Edoxaban Group Research Articles

Efficacy and safety of long-term edoxaban treatment for low body weight cancer patients with isolated distal deep vein thrombosis: a post-hoc subgroup analysis of the ONCO DVT study

Abstract Background Low body weight is known to be a bleeding risk in the anticoagulation treatment. ONCO DVT study revealed that 12-month edoxaban treatment for cancer patients with isolated distal deep vein thrombosis (DVT) reduced a composite outcome of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death compared with 3-month edoxaban treatment. However, the efficacy and safety of long-term edoxaban treatment for cancer patients with low body weight is unclear. Purpose In this subgroup analysis, we assessed the efficacy and safety of 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT. Methods We conducted a post-hoc subgroup analysis of the ONCO DVT study in the low body weight patients. ONCO DVT study was a multicenter, open-label, adjudicator-blinded, randomized clinical trial. Cancer patients with isolated distal DVT were assigned to 12-month or 3-month edoxaban treatment. The primary endpoint was a composite outcome of a symptomatic recurrent VTE or VTE-related death at 12 months. The major secondary endpoint was major bleeding at 12 months. We enrolled patients who met low body weight defined in Japanese Version of High Bleeding Risk criteria (<55 kg for men, <50 kg for women) and evaluated the efficacy and safety of 12-month edoxaban treatment using logistic regression models and log-rank test. Results Among 601 patients in the intention-to-treat population of ONCO DVT study, 322 patients (53.6%) met low body weight: 151 patients were in 12-month edoxaban group and 171 patients were in 3-month edoxaban group. The body weight was similar between two group (47.1±5.2 kg in 12-month edoxaban group vs. 46.9±5.4 kg in 3-month edoxaban group; P=0.77). All of them used a lower dose edoxaban (30 mg once daily) following the dose reduction criteria. 12-month edoxaban group had lower rates of the primary endpoint compared with 3-month edoxaban group (2 patients (1.3%) vs. 10 patients (5.8%); Odds ratio 0.22 [95% CI, 0.05–1.00]; Log-rank P=0.036). There was no significant difference in the major secondary endpoint of major bleeding (12 patients (7.9%) in 12-month edoxaban group vs. 16 patients (9.4%) in 3-month edoxaban group; Odds ratio 0.83 [95% CI, 0.38–1.83]; Log-rank P=0.65). All clinically relevant bleeding events occurred in 22 patients (14.6%) in 12-month edoxaban group and in 27 patients (15.8%) in 3-month edoxaban group (Odds ratio 1.40 [0.90–2.19]; Log rank P=0.13), resulting in the comparable risk of bleeding in the 12-month edoxaban group. Conclusions Our study suggests that 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT prevents recurrent VTE or VTE-related death without increasing the risk of bleeding compared to 3-month edoxaban treatment.primary endpointsecondary endpoint

Randomized Comparison of Progression of Atherosclerotic Plaques and Calcification of Coronary Artery in Atrial Fibrillation Patients Treated With Edoxaban Versus Warfarin (The REPRESENT-AF trial)

Although the adverse effects of long-term use of vitamin K oral anticoagulant (OAC), warfarin, on the coronary vasculature are well-established, it remains unknown whether nonvitamin K oral anticoagulants play a role in the attenuation of plaque progression and coronary calcification. This study aimed to compare the changes in atherosclerotic plaques and calcification of the coronary arteries in patients with atrial fibrillation (AF) treated with edoxaban and warfarin. A total of 150 OAC-naïve patients with AF and atherosclerotic lesions on coronary computed tomography angiography (CCTA) were enrolled and randomly assigned to the edoxaban or warfarin treatment groups. All enrolled patients received rosuvastatin 10 mg and 119 patients completed the entire study protocol. A total of 12 months after the assigned OAC treatment, follow-up CCTA was performed and changes in plaque and calcium volumes of the coronary arteries were analyzed. The baseline characteristics of the 2 groups were well-balanced. The percentage of time in therapeutic range in the warfarin group was 61.1%. Compared with the baseline CCTA, there was a significant reduction in plaque volume after 12 months of OAC and rosuvastatin administration in both groups, and the extent of regression did not differ significantly between the groups. The increase in calcium volume was greater in the warfarin group than in the edoxaban group; however, the difference was not significant. In OAC-naïve patients with AF and atherosclerotic coronary lesions who were treated with moderate-intensity statin, edoxaban use did not have a positive effect on atherosclerotic plaques and coronary calcification compared with warfarin use over a 12-month follow-up period.

Prognosis of Patients With Ischemic Stroke With Prior Anticoagulant Therapy: Direct Oral Anticoagulants Versus Warfarin.

Direct oral anticoagulants (DOACs) have been the drug of choice for preventing ischemic stroke in patients with atrial fibrillation since 2014. In previous studies, the stroke risk while taking warfarin was 2 per 100 patient-years and 1.5% per year while taking DOACs. We hypothesized that even if ischemic stroke occurred during anticoagulation therapy with DOACs, the prognosis was likely to be better than that with warfarin. Data from 2002 to 2019, sourced from a nationwide claims database, were used to identify atrial fibrillation patients using International Classification of Diseases codes. Patients who experienced an ischemic stroke during anticoagulation were categorized by the drugs used (warfarin, dabigatran, apixaban, rivaroxaban, and edoxaban). The primary outcome was mortality within 3 months and 1 year after the ischemic stroke. Among the 9578 patients with ischemic stroke during anticoagulation, 3343 received warfarin, and 6235 received DOACs (965 dabigatran, 2320 apixaban, 1702 rivaroxaban, 1248 edoxaban). The DOACs group demonstrated lower risks of 3-month (adjusted hazard ratio [HR], 0.550, [95% CI, 0.473-0.639]; P<0.0001) and 1-year mortality (adjusted HR, 0.596 [95% CI, 0.536-0.663]; P<0.0001) than the warfarin group. Apixaban and edoxaban within the DOAC group exhibited particularly reduced 1-year mortality risk compared with other DOACs (P<0.0001). Our study confirmed that DOACs have a better prognosis than warfarin after ischemic stroke. The apixaban and edoxaban groups had a lower risk of death after ischemic stroke than the other DOAC groups.

Risk Factors of Ischemic Stroke in Patients With Atrial Fibrillation After Transcatheter Aortic Valve Implantation from the Randomized ENVISAGE-TAVI AF Trial

In patients with prevalent or incident atrial fibrillation (AF) after successful transcatheter aortic valve implantation (TAVI) enrolled in the EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation - in Atrial Fibrillation (ENVISAGE-TAVI AF) trial, the incidence of ischemic stroke (IS) and any stroke was numerically less in the edoxaban group than in the vitamin K antagonist (VKA) group. The present study aimed to identify risk factors associated with IS in an on-treatment subanalysis in patients from ENVISAGE-TAVI AF who received ≥1 dose of edoxaban or VKA. Baseline patient characteristics were compared in patients with and those without IS. Numerical variables were compared using a 1-way analysis of variance; categorical variables were compared using Fisher's exact test. Stepwise Cox regression determined patient characteristics associated with the first IS event. Of 1,377 patients, 41 (3.0%) experienced an IS, and 1,336 (97.0%) did not; baseline demographics and clinical characteristics were well balanced between groups. Most ISs occurred within 180 days of TAVI for edoxaban (57.9%) and VKA (68.2%). The rate of IS was 2.0/100 person-years for edoxaban versus 2.7/100 person-years for VKA. Independently associated with IS were history of systemic embolic events (hazard ratio 2.96, 95% confidence interval 1.26 to 7.00, p = 0.01) and pre-TAVI use of VKAs (hazard ratio 2.17, 95% confidence interval 1.12 to 4.20, p = 0.02). In conclusion, although the overall incidence of IS was small for patients with AF on edoxaban or VKA after successful TAVI, patients with a history of systemic embolic events or pre-TAVI use of VKAs may be at greater risk of IS after TAVI.

The Effectiveness and Safety of Rivaroxaban and Edoxaban in the Treatment of Lower Extremity Deep Vein Thrombosis

IntroductionDeep vein thrombosis (DVT) is a medical condition characterized by forming a blood clot, or thrombus, in one of the deep veins, typically in the legs. It is a type of venous thromboembolism (VTE), which refers to the formation of blood clots in the veins. It is caused by Virchow's triad (stasis, hypercoagulation, and endothelial injury). ObjectiveOur main objective is to explore the effectiveness and safety of Rivaroxaban and Edoxaban in treating lower extremity deep vein thrombosis. MethodsWe conducted a retrospective study involving 406 patients subjected to DVT treatment using DOACs (Edoxaban and Rivaroxaban) at our hospital. We recruited adult patients (18 years and above) diagnosed with lower extremity deep vein thrombosis and received treatment with either Rivaroxaban or Edoxaban as the primary anticoagulant therapy for DVT. We excluded patients who received treatment with other anticoagulant medications (warfarin heparin) as the primary therapy for DVT. ResultsThe groups showed statistically significant differences in red blood cell count and haemoglobin levels, with the Edoxaban group having high values. However, the two groups observed no statistically significant differences in creatinine clearance, white blood cell count, platelet count, C-reactive protein, and D-dimer levels. The difference in the incidence of PE between the two groups was statistically significant (P value < 0.001). The Edoxaban group had fewer PE patients than the rivaroxaban group. The reduction in recurrent thrombosis was significantly higher in the rivaroxaban group compared to the Edoxaban group. There were no significant differences in the major bleeding at various sites across the two treatment groups (p > 0.05). ConclusionRivaroxaban's pharmacokinetic profile includes rapid absorption and a relatively short half-life. It means that once administered, Rivaroxaban quickly reaches its peak concentration in the blood and is subsequently eliminated from the body within a relatively short period. Edoxaban's pharmacokinetic profile may include slower absorption and a longer half-life than Rivaroxaban. It can result in a slower rate of achieving peak concentration and a more prolonged presence in the bloodstream. These results emphasize the need for careful consideration of anticoagulant therapy in patients with underlying cancer and underscore the importance of managing risks while providing adequate anticoagulation to prevent thrombotic events.

Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.

Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups. The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group. The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

One-year effectiveness and safety outcomes of edoxaban treatment in Chinese patients with atrial fibrillation: First snapshot of more than 4,800 patients from the ETNA-AF-China study

Abstract Background Direct oral anticoagulants (DOACs) have become the first-line therapy for ischaemic stroke prevention in atrial fibrillation (AF) patients. Data on the effectiveness and safety of single DOAC in large Chinese populations are scarce. Purpose We firstly present the one-year outcome data of edoxaban treatment in 5001 Chinese AF patients. Methods This is a multi-centre, prospective, observational study, ETNA-AF-China, conducted in 89 centres from four economic regions in Mainland of China with a follow-up of two years. Primary endpoint of safety [bleeding events including intracranial hemorrhage (ICH), all-cause and cardiovascular (CV) mortality] and efficacy endpoints [stroke, systemic embolic events (SEE), transient ischemic attack (TIA)] were adjudicated. Annualised event rates and Kaplan­Meier (KM) survival curves are given. Results A total of 4822 patients (57.1% male) using edoxaban (60 mg OD: n=2614, 30 mg OD: n=2208) who completed one-year follow-up were included in the full analysis set. The mean (SD) age of the overall patient population was 70.3 (9.5) years, CHA2DS2-VASc and HAS-BLED scores were 2.9 (1.4), 1.7 (1.0), with creatinine clearance (CrCl) of 71.2 (27.7) mL/min. Patients receiving 30 mg OD edoxaban at baseline were older (73.4 vs 67.7 years), with higher CHA2DS2-VASc score (3.3 vs 2.6), larger percentage of frail (9.9% vs 3.4%), and higher renal impairment (defined as CrCl ≤80 mL/min, 70.3% vs 42.9%). Annualised rates for all-cause and cardiovascular death in the overall population were very low with 2.22%/year and 0.41%/year, respectively. (Figure 1) The death rates were nearly three times lower in those receiving standard dose (60 mg) than reduction dose (30 mg) of edoxaban. Annualised event rates for all stroke/SEE (1.03%/year) and ischemic stroke (0.60%/year) were similar between two dose groups. Overall, annualised rates for major bleeding (1.03%/year), ICH (0.18%/year), major gastrointestinal (GI) bleeding (0.48%/year) events were relatively low, and those on 60 mg dose experienced less above bleeding events. Cumulative survival analysis demonstrated a slow increase in time-to-first event curve of all-cause death; and from baseline to 1-year follow-up, significant lower events of all-cause death (log-rank p&amp;lt;0.001), major bleeding (p=0.002) in 60 mg vs 30 mg edoxaban groups. (Figure 2). Conclusion Low incidences of major bleeding, notably ICH, major GI bleeding, and CV death were observed in unselected 4822 patients with AF during 1-year of edoxaban treatment. These findings confirm the effectiveness and safety of routine edoxaban use in China, consistent with other countries, and reinforce the results of the ENGAGE AF-TIMI 48 trial.Figure 1Figure 2

Effectiveness of edoxaban in portal vein thrombosis associated with liver cirrhosis

Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child–Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Edoxaban for the treatment of hypercoagulability and cerebral thromboembolism associated with cancer: A randomized clinical trial of biomarker targets.

This study aimed compare efficacy of edoxaban and enoxaparin upon biomarkers of hypercoagulability in patients with cancer-related embolic stroke of undetermined source (ESUS). In this open-label, randomized, pilot trial, patients with cancer-related ESUS within 30 days of diagnosis were randomly assigned (1:1) to receive edoxaban (60 mg once daily) or enoxaparin (1 mg/kg twice daily) for 90 days. The primary endpoint was interval change of serum D-dimer level between days 0 and 7. The secondary endpoints were microembolic signals detected by transcranial Doppler at 7 and 90 days, the modified Rankin scale score, and stroke recurrence during 90 days. Safety outcomes included major bleeding and all-cause death at 90 days. Of 303 patients with ischemic stroke and cancer, 40 fully met enrollment criteria and were randomized. Baseline D-dimer levels were numerically higher in the edoxaban group (22.9 ± 15.9 μg/mL vs 16.9 ± 16.9 μg/mL). D-dimer level change (%) between days 0 and 7 was similar in the two groups (53.2 ± 25.7 vs 52.2 ± 52.0; P = 0.11). Microembolic signals were detected in 41.1% and 43.8% at baseline, 41.2% and 42.9% at day 7, and 25.0% and 28.6% at day 90 in the edoxaban and enoxaparin groups, respectively. Non-significantly higher major bleeding (35.0% vs 10.0%, P = 0.06) and 90-day mortality (40.0% vs 25.0%, P = 0.31) were noted in the edoxaban group. Edoxaban and enoxaparin were comparable with respect to the biomarkers of hypercoagulability and cerebral thromboembolism. Larger trials are warranted to compare effects of edoxaban and enoxaparin upon recurrent stroke and major bleeding in patients with cancer-related ESUS. clinicaltrials.gov Identifier: NCT03570281 (https://clinicaltrials.gov/ct2/show/NCT03570281).

Clinical Characteristics and Outcomes of Patients With Venous Thromboembolism Receiving Edoxaban in the Real World.

The effectiveness and safety of edoxaban for venous thromboembolism (VTE) in unselected real-world patients have not been fully evaluated. In the Japanese nationwide administrative database, we identified 6,262 VTE patients in whom edoxaban was initiated; these patients were divided into 3 groups based on their index doses: 15 mg/day (n=235), 30 mg/day (n=4,532), and 60 mg/day (n=1,495). We evaluated patient characteristics, recurrent VTEs, and a composite endpoint of intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding. Patient characteristics among the 15-, 30-, and 60-mg edoxaban groups varied widely regarding several aspects, including age (mean 81.0, 76.2, and 65.0 years, respectively) and body weight (mean 49.5, 51.8, and 70.3 kg, respectively). At 180 days, the cumulative incidence of recurrent VTEs in the 15-, 30-, and 60-mg edoxaban groups was 4.4%, 2.6%, and 1.8%, respectively, whereas that of ICH or GI bleeding was 7.3%, 5.4%, and 3.3%, respectively. Subgroup analyses showed that the cumulative incidence of ICH or GI bleeding in patients in the 15-mg edoxaban group was 3.6% for patients aged ≥80 years, 8.4% for those with a body weight <60 kg, and 31.3% for those with renal dysfunction. Only a minority of patients with VTEs received a super low dose (15 mg) of edoxaban, and these patients may be at higher risk of bleeding as well as VTE recurrence.

Low- or standard-dose edoxaban versus antiplatelet therapy for leaflet thrombus and cerebral thromboembolism after TAVR: A prespecified analysis of randomized ADAPT-TAVR trial

The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P = .03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P = .58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction.

Baseline Characteristics and 3-Year Outcome of Nonvalvular Atrial Fibrillation Patients Treated with the Four Direct Oral Anticoagulants (DOACs)

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p=0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p=0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p=0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p=0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed.

Abstract TMP97: Comparison Of Severity And Mortality Among Patients With Atrial Fibrillation Who Developed Ischemic Stroke During Anticoagulation With Warfarin And Non-vitamin K Antagonist Oral Anticoagulants

Introduction: Non-vitamin K antagonist oral anticoagulant (NOAC) has been the drug of choice for preventing ischemic stroke in patients with atrial fibrillation since 2014. In previous studies, the stroke risk while taking warfarin was known to be 2 per 100 patient-years and 1.5% per year while taking NOACs. We hypothesized that even if ischemic stroke occurred during anticoagulation therapy with NOACs, the prognosis was likely to be better than that of warfarin. Methods: We obtained data from the nationwide claim database from 2009 to 2019. Patients with atrial fibrillation were identified using the International Classification of Disease Codes. After the diagnosis of atrial fibrillation, patients who developed ischemic stroke during anticoagulation were extracted. The severity of ischemic stroke in the patients was evaluated by the stroke severity index (SSI) calculated by the combination of claim codes. Patients who died within 3-months and within 1-year after ischemic stroke were identified. The patients were divided according to the drug of anticoagulation (warfarin, dabigatran, apixaban, rivaroxaban, edoxaban). Results: A total of 206,848 patients who were newly diagnosed with atrial fibrillation and started anticoagulation therapy were analyzed. Among them, 10,658 patients developed ischemic stroke during follow-up. The anticoagulants administered to these patients were warfarin in 4,423, dabigatran in 965, apixaban in 2,320, rivaroxaban in 1,702, and edoxaban in 1,248. The SSI was highest in the warfarin group (11.43±3.85), and lower in the edoxaban group (8.93±4.03). The order of mortality at 3-months after ischemic stroke was warfarin (17.88%), rivaroxaban (12.34%), dabigatran (9.53%), apixaban (8.28%), and edoxaban group (8.25%). The 1-year mortality rate also showed the same trend. Among NOACs, apixaban had the lowest hazard ratio (HR), HR for 3-months mortality was 0.431 (95% CI 0.367-0.505, p&lt;0.0001), and HR for 1-year mortality was 0.455 (95% CI 0.407-0.510, p&lt;0.0001). Conclusions: In our study, we confirmed that NOAC could lower the risk of death from ischemic stroke than warfarin in patients with atrial fibrillation. Except for rivaroxaban, there was no difference in mortality in the other three NOAC groups.

A Comparison among Nonvitamin K Antagonist Oral Anticoagulants in Asian Patients with Venous Thromboembolism: A Multi-Institutional Study

The comparison of clinical effectiveness and safety across different nonvitamin K antagonist direct oral anticoagulants (DOACs) in Asian patients with venous thromboembolism (VTE) remains unclear. Therefore, we assessed the real-world benefits of different DOACs in these patients. A cohort of 1480 patients with VTE were identified from the Chang Gung Research Database between 1 January 2012, and 31 December 2019. The composite outcomes of recurrent VTE and major bleeding were evaluated for four DOACs. The composite outcomes of recurrent VTE and major bleeding occurred in 9.06%, 9.80%, 8.61%, and 10.86% of the apixaban, dabigatran, edoxaban, and rivaroxaban groups, respectively, within 12 months of treatment initiation. The risk of the composite outcomes was similar in the rivaroxaban group and the apixaban, dabigatran, and edoxaban groups, with a subdistribution hazard ratio (SHR) of 0.80 (95% CI, 0.49-1.29), 0.81 (95% CI, 0.34-1.95), and 0.76 (95% CI, 0.42-1.39), respectively. No significant differences in the rates of recurrent VTE or major bleeding were observed between the rivaroxaban and other DOAC groups at the 12-month follow-up. According to real-world practice in Asian patients with VTE, the DOAC type was not associated with the differences in the risk of recurrent VTE or major bleeding within 12 months of treatment initiation.

Outcomes and Safety of Very-Low-Dose Edoxaban in Frail Patients With Atrial Fibrillation in the ELDERCARE-AF Randomized Clinical Trial

The prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment. To compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. This is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022. Edoxaban (15 mg) once daily or placebo. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding. A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups. Regardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

Short-term efficacy and safety of edoxaban for venous thromboembolism after total hip or knee arthroplasty: a systematic review and meta-analysis.

Previous preliminary clinical trials have confirmed that edoxaban can be efficacious for venous thromboembolism (VTE). This meta-analysis was considered to evaluate edoxaban's short-term efficacy and safety for venous thromboembolism after arthroplasty. A comprehensive search was performed in these databases: PubMed, MEDLINE, Web of Science, and EMBASE on March 2022. All eligible trials should be randomized controlled trials (RCTs) when evaluating short-term efficacy and safety outcomes of edoxaban for VTE after total hip or knee arthroplasty. Nine RCTs with 4274 patients were involved in this meta-analysis. Edoxaban in the VTE group prevented the incidence of VTE and indicated valuable clinical efficacy. The incidence of adverse events (AEs) and adverse drug reactions (ADRs) in the edoxaban group was decreased than that in other groups. Edoxaban increased the incidence of all bleeding events. However, in the edoxaban group and other groups, there was no statistical difference between major bleeding events and clinically relevant non-major or minor bleeding events. Edoxaban subgroups included edoxaban 15 mg, edoxaban 30 mg and edoxaban 60 mg prevented the incidence of VTE. Edoxaban 30 mg and 60 mg group increased the risk of all bleeding events. Edoxaban 30 mg can increase the incidence of major bleeding events. There was no difference in clinically relevant non-major or minor bleeding events. Edoxaban 30 mg can decrease the incidence of AEs. Edoxaban was an efficacious and safe option to prevent and treat VTE in patients undergoing arthroplasty. However, we need further trials to explore edoxaban's long-term efficacy and safety.

Beneficial Effect of Edoxaban on Preventing Atrial Fibrillation and Coagulation by Reducing Inflammation via HBG1/HBD Biomarkers.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The effectiveness and mechanism of edoxaban in preventing stroke after atrial fibrillation remain unclear. Methods: The expressions of HBG1 and HBD in red blood cells were tested in AF. Sixty C57B/6J mice were randomly divided into the following groups: the control (CON) group, atrial fibrillation (AF) group, AF + edoxaban group, and AF + rivaroxaban group. H&E staining assay and reticular fiber staining were performed. Myocardial fibrosis was evaluated by the Masson staining assay, Sirius red staining assay, and immunohistochemical assay for the expressions of α-SMA and COL1A1. ELISA and RT-PCR assay were performed for the detection of inflammatory parameters (TNF-α, IL-1β, IL-6, and IL-10). Blood lipids were detected by using the Beckman automatic biochemical analyzer. Furthermore, four items of coagulation were detected, and molecular docking among HBG1, HBD, and MASP1 (Xa) was performed by PyMOL 2.1 software. The BP neural network model, cubic spline interpolation, and support vector machine model were constructed to predict prothrombin time based on HBG1 and HBD expressions. COIP assay was performed to construct the interaction between HBG1 and HBD. The functional enrichment analysis was performed by DAVID and Metascape tools. Results: The expressions of HBG1 and HBD in red blood cells of the patients with atrial fibrillation were decreased. The results showed a lower level of hemoglobin in red blood cells with HBG1-siRNA and HBG1-siRNA. Compared with the AF group, the collagen fiber percentage in the AF + edoxaban group was decreased (p < 0.05). After using edoxaban, the expressions of TNF-α, IL-1β, IL-6, and IL-10 were significantly decreased (p < 0.05). The LDL-C, TC, and TG levels were downregulated in the AF + edoxaban group. The PT and APTT levels in the AF + edoxaban group were more increasing than in the AF mice (p < 0.05). Compared with the AF group, the expressions of HBG1 and HBD were downregulated in the AF + edoxaban group (p < 0.05). HBG1 protein matched well with HBD and MASP1(Xa) protein surfaces. There exists a significant interaction between HBG1, HBD, and PT via the BP neural network and support vector machine. Enrichment analysis showed that HBG1 and HBD were mainly enriched in blood coagulation. Conclusion: Edoxaban could prevent atrial fibrillation and coagulation by reducing inflammation, lipids, and fibrosis via HBG1/HBD biomarkers effectively, and the effect was superior to that of rivaroxaban.

The impact on renal function after long-term use of anticoagulants in atrial fibrillation patients

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): This study was supported by the research program of the Chang Gung Memorial Hospital. Objective Long-term oral anticoagulant should be considered or recommended in patients with atrial fibrillation (AF) and CHA2DS2VASc score ≥1 for stroke prevention. Warfarin and different direct oral anticoagulants (DOACs) are metabolized differently by the kidney. The impact on renal function after long-term use of anticoagulants in the patients with AF remains unclear. This study aimed to compare DOACs and warfarin’s impact on the decline in renal function from a large cohort with AF. Methods This study included patients with nonvalvular AF from 2000 to 2018, mainly through the medical history (ICD code) of the Chang Gung Research Database. Baseline estimated glomerular filtration rate (eGFR), follow-up eGFR and the change in eGFR between 2-year eGFR and baseline eGFR were compared between different DOACs and warfarin after propensity score matching. The primary study endpoint was acute kidney injury (AKI). Results 3657 patients were enrolled in this study and the mean observation time was 3.3 ± 0.9 years. During the observation period, there was a significantly higher incidence of AKI during follow-up in the warfarin group than in the different DOAC groups before and after propensity score matching (before: warfarin vs. DOAC: 9.2% vs. 5.2%, p&amp;lt;0.001; after: warfarin vs. DOAC: 8.9% vs. 4.4%, p&amp;lt;0.001). There was no difference in the incidence of AKI between dabigatran group and anti-factor Xa inhibitor group after propensity score matching. The incidence of AKI was similar among rivaroxaban, apixaban and edoxaban groups after propensity score matching. The change in eGFR between 2-year eGFR and baseline eGFR did not differ between the warfarin and DOAC groups after propensity score matching (warfarin vs. DOAC: -1.27 ± 20.32 vs. -1.94 ± 17.24 mL/min/1.73 m2, p=0.461). Conclusions During the mean observation time of 3.3 ± 0.9 years, warfarin was associated with a higher incidence of AKI compared with DOACs. The decline in renal function did not differ among warfarin and different DOAC groups.

Edoxaban Versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism After TAVR: The ADAPT-TAVR Randomized Clinical Trial.

It is unknown whether the direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic valve replacement. In addition, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear. We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (aspirin plus clopidogrel) in patients who had undergone successful transcatheter aortic valve replacement and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on 4-dimensional computed tomography at 6 months. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging and the serial changes of neurological and neurocognitive function between 6 months and immediately after transcatheter aortic valve replacement. A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group compared with the dual antiplatelet therapy group (9.8% versus 18.4%; absolute difference, -8.5% [95% CI, -17.8% to 0.8%]; P=0.076). The percentage of patients with new cerebral lesions on brain magnetic resonance imaging (edoxaban versus dual antiplatelet therapy, 25.0% versus 20.2%; difference, 4.8%; 95% CI, -6.4% to 16.0%) and median total new lesion number and volume were not different between the 2 groups. In addition, the percentages of patients with worsening of neurological and neurocognitive function were not different between the groups. The incidence of any or major bleeding events was not different between the 2 groups. We found no significant association between the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function. In patients without an indication for long-term anticoagulation after successful transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effects on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the 2 groups. Because the study was underpowered, the results should be considered hypothesis generating, highlighting the need for further research. URL: https://www. gov. Unique identifier: NCT03284827.

The effect of contrast agents on the anticoagulant properties of oral factor Xa inhibitors.

Contrast agents may affect the anticoagulant properties of novel oral anticoagulants. To evaluate the effect of iohexol as a contrast agent on the anticoagulant activity of oral factor Xa inhibitors. The study included 65 individuals who underwent contrast computed tomography(CT). Group 1 comprised 20 patients using rivaroxaban, Group 2, 20 patients using apixaban, and Group 3, 20 patients using edoxaban. Group 4 was the control group of five healthy volunteers. Iohexol (60 mL) was used as a contrast agent. Blood samples of 2 mL were withdrawn into two tubes at 4 h after the drug dose and 1 h after the contrast CT (CT was performed 3 h after the drug was taken) from all the patients, and for the control group, at any time before and 1 h after contrast CT. The anticoagulant properties of rivaroxaban, apixaban, and edoxaban were evaluated using anti-factor Xa levels. The anti-factor Xa level was increased after using the contrast agent in the rivaroxaban group (0.66 ± 0.32 U/mL vs. 0.67 ± 0.32 U/mL; P = 0.01) and the edoxaban group (0.74 ± 0.35 U/mL vs. 0.76 ± 0.36 U/mL; P = 0.006). No significant difference was observed in the apixaban group (0.66 ± 0.33 U/mL vs. 0.66 ± 0.32 U/mL; P = 0.21) and control group (0.02 ± 0.01 U/mL vs. 0.03 ± 0.01 U/mL; P = 0.33). The anticoagulant properties of rivaroxaban and edoxaban tended to increase significantly, but there was no statistically significant difference in the anticoagulant properties of apixaban after the administration of contrast agent. To determine whether the small laboratory difference has a clinical effect, there is a need for larger clinical trials (NCT04611386).