Edoxaban

To evaluate the effect of age on “hemorrhagic reactions,” the reports were stratified into the following age groups: 0-59 years and more than 60 years. According to the definition of the World Health Organization (WHO) of the United Nations, elderly people are those who are aged 65 years or more.
Using established pharmacovigilance indices 23 (link), we evaluated the ROR to establish the effects of DOACs on “hemorrhagic reactions.” “Cases” were defined as patients who reported “hemorrhagic reactions,” while “non-cases” consisted of patients associated with all other reports. The ROR is the ratio of the odds of reporting ARs versus all other reactions associated with DOACs compared with the reporting odds for all other drugs present in the database. To compare the “cases” and “non-cases,” we calculated the RORs as (a:c) / (b:d). The RORs were expressed as point estimates with a 95% confidence interval (CI). The signal was considered positive if the lower limit of 95% CI was > 1 and the reported number was ≥ 2 36 (link).
The use of ROR allows adjustment using multiple logistic regression analysis and provides the advantage of controlling covariates 37 (link),38 (link). In this analysis, the results were refined by dedicated correction to detect confounding factors that may be present in the database. We calculated the adjusted ROR to control the covariates using the multiple logistic regression analysis. The report was stratified according to age as follows: 0-59- and ≥ 60-year-old group. To construct a multiple logistic model that coded report year, sex, stratified age group, and drug, the following multiple logistic model was used for analysis:
(Y = reporting year, S = sex, A = stratified age group, and D = drug (apixaban, rivaroxaban, edoxaban, and dabigatran)).
The adjusted ROR was calculated using the 0-59-year-old group as the control group. The effectiveness of explanatory variables was evaluated using a stepwise method with a significance level of 0.05 (forward, and backward) 27 (link),28 (link). Using the likelihood ratio test, the influence of explanatory variables was evaluated. As the difference of -2log likelihood follows chi-square distribution with one degree of freedom, the results with p ≤ 0.05 were considered statistically significant. Data analysis was performed using JMP software version 12.0 (SAS Institute Inc., Cary, NC, USA).
Time-to-onset duration was calculated from the time of a patient's first prescription to the occurrence of hemorrhagic reactions. The records with completed AR occurrence and prescription start date were used for the time-to-onset analysis. It was necessary to consider right truncation when evaluating the time-to-onset of ARs. We determined an analysis period of 365 days after the start of administration. The median duration, quartiles, and Weibull shape parameters (WSPs) were used to evaluate the time-to-onset data. The scale parameter α of Weibull distribution determines the scale of the distribution function. A larger scale value (α) stretches the distribution, whereas a smaller scale value (α) shrinks data distribution. The WSP β of Weibull distribution determines the shape of distribution function. Larger and smaller shape values produce left- and right-skewed curves, respectively. The shape parameter β of Weibull distribution was used to indicate the level of hazard over time without a reference population. When β is equal to 1, the hazard is estimated to be constant over time. If β is greater than 1 and 95% CI of β excluded the value 1, the hazard was considered to increase with time 30 (link),31 (link),39 (link). The time-to-onset analysis was performed using JMP software version 12.0 (SAS Institute Inc., Cary, NC, USA).

The Edoxaban Treatment in Routine Clinical Practice for Patients With Non Valvular Atrial Fibrillation (ETNA-AF-Europe) was designed as part of the risk management plan of edoxaban in order to assess the risks and benefits of the drug in routine care in unselected European patients with AF. ETNA-AF-Europe is part of the global ETNA initiative, which is composed of separate, non-interventional prospective ETNA-AF registries in Europe, East Asia, Brazil and Japan. The final ETNA-AF-Europe protocol was developed based on discussions with, and finally approved by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency. The primary objective of ETNA-AF Europe is to assess the safety of edoxaban by evaluating bleeding events, including intracranial haemorrhage; drug related adverse events, such as liver adverse events; and cardiovascular (CV) as well as all-cause mortality in routine care patients with AF treated with edoxaban up to 4 years, with regard to onset (relative to treatment with edoxaban) of the event, duration, severity and outcomes.
Details of the design of ETNA-AF-Europe including the statistical rationale have been published [21 (link)]. In short, ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study (Clinicaltrials.gov: NCT02944019) conducted in 825 sites (with at least one patient enrolled) in 10 European countries. All patients with non-valvular AF treated with edoxaban according to the summary of product characteristics (SmPC), could participate in the study with prior provision of written informed consent and no simultaneous participation in an interventional trial. No explicit exclusion criteria were defined. Over a period of 3 years, ETNA-AF-Europe enrolled 13,980 patients with AF confirmed within the last 12 months before enrolment. AF had to be confirmed by the investigators by electrical tracing (e.g., ECG, Holter monitoring, pacemaker or other implantable device). Detailed information on AF history and diagnosis, and on previous AF-related therapies was collected, including former anticoagulant treatment with VKAs, NOACs or heparins; previous or current antiplatelet drugs, antiarrhythmic and rate-control drugs and other therapies. The CHA₂DS₂-VASc and HAS-BLED scores were both reported by the investigators as well as calculated based on the baseline clinical characteristics of the patients. For the analysis here reported, calculated scores are used. Specific subgroup analyses are planned by edoxaban dose, patient age and country. Figure 1 provides an overview of the patient disposition in ETNA-AF-Europe. Of 13,980 enrolled patients, 13,638 were included in the baseline analysis set. Patients are to be followed up once a year for a total of 4 years.Fig. 1

Overview of the ETNA-AF-Europe registry. *Some patients fulfilled more than one exclusion criteria

The patient baseline characteristics from ENGAGE AF-TIMI 48 are used as an external comparator to the baseline data collected in ETNA-AF-Europe to better understand how the usage of edoxaban in routine clinical practice reflects on the trial setting in which edoxaban was tested. The ENGAGE AF-TIMI 48 cohort used for this purpose includes patients from only those European countries that are also participating in the ETNA-AF-Europe registry.

Edoxaban (MedChem Express, Monmouth Junction, NJ) was used for the in vitro study. SECs were allocated to two H/R groups and then cultured (n = 5 per group). The Edoxaban and vehicle groups were pretreated with 1 μM of Edoxaban in endothelial cell medium and vehicle (0.1% DMSO equivalent to that used to dissolve Edoxaban) for 1 hour. Following the pretreatment, the SECs in both groups were exposed to 90-minute hypoxia and 4 hours reoxygenation using an AnaeroPack jar system. A dose of 1 μM had a significant effect (p = 0.008), we decided to use 1 μM of Edoxaban (S2 Fig).

A potent and highly selective FXa inhibitor, edoxaban tosylate monohydrate (Ex) (MedChem Express, Monmouth Junction, NJ), an orally active prodrug of edoxaban, was administered to mice through oral gavage. Ex was dissolved in 0.5 w/v% methylcelluloses 400 solution (0.5% MC; FUJIFILM Wako Pure Chemical Industries, Ltd., Osaka, Japan) [29 (link)]. In our model, Ex was administered orally to mice because it must undergo chemical conversion by metabolic processes through oral intake for activation. Previously, sufficient anticoagulant effects on mice were observed at 60 minutes after oral administration of 10 mg/kg Ex [30 (link)], and renal protective effects for diabetic nephropathy mice model were observed with 50 mg/kg/day [31 (link),32 (link)]. Following these reports, to examine the effect of Ex treatment in our mice hepatic IRI model, based on serum alanine transaminase (ALT) levels at 4 hours after reperfusion, we set the doses of Ex as 3, 10, 30, and 50 mg/kg, and administered them orally 60 minutes before ischemia (n = 5 per group). A dose of 50 mg/kg had a significant effect: 1,008 [800–1,474] IU/L in controls (Vehicle) vs. 89 [35–242] IU/L in the edoxaban group (p = 0.05) (S1 Fig). Accordingly, we decided to administer 50 mg/kg of Ex.

The eligibility criteria for the ELDERCARE‐AF trial included the following: age ≥80 years; CHADS₂ risk score (congestive heart failure, hypertension, age ≥75 years, diabetes, and history of stroke) ≥2.
⁴ (link),
⁸ (link) All patients were of Japanese ethnicity and had to be considered ineligible for OACs such as warfarin, apixaban, dabigatran, edoxaban, or rivaroxaban at the recommended therapeutic strength or the approved doses due to at least 1 of the following reasons: low creatinine clearance (15–30 mL/min); history of bleeding from a critical area/organ or gastrointestinal bleeding; low body weight (≤45 kg); ongoing use of nonsteroidal anti‐inflammatory drugs; and current use of an antiplatelet medication. Excluded from the study were patients with moderate–severe mitral stenosis and/or mechanical heart valves.
For this subanalysis, 45 kg was used as a cutoff to stratify patients into 2 body weight groups (ie, ≤45 and >45 kg). This cutoff was defined based on the design of the main ELDERCARE‐AF trial,
⁴ (link),
⁸ (link) in which a body weight of ≤45 kg was specified as one of the ineligibility criteria for OAC therapy at the recommended therapeutic strength or the approved doses. As a result of this enrollment criterion, many patients included in the overall ELDERCARE‐AF population had a body weight of 40 to 45 kg, thereby ensuring sufficient patient numbers in each body weight subgroup for comparative analysis. In addition, an exploratory analysis was performed with all patients divided into 4 subgroups based on quartiles of body weight: >57.9 kg, >49.0 to ≤57.9 kg, >42.0 to ≤49.0 kg, and ≤42.0 kg.