Edoxaban Therapy Research Articles

The Authors' Reply to "Efficacy and Feasibility of Edoxaban Therapy without Prior Parenteral Anticoagulants in Patients with Venous Thromboembolism".

The Authors' Reply to "Efficacy and Feasibility of Edoxaban Therapy without Prior Parenteral Anticoagulants in Patients with Venous Thromboembolism".

Efficacy and Feasibility of Edoxaban Therapy without Prior Parenteral Anticoagulants in Patients with Venous Thromboembolism.

Efficacy and Feasibility of Edoxaban Therapy without Prior Parenteral Anticoagulants in Patients with Venous Thromboembolism.

Persistence and predictors for non-persistence to edoxaban therapy in patients with atrial fibrillation: 4-year follow-up data from the ETNA-AF-Europe study

Abstract Background Non-persistence to non-vitamin K antagonist oral anticoagulants (NOACs) is associated with increased stroke risk in atrial fibrillation (AF) patients. To date, most NOAC persistence studies have been retrospective and often did not include patients receiving edoxaban. Identifying predictors for non-persistence may be useful when considering the design of future studies and help develop strategies to reduce non-persistence in clinical practice. Purpose To define and describe patients who did not reach the end of the study period and were non-persistent to edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe was a prospective, observational study conducted in AF patients receiving edoxaban. In this subanalysis, patients not reaching the end of the study period and patients who were non-persistent (defined as permanent discontinuation of edoxaban) after 4 years of treatment were examined, including patients switching to other NOACs and reasons for discontinuation. Baseline predictors for not reaching the end of the study period and baseline predictors for non-persistence with edoxaban treatment during 4 years of follow-up were also examined. Persistent patients may have missed dose/interruption. Results Overall, 13,164 patients were included in the analysis. During the whole study period, 14.3% died. At the end of the study, 27.3% of patients prematurely terminated the study and 71.5% were classified as completing the study. Of patients who left the study (n=3598), 30.2% were lost-to-follow-up, 6.9% withdrew consent, and 5.9% transferred to another institution. Of patients who completed the study (n=9417), 87.4% were classified as persistent within the 4 years. Only 6.2% permanently discontinued edoxaban without switching to another NOAC (Table). Following backwards elimination, baseline characteristics associated with premature study termination (excluding death) were male sex, low body mass index, low renal function, chronic hepatic disease, long standing persistent/permanent AF, smoking, low compliance as judged by investigator, vitamin K antagonist-naïve, and no rate/rhythm control drug at baseline. Characteristics associated with non-persistence were increasing age, male sex, body weight extremes, low renal function, heart failure, vascular disease, chronic hepatic disease, alcohol use, perceived frailty, chronic obstructive pulmonary disease, smoking, current AF symptoms, and ablation (Figure). The criterion for backward elimination was p=0.05. Conclusions Most patients in ETNA-AF-Europe reached the end of the study. Less than a quarter were classified as non-persistent during the 4-year follow-up. The majority of patients who were non-persistent switched to another NOAC with a small number completely stopping anticoagulant therapy. Male sex, low renal function, chronic hepatic disease, and smoking were associated with both treatment discontinuation and non-persistence.Termination and persistence

Impact of body weight and body mass index on clinical outcomes of edoxaban therapy in atrial fibrillation patients included in the ETNA-AF-Global registry

Abstract Background In atrial fibrillation (AF) patients (pts) receiving non-vitamin K antagonist oral anticoagulant therapy, extreme body weights, both obesity and low body weight, may impact clinical outcomes. Purpose To determine the impact of body weight and body mass index (BMI) on clinical outcomes in AF pts receiving edoxaban from the Global ETNA program (Europe [NCT02944019], Japan [UMIN000017011], Korea/Taiwan [NCT02951039], Hong Kong [NCT03247582] and Thailand [NCT03247569]). Methods ETNA-AF-Global, a multinational, prospective, observational study collected demographic and clinical outcomes data for AF pts receiving edoxaban. In this subanalysis, pts were categorised into the following body weight groups: ≤60kg, >60 to 80kg (reference body weight), >80 to ≤100kg and >100kg; and BMI groups: <18.5kg/m², ≥18.5 to <25.0kg/m² (reference BMI), ≥25.0 to <30.0kg/m², ≥30.0 to <40.0kg/m² and ≥40.0kg/m². Clinical outcomes at 2-year follow-up were compared across body weight and BMI groups. Results 26,805 pts were included in this analysis. Mean ± standard deviation body weight was 72.2 ± 18.1kg and mean BMI was 26.4 ± 5.0kg/m². 43.7% of pts were categorised into the >60 to 80kg reference body weight group. [other groups: ≤60kg, 28.1%; >80 to ≤100kg, 21.7%; >100kg, 6.5%] and 40.0% of pts into the ≥18.5 to <25.0kg/m² reference BMI group [other groups: <18.5kg/m², 3.0%; ≥25.0 to <30.0kg/m², 37.3%; ≥30.0 to <40.0kg/m², 18.0%; ≥40.0kg/m², 1.7%]. Clinical outcomes are shown in Fig. 1 as unadjusted hazard ratios vs. reference group according to weight and in Fig. 2 according to BMI. Among body weight groups, pts weighing ≤60kg had the highest annualised rates of any stroke or systemic embolic event (SEE; 1.24%), ischemic stroke (0.97%), all-cause death (3.96%), major bleeding events (1.49%), and major bleeding or clinical-relevant non-major (CRNM) bleeding events (3.45%). Pts in the reference body weight group had the lowest annualised rates of all-cause death (2.81%). Annualised rates of major bleeding, major bleeding or CRNM bleeding events and any stroke or SEE were lowest in pts weighing >100kg. Among BMI groups, annualised rates of all effectiveness and safety outcomes were highest in pts with a BMI <18.5kg/m². Pts in the ≥25.0 to <30.0kg/m² BMI group had the lowest annualised rates of all-cause death (2.85%) and pts in the ≥18.5 to <25.0kg/m² BMI group had the lowest annualised rates of CV death (0.73%). Conclusions In the Global ETNA-AF program, clinical outcomes varied between different body weight and BMI subgroups. These findings highlight the need to consider the clinical implications of low body weight and/or low BMI, as AF pts who belong to these categories may be at higher risk of adverse outcomes during long-term anticoagulant treatment.Figure 1.Figure 2.

Oral anticoagulation with Edoxaban for stroke prevention in patients with atrial fibrillation: Analysis of 1-year follow-up data of routine clinical practice in Germany, Austria and Switzerland (DACH) from the ETNA-AF registry

Non-vitamin-K oral anticoagulants (NOACs) are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of Edoxaban in routine care in Germany, Austria and Switzerland (DACH) are limited. We report one-year outcomes in patients with AF treated with Edoxaban in routine care. The ETNA-AF-Europe study (Clinicaltrials.gov:NCT02 944 019) is a multicenter, prospective, observational study that enrolled 13 092 patients with AF treated with Edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). The DACH-cohort consists of 5457 (41,7 %) patients of sites in Germany, Austria and Switzerland. Patients had a mean age of 74 years (2384 [44 %]women) and a mean CHA2DS2-VASc-score of 3.2 ± 1.4. A label-conform dosing of Edoxaban was administered to 4309 patients (78,9 %). At the one-year-follow-up a stroke or systemic embolism occurred in 42 patients (0,8 %/year), and severe bleeding was reported in 36 patients (0,7 %/year). Ten patients (0,2 %/year) suffered intracranial and 13 patients (0,3 %/year)gastrointestinal bleeding. Numbers of death from all causes and cardiovascular death occurred in 179 patients (3,4 %/year) and 85 patients (1,6 %/year), respectively. Age > 75 years, frailty and a CHA2DS2-VASc score ≥ 4 were associated with a higher all-cause mortality - and those patients were more likely to suffer a stroke or a major bleeding event. In Germany, Austria and Switzerland in patients with AF on Edoxaban therapy for stroke prevention the number of stroke and major bleeding events is low. Increasing morbidity is associated with a higher number of important clinical events.

Management of edoxaban therapy in patients undergoing emergency/urgent procedures: a subanalysis of the global, prospective, observational, multinational EMIT-AF/VTE programme

Abstract Background Physicians are often unable to follow recommendations for preprocedural oral anticoagulant interruption before emergency/urgent (unplanned) procedures, which may lead to a higher incidence of adverse outcomes in these patients compared with those who undergo planned procedures. The Global EMIT-AF/VTE programme found low bleeding and thromboembolic event rates for patients receiving edoxaban who underwent diagnostic or therapeutic procedures. However, edoxaban management and clinical outcomes may differ among the subgroup of patients with emergency/urgent procedures. Purpose To describe periprocedural edoxaban management and clinical outcomes for patients in the EMIT-AF/VTE programme who underwent emergency/urgent procedures. Methods In this subanalysis, only physician-reported unplanned (emergency/urgent) procedures were included, of which dental and dermatological procedures were excluded. Only a patient’s first emergency procedure was included, with the exception of 3 patients having 2 procedures on the same day (in these cases the 2 procedures were combined). Procedure bleeding risk was classified according to EHRA criteria, and baseline characteristics and edoxaban interruption data were collected. Clinical event and procedure dates were compared to determine whether they were related. Results Among 156 patients undergoing emergency/urgent procedures, the mean ± standard deviation age at baseline was 74.5 ± 8.7 years, and the CHA2DS2-VASc score was 3.8 ± 1.6. Medical histories of hypertension and dyslipidaemia were reported in 84.0% and 40.4% of patients, respectively; approximately one-quarter of patients had diabetes mellitus (26.9%) or creatinine clearance ≤50 mL/min (24.4%). The most common procedure types were vascular access and transcatheter diagnostics/interventions (34.6%) and gastroenterological procedures (27.6%). Procedures were more often EHRA-classified as minor (35.9%) or low (35.3%) vs high risk (20.5%). Preprocedure edoxaban interruption rates ranged from 39.3%–50.9% across risk groups, with more than half of the procedures being performed with edoxaban interruption (53%–66%; Figure). By 20 days postprocedure, edoxaban therapy was resumed in approximately 86% and 88% of patients with minor- or low-risk procedures vs 70% with high-risk procedures. Overall, 33 clinical events were recorded, of which 18 (54.5%) preceded a procedure (Table). Five bleeding events and one thrombotic event occurred after and were caused by the procedure. Conclusions Edoxaban resumption was protracted after high- vs minor- or low-risk procedures. Bleeding and thrombotic events resulting from a procedure occurred in <4% of patients, indicating that postprocedure edoxaban therapy can be effectively tailored to optimise clinical outcomes.FigureTable

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study

BackgroundOptimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type.MethodsThis subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians’ decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min).ResultsWe included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups.ConclusionIn this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries.Trial registrationNCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Prevalence, contemporary trends and associated factors of potentially inappropriate prescription of edoxaban in real-world clinical practice: A subanalysis of the SUNSHINE registry.

As the direct oral anticoagulant most recently approved in China, data pertaining to clinical edoxaban use are still scarce. This study investigated the prevalence of and contemporary trends in edoxaban prescription among Chinese patients as well as factors associated with its inappropriate use in a multicentre registry of patients treated in real-world clinical practice. This real-world, prospective, multicentre and non-interventional study included 1005 inpatients treated with edoxaban. According to National Medical Products Administration and European Heart Rhythm Association guidelines, edoxaban therapy was determined to be appropriate or inappropriate in each case. The median patient age was 70.0years (interquartile range 61.0-78.0years) and 46.3% were women. Overall, 456 (45.4%) patients received inappropriate edoxaban therapy, and common issues included an inappropriately low dosage (183, 18.2%) or wrong drug selection (109, 10.8%), high dosage (73, 7.3%), unreasonable off-label use (49, 4.9%), contraindicated medication combinations (27, 2.7%) and incorrect administration timing (16, 1.6%). Several factors, such as age ≥75 years (odds ratio [OR] = 1.921, 95% confidence interval [CI] 1.355-2.723, P < 0.001), weight >60 kg (OR = 2.657, 95%CI 1.970-3.583, P < 0.001), severe renal insufficiency (OR = 1.988, 95% CI 1.043-3.790, P = 0.037), current anaemia (OR = 1.556, 95% CI 1.151-2.102, P = 0.004) and history of bleeding (OR = 2.931, 95% CI 1.605-5.351, P < 0.001) were associated with an increased risk of inappropriate edoxaban therapy, whereas factors associated with cardiovascular specialties, such as admission to a cardiovascular department (OR = 0.637, 95% CI 0.464-0.873, P = 0.005), dronedarone use (OR = 0.065, 95% CI 0.026-0.165, P < 0.001) and amiodarone use (OR = 0.365, 95% CI 0.209-0.637, P < 0.001) decreased this risk. In this real-world study, 45.4% of patients received an inappropriate treatment with edoxaban. Multiple clinical characteristics can help identify patients who should receive edoxaban. Further development and implantation of educational activities and management strategies are needed to ensure the correct use of edoxaban.

Prolonged Secondary Stroke Prevention with Edoxaban: A Long-Term Follow-Up of the SATES Study.

Little evidence is available on the long-term efficacy and safety of edoxaban, mainly due to the recent release date. The primary objective of the study was to evaluate the safety of edoxaban, defined by the incidence of major bleedings. We then aimed to evaluate the incidence of thromboembolic events and the persistence of edoxaban therapy in the long-term. In this observational cohort study, we included ischemic stroke patients enrolled in a previous study to evaluate the safety and efficacy of long-term edoxaban treatment. Data were collected by a trained investigator through a structured telephone interview. Sixty-three subjects (median age 81.0 (73.5-88.0) years, 38.1% male) were included in the study, with a mean follow-up of 4.4 ± 0.7 years (range: 3.2-5.5 years). Only one patient (1.6%, 0.4%/year) presented a major extracranial bleeding, and none had cerebral hemorrhage. Six thromboembolic events occurred in five patients (7.9%): three recurrent strokes, two transient ischemic attacks, and one myocardial infarction (2.2%/year). Over a follow-up period of more than three years, 13 patients discontinued edoxaban (20.6%). Conclusions: Edoxaban seems to be effective and safe in the long-term. The persistence rate of edoxaban therapy is optimal after more than three years of treatment.

P393 EDOXABAN: NEW PERSPECTIVE IN A PATIENT WITH CANCER–ASSOCIATED THROMBOSIS COMPLICATED BY BRAIN METASTASES. A RARE CLINICAL CASE

Abstract Herein, we present the case of a 58 y–o Caucasian man with unremarkable cardiovascular history and a strong family history for cancer. He was diagnosed with lung adenocarcinoma IVb (pleura, pleural effusion, lymph nodes), PDL1: 2% TPS and absence of actionable driver mutations on DNA and RNA NGS (only ERBB2 mutation). Started first–line chemotherapy with cisplatin–pemetrexed regimen and immunotherapy with pembrolizumab. He developed common/superficial femoral and popliteal deep vein thrombosis (DVT) and pulmonary embolism (PE). The patient started low–molecular–weight heparin (LMWH) namely enoxaparin 1 mg/kg x 2/d (weight: 65 Kg). After 1 mo, CT showed PE resolution. Due to DVT persistence and patient’s preference for oral administration, LMWH was replaced with direct oral anticoagulant (DOAC) namely edoxaban 60 mg 1 cp/d. After 2 mo, resolution of common femoral and popliteal vein thrombosis with partial recanalization of superficial femoral DVT were detected. However, he developed brain metastases treated with WB radiotherapy. We decided for edoxaban full dose long–term anticoagulant treatment with monthly cardioncological surveillance. After 6 mo since cancer diagnosis, the patient was still adherent to DOAC therapy, although in a maintenance combined regimen pemetrexed–pembrolizumab based, without both drug–drug interactions and brain bleeding. Conclusions Thromboembolism is the second leading cause of death in malignancy. In this clinical case, a man with advanced lung cancer developed extended cancer–associated thrombosis (CAT). However, the appearance of brain metastases has posed a clinical dilemma: to continue or to withdraw the anticoagulant therapy and, also, which drug to choose between LMWH and DOAC. Literature is limited on the use of DOACs in cancer patients with brain metastases. Besides, current guidelines neither advocate contraindication to DOAC, nor suggest caution as requested for gastrointestinal and genitourinary sites of cancer. We decided to proceed with edoxaban therapy, despite chemotherapy combined to immunotherapy were still ongoing and the concurrent appearance of brain metastases, with good results in efficacy, patient’s adherence and, mostly, safety. In conclusion, in regard to our clinical experience, we point out DOAC as a reliable and manageable therapeutical choice in CAT, also in active cancer patients with brain metastases receiving chemo–immunotherapy.

Efficacy and Safety of Edoxaban in Cancer-Associated Venous Thromboembolism: A Real World Retrospective Study.

Introduction Few data exist on the use of edoxaban in cancer-associated venous thromboembolism (VTE) outside of clinical trials. Aim of this study was to evaluate the characteristics and outcomes of these patients in a real world clinical setting. Methods We retrospectively analyzed the characteristics of patients with cancer-associated VTE who were prescribed edoxaban. Follow-up at 3, 6, and 12 months was performed: VTE recurrences, bleedings, mortality, cancer progression and treatment, edoxaban interruption and its reason were assessed. Results Fifty-four patients, 38 females (70.4%), mean age 71 ± 14 years, were enrolled. In 38 patients (70.4%), the episode of VTE was the first one, in 28 (51.8%) it was an isolated deep vein thrombosis (DVT), in 13 (24.1%) a pulmonary embolism (PE) associated with DVT, in 13 (24.1%) an isolated PE. Median time between cancer and VTE diagnosis was 6 (interquartile range [IQR] 2–47) months. Median time between VTE diagnosis and edoxaban prescription was 36 (IQR 7–117) days. At 3, 6, and 12 months the incidence of all-cause mortality was 16.6, 22.2, and 38.8%, that of VTE recurrence 1.8, 1.8, and 3.7%, and that of major bleeding 7.4, 9.2, and 12.9%, respectively. No bleeding was fatal. Of the 33 patients alive at 12 months, 32 (96.9%) were still on edoxaban therapy, in seven (21.2%) cancer was in progression. Conclusion Our study, conducted on a real world population of patients with cancer-associated VTE, confirms the results of randomized controlled clinical trials, and supports the use of edoxaban as effective and safe treatment in this context.

A Prospective Study to Evaluate the Effectiveness of Edoxaban for the Resolution of Left Atrial Thrombosis in Patients with Atrial Fibrillation.

Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).

Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey Study: Design and Rationale

Safety and effectiveness of edoxaban was demonstrated in phase III, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF-TIMI 48) trial and is being confirmed in the post-authorization Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study in patients with atrial fibrillation. However, any post-authoriza tion safety study focusing on the safety of edoxaban treatment in Turkey with a prospective design has not been performed yet. The Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey (ETAF-TR) study is designed to evaluate the safety and effectiveness of edoxaban treatment in atrial fibrillation in routine practice. The present article describes the design and rationale for the ETAF-TR Study.The ETAF-TR (NCT04594915) is a national, multicenter, prospective, observational study that enrolled 858 patients from 32 centers. The primary outcome of the ETAF-TR study is any overt bleeding (consisting of major bleeding or clinically relevant nonmajor bleeding or any bleeding that does not meet this definition but is considered as overt bleeding by the par ticipating physician). Effectiveness, treatment persistence, and posology will also be evaluated in an explorative manner. The overall duration of follow-up will be 1 year; the first patient was enrolled in August 2020.Results of ETAF-TR will add data from clinical practice to those from ENGAGE-AF trial and also ETNA-AF study. Comparing their results will enable to test the external validity of ENGAGE-AF trial in the country conditions.

Temporal trend of clinical events in patients with atrial fibrillation on edoxaban therapy: results from the non-interventional global ETNA-AF program

Abstract 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 &amp;gt;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

Factors Associated With Edoxaban Concentration Among Patients With Atrial Fibrillation.

Background and Purpose: Edoxaban exposure varies across different ethnicities. The purpose of our study was to examine the risk factors associated with high or low edoxaban concentrations in Asian populations.Methods: Participants with atrial fibrillation who were undergoing edoxaban therapy were enrolled. Peak (1–4 h after edoxaban administration) and trough (24 ± 4 h from the last edoxaban dose) blood samples were collected to measure edoxaban concentrations using ultrahigh-performance liquid chromatography with tandem mass spectrometry. The edoxaban concentrations were compared to those observed in clinical trials to define a higher- or lower-than-expected range. Multivariate logistic regression was used to analyze the risk factors associated with high or low edoxaban concentrations.Results: Eighty participants (49 men, 61.3%) were enrolled and provided 78 trough and 76 peak samples. Twenty participants (25.6%) were determined to have low trough concentrations, which was associated with higher creatinine clearance and the use of the 30 mg regimen (odds ratio [OR] and 95% confidence interval [CI], 1.06 [1.01, 1.11], p = 0.01 and 5.77 [1.34, 24.75], p = 0.02, respectively). In contrast, 21 participants (27.6%) had high peak concentrations, which was associated with an off-label overdosing regimen (OR = 4.68 [1.23, 17.70], p = 0.02).Conclusion: Our study identified factors associated with increased or decreased edoxaban exposure. The measurement of edoxaban concentration may be recommended for patients with selected characteristics.

Impact of Weight on Clinical Outcomes of Edoxaban Therapy in Atrial Fibrillation Patients Included in the ETNA-AF-Europe Registry.

Background: Extremes of body weight may alter exposure to non-vitamin K antagonist oral anticoagulants and thereby impact clinical outcomes. This ETNA-AF-Europe sub-analysis assessed 1-year outcomes in routine care patients with atrial fibrillation across a range of body weight groups treated with edoxaban. Methods: ETNA-AF-Europe is a multinational, multicentre, observational study conducted in 825 sites in 10 European countries. Overall, 1310, 5565, 4346 and 1446 enrolled patients were categorised into ≤60 kg, >60–≤80 kg (reference weight group), >80–≤100 kg and >100 kg groups. Results: Patients weighing ≤60 kg were older, more frail and had a higher CHA2DS2-VASc score vs. the other weight groups. The rates of stroke/systemic embolism, major bleeding and ICH were low at 1 year (0.82, 1.05 and 0.24%/year), with no significant differences among weight groups. The annualised event rates of all-cause death were 3.50%/year in the overall population. After adjustment for eGFR and CHA2DS2-VASc score, the risk of all-cause death was significantly higher in extreme weight groups vs. the reference group. Conclusions: Low rates of stroke and bleeding were reported with edoxaban, independent of weight. The risk of all-cause death was higher in extremes of weight vs. the reference group after adjustment for important risk modifiers, thus no obesity paradox was observed.

Safety and effectiveness of edoxaban in a real-world clinical setting: Two-year follow-up of the ETNA-AF-Europe study

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Oral anticoagulation (OAC) for stroke prevention is essential in the management of patients with atrial fibrillation (AF). The assessment of OAC use in routine clinical care and the effects of this therapy on outcomes and safety are important. Purpose: We analysed two-year outcome data with adjudicated follow-up results in 13,417 patients with AF treated with edoxaban. Methods: ETNA-AF-Europe (Clinicaltrials.gov: NCT02944019) enrolled 13,417 consecutive patients with AF treated with edoxaban in 825 centres in 10 European countries and 2-year prospectively collected, real world data is presented. Results: Edoxaban was prescribed according to licence recommendations in 83.1% (n = 11,146) of patients (Table). Whilst three quarters of patients were prescribed edoxaban 60 mg (n = 10,248, 76.4%), the quarter prescribed edoxaban 30 mg were older (79.5 versus 71.8 years), had a higher stroke risk (CHA2DS2-VASc score: 3.9 versus 3.0) and a higher bleeding risk (HAS-BLED score: 2.9 versus 2.4). Thromboembolic and bleeding events were more common in patients receiving edoxaban 30 mg OD without differences in intracranial haemorrhage (ICH) (Figure). Patients prescribed a non-recommended dose of edoxaban had a numerically higher stroke risk (CHA2DS2-VASc score: 3.6 versus 3.1) with subsequent higher rates of ischemic stroke and mortality, however they also had higher bleeding rates, with the exception of ICH (table) despite a similar initial bleeding risk (HAS-BLED score: 2.7 versus 2.5). Conclusions: In this large, European data set reporting two-year outcomes on edoxaban therapy, no additional safety signals were observed and event rates were in line with those observed in ETNA-AF after 1 year and in ENGAGE AF-TIMI 48, re-affirming the safety and effectiveness of edoxaban licence recommendations in a real world setting of patients with AF. All key events of interest, other than intracranial haemorrhage, were numerically lower in patients prescribed the licenced recommended dose. Outcomes with rec. vs non-rec. dosesn (%/year [95%CI])Recommended dose (n = 11,146; 83.1%)Non-recommended dose (n = 2271; 16.9%)Any stroke/SEE138 (0.68 [0.57;0.80])31 (0.76 [0.51;1.07])Ischaemic stroke99 (0.48 [0.39;0.59])26 (0.63 [0.41; 0.93])Major bleeding189 (0.93 [0.80;1.07])49 (1.20 [0.89;1.59])Intracranial haemorrhage43 (0.21 [0.15;0.28])7 (0.17 [0.07;0.35])All-cause mortality729 (3.55 [3.30;3.82])208 (5.04 [4.38;5.78])CV mortality405 (1.97 [1.79;2.18])113 (2.74 [2.26;3.30])CI, confidence interval; CV, cardiovascular; rec., recommended; SEE, systemic embolic event.Abstract Figure. Annualised event rates at 2-year FU

The association of fracture risk in atrial fibrillation patients and long-term anticoagulant therapy category: a systematic review and meta-analysis.

ObjectiveOur study aimed to assess the risk of all fractures and hip fractures in patients with atrial fibrillation (AF) who took non-vitamin K antagonist oral anticoagulants (NOACs) compared to warfarin.MethodsWe searched PubMed, Embase, and Cochrane Library and Clinical Trials.gov Website. Reviewed related researches up to January 31, 2020, to identify studies with more than 12 months of follow-up data. The protocol for this systematic review and meta-analysis has been registered in the International Prospective Register of Systematic Reviews (PROSPERO Number: CRD42020156893).ResultsWe included five RCT studies, and five observational studies that contained a total of 326,846 patients in our meta-analysis. Our meta-analysis showed that patients taken NOACs had no significant all fracture risk (RR = 0.91, 95% CI [0.81–1.01]) and hip fracture risk (RR = 0.92, 95% CI [0.82–1.03]) compared with those taken warfarin. Subanalysis showed that the risk of all fractures and hip fractures treated by NOACs were significant lower compared with warfarin in observational studies compared with RCT studies. Also, a subanalysis across the duration of anticoagulation showed the NOACs users have lower all fracture risk than warfarin users when the duration of anticoagulation ≤2 years (RR = 0.89, 95% CI [0.80–0.99]). Further analysis, significant lower all fracture risk in the rivaroxaban therapy (RR = 0.81; 95% CI [0.76–0.86]) compared with warfarin but no statistical significance in hip fracture. There were no significant difference of all fracture risk and hip fracture risk in dabigatran, apixaban, and edoxaban therapy compared with warfarin.ConclusionThe meta-analysis demonstrated that NOACs associated with a significantly lower all fracture risk compared with warfarin when the duration of anticoagulation more than 2 years. Rivaroxaban users had lower risk of all fracture than warfarin users in AF patients. But there was no evidence to verify apixaban, edoxaban, and dabigatranin could decrease all fracture and hip fracture risk compared with warfarin.

Abstract 15194: The Distribution of Anti-factor Xa Activity Values, Prothrombin Time and Activated Partial Thromboplastin Time Assessed at Multiple Points in Patients on Edoxaban Therapy

Introduction: Edoxaban is one of the direct oral anticoagulants (DOACs) used for non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Chromogenic anti-factor Xa activity (AXA) is the appropriate assay to measure the pharmacodynamics of a factor Xa inhibitor and to estimate plasma drug concentrations. Although patients taking DOACs do not require routine coagulation monitoring, the distributions of AXA values have not been assessed at multiple points in the previous study. Purpose: To clarify the distribution of AXA values at two-hour intervals in patients taking edoxaban. Methods: Sixteen patients (66.8 ± 9.6 years, 11 males) with NVAF or VTE on edoxaban therapy were enrolled in the study. We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, at two-hour intervals (from immediately before the intake of edoxaban to 8 hours after the intake). The dosage of edoxaban was 30 mg (n=11) once daily (OD) or 60 mg (n=5) OD according to the prescribing information. Results: The distributions of AXA values of 30 mg OD at 0, 2, 4, 6 and 8 hours after the intake of edoxaban were 0.12±0.08, 0.80±0.48, 0.94±0.48, 0.72±0.34 and 0.53±0.32 (IU/mL), respectively. The distributions of AXA values of 60 mg OD at 0, 2, 4, 6 and 8 hours after the intake of edoxaban were 0.17±0.04, 1.59±0.76, 1.43±0.34, 1.29±0.32 and 0.96±0.21 (IU/mL), respectively. Conclusions: Our findings reveal that the peak time of AXA values might be different depending on the dosage. The peak time of 30 mg OD is between 0 to 4 hours, whereas that of 60 mg OD is between 2 to 6 hours after the intake of edoxaban. In addition, the AXA values of 60 mg OD are almost twice as much as that of 30 mg at each point.

Thrombocytopenia-Related Problems in Patients with Concomitant Atrial Fibrillation Requiring Antithrombotic Prevention: A Retrospective Cohort Study.

ResumoBaixas doses de edoxabana e enoxaparina sódica foram objeto de uma comparação retrospectiva implementada com a técnica do escore de propensão a fim de mitigar os efeitos das diferenças nas características clínicas basais de duas coortes e minimizar o risco de viés.Posteriormente, usando um modelo de riscos proporcionais de Cox, avaliou-se a associação de cada tipo de terapia com o risco do composto de morte por todas as causas, acidente vascular cerebral/ataque isquêmico transitório, hospitalizações e ocorrência de sangramentos maiores. Para essa análise, um valor de p < 0,05 foi considerado estatisticamente significante. A terapia com enoxaparina e cirrose hepática como causadora de trombocitopenia estiveram associadas ao aumento do risco do endpoint composto (enoxaparina: hazard ratio (HR): 3,31; IC 95%: 1,54 a 7,13; p = 0,0023; cirrose hepática, HR: 1,04; 95% CI: 1,002 a 1,089; p = 0,0410). Por outro lado, a terapia com edoxabana mostrou-se significativamente associada à diminuição do risco do endpoint composto (HR: 0,071; 95% CI: 0,013 a 0,373; p = 0,0019). Com base nessa análise retrospectiva, o edoxaban em doses baixas seria uma ferramenta farmacológica segura e eficaz para a profilaxia de eventos cardioembólicos em pacientes com FA e trombocitopenia.