Edoxaban Treatment In routiNe Clinical prActice Research Articles

Impact of different dose reduction criteria on dose assignment of current DOACs and related outcomes: an analysis from 4-year data of the ETNA-AF Europe programme

Abstract Background Direct oral anticoagulants (DOACs) are the standard treatment for stroke prevention in patients with atrial fibrillation (AF). Pharmacological characteristics and dose reduction criteria of the four currently available DOACs are different. Several studies have reported frequent use of non-recommended doses of DOACs associated with worse clinical outcomes. Data from real-world studies, such as the edoxaban Treatment in routiNe clinical prActice (ETNA)-AF, may help assessing the size of this phenomenon and its impact on clinical outcomes. Purpose To evaluate the distribution of dose reduction criteria and explore associated outcomes in a large, unselected, real-world population using 4-year data from the ETNA-AF EU study. Methods The ETNA-AF EU is a prospective, observational, study to evaluate safety and effectiveness of edoxaban in patients with AF from Europe. Patients with available data regarding the SmPC dose reduction criteria of the four currently available DOACs were included. Patients with a creatinine clearance <30 mL/min were excluded. Patients were classified by dose reduction criteria for the different DOACs (i.e., full dose for all [FULL], reduced dose for all [REDUCED], patients not included in previous groups [INTERMEDIATE]). Results We included 12,866 patients from the ETNA-AF EU study. According to the SmPC dose reduction criteria, the percentage of patients that would be eligible for a dose reduction in the ETNA population was highly heterogenous across different DOACS: 5.7% for apixaban, 16.8% for rivaroxaban, 23.8% for edoxaban and 52.9% for dabigatran. Moreover, differences in the dose reduction criteria included in each SmPC was reflected by the distribution of patients in the three pre-specified groups. Among the 11,003 assignable patients, 42.4% would receive a full dose, 5.1% would receive a reduced dose and the largest percentage, 52.5%, was in the INTERMEDIATE group, which would receive either a full or reduced dose of any DOAC depending on the selected agent. Of the patients included in the INTERMEDIATE group, 65.2% received a full dose of edoxaban due to its specific labelling. Interestingly, the INTERMEDIATE group included the vast majority of patients known to be at risk of adverse events: very elderly (i.e., ≥85 yrs; 76.5%), frail as per investigator (73.3%), history of previous stroke (60.4%) or history of bleeding (61.3%). Clinical outcomes at four years were significantly higher in both the INTERMEDIATE and the REDUCED groups compared to the FULL group, with the only exception of haemorrhagic stroke (Table). Conclusion(s): According to the different dose reduction criteria of currently available DOACs, notable percentage of patients could receive either a full or a reduced dose depending on the DOAC chosen by the physician. Considering that the chosen dose of the DOAC has an impact on clinical outcomes, patients in the INTERMEDIATE group need careful assessment, which warrants further analysis.

Prescribing Patterns and Outcomes of Edoxaban in Atrial Fibrillation Patients From Asia - One-Year Data From the Global ETNA-AF Program.

Background: This study reports prescribing patterns and the 1-year effectiveness and safety of edoxaban in an Asian cohort of Edoxaban Treatment in routiNe clinical prActice (ETNA)-Atrial Fibrillation (AF) patients. Methods and Results: The Global ETNA-AF program integrates prospective, observational, noninterventional regional studies, collecting data on characteristics and clinical outcomes of patients with AF receiving edoxaban for stroke prevention. Baseline characteristics, medical history, and 1-year clinical event rates were assessed in patients from South Korea, Taiwan, Hong Kong, and Thailand. Clinically relevant events assessed at 12 months included all-cause death, cardiovascular death, ischemic and hemorrhagic stroke, systemic embolic events (SEEs), bleeding, and net clinical outcome (NCO). Overall, 3,359 patients treated with edoxaban 60 or 30 mg once daily completed 1-year follow-up; 70.9% of patients received recommended dosing according to local labels. Baseline mean±standard deviation age was 71.7±9.6 years, CHA2DS2-VASc score was 3.1±1.5, and modified HAS-BLED score was 2.3±1.1. Mean age and sex were similar across countries/regions. The 1-year event rate for all-cause death was 1.8%; major bleeding, 1.3%; ischemic stroke, 1.1%; cardiovascular mortality, 0.7%; hemorrhagic stroke, 0.3%; SEEs, 0%; and NCO, 4.1%; with differences observed between countries/regions and dosing groups. Conclusions: Most Asian patients with AF were prescribed recommended edoxaban dosing in routine care settings. At 1-year follow-up, this analysis supports the effectiveness and safety of edoxaban in these patients.

Persistence to edoxaban treatment in patients with atrial fibrillation: Analysis from the Global ETNA-AF program

Abstract Background/Introduction Direct oral anticoagulants (DOACs) are now the standard treatment for stroke prevention in most patients with atrial fibrillation (AF). However, many studies have reported suboptimal adherence and persistence to DOAC treatment. Data collected in routine care, such as in the Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program, may provide insight into factors associated with treatment persistence. Purpose Evaluate the persistence to edoxaban treatment in a large, unselected, real-world population using 2-year data from the Global ETNA-AF study. Methods The Global ETNA-AF program is a predefined integration of prospective, observational, non-interventional regional studies from Europe, Japan, and other Asian countries to evaluate the safety and effectiveness of edoxaban in patients with AF. Demographic and clinical characteristics were collected at baseline. In this analysis, patients were stratified by persistence to edoxaban treatment during a 2-year follow-up period (ie, persistence [PERS], suspension [SUS], permanent discontinuation [PERD], and suspension with later permanent discontinuation [SUS+PERD]). Results Overall persistence was high, with 87.1% of patients under edoxaban treatment at 2 years considering both groups that discontinued edoxaban at any time (PERD and SUS+PERD). Mean patient age, creatinine clearance, CHA2DS2-VASc, and HAS-BLED score were similar between the PERS (n = 20,053), SUS (n = 3088), PERD (n = 2936), and SUS+PERD (n = 503) groups (Table). In the PERS group, there were slightly fewer patients who received previous anticoagulation (vitamin K antagonist or DOAC) and were concomitantly using anti-platelet drugs at baseline. A larger proportion of SUS+PERD vs all other patients had a history of ischaemic stroke and/or major bleeding. Overall mortality was lower in patients in the PERS and SUS groups (0.79% [95% confidence interval {CI} 0.70–0.89] and 1.85% [95% CI 1.53–2.24], respectively) compared with patients who discontinued the treatment (PERD: 22.50% [95% CI 21.12–23.98]; SUS+PERD: 13.05% [95% CI 10.73–15.88]). Notably, persistence in the Global ETNA-AF program was generally higher than reported in GLORIA-AF at 2 years (70.9%) and XANTUS at 1 year (77.4%), despite a more compromised health profile especially considering the advanced patient age. Conclusions Treatment with edoxaban in routine clinical practice is associated with high persistence (87%) at 2 years in elderly patients with AF and multiple comorbidities. Persistence to edoxaban treatment was associated with better survival during the 2-year follow-up period. Further investigation is ongoing to determine the specific causes and consequences of edoxaban suspension and discontinuation to improve personalization of thromboembolic prophylaxis in patients with AF.Table 1

Baseline demographic and clinical characteristics as predictors of adverse outcomes to improve management of patients with AF receiving edoxaban: a subanalysis of the ETNA-AF registry

Abstract Background/Introduction Atrial fibrillation (AF) is associated with substantial morbidity and mortality for patients, and significant burden for societal health and health economy. Even optimal oral anticoagulation and treatment of concomitant conditions leave an unacceptable remaining morbidity and mortality. Aim The purpose of this analysis was to identify clinical parameters associated with cardiovascular events in patients with AF receiving adequate anticoagulation. Methods The Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF observational, non-interventional programme prospectively collects data on characteristics and clinical outcomes in patients treated with the direct oral factor Xa inhibitor edoxaban for stroke prevention in AF from Europe, Japan, and other Asian countries. A risk prediction model was built and evaluated for two dependent variables: composite endpoint 1, consisting of cardiovascular (CV) death, all stroke or systemic embolism or transient ischaemic attack (TIA), myocardial infarction (MI), and venous thromboembolism (VTE); and composite endpoint 2, consisting of CV death, all stroke, and MI. Independent variables used to identify predictors of the composite endpoints included the following parameters at baseline: age, history of any stroke/TIA, peripheral arterial disease (PAD), heart failure (HF), coronary artery disease (CAD), major or clinically relevant non-major gastrointestinal bleeding, chronic obstructive pulmonary disease, body mass index <18.5 kg/m2, weight, creatinine clearance (CrCl), history of valvular disease, history of diabetes mellitus, smoking history, age ≥85 years, and hepatic impairment. Multivariable Cox analysis with stepwise selection was used to identify baseline predictors of the composite endpoints. Results Overall, 26,580 edoxaban patients were included in the analysis. At baseline, 3034 (11.4%) patients were ≥85 years. Additional baseline demographics and clinical characteristics are reported in Table 1. All clinical variables were significant predictors (P <0.05) of both composite endpoints. Stronger predictors of composite endpoint 1 included history of any stroke/TIA, PAD, HF, higher weight, and lower CrCl (all P <0.0001; Figure 1). Most significant predictors of composite endpoint 2 included a history of ischaemic stroke, PAD, HF, and weight (P <0.0001; Figure 1). Conclusion A history of ischemic stroke, peripheral artery disease, heart failure, and weight identify patients with atrial fibrillation at risk of cardiovascular events on optimal current therapy. These patients may benefit from targeted interventions including early rhythm control and intensified, integrated management. Additional external validation will be performed to further the additive value of the analysis presented here.Table 1Figure 1

Annualized clinical event rates during two-year follow-up are low in 27,617 atrial fibrillation patients on edoxaban: results from the global noninterventional ETNA-AF program

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

Factors associated with the dosing of edoxaban for stroke prevention in patients with atrial fibrillation from South Korea and Taiwan: 1-year data from the Global ETNA-AF Program.

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

Safety and Effectiveness of Edoxaban in Atrial Fibrillation Patients in Routine Clinical Practice: One-Year Follow-Up from the Global Noninterventional ETNA-AF Program.

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

The global Edoxaban Treatment in routine cliNical prActice (ETNA) noninterventional study program: rationale and design.

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