Clinical factors related to successful or unsuccessful cardioversion in the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) randomized trial.

BACKGROUND: EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation evaluated use of nonvitamin K antagonist oral anticoagulant edoxaban vs enoxaparin-warfarin in patients with nonvalvular atrial fibrillation undergoing electrical cardioversion. HYPOTHESIS: To assess clinical factors related to successful or unsuccessful cardioversion. To evaluate whether differences in adverse events based on anticoagulation strategy may exist. METHODS: In this multicenter prospective randomized open-label blinded end-point evaluation trial, 2199 patients were randomized to edoxaban 60 mg once daily (30 mg for creatinine clearance 15-50 mL/min, weight ≤ 60 kg, and/or concomitant use of P-glycoprotein inhibitor) or enoxaparin-warfarin. Successful cardioversion was confirmed by 12-lead electrocardiography-documented sinus rhythm. RESULTS: Cardioversion was successful in 1578 patients; in 355 patients, cardioversion was unsuccessful. Male, high body weight, high body mass index (BMI), coronary artery disease, concomitant aspirin, or prior statins use were more common in patients with unsuccessful cardioversion; international normalized ratio control did not differ by cardioversion success. On multivariate analysis, gender (P < .05), body weight (P = .0196) and BMI (P = .0377) emerged as independent predictors of successful cardioversion. There were no significant differences in primary efficacy (a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during overall study period) regardless of cardioversion success. There were no significant differences in bleeding rates, regardless of cardioversion outcome; notwithstanding low numbers, edoxaban and enoxaparin-warfarin did not differ. CONCLUSIONS: Male gender, higher mean weight and higher mean BMI were associated with unsuccessful cardioversion. Efficacy and safety outcomes were low and did not differ by cardioversion success.

Edoxaban versus warfarin in vitamin K antagonist experienced and naïve patients from the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomised trial.

BACKGROUND: In ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin-warfarin (enox-warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. OBJECTIVES: To evaluate the efficacy and safety of edoxaban versus enox-warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial. METHODS: The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days. RESULTS: Of 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox-warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox-warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72-6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15-3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06-6.04, OR 0.48, 95% CI 0.01-9.25, respectively). CONCLUSIONS: Edoxaban had comparable efficacy and safety to optimized anticoagulation with enox-warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.

Determinants of left atrium thrombi in scheduled cardioversion: an ENSURE-AF study analysis.

AIMS: ENSURE-AF (NCT02072434) was the largest prospective randomized clinical trial of anticoagulation for cardioversion in atrial fibrillation (AF), which also provides the largest prospective dataset for transoesophageal echocardiography (TOE) prior to cardioversion. This ancillary analysis investigated determinants of TOE-detected left atrium thrombi (LAT) in patients scheduled for electrical cardioversion (ECV). METHODS AND RESULTS: The ENSURE-AF multicentre PROBE evaluation trial compared edoxaban 60 mg once daily (QD) with enoxaparin/warfarin in 2199 subjects undergoing ECV of non-valvular AF. Patients were stratified by the use of TOE, anticoagulant experience, and selected edoxaban dose. Electrical cardioversion was cancelled or deferred when TOEdetected LAT. In total, 1183 subjects were stratified to the TOE arm and LAT was reported in 91 (8.2%). In univariate analysis, age ≥75 years (26.4% vs. 16.9%, P = 0.0308), lower weight (86.5 ± 15.0 vs. 90.7 ± 18.0 kg, P = 0.0309), lower creatinine clearance (80.1 ± 30.6 vs. 93.2 ± 33.9 mL/min, P = 0.0007), heart failure (59.3% vs. 43.0%, P = 0.0029), and diuretic treatment (53.9% vs. 40.1%, P = 0.0141) were more prevalent in the LAT group. Non-significant trends were seen for higher mean CHA2DS2-VASc score (3.0 ± 1.41 vs. 2.7 ± 1.48, P = 0.0571) and more prevalent anticoagulation use prior to enrolment (60.4% vs. 50.3%, P = 0.0795) in the LAT group. In logistic regression analysis, age (P = 0.0202) and heart failure (P = 0.0064) were independently associated with LAT. CONCLUSION: Elective ECV is commonly cancelled or deferred due to TOE-detected LAT in patients with non-valvular AF. Age ≥75 years and heart failure were associated with the presence of LAT.

Impact of Body Mass Index on Outcomes in the Edoxaban Versus Warfarin Therapy Groups in Patients Underwent Cardioversion of Atrial Fibrillation (from ENSURE-AF).

In the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation study (NCT 02072434), edoxaban showed similar efficacy and safety versus enoxaparin-warfarin in patients underwent electrical cardioversion of nonvalvular atrial fibrillation. In this ancillary analysis, we compared the primary efficacy (composite of stroke, systemic embolic event, myocardial infarction, cardiovascular death, and overall study period) and safety (composite of major and clinically relevant nonmajor bleeding, on-treatment) end points in relation to body mass index (BMI; <30 vs ≥30 kg/m2). We also compared cardioversion outcomes in relation to BMI. Of 2,199 patients enrolled, 1,095 were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64 ± 10 and 64 ± 11 years and mean BMI 30.6 and 30.7 kg/m2, respectively. Cardiovascular and metabolic diseases were more prevalent in obese (n = 1067) than nonobese patients. Overall ischemic event rates were low; rates in the BMI <30 kg/m2 subgroup were numerically lower than the ≥30 kg/m2 subgroup, but not significantly different (odds ratio [OR], 0.74 [95% confidence interval 0.23, 2.24]). Composite major + clinically relevant nonmajor bleeding rates were low and numerically lower, but not significantly different (OR 0.88 [0.38, 2.04]), between the edoxaban and enoxaparin-warfarin arms and across weight categories. Successful cardioversion rate was higher in the BMI <30 versus ≥30 kg/m2 subgroup (73.9% vs 69.9%; OR 1.22 [1.01 to 1.48]). In EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation, BMI did not significantly impact the relative efficacy and safety of edoxaban versus enoxaparin-warfarin. Nevertheless, the nonobese group had a higher rate of cardioversion success than the obese group.

Impact of age, comorbidity, and polypharmacy on the efficacy and safety of edoxaban for the treatment of venous thromboembolism: An analysis of the randomized, double-blind Hokusai-VTE trial.

BACKGROUND: Many patients with venous thromboembolism (VTE) are elderly, have multiple comorbidities and take several concomitant medications. Physicians may prefer warfarin over direct oral anticoagulants (DOACs) in such patients because comparative data are lacking. This analysis was designed to determine the effects of advanced age, comorbidities, and polypharmacy on the efficacy and safety of edoxaban and warfarin in patients with VTE. METHODS: Using data from the Hokusai-VTE study, we report rates of recurrent VTE and of clinically relevant bleeding by age category (<65, 65-75, and ≥75; <80 versus ≥80years), and by number of comorbidities (0, 1-2, >2) and concomitant medications (<3, 3-5, >5). Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for edoxaban versus warfarin were determined and Kaplan-Meier methodology was used to construct time-to-event curves. At 3months, pre- and postdose levels of edoxaban were measured using mass spectrometry. For warfarin-treated patients, the time in therapeutic range was calculated. The study was approved by institutional review boards; informed consent was obtained. RESULTS: Recurrent VTE increased with advanced age, multiple comorbidities, and polypharmacy in warfarin-treated patients but not with edoxaban. Edoxaban was more effective than warfarin in patients ≥75years of age and in those with multiple comorbidities. In the 517 patients over 80years of age, recurrent VTE occurred in 2.8% given edoxaban and in 5.7% given warfarin (HR 0.51, 95% CI 0.21-1.24). Bleeding increased with age, comorbidity, and polypharmacy regardless of treatment, but the relative safety of edoxaban versus well-managed warfarin was maintained. Age, comorbidity, and polypharmacy did not impact edoxaban concentrations. CONCLUSIONS: These data suggest that a once-daily fixed dose of edoxaban is more effective and at least as safe as warfarin in high-risk VTE patients identified by older age, more comorbidities, and polypharmacy. CLINICAL TRIAL REGISTRATION: NCT00986154.

Relation of Stroke and Bleeding Risk Profiles to Efficacy and Safety of Edoxaban for Cardioversion of Atrial Fibrillation (from the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation [ENSURE-AF] Study).

In the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study, edoxaban was compared with enoxaparin-warfarin in patients who underwent electrical cardioversion of nonvalvular atrial fibrillation, showing comparable low rates of bleeding and thromboembolism. The present study is an ancillary analysis investigating differences in relation to stroke and bleeding risk profiles. It also determined the relation of patients' clinical risk profiles to the quality of anticoagulation control in the warfarin arm. Primary efficacy (composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death) and safety (composite of major and clinically relevant nonmajor bleeding) outcomes and time to therapeutic range (TtTR) and time in therapeutic range (TiTR) were analyzed in relation to CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, stroke (2 points), vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, age, stroke, bleeding tendency/predisposition, labile INRs, elderly age/frailty, drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess) scores. A total of 1,095 patients were randomized to edoxaban and 1,104 received enoxaparin-warfarin. Mean age was 64.3 ± 10 and 64.2 ± 11 years, respectively. Mean CHA2DS2-VASc score was 2.6 (standard deviation [SD] 1.5 and 1.4, respectively) and mean HAS-BLED score was 0.9 (SD 0.8) in both arms. There were nonsignificant trends toward lower odds ratios (ORs) for the efficacy end point in patients with CHA2DS2-VASc scores >2 and higher ORs with HAS-BLED score ≥3. Mean TiTR was >67%, with no differences between stroke or bleeding risk strata. The correlation between CHA2DS2-VASc and TtTR (p = 0.0286) and HAS-BLED and TiTR (p = 0.0286) were statistically significant. In patients who were at high risk of stroke, edoxaban had numerically lower primary efficacy end-point events and showed a trend for higher ORs, with HAS-BLED scores ≥3 compared with enoxaparin-warfarin. TtTR was shorter with higher CHA2DS2-VASc scores, whereas bleeding risk was inversely correlated with quality of anticoagulation control.

Outpatient Management in Patients with Venous Thromboembolism with Edoxaban: A Post Hoc Analysis of the Hokusai-VTE Study.

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

Anticoagulation Control in Warfarin-Treated Patients Undergoing Cardioversion of Atrial Fibrillation (from the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation Trial).

In the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) study (NCT 02072434), edoxaban was compared with enoxaparin-warfarin in 2,199 patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). In this multicenter prospective randomized open blinded end-point trial, we analyzed patients randomized to enoxaparin-warfarin. We determined time to achieve therapeutic range (TtTR); time in therapeutic range (TiTR); their clinical determinants; relation to sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) score; and impact on primary end points (composite of stroke, systemic embolic event[SEE], myocardial infarction [MI], and cardiovascular death [CVD] and composite of major + clinically relevant nonmajor bleeding). Among 1,104 patients randomized to enoxaparin-warfarin, 27% were naïve to oral anticoagulants. Mean age was 64.2 ± 11 years and mean congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching an international normalized ratio of 2.0 to 3.0 was 71%. In 695 patients who had an INR <2.0 before the first dose and who reached an INR ≥2.0, 436 had a SAMe-TT2R2 score ≤2 and 259 had a score >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (p = 0.02). TtTR was marginally related to stroke/SEE/MI/CVD (p = 0.06; odds ratio 0.23, 95% confidence interval 0.02 to 1.17) but not to any bleeding. Independent predictors of TiTR were previous vitamin K antagonist experience (p<0.01) and low hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, age >65, concomitant drugs or alcohol (HAS-BLED) score (p = 0.02). TiTR was related to any bleeding (p = 0.02; odds ratio 0.39, 95% confidence interval 0.16 to 0.88), but not stroke/SEE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.

Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists.

Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.

Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study.

BACKGROUND: There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months. METHODS: The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done. FINDINGS: In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis. INTERPRETATION: Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism. FUNDING: Daiichi Sankyo.