Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

Abstract Background The safety and effectiveness of edoxaban in real‐world clinical settings have not yet been elucidated thoroughly among Japanese patients with nonvalvular atrial fibrillation (NVAF). We report the one‐year interim results of ETNA‐AF‐Japan (Edoxaban Treatment in routiNe clinical prActice in patients with nonvalvular Atrial Fibrillation: UMIN000017011), an ongoing two‐year study. Methods ETNA‐AF‐Japan is a prospective, real‐world multicenter observational study that analyzes the long‐term safety and effectiveness of edoxaban. Physicians recorded clinical characteristics, bleeding events, and clinical events of ischemic stroke and systemic embolism, among others. Results In total, 11 569 patients with NVAF were enrolled. The demographic and clinical characteristics of the patients in the safety analysis set (n = 11 107) were a mean age of 74.2 ± 10.0 years; female sex, 40.6%; age ≥75 years, 52.4%; body weight ≤60 kg, 54.3%; creatinine clearance ≤50 mL/min, 31.2%; mean CHADS2 score of 2.2 ± 1.3. The mean treatment period was 311.2 days (median; 366.0 days), and ~80% of patients continued edoxaban treatment. In the safety analysis, the incidence of all bleeding events was 6.32% [95% CI: 5.87, 6.79] (n = 702), and for major bleeding, it was 1.08% [0.90, 1.29] (n = 120). In the effectiveness analysis set (n = 11 059), the incidence of ischemic stroke (excluding TIA) or systemic embolism was 1.10% [0.92, 1.32] (n = 122). Conclusions At one‐year follow‐up, the results showed no major concerns about the safety and effectiveness of edoxaban in Japanese patients with NVAF in a real‐world clinical setting.


| INTRODUC TI ON
In patients with nonvalvular atrial fibrillation (NVAF), treatment with a direct oral anticoagulant (DOAC) [1][2][3][4] for ischemic stroke prevention is now preferred over warfarin and especially considered for use in patients who are planning to start anticoagulant therapy as described in the "2013 Guidelines for Pharmacotherapy of Atrial Fibrillation" (JCS 2013) of the Japanese Circulation Society 5,6 and the 2018 European Heart Rhythm Association Practical Guide. 7 However, the guides have pointed out that patients with atrial fibrillation (AF) typically have concomitant diseases and other risk factors, and their long-term, day-to-day experience with the treatment warrants further investigation. A study of the long-term use of a DOAC in a large sample-size (≥10 000 patients) that analyzes the reduction in risk of ischemic stroke and systemic embolism and the occurrence of bleeding episodes would help physicians understand the most appropriate way to treat patients, particularly elderly patients. This is critical in Japan where ≥25% of the population is ≥65 years old (2015 census), and those with AF are a little over three-quarters of a million. 8,9 Edoxaban is a once-daily DOAC that directly and reversibly inhibits factor Xa and is indicated for long-term use in patients with NVAF to prevent ischemic stroke and systemic embolism. [10][11][12][13] Edoxaban is available in two formulations: tablet and orally disintegrating (OD). Swallowing is a concern for elderly patients, and so the OD formulation is particularly useful because it helps them take the drug daily and consistently in the long-term. Edoxaban has two more indications: treatment and prevention of recurrence of venous thromboembolism, and prevention of postoperative venous thromboembolism after lower extremity orthopedic surgery.
The efficacy and safety of edoxaban were confirmed in phase-3 ENGAGE AF-TIMI-48; 1 because it was a pivotal confirmatory study and designed as a randomized controlled trial (RCT), the patient population had strict inclusion and exclusion criteria. Since these studies do not include all patients who would potentially benefit from taking the drug, it is necessary to investigate the safety and effectiveness of edoxaban in a real-world clinical setting. ETNA-AF-Japan (UMIN000017011) was initiated to collect such data over a two-year period.
We have published three-month interim analysis results in September 2018 14 that reported on patient demographics, clinical characteristics, and dosing status. Here, we report on the one-year interim analysis of data that also includes safety and effectiveness analyses of edoxaban. Furthermore, we analyzed the safety and effectiveness of treatment in patients with a specific background, such as those ≥75 years old, including patients whose body weight is ≤60 kg and who have other factors.

| Study design
ETNA-AF-Japan is a real-world, prospective, multicenter observational study that aims to collect the baseline and clinical characteristics of Japanese patients with NVAF and analyze the safety and effectiveness of edoxaban in these patients. This postmarketing surveillance (PMS) was conducted according to the "Good Post-marketing Study Practice of the Ministry of Health, Labor, and Welfare of Japan." Detailed methods of this study were published in the three-month report. 14

| Patient population
Eligible patients were adults with NVAF who were to receive edoxaban for the first time to prevent ischemic stroke and systemic embolism. Further requirements for enrollment were the ability to start treatment during the enrollment period, availability for long-term follow-up, and agreement to provide written informed consent to participate at the time of registration.

| Starting daily dose and administration
The recommended daily oral dose, as described in the package insert (PI) in Japan, was 60 mg for adult patients weighing >60 kg and 30 mg for those weighing ≤60. 11 The 30 mg dose was also recommended for patients with one or more of the following: renal dysfunction (creatinine clearance, CLcr ≤50 mL/min), and concomitant use of the following P-glycoprotein (P-gp) inhibitors: quinidine, verapamil, erythromycin, or cyclosporine.

| Statistical analysis
For categorical variables, proportions were calculated. For continuous variables, summary statistics (mean, SD) were calculated. To determine the one-year outcomes, we analyzed data up to the 390day follow-up period for each patient. The Kaplan-Meier Plots were presented for bleeding events and clinical events, respectively. All statistical analyses were performed using SAS System Release 9.2 (SAS Institute Inc).

| Disposition of patients
In total, 11 569 patients with NVAF were enrolled. At one-year, we had collected case report forms for 11 469 patients and ex-

| Starting daily dose and adjustment factors
The starting daily dose of edoxaban prescribed to patients in the safety analysis set was 60 mg in 27.6% and 30 mg in 72.4% ( Note: Data are presented as number (%) unless otherwise indicated.
Abbreviation: SD, standard deviation. a Neither labile international normalized ratio nor alcohol use were counted; thus, the highest total score was seven.
for dose adjustment factors were excluded. Thus, background information for 10 877 patients was used to determine how edoxaban was used, as described in the PI (Figure 1

| Edoxaban treatment status
The mean and median duration of edoxaban treatment during the and plan to receive an invasive procedure (n = 25, 0.2%).

| Safety analyses
The cumulative incidence rate of bleeding events has increased over the year ( Figure 2). Figure 3A shows the incidence of bleeding events during the edoxaban treatment period (details in Supplement 3). In the safety analysis set (n = 11 107), the incidence of all bleeding events was 6.32% (n = 702); major bleeding was 1.08% (n = 120), and CRNMB was 2.81% (n = 312). Gastrointestinal bleeding was the

P-gp inhibitors c)
Others most common type (Supplement 3). The incidence of all bleeding events was 6.26% for the 60 mg dose group and 6.34% for 30 mg; for major bleeding, these were 0.72% and 1.22%. Figure 3B shows the incidence of major bleeding events categorized by HAS-BLED scores. Patients with scores of 2, 3, or 4 had an incidence of 1.30%, and those with scores of 0 or 1 had an incidence of 0.47%. Patients with a score of ≥5 had an incidence of 7.55% for major bleeding.

| Effectiveness analyses
The cumulative incidence rate of clinical events has increased over the year ( Figure 2). Figure 4A summarizes the incidence of clinical events during the edoxaban treatment period. In the effectiveness analysis set (n = 11 059), the incidence of thromboembolic events (ischemic stroke [excluding TIA] or systemic embolism) was 1.10% (n = 122): 1.05% (n = 32) at the 60 mg dose and 1.12% (n = 90) at the 30 mg dose.
The incidence of thromboembolic events categorized by CHADS 2 and CHA 2 DS 2 -VASc risk scores are shown in Figure 4B,C, respectively. For CHADS 2 , the incidence of thromboembolic events in patients with lower risk scores (0 and 1) was 0.64%, and was 1.35% for those with higher risk scores (≥2). For CHA 2 DS 2 -VASc, the incidence of events was 0.72% for patients with lower risk scores (0-3) and was 1.53% for patients with higher risk scores (≥4). Table 4 shows the safety and effectiveness of recommended doses of edoxaban treatment in patients with a specific background. Patient groups whose incidence of major bleeding was more than double that of all patients (1.13%) were the dual antiplatelet therapy (DAPT) use group (4.35%) and severely low body weight (<40 kg) group (3.00%). Moreover, patient groups whose incidence of thromboembolic events was more than double that of all patients (1.19%) were the DAPT use group (4.97%), cerebrovascular disease group (2.74%), and antiplatelet agent use group (2.56%).

| D ISCUSS I ON
ETNA-AF-Japan is an observational study of over 10 000 NVAF patients treated with edoxaban. ETNA-AF-Japan, a real-world study in contrast to an RCT such as ENGAGE AF-TIMI 48, includes various types of patients with multiple risk factors. Therefore, the study could provide information to aid in the physicians' understanding of bleeding risks and the clinical benefits of anticoagulation with edoxaban. 19 We report here the one-year follow-up on the safety and effectiveness of edoxaban.

| Baseline demographics and clinical characteristics
As reported previously, 14 patient backgrounds in this study were somewhat different from those in the phase-3 study (ENGAGE AF-TIMI 48). 1 ETNA-AF-Japan included patients with CHADS 2 score ≤1, severe renal dysfunction (CLcr <30 mL/min) and DAPT use, which were excluded from ENGAGE AF-TIMI 48. 1 Patient backgrounds such as age, body weight, and risk scores in terms of ETNA-AF-Japan were similar to those in the real-world SAKURA AF Registry, 20,21 Fushimi AF Registry, 22 and other DOAC observational studies, [23][24][25][26][27] suggesting that ETNA-AF-Japan reflected a real-world population of Japanese patients with NVAF.

| Dose levels and adjustment factors
The lower dose of 30 mg edoxaban was administered to approxi-

| Clinical outcomes (safety and effectiveness)
At one-year follow-up, the incidence of all bleeding events was 6.32%, and was 1.08% for major bleeding. Although a direct comparison is inappropriate, the incidence of major bleeding was lower in the present study than in ENGAGE AF-TIMI 48 overall data (2.75% of patients/year) 1 and in ENGAGE AF-TIMI 48 Japanese patient data (3.38% of patients/year). 31 Major bleeding events were mostly gastrointestinal bleeding, which was similar to that of ENGAGE AF-TIMI 48. In the SAKURA AF Registry 20 and Fushimi AF Registry, 22 the incidence rate of major bleeding was 1.21% and 1.8% of patients/ year, respectively. Although these observational studies differ from ETNA-AF-Japan in terms of the follow-up period and drugs prescribed, the incidence of major bleeding in ETNA-AF-Japan (1.08%) was not higher than those in other registries. At one-year followup, the incidence of clinical events was 1.

| Safety and effectiveness in the 60 mg and 30 mg groups
The mean HAS-BLED, CHADS 2 , and CHA 2 DS 2 -VASc score in the 30 mg group (2.1 ± 0.9, 2.3 ± 1.4 and 3.8 ± 1.6) were higher than those of the 60 mg group (1.7 ± 1.0, 1.8 ± 1.3 and 2.7 ± 1.5). These results suggest that the lower dose (30 mg) was given not only to patients at high risk of bleeding but also to patients at high risk of stroke. Thus, the safety and effectiveness results for the 30 mg group are particularly important. The incidence of all bleeding in the 30 mg (6.34%) and 60 mg (6.26%) groups were similar, and the incidence of major bleeding in the 30 mg (1.22%) was higher than 60 mg (0.72%) group. However, the incidence of major bleeding in the 30 mg group (1.22%) was not higher than that in other real-world studies (SAKURA AF Registry, 1.21% of patients/ year; Fushimi AF Registry, 1.8% of patients/year). The incidence of thromboembolic events was similar in the 30 mg (1.12%) and 60 mg (1.05%) groups. Therefore, these preliminary, one-year results suggested that there are no major concerns about the safety and effectiveness of edoxaban at the lower dose in a real-world clinical setting.

| Safety and effectiveness outcomes in patients with a specific background
Patients with a specific background (eg, low body weight, patients  provide information about the safety and effectiveness profile of these patients, which may be helpful for physicians in clinical practice. The incidence of major bleeding was more than double in patients who had factors of DAPT use and severely low body weight than in all patients in the study. In the phase 3 study, patients using DAPT were excluded, and information on low-weight patients weighing <40 kg was limited. However, the results of this study point to a higher incidence of major bleeding in these patient groups. The factors for which the incidence of thromboembolic events was more than double that of all patients in the study were history of cerebrovascular disease, antiplatelet agent use, and DAPT use. Cerebrovascular disease includes a history of ischemic stroke, which had a high probability of recurrence. Moreover since an antiplatelet agent or DAPT is administered to patients who are at a high risk of a thromboembolic event, it is expected that incidence rates for these patients would be high. Therefore, it becomes necessary to monitor patients carefully for bleeding or thromboembolic events in the presence of the following factors: severely low body weight, cerebrovascular disease, antiplatelet agent use, or DAPT use.

| Limitations
First, the present study was an open-label observational study with no comparative arm. Therefore, it is not possible to compare edoxaban

ACK N OWLED G EM ENTS
The authors express their deepest gratitude to the investigators who conducted this survey and provided valuable data. This study was funded by Daiichi Sankyo Co. Ltd. Writing and editorial assistance was provided by Kazuhiro Kanmuri PhD, Inter-Professional Inc.