59.4 60.2 56.6 Weight [kg], median (IQR) 69 (58, 81) 59 (51, 68) 65 (57, 73) 80 (70, 90) CrCL [mL/min], mean (SD) 68.7 (28.4) 63.9 (25.8) 63.4 (23.7) 74.4 (30.5) CHA2DS2-VASc, mean (SD) 3.3 (1.5) 3.5 (1.7) 3.1 (1.4) 3.2 (1.4) Mod. HAS-BLED≠, mean (SD) 2.4 (1.1) 2.4 (1.1) 2.3 (1.1) 2.5 (1.1) Edoxaban 60mg/30mg, % 53.5 / 46.5 27.6 / 72.4 48.8 / 51.2 76.4 / 23.6 2-year clinical events, N (%/year), [95% CI] Major Bleeding (ISTH) 477 (1.02) [0.93; 1.11] 188 (1.09) [0.94; 1.25] 51 (1.00) [0.74; 1.31] 238 (0.97) [0.85; 1.11] Intracranial Hemorrhage 135 (0.29) [0.24; 0.34] 68 (0.39) [0.30; 0.50] 17 (0.33) [0.19; 0.53] 50 (0.20) [0.15; 0.27] Major GI Bleeding 241 (0.51) [0.45; 0.58] 122 (0.70) [0.58; 0.84] 18 (0.35) [0.21; 0.55] 101 (0.41) [0.33; 0.50] Any Stroke 455 (0.97) [0.88; 1.06] 244 (1.41) [1.24; 1.60] 54 (1.06) [0.80; 1.38] 157 (0.64) [0.54; 0.75] Ischemic Stroke 347 (0.74) [0.66; 0.82] 179 (1.03) [0.89; 1.20] 43 (0.84) [0.61; 1.13] 125 (0.51) [0.42; 0.61] Hemorrhagic Stroke 99 (0.21) [0.17; 0.26] 67 (0.39) [0.30; 0.49] 9 (0.17) [0.08; 0.33] 23 (0.09) [0.06; 0.14] All-cause Death 1479 (3.13) [2.98; 3.30] 470 (2.70) [2.46; 2.96] 72 (1.40) [1.09; 1.76] 937 (3.80) [3.56; 4.05] CV Death 684 (1.45) [1.34; 1.56] 140 (0.80) [0.68; 0.95] 26 (0.50) [0.33; 0.74] 518 (2.10) [1.92; 2.29] ≠Excluding labile INR.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Periprocedural management of patients on direct oral anticoagulants undergoing insertion of permanent pacemaker (PPM) and cardiac monitoring devices is mainly based on pharmacokinetic considerations, clinical experience, and expert opinion. Purpose To describe the characteristics, periprocedural management, and events of edoxaban patients undergoing implantation of PPM/monitoring devices. Methods From the global EMIT-AF/VTE registry, which includes edoxaban patients undergoing any diagnostic or therapeutic procedures, those with PPM/cardiac monitoring device implantation were observed from five days prior to 30 days post procedure. Events documented included the incidence of International Society on Thrombosis and Haemostasis defined Major Bleeding, Clinically Relevant Non-Major Bleeding (CRNMB), acute thromboembolic events (ATE) and perioperative edoxaban interruption times. Results PPM or invasive cardiac monitoring devices were implanted in 136 patients. Conformance with European Heart Rhythm Association Guidance for the interruption of anticoagulation was variable: of the cardiac monitoring patients, 62.5% had interruption of treatment, whereas in PPM procedures 23.4% had no interruption. One case of CRNMB and two cases of minor bleeding were documented. All bleedings seem non procedure-related since they occurred > three days post procedure. There were no ATE. Conclusions Relevant complications for edoxaban treated patients undergoing PPM or invasive cardiac monitoring procedures were rare. This population of patients is apparently well managed in routine practice, but further investigation of risk factors is justified. TablePatient characteristics Parameter All subjectsN = 136 All pacemakerN = 128 Insertion first pacemakerN = 89 Change pacemakerN = 39 Monitoring deviceN = 8 Age, mean (SD)Male, n (%) 75.1 (10.1)85 (62.5) 75.0 (10.3)83 (64.8) 75.7 (9.9)57 (64.0) 73.5 (11.2)26 (66.7) 76.3 (4.3)2 (25.0) BMI, mean (SD) 27.1 (5.5) 27.2 (5.6) 27.2 (6.0) 27.3 (4.5) 25.2 (4.3) AF, n (%)‡ 135 (99.3) 127 (99.2) 89 (100.0) 38 (97.4) 8 (100.0) VTE, n (%)‡ 3 (2.2) 3 (2.3) 1 (1.1) 2 (5.1) 0 CrCL, mean (SD) 63.8 (26.4) 64.1 (26.7) 62.3 (26.2) 68.3 (27.9) 58.9 (21.8) CrCL, ≤50, n (%) 43 (31.6) 41 (32.0) 33 (37.1) 8 (20.5) 2 (25.0) HAS-BLED Score, mean (SD) 2.0 (1.2) 1.9 (1.2) 1.9 (1.0) 2.1 (1.6) 2.6 (0.5) CHA2DS2-VASc Score, mean (SD) 3.7 (1.6) 3.7 (1.6) 3.7 (1.5) 3.8 (1.9) 3.1 (0.6) Edoxaban 30 mg/day, n (%) 49 (36.0) 46 (35.9) 32 (36.0) 14 (35.9) 3 (37.5) Edoxaban 60 mg/day, n (%) 86 (63.2) 81 (63.3) 56 (62.9) 25 (64.1) 5 (62.5) AF, atrial fibrillation; BMI, body mass index; CrCL, creatinine clearance; VTE, venous thromboembolism. ‡Two patients had both AF and VTE.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background The optimal periprocedural management of direct oral anticoagulants (DOAC), including edoxaban, in patients undergoing catheter-based cardiovascular procedures is unknown, and mainly based on physician opinion and experience. Purpose To assess real-world management of edoxaban in patients undergoing cardiovascular procedures, and to report their clinical events. Methods Global EMIT-AF/VTE is a prospective study of periprocedural management in edoxaban-treated patients undergoing diagnostic and therapeutic procedures. We report the data from patients undergoing cardiovascular procedures. Timing and duration of edoxaban interruption were at the treating physician’s discretion. Outcomes were collected from 5 days before until 30 days post procedure. Primary outcome was the incidence of major bleeding (MB); secondary outcomes included incidence of clinically relevant non-major bleeding (CRNMB) and acute thromboembolic events (ATE). Results Data was collected from 301 and 311 procedures with arterial or venous access, respectively. Baseline characteristics are shown in Table 1. Edoxaban was not interrupted in 36.9% of arterial and 52.7% of venous procedures. Edoxaban was interrupted pre-procedure in 41% of arterial and 32.8% of venous procedures. The median periprocedural interruption was 2 days. The overall incidence of bleeding was very low. Any bleeding was reported in 8 patients undergoing arterial and 10 patients undergoing venous procedures (2.7% and 3.2%). MB or CRNMB occurred in 2 arterial and 3 venous procedures (0.7% and 1.0%) and ATE occurred in 5 arterial and 1 venous procedure (1.7% and 0.3%, Table 1). Conclusions In this study, the periprocedural risks of bleeding and thrombotic events were low. About a third of arterial access procedures and half of venous access procedures were performed without edoxaban interruption. Arterial(n = 301) Venous(n = 311) Baseline characteristics Age, year, mean (SD)Male, n (%)Weight (kg), mean (SD) 71.9 (8.5)211 (70.1%)80.8 (16.7) 64.6 (11.1)215 (69.1%)84.1 (17.4) CrCL (mL/min), mean (SD) CHA2DS2-VASc score, mean (SD)HAS-BLED score, mean (SD) 73.5 (29.8) 3.3 (1.5)2.0 (1.0) 88.9 (35.5) 2.2 (1.5)1.3 (1.0) Edoxaban 60 mg / 30 mg, % 73% / 26% 88% / 26% Coronary heart disease, n (%) Congestive heart failure, n (%) 101 (33.6%) 58 (19.3%) 51 (16.4%) 33 (10.6%) Interruption of edoxaban, n (%) No interruption Pre-procedure only Post-procedure only Pre- and post-procedure 111 (36.9%)125 (41.5%)12 (4.0%)53 (17.6%) 164 (52.7%)102 (32.8%)8 (2.6%)37 (11.9%) Clinical events, n (%) MB or CRNMBACSStroke/Transient ischemic attackCV mortalityAll-cause mortality 2 (0.7%)2 (0.7%)3 (1.0%)1 (0.3%)2 (0.7%) 3 (1.0%) 01 (0.3%)00

Annually 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated.Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality.Of the 1442 patients, 280 (19%) were 65, 550 (38%) were 65-74, 514 (36%) 75-84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those 65, and seven in patients aged 75 years.Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed.NCT# 02950168, October 31, 2016.

Edoxaban is approved for stroke prevention in nonvalvular atrial fibrillation (AF) patients in numerous countries. Outcome data are sparse on edoxaban treatment in AF patients from routine clinical practice, especially in Asian patients. Global ETNA (Edoxaban in rouTine cliNical prActice) is a noninterventional study that integrates data from patients from multiple regional registries into one database. Here, we report the 1-year clinical events from AF patients receiving edoxaban in South Korea and Taiwan. Clinical events assessed included bleeding, strokes, systemic embolic events, transient ischemic attacks (TIAs), and all-cause and cardiovascular death. Overall, 2677 patients (mean (range) age 72 (66–78) years, male 59.7%, mean CHA2DS2-VASc score ± standard deviation 3.1 ± 1.4) were treated with 60 or 30 mg edoxaban and had 1-year follow-up data. The annualized event rates for major bleeding and clinically relevant non-major (CRNM) bleeding were 0.78% and 0.47%, respectively. Annualized event rates for ischemic stroke and hemorrhagic stroke were 0.90% and 0.19%, respectively. Event rates for major and CRNM bleeding and rates of ischemic stroke and TIA were higher in Taiwanese patients than in Korean patients. Event rates were low and similar to those found in other studies of edoxaban in Korean and Taiwanese AF patients, thus supporting the safety and effectiveness of edoxaban in this population.

Non-vitamin K antagonist oral anticoagulants such as edoxaban are the standard of care for stroke prevention in patients with atrial fibrillation (AF). The Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program integrates prospective, observational, noninterventional regional studies from Europe, Japan, and other Asian countries, collecting data on patient characteristics and clinical outcomes in unselected patients treated with edoxaban for stroke prevention in AF. Overall, 26,823 patients completed a 1-year follow-up and were treated with edoxaban, either 60 or 30 mg once daily. The majority (82.6%) of patients received the recommended doses according to the local label. At baseline, the median (interquartile range) age was 75 (68, 80) years, the CHA2DS2-VASc score was 3.0 (2.0, 4.0), and the hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs, or alcohol (HAS-BLED) score was 2.0 (2.0, 3.0). At one year, there were 273 (1.12%/year) major bleeding events, including 75 (0.31%/year) intracranial hemorrhages and 140 (0.57%/year) major gastrointestinal (GI) bleeds. There were 214 ischemic strokes (0.87%/year). Mortality was 3.03%/year (745 deaths), and cardiovascular mortality accounted for 40% of all deaths (1.22%/year, 299 cardiovascular deaths). In conclusion, stroke, intracranial hemorrhage, and other major bleeding events were low in patients with AF treated with edoxaban in routine care. Even on anticoagulation, cardiovascular death remained common.

Background In AF patients on direct oral anticoagulants (DOAC), safety and effectiveness vary with dose. This might impact treatment decisions. Purpose To investigate the effects of dosing of the DOAC edoxaban in AF patients on safety and effectiveness during 1-year observation in a real-world setting. Methods The Global ETNA-AF NIS included 26,823 patients. Baseline data by edoxaban dosing (60mg/30mg) and their influences on the safety (major bleeding [MB], clinically relevant non-major bleeding [CRNMB]), and effectiveness (stroke, systemic embolism, myocardial infarction [MI], death) were investigated (Table). Results Figure shows the breakdown by dose (60mg vs 30mg) and recommended (rec) vs non-recommended (non-rec) dosing. Patients on non-rec 30mg vs on rec 60mg edoxaban were older (mean ± SD: 74±9 vs 70±9 y); had lower creatinine clearance (72.2±20.6 vs 85.8±26.8 mL/min); and had more comorbidities, history of MB (2.1% vs 1.1%), and strokes (11.0% vs 8.6%). Non-rec 60mg vs rec 30mg patients were younger (75±9 vs 78±9 y), had fewer comorbidities, history of MB (1.2% vs 2.6%), and strokes (10.2% vs 16.4%). In non-rec 30mg vs rec 60mg, MB was not lower and ischaemic events were not higher. In non-rec 60mg vs rec 30mg, no increase in MB, CRNMB or ischaemic events was seen. Conclusion Edoxaban was prescribed at the label recommended dose in the vast majority of patients. Non-rec 30mg patients were sicker than rec 60mg patients while non-rec 60mg patients were less sick than rec 30mg patients. Overall event rates were low, and ischaemic event rates of non-rec 30mg and bleeding event rates of non-rec 60mg were not numerically higher than that of corresponding rec dosing groups. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Neuroblastoma (NB) is the most common extracranial solid tumor in children. The outcomes for aggressive forms of NB remain poor. The aim of this study was to develop a new molecular-targeted therapy for NB using an antisense oligonucleotide (ASO) and superparamagnetic iron oxide (SPIO) nanoparticles (NPs), as a delivery vehicle, targeting the transcription regulator MAX dimerization protein 3 (MXD3). We previously discovered that MXD3 was highly expressed in high-risk NB, acting as an anti-apoptotic factor; therefore, it can be a good therapeutic target. In this study, we developed two ASO-NP complexes using electrostatic conjugation to polyethylenimine-coated SPIO NPs and chemical conjugation to amphiphilic polymers on amine-functionalized SPIO NPs. Both ASO-NP complexes demonstrated MXD3 knockdown, which resulted in apoptosis in NB cells. ASO chemically-conjugated NP complexes have the potential to be used in the clinic as they showed great efficacy with minimum NP-associated cytotoxicity.

Pulmonary embolism (PE) studies used direct oral anticoagulants (DOACs) with or without initial heparin. We aimed to (1) evaluate if PE patients benefit from initial heparin; (2) describe patient characteristics in the DOAC studies; and (3) investigate whether the anatomical extent of PE correlates with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, cause of PE, and recurrence rate. Our methods were (1) an indirect meta-analysis comparing the recurrence risk in DOAC-treated patients with or without initial heparin to those patients given heparin/vitamin K antagonist (VKA). (2) To compare the PE studies, information was extracted on baseline characteristics including anatomical extent. (3) The Hokusai-VTE study was used to correlate anatomical extent of PE with NT-proBNP levels, causes of PE, and recurrent venous thromboembolism (VTE). The meta-analysis included 11,539 PE patients. The relative risk of recurrent VTE with DOACs versus heparin/VKAs was 0.8 (95% confidence interval [CI]: 0.6–1.1) with heparin lead-in and 1.1 (95% CI: 0.8–1.5) without heparin. In the DOAC studies, the proportion of patients with extensive PE varied from 24 to 47%. In Hokusai-VTE, NT-proBNP was elevated in 4% of patients with limited and in over 60% of patients with extensive disease. Cause of PE and anatomical extent were not related. Recurrence rates increased from 1.6% with limited to 3.2% with extensive disease in heparin/edoxaban-treated patients, and from 2.4 to 3.9% in heparin/warfarin recipients. In conclusion, indirect evidence suggests a heparin lead-in before DOACs may be advantageous in PE. Anatomical extent was related to elevated NT-proBNP and outcome, but not to PE cause.

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

Introduction Periprocedural management of patients on direct oral anticoagulants (DOAC) undergoing major surgical procedures is mainly based on pharmacokinetic considerations, clinical experience as described in the Dresden Registry (Beyer-Westendorf et al. Eur Heart J. 2014;35: 1888-186.) and the PAUSE study (Douketis JD et al. JAMA Intern Med. 2019;2019;179:1469-78), and on expert opinion. The objective of this study was to describe the background characteristics, periprocedural management, and outcomes of patients taking edoxaban who underwent major surgery in routine clinical practice. Methods Patients evaluated were participants in the EMIT AF/ VTE study (Colonna P et al. Clin Cardiol. 2020 Jul;43:769-80) which analyzed data on the risks of bleeding and thromboembolic events in 1,479 patients taking edoxaban who underwent unselected diagnostic or therapeutic procedures in routine clinical practice. Patients undergoing major surgery were compared with those who underwent non-major surgery. Physicians directed management of edoxaban, especially for dosing interruption, in accordance with locally approved labelling and guidelines such as those of the European Heart Rhythm Association (EHRA). Patients were evaluated from five days before until 29 days after the procedure. The primary outcome was the incidence of major bleeding as defined by the International Society on Thrombosis and Haemostasis; secondary outcomes included the incidence of clinically relevant non-major bleeding (CRNM), acute coronary syndrome (ACS), acute thromboembolic events (ATE) as well as the perioperative interruption times and use of bridging agents. Results Of the 1,478 patients, 128 (8.7%) underwent major-surgery as defined in the Dresden registry and PAUSE study. Background characteristics are summarized in Table 1 and medical history in Table 2. Surgeries by medical specialties are listed in Table 3. Major surgery vs non-major surgery patients had more often atrial fibrillation and dyslipidemia and exhibited higher CHA 2DS 2-VASc and HAS-BLED scores. Peri-procedurally, heparin was used significantly more often in patients with major surgery vs non-major surgery (42/128 (32%) vs 142/1351 (10.5%), p Outcomes are summarized in Table 4. There were no significant differences in severe adverse outcomes between the two groups. Pre-procedural and post procedural interruption of edoxaban was longer in the major surgery group. See Table 5. Discussion The edoxaban interruption pattern was statistically different between major and non-major surgery patients. The rates of peri-procedural bleeding and acute thromboembolic events were low when patients were managed according to a clinical experience-driven management protocol. This is in line with the results in prior publications evaluating other direct oral anticoagulants. These results are important to optimize clinical management of patients undergoing elective procedures and will help to support guidelines for the peri-procedural management of edoxaban. Figure 1 Figure 1. Disclosures von Heymann: Daiichi Sankyo: Honoraria, Research Funding; Bayer AG: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; NovoNordisk Pharma: Honoraria, Research Funding; Mitsubishi Pharma: Honoraria, Research Funding; Biotest GmbH: Honoraria, Research Funding; Grunenthal GmbH: Honoraria, Research Funding; HICC GbR: Honoraria, Research Funding; German Society of Anaesthesiology and Intensive Care Medicine: Honoraria, Other: Other Mandated to write several guidelines and part of writing groups of guidelines, Research Funding; European Society of Cardiothoracic Anesthesiologists: Other: Other Mandated to write several guidelines and part of writing groups of guidelines; Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: Honoraria, Research Funding; European Society of Anaesthesiology and Intensive Care (ESAIC): Other: Mandated to write several guidelines and part of writing groups of guidelines. Unverdorben: Daiichi Sankyo: Current Employment. Colonna: Boehringer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; European Society of Cardiology: Other: Mandated to write ESC-Guidelines on AF; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Ortiz: Bayer: Consultancy; Daiichi Sankyo: Consultancy; Boehringer: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Saxena: Recor Medical Inc: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding, Speakers Bureau; The Medicines Company: Consultancy, Research Funding, Speakers Bureau; Ablative Solutions Inc: Consultancy, Research Funding, Speakers Bureau; Vascular Dynamics Inc: Consultancy, Honoraria, Speakers Bureau; Esperion Inc: Consultancy, Honoraria, Speakers Bureau; Vifor Pharma: Honoraria, Speakers Bureau. Vanassche: Bayer: Consultancy, Speakers Bureau; Boehringer Ingelheim,: Consultancy, Speakers Bureau; Pfizer/BMS: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Weitz: Daiichi Sankyo: Consultancy, Speakers Bureau. Wilkins: Daiichi Sankyo: Honoraria. Chen: Daiichi Sankyo: Current Employment.

BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real-time reverse transcription PCR, and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single-agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide - common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, on combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionThese results indicate that MXD3 is a potential new target and that the use of MXD3 siRNA nanocomplexes is a novel therapeutic approach for neuroblastoma.

Background Many patients with venous thromboembolism (VTE) are elderly, have multiple comorbidities and take several concomitant medications. Physicians may prefer warfarin over direct oral anticoagulants (DOACs) in such patients because comparative data are lacking. This analysis was designed to determine the effects of advanced age, comorbidities, and polypharmacy on the efficacy and safety of edoxaban and warfarin in patients with VTE. Methods Using data from the Hokusai-VTE study, we report rates of recurrent VTE and of clinically relevant bleeding by age category ( 2) and concomitant medications ( 5). Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for edoxaban versus warfarin were determined and Kaplan-Meier methodology was used to construct time-to-event curves. At 3 months, pre- and postdose levels of edoxaban were measured using mass spectrometry. For warfarin-treated patients, the time in therapeutic range was calculated. The study was approved by institutional review boards; informed consent was obtained. Results Recurrent VTE increased with advanced age, multiple comorbidities, and polypharmacy in warfarin-treated patients but not with edoxaban. Edoxaban was more effective than warfarin in patients ≥ 75 years of age and in those with multiple comorbidities. In the 517 patients over 80 years of age, recurrent VTE occurred in 2.8% given edoxaban and in 5.7% given warfarin (HR 0.51, 95% CI 0.21–1.24). Bleeding increased with age, comorbidity, and polypharmacy regardless of treatment, but the relative safety of edoxaban versus well-managed warfarin was maintained. Age, comorbidity, and polypharmacy did not impact edoxaban concentrations. Conclusions These data suggest that a once-daily fixed dose of edoxaban is more effective and at least as safe as warfarin in high-risk VTE patients identified by older age, more comorbidities, and polypharmacy. Clinical trial registration: NCT00986154

Background: The optimal interruption schedule for NOACs in patients undergoing invasive procedures has not been determined. This analysis describes periprocedural interruption of edoxaban in real world EMIT AF/VTE study. Methods: EMIT AF/VTE was a prospective, non-interventional study conducted in 7 European countries that collected detailed information on periprocedural management of edoxaban from 5 days before to 30 days after procedure in patients with AF or VTE. Results: Among 1155 patients, pre-procedural interruption occurred in 781 (68%) patients (median 2 days, IQR 1.0-2.0) and post-procedural interruption in 308 (27%) patients (median 3 days, IQR 1.0-8.0); 279 (24.2%) patients had both pre- and post-procedural interruption. Edoxaban interruption in some patients differed from 2018 EHRA Recommendations for NOAC use in AF. Of 294 patients receiving minor risk procedures, for whom no interruption is recommended, 173 (58.8%) had preprocedural interruption (median 1 day). Of 581 patients with low bleeding risk procedures, for whom ≥24h preprocedural interruption is recommended, 188 (32.4%) had no interruption. Of 280 patients receiving high bleeding risk procedures, for whom ≥48h interruption is recommended, 46 (16.4%) had no interruption. Clinical events are shown in Table. Conclusion: Edoxaban interruption schedules in routine practice were not always consistent with EHRA guidelines; nevertheless, rates of clinically significant bleeding or acute thromboembolic events or coronary syndromes were low in the EMIT study. Table Disclosures Colonna: Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; BayerAG: Honoraria; Italian Cardiology Association: Other: Non-financial support; European Society of Cardiology: Other: Non-financial support; Pfizer/BMS: Honoraria. von Heymann:Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bayer AG: Honoraria; Pfizer GmBH: Honoraria; CSL Behring: Honoraria; NovoNordisk Pharma: Honoraria; EACTA and EACTS: Other; DGGG: Other; Mitsubishi Pharma: Honoraria; Ferring GmbH: Honoraria; Biotest GmbH: Honoraria; Leo Pharma GmBH: Honoraria; German Society of Anaesthesiology and Intensive Care Medicine: Other. Saxena:Daiichi Sankyo: Honoraria, Research Funding. Vanassche:Boehringer Ingelheim: Honoraria; 367 Leo Pharma: Honoraria; Bayer: Honoraria; Daiichi Sankyo: Honoraria, Research Funding. Jin:Daiichi Sankyo: Current Employment. Wilkins:Daiichi Sankyo: Honoraria. Chen:Daiichi Sankyo: Current Employment. Unverdorben:Daiichi Sankyo: Current Employment.

Background Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban. Methods The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication‐specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow‐up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported. Results Globally, enrollment began in early 2015 and is ongoing. Conclusions Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness.

Summary Background In patients with pulmonary embolism, right ventricular dysfunction is associated with early mortality. The Hokusai-VTE study used N-terminal pro-brain natriuretic peptide (NT-proBNP) and right to left ventricular diameter ratio on CT as indicators of right ventricular dysfunction and reported that recurrent venous thromboembolism rates were lower with edoxaban than warfarin. The aim of the current study was to further explore the significance of right ventricular dysfunction and investigate potential explanations for the superiority of edoxaban—ie, differences in baseline clinical characteristics, duration of initial heparin treatment, bleeding rates, or quality of warfarin treatment. Methods The Hokusai-VTE trial was a randomised, double-blind, event-driven non-inferiority trial in patients from centres in 37 countries that compared edoxaban with warfarin in the treatment of acute venous thromboembolism. Patients received treatment for at least 3 months and up to a maximum of 12 months. Patients were followed up for 12 months. Outcome data at 12 months was collected for all patients irrespective of treatment duration. This prespecified subgroup analysis focuses on the included patients with pulmonary embolism. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism defined as a composite of deep vein thrombosis or non-fatal or fatal pulmonary embolism at 12 months. Recurrence rates with edoxaban and warfarin were compared in patients with and without right ventricular dysfunction. In those with NT-proBNP concentrations of 500 pg/mL or higher, we compared baseline characteristics, duration of heparin treatment, and bleeding leading to study drug discontinuation in the edoxaban and warfarin groups. We also assessed quality of warfarin treatment. All analyses were done with the modified intention-to-treat population. The Hokusai-VTE trial is registered with ClinicalTrials.gov, number NCT00986154. Findings Between Jan 28, 2010, and Oct 5, 2012, 8292 patients were enrolled from 439 centres, of whom 8240 received at least one dose of study drug. 3319 patients had pulmonary embolism. NT-proBNP was 500 pg/mL or higher in 465 (30%) of 1565 patients given edoxaban and in 507 (32%) of 1599 given warfarin. Recurrent venous thromboembolism occurred in 14 (3%) of 465 patients in the edoxaban group and 30 (6%) of 507 in the warfarin group (hazard ratio [HR] 0·50, 95% CI 0·26–0·94; p=0·033). The right to left ventricular diameter ratio was 0·9 or higher in 414 (44%) of 937 patients in the edoxaban group and 427 (45%) of 946 in the warfarin group. Recurrent venous thromboembolism occurred in 11 (3%) of 414 and 20 (5%) of 427 patients in the edoxaban and warfarin groups (HR 0·57, 95% CI 0·27–1·17; p=0·13). Baseline characteristics, duration of heparin treatment, and rates of bleeding leading to study drug discontinuation were similar in the edoxaban and warfarin groups and the quality of warfarin management was adequate for patients with NT-proBNP concentrations of 500 pg/mL or higher. Interpretation Findings from our analysis suggest that edoxaban is more effective than warfarin in the treatment and prevention of recurrent venous thromboembolism in patients with pulmonary embolism and evidence of right ventricular dysfunction. Funding Daiichi Sankyo.

Children have historically been underrepresented or, indeed, omitted entirely, in drug trials, leading to a relative dearth of evidence in support of appropriate drug treatments for many pediatric diseases.[1][1], [2][2] Recent legislative initiatives in the United States and the European Union (EU

Transcatheter aortic valve implantation, also called transcatheter aortic valve replacement (TAVR), is the treatment of choice for patients with severe aortic stenosis and intermediate to high operative risk. A significant portion of TAVR patients have atrial fibrillation (AF) requiring chronic oral anticoagulation. In moderate- to high-risk AF patients, the direct factor Xa inhibitor edoxaban is noninferior to vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism with less bleeding and cardiovascular deaths. ENVISAGE-TAVI AF (NCT02943785) is a multinational, multicenter, prospective, randomized, open-label, blinded end point evaluation study comparing edoxaban to VKA-based therapy in approximately 1,400 patients with an indication for chronic oral anticoagulation after successful transfemoral TAVR. The coprimary end points are to assess the differential effects of the 2 treatments (a) on net adverse clinical events (the composite of all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, and major bleeding events) and (b) on major bleeding. Twelve hours to 5 days after successful TAVR, patients will be randomized to 60 mg daily oral edoxaban or any VKA (international normalized ratio: 2.0-3.0 or 1.6-2.6 [numbers inclusive] in Japan if age ≥ 70 years). Antiplatelet therapy may be administered per physician's discretion. Randomization will be stratified by edoxaban dose reduction (per local label). Treatment duration will be up to 36 months. The study is powered (80%) to detect noninferiority (margin for the hazard ratio: 1.38) for the composite primary end points, followed by superiority testing.

MXD3 is a transcription factor that plays an important role in proliferation of human DAOY medulloblastoma cells. Here, we demonstrate that MXD3 is highly enriched in human precursor B acute lymphoblastic leukemia (preB ALL) samples compared to mobilized peripheral blood mononuclear cells, bone marrow, or hematopoietic stem cells from healthy donors. MXD3 knock-down in the preB ALL cell line Reh resulted in decreased cell numbers with no change in G0/G1, S or G2/M populations but increased apoptosis compared to control cells. Our results suggest that MXD3 is important for survival of Reh preB ALL cells, possibly as an anti-apoptotic factor.