Safety Of Edoxaban In Patients Research Articles

Long-term effectiveness and safety of edoxaban in patients with atrial fibrillation: 4-year data from the ETNA-AF-Europe study

BackgroundTo assess long-term effectiveness and safety of edoxaban in Europe. Methods and resultsETNA-AF-Europe, a prospective, multinational, multi-centre, post-authorisation, observational study was conducted in agreement with the European Medicines Agency. The primary and secondary objectives assessed real-world safety (including bleeding and deaths) and effectiveness (including stroke, systemic embolic events and clinical edoxaban use), respectively.Median (interquartile range) age of the 13,164 patients was 75.0 (68.0–80.0) years; CHA2DS2-VASc and HAS-BLED scores were 3.0 (2.0–4.0) and 2.0 (1.0–2.0), respectively. Follow-up duration was 3.98 (3.21–4.05) years. Patients on edoxaban 30 mg (n = 3042) at baseline were older (80.0 vs 73.0 years), more likely assessed as frail by investigators (27.0% vs 6.6%) and had more comorbidities than those on edoxaban 60 mg (n = 9617; missing dosing information for n = 505). Annualised event rates of all-cause and cardiovascular death in the overall population, edoxaban 60 mg and edoxaban 30 mg groups were 4.1%, 2.8% and 8.4%, and 1.0%, 0.7% and 2.0%, respectively. Annualised rates of stroke were relatively constant throughout the follow-up, transient ischaemic attack and systemic embolism were < 1% in the overall population. Rates of any major and major gastrointestinal bleeding were low, with slightly higher rates for edoxaban 30 vs 60 mg group. Intracranial haemorrhage was uncommon (0.2%). ConclusionsIn European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding. Differences in outcomes between the two approved doses are attributable to differences in clinical characteristics.

Long-term effectiveness and safety of edoxaban in patients with atrial fibrillation: 4-year follow-up of more than 13,000 patients from the ETNA-AF-Europe study

Abstract Background Direct, non-vitamin K antagonist oral anticoagulants (DOACs/NOACs) have become the first-choice therapy for stroke prevention in patients with atrial fibrillation (AF) at risk of stroke. Data on long-term effectiveness and safety of NOACs are scarce and not available from randomised clinical trials. Purpose We analysed 4-year outcome data in 13,632 European patients with AF treated with the NOAC, edoxaban. Methods This is the first report of the four-year follow-up information collected in the ETNA-AF-Europe (NCT02944019) study. It is a prospective registry, conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Design and follow-up were agreed with the European Medicines Agency as part of the post-approval safety assessment of edoxaban. Key efficacy and safety outcomes were adjudicated. Results 13,164 patients (56.7% males) with AF treated with edoxaban (60 mg OD n=9617; 30 mg OD n=3042; missing dose n=505) were analysed: median (interquartile range [IQR]) age was 75 (68–80) years, weight 80 (70–90) kg, creatinine clearance (CrCl) 68.9 (52.7–87.9) mL/min, modified CHA2DS2-VASc and HAS-BLED scores 3 (2–4) and 2 (1–2), respectively in the overall population. Annualised all-cause and cardiovascular deaths in the overall population were 4.1%/year and 1.0%/year, respectively; higher in the edoxaban 30 mg vs 60 mg cohort (Figure 1). Annualised rates of stroke, transient ischaemic attack and systemic embolic events rates were &amp;lt;1% (0.6%/year, 0.3%/year and 0.1%/year, respectively); these proportions were similar between the two dose cohorts (Figure 1). The time-to-first event curves for all-cause death, stroke and major bleeding were almost linear throughout the 4-year follow-up (Figure 2), irrespective of dose cohort. Compared with patients receiving edoxaban 60 mg, those prescribed 30 mg were older (median [IQR] age: 80 [75–85] vs 73 [66–78] years), had greater frail proportion (27.0% vs 6.6%), a lower CrCl (46.1 [37.4–59.0] vs 75.9 [61.9–93.8] mL/min) and a higher CHA2DS2-VASc score (4 [3–5] vs 3 [2–4]). Annualised bleeding rate was 3.0%/year and higher in the 30 mg vs 60 mg cohort (Figure 1). Annualised major bleeding, intracranial haemorrhage (ICH) and major gastrointestinal (GI) bleeding rates were low (0.9%/year, 0.2%/year and 0.4%/year, respectively), with higher major bleeding and major GI bleeding rates in patients treated with edoxaban 30 mg OD (Figure 1). ICH rates were similar in both dose cohorts. Conclusion These findings illustrate the long-term effectiveness and safety of edoxaban. Treatment with edoxaban over 4 years in patients with AF is associated with a relatively low, linearly increasing rate of all-cause death and ischaemic stroke. Rates of bleeding and especially ICH rates were low.

Real-world effectiveness and safety of edoxaban in patients with and without a history of ischaemic stroke: results from the ETNA-AF programme

Abstract Background Atrial fibrillation (AF) patients with a history of ischaemic stroke (IS) have a higher risk for recurrent IS events and were largely excluded from the pivotal, randomised, controlled phase 3 trials on oral anticoagulants. Thus, the effectiveness and safety of edoxaban in these patients need to be studied in a real-world setting. Purpose To compare edoxaban real-world effectiveness and safety in AF patients with or without an IS history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics with medical history and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (including major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without IS history. Results Data from 27,333 patients (3215 with prior IS and 24,118 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with IS history were significantly older, more likely ≥75 years of age, and had a lower mean body weight and creatinine clearance (P&amp;lt;0.0001 for all; Table). Patients with IS history also had significantly higher baseline stroke (CHA2DS2-VASc) and bleeding (HAS-BLED) risk scores (P&amp;lt;0.0001 for both; Table). A significantly higher percentage of patients with IS history had previous transient ischaemic attacks (TIA), MB, and ICH (P&amp;lt;0.0001 for all; Table). Patients with IS history more likely received edoxaban 30 mg vs 60 mg at baseline (P&amp;lt;0.0001). Effectiveness and safety outcomes hazard ratios are shown in the Figure. Patients with IS history had significantly higher rates of all-cause death (4.5% vs 3.0%; P&amp;lt;0.0001), CV death (1.9% vs 1.4%; P=0.004), IS (2.5% vs 0.5%; P&amp;lt;0.0001), any stroke (3.1% vs 0.7%; P&amp;lt;0.0001), and TIA (0.5% vs 0.2%; P=0.0002). Patients with IS history had significantly higher annualised rates of MB (1.6% vs 1.0%; P&amp;lt;0.0001), major GI bleeding (0.8% vs 0.5%; P=0.003), ICH (0.6% vs 0.3%; P&amp;lt;0.0001), haemorrhagic stroke (0.5% vs 0.2%; P&amp;lt;0.0001), CRNMB (2.3% vs 1.3%; P&amp;lt;0.0001), and any bleeding (6.1% vs 4.1%; P&amp;lt;0.0001). Conclusions Patients with AF who have a history of IS are more likely elderly; have histories of MB, ICH, and TIA; and have high baseline stroke and bleeding risk scores. Patients with IS history receiving edoxaban have a considerably higher likelihood of experiencing IS or TIA, whereas the risk of experiencing any bleeding event (with the exception of ICH) is only modestly higher than in those without IS history. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Efficacy and safety of edoxaban in patients with chronic thromboembolic pulmonary hypertension: protocol for a multicentre, randomised, warfarin-controlled, parallel group trial - KABUKI trial

IntroductionChronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent...

Effectiveness and safety of edoxaban in 27,333 patients from ETNA-AF with and without a history of intracranial haemorrhage after 2 years of treatment

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo, Inc. Medical writing and editorial support were provided by Atreju Lackey, PhD of AlphaBioCom, LLC, and funded by Daiichi Sankyo, Inc. Background/Introduction Once-daily edoxaban significantly reduced the risk of intracranial haemorrhage (ICH) compared with well-managed warfarin in atrial fibrillation (AF) patients in the ENGAGE AF-TIMI 48 trial. The effectiveness and safety of edoxaban in patients with prior ICH is unknown. Purpose To compare the effectiveness and safety of edoxaban in AF patients with or without a history of ICH. Methods The Global ETNA-AF programme is composed of and, thus, integrates data from multiple prospective, observational, and noninterventional regional studies collecting data of AF patients treated with edoxaban for stroke prevention. This snapshot analysis presents global and regional baseline characteristics with medical history and 2-year annualised rates of all-cause mortality, stroke (haemorrhagic, ischaemic, any), and bleeding (major bleeding [MB] including ICH, clinically relevant nonmajor bleeding [CRNMB], any bleeding), in patients with or without ICH history. Results Overall, 27,333 patients from Europe, Japan, South Korea, and Taiwan were analysed, including 367 with prior ICH and 26,966 without prior ICH. There were proportionally fewer patients with a history of ICH in the European population. Patients with a history of ICH were older (P=0.006), had a lower body mass index (P&amp;lt;0.0001), had a lower creatinine clearance (P=0.0001), and had more comorbidities, with a higher percentage of patients with a history of stroke, transient ischaemic attack (TIA), or MB (Table 1); the higher level of comorbidities noted in patients with a history of ICH was also reflected by higher baseline CHA2DS2-VASc and HAS-BLED scores (Table 1). Patients with a history of ICH were more likely receiving 30 mg edoxaban at baseline, whereas patients without ICH history were more often on 60 mg edoxaban (each P&amp;lt;0.0001). In patients with vs without ICH history, all-cause mortality (5.10% vs 3.14%; P=0.01), ischaemic stroke (1.79% vs 0.73%; P=0.006), and any stroke rates (3.25% vs 0.95%; P&amp;lt;0.0001) were higher (Table 2). Patients with vs without ICH history had higher annualised rates of MB (2.50% vs 1.00%; P=0.001), ICH (1.42% vs 0.27%; P&amp;lt;0.0001), haemorrhagic stroke (1.42% vs 0.20%; P&amp;lt;0.0001), CRNMB (2.49% vs 1.40%; P=0.04), and any bleeding (7.57% vs 4.27%; P=0.001), but these rates were low compared to other high-risk populations. ICH was not selected as a predictor of cardiovascular outcomes on multivariate prediction modelling. ICH had non-significant effects in predicting all-cause death (HR 1.22), ischemic stroke (HR 1.14), and major bleeding (HF 1.37) and repeat ICH (HR 1.94). Conclusions Patients with a history of ICH are a small, elderly, multimorbid subgroup of patients with AF. Treatment with the non-vitamin K antagonist oral anticoagulant edoxaban resulted in relatively low rates of major events.

Efficacy and safety of edoxaban in patients early after surgical bioprosthetic valve implantation or valve repair: A randomized clinical trial

ObjectiveEarly warfarin anticoagulation is recommended in patients undergoing surgical bioprosthetic valve implantation or valve repair. It is unclear whether non-vitamin K antagonist oral anticoagulants can be a full alternative to warfarin. This study aimed to compare efficacy and safety of edoxaban with warfarin in patients early after surgical bioprosthetic valve implantation or valve repair. MethodsThe Explore the Efficacy and Safety of Edoxaban in Patients after Heart Valve Repair or Bioprosthetic Valve Replacement study was a prospective, randomized (1:1), open-label, clinical trial conducted from December 2017 to September 2019. Patients were randomly assigned to receive edoxaban (60 mg or 30 mg once daily) or warfarin for the first 3 months after surgical bioprosthetic valve implantation or valve repair. The primary efficacy outcome was a composite of death, clinical thromboembolic events, or asymptomatic intracardiac thrombosis. The primary safety outcome was the occurrence of major bleeding. ResultsOf 220 participants, 218 (109 per group) were included in the modified intention-to-treat analysis. The primary efficacy outcome occurred in 4 patients (3.7%) taking warfarin and none taking edoxaban (risk difference, −0.0367; 95% confidence interval, –0.0720 to –0.0014; P < .001 for noninferiority). The primary safety outcome occurred in 1 patient (0.9%) taking warfarin and 3 patients (2.8%) taking edoxaban (risk difference, 0.0183; 95% confidence interval, –0.0172 to 0.0539; P = .013 for noninferiority). ConclusionsEdoxaban is noninferior to warfarin for preventing thromboembolism and is potentially comparable for risk of major bleeding during the first 3 months after surgical bioprosthetic valve implantation or valve repair.

Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AF-TIMI 48 trial

BackgroundDiabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). ResultsOn average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p < 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions > 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). ConclusionPatients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes.

Effectiveness and safety of edoxaban in patients with atrial fibrillation: data from the Danish Nationwide Cohort.

Edoxaban treatment for stroke prevention in atrial fibrillation (AF) has mainly been investigated in randomized controlled trials, and data reflecting clinical practice are limited. We ascertained the clinical effectiveness and safety of edoxaban 30 and 60 mg once daily among Danish patients with AF. This was an observational study based on Danish nationwide registries collecting information for administrative purposes. From June 2016 through November 2018, we identified 3405 patients initiating edoxaban. After exclusions, 2285 AF patients were followed for the effectiveness outcome of thromboembolism (ischaemic stroke and/or systemic embolism) and bleeding outcomes (composite of major bleeding, gastrointestinal bleeding, and intracranial haemorrhage), as well as bleeding requiring hospitalization. Population mean age was 75 years and 43% were female; 643 patients received the 30 mg edoxaban dosage regimen and 1642 initiated 60 mg edoxaban. During follow-up, we observed 41 thromboembolic events and 89 bleeding events of which 40 events required hospitalization. Among patients with 30 mg edoxaban, the rate (per 100 person-years) of thromboembolism was 2.07 vs. 1.62 for 60 mg edoxaban. Rates of bleeding were similar for the two dosages at ∼3.85. Bleeding requiring hospitalization occurred at a rate of 1.74 for 30 mg edoxaban and 1.69 with 60 mg edoxaban. In this nationwide cohort of Caucasian AF patients treated with edoxaban for stroke prevention, the clinical effectiveness and safety were in line with data from the ENGAGE AF-TIMI 48 trial. Studies investigating comparative effectiveness and safety for edoxaban in comparison with other choices of antithrombotic treatment options are needed.

457Efficacy and safety of uninterrupted periprocedural edoxaban in patients undergoing catheter ablation for atrial fibrillation: Prospective KYU-RABLE study

Abstract Background/Introduction Catheter ablation (CA) has been established as a first-line therapy in the treatment of non-valvular atrial fibrillation (NVAF), and uninterrupted direct oral anticoagulants (DOACs) have become mainstream for the management of periprocedural thromboembolic events. Since 2014, edoxaban has been used for anticoagulation therapy for AF in Japan. However, evidence for uninterrupted use of edoxaban during the periprocedural period of CA in NVAF patients is limited. Purpose KYU-RABLE is a prospective, multicenter, single-arm interventional study, conducted in 23 institutions in Japan to evaluate the efficacy and safety of uninterrupted periprocedural oral edoxaban in patients undergoing CA. The plasma concentration of edoxaban and its relation with plasma coagulative biomarker levels during the periprocedural period were also evaluated. Methods A total of 537 Japanese NVAF patients were enrolled in Japan from December 2017 to September 2018. Edoxaban 60mg (30 mg in patients indicated for dose adjustment) was administered once daily in the morning for at least 4 weeks before CA and continued for at least 4 weeks after CA. On the day of CA, edoxaban was administered immediately after confirmation of hemostat. The primary endpoint was the composite incidence of thromboembolism and major bleeding events during 4 weeks from the procedural day. Plasma concentration of edoxaban and plasma levels of coagulative biomarkers including D-dimer, soluble fibrin monomer complex (SFMC) and prothrombin fragment 1+2 (F1+2) were also measured. Results Among the total 513 patients who underwent CA, 75.2% had radiofrequency CA and 23.0% had cryoballoon CA. The majority of CA patients (65%) received edoxaban 60mg/day, while others (35%) received 30mg/day. As for the primary endpoint, one major bleeding (cardiac tamponade) event was observed and no thromboembolism occurred. Clinically relevant non-major bleeding events occurred in six patients (1.2%), the most were puncture site hemorrhage. The plasma concentration of edoxaban at CA was dependent upon the duration from last administration of edoxaban before CA. However, plasma levels of coagulative biomarkers (D-dimer, SFMC, F1+2) were maintained within appropriate range during the periprocedural period, irrespective of the edoxaban concentration. We also report changes of plasma levels of coagulative biomarkers in sub group analyses by CHADS2 scores and types of AF. Conclusion The KYU-RABLE study demonstrated the first evidence of the efficacy and safety of uninterrupted periprocedural edoxaban administered once daily on the morning for NVAF patients underwent CA. Edoxaban treatment was associated with a low risk of periprocedural bleeding and thromboembolic complications. Furthermore, these low event risks were considered to be associated with the maintained plasma level of coagulative biomarkers, regardless of the change in edoxaban plasma concentration. Acknowledgement/Funding Daiichi Sankyo Co. Ltd.

Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF - TIMI 48 Trial.

BackgroundAnticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse.Methods and ResultsThe ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230–771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78–3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07–2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83–1.42). Relative outcomes with higher‐dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism (HR, 0.60 [95% CI, 0.31–1.15] for malignancy versus HR, 0.89 [95% CI, 0.76–1.05] for no malignancy; interaction P=0.25) and major bleeding (HR, 0.98 [95% CI, 0.69–1.40] for malignancy versus HR, 0.79 [95% CI, 0.69–1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher‐dose edoxaban versus warfarin in patients with malignancy (HR, 0.54; 95% CI, 0.31–0.93) compared with no malignancy (HR, 1.02; 95% CI, 0.88–1.18; interaction P=0.026).ConclusionsIn patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Safety of Uninterrupted Periprocedural Edoxaban Versus Phenprocoumon for Patients Who Underwent Left Atrial Catheter Ablation Procedures

Data about the safety of edoxaban in patients who underwent left atrial (LA) radiofrequency (RF) ablation procedures are lacking. This study sought to compare the safety of uninterrupted edoxaban with uninterrupted phenprocoumon administration during LA RF ablation for atrial fibrillation and atrial tachycardia. In total, 231 patients (mean age 64 ± 11years, male 71%) who underwent LA RF ablation under continuous oral anticoagulation (OAC) with edoxaban or phenprocoumon were included in the study. Patients on uninterrupted edoxaban (60 mg or 30 mg/day for at least 4 weeks) were matched for gender, age and type of arrhythmia with 2 patients on uninterrupted phenprocoumon (international normalized ratio 2 to 3). We identified 77 consecutive patients on edoxaban and n = 154 patients on phenprocoumon. Heparin was administered periprocedurally to achieve an activated clotting time of 280 to 300 seconds. No protamine was administered periprocedurally. The primary end point was a composite of bleeding, thromboembolic events, and death. The primary end point was met in 9 patients in the edoxaban group and in 22 patients in the phenprocoumon group (p = 0.69). No patient in either group died or had a thromboembolic complication. No major bleeding complication was observed in the edoxaban group, whereas one was found in 1 patient in the phenprocoumon group (p ≥0.99). Minor bleeding complications occurred in 9 patients (12%) in the edoxaban group and in 21 patients (14%) in the phenprocoumon group (p = 0.84). Uninterrupted OAC with edoxaban appeared to be as safe as uninterrupted OAC with phenprocoumon in patients who underwent LA RF ablation procedures.