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Introduction: Emergent endovascular thrombectomy (EVT) is effective in improving outcomes in patients with stroke caused by large vessel occlusion. However, there are limited data on the use of EVT in patients taking an oral vitamin K antagonist (VKA), constraining guideline development around EVT use in this vulnerable population. Methods: To address this knowledge gap, we performed a retrospective, observational, cohort study based on a population-based sample of stroke admissions in the US (the AHAs “Get With The Guidelines-Stroke" Program) between October 2015 and March 2020. We aimed to determine whether use of VKA was associated with the risk of symptomatic intracranial hemorrhage (sICH) and functional outcomes in patients undergoing EVT within 6 hours of time last known well after adjusting for pre-specified confounders. Results: Of 32,715 patients (median age 72 years; 50.7% female), 3,087 were taking a VKA and 29,628 were not on an OAC prior to stroke. Patients taking VKAs were older (median age 78 vs. 71 years) but stroke severity was similar between the groups (median NIHSS 18 vs. 17). Of patients taking a VKA, 211 (6.8%) suffered a sICH whereas 1,904 (6.4%) patients not on OAC developed a sICH. VKA was not associated with sICH (adjusted odds ratio 1.20, 95% CI: 0.96-1.49). VKA use was associated with a higher risk of life-threatening systemic hemorrhage (1.2% vs. 1.02%; aOR 1.93 (1.17-3.19)) but not with mortality/discharge to hospice (27.1% vs. 20.6%; aOR 1.02 (0.90-1.14)). Patients taking a VKA prior to EVT were more likely to be able to be ambulatory at discharge (aOR 1.24 [1.11-1.39]) and to have an mRS of 0-2 (aOR 1.23 [1.07-1.42]). Conclusions: Among patients with acute ischemic stroke on VKA, EVT appears to be well tolerated without prohibitive risks of sICH. Our results provide support for the deployment of this critical, disability-reducing therapy in this population of patients with a large vessel occlusion presenting within 6 hours of time last known well.

Introduction Limited data were published on the management of direct oral anticoagulants in the insertion of pacemaker and cardiac monitoring devices. This study describes the management and outcomes of edoxaban, a direct oral factor Xa inhibitor, in patients undergoing pacemaker or monitoring device implantation in routine clinical practice. Methods and results EMIT-AF/VTE collected data of patients from Europe, Korea, and Taiwan. Timing and duration of peri-procedural interruption of edoxaban were at the treating physician's discretion. Pacemakers or monitoring devices were implanted into 136 patients who were evaluated from five days pre- until 30 days post-procedure. The primary outcomes were the incidences of acute thromboembolic events (ATE), ischemic events, and International Society on Thrombosis and Haemostasis defined Major Bleeding; secondary outcomes included incidence of Clinically Relevant Non-Major Bleeding (CRNMB) and perioperative edoxaban interruption times. Conformance with European Heart Rhythm Association (EHRA) Guidance on interruption of DOAC therapy was variable: of the cardiac monitoring device patients, where no interruption of therapy would be expected, nonetheless, 62.5% had interruption of treatment, whereas in pacemaker procedures, where interruption would be expected, 23.4% had no interruption. No ATE or ischemic events occurred. One case of CRNMB and two of minor bleeding occurred. All bleedings occurred more than three days after the procedure. Conclusion/relevance The periprocedural complication risk for edoxaban treated patients undergoing pacemaker or invasive cardiac monitoring implantation was low. This population of patients was well managed in routine practice. This article is protected by copyright. All rights reserved.

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

BACKGROUND: Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38-1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45-3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT. CONCLUSIONS: In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.

Background 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. Methods 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. Results 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. Conclusion 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.

BACKGROUND: In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES). OBJECTIVES: This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR. METHODS: The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses. RESULTS: A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types. CONCLUSIONS: At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:75 issue:21 pages:2664-2678 ispartof: location:United States status: published

BACKGROUND: Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion. HYPOTHESIS: EMIT-AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice. METHODS: Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre- until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding, acute coronary syndrome, and acute thromboembolic events. RESULTS: Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non-major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred. CONCLUSIONS: The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban. ispartof: CLINICAL CARDIOLOGY vol:43 issue:7 pages:769-780 ispartof: location:United States status: published

Background/Introduction ETNA-AF (ETNA) is a multinational, prospective, observational study evaluating the experience with edoxaban in the clinical practice of patients with atrial fibrillation (AF). ENGAGE AF-TIMI 48 was a randomized double-blind trial that tested the clinical benefits of edoxaban versus warfarin. The recommended dose is 60 mg, dose-reduced to 30 mg daily in patients with at least 1 of 3 label-indicated criteria (renal impairment [creatinine clearance: 15–≤50 mL/min], weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors). Purpose We assessed whether the effectiveness and safety of edoxaban in clinical practice were consistent with findings from the pivotal randomized clinical trial. Methods We obtained patient-level data from ETNA and ENGAGE AF-TIMI 48. We initially extracted patients from similar geographic regions, and then used propensity-score matching (PSM) to adjust key baseline characteristic differences between studies. The primary effectiveness endpoint was all stroke or systemic embolism (SSE) and mortality; the safety endpoint was major bleeding (MB). We used Cox proportional hazards models to compare event rates for the clinical outcomes between ETNA and ENGAGE AF-TIMI 48. Results 8,615 AF patients with CHADS2 score ≥2 received the 60 mg edoxaban recommended dose (5,462 ETNA; 3,153 ENGAGE AF-TIMI 48). After PSM, key baseline characteristics were well-balanced between the studies: mean age 71.0 years (SD: 9.07); for both ETNA and ENGAGE AF-TIMI 48 median CHA2DS2-VASc score and median HAS-BLED score were 4 and 2. The annualized incidence rate of SSE was 1.65% in ETNA vs 1.53% in ENGAGE AF-TIMI 48 (HR 0.98; 95% CI 0.49, 1.93; p=0.94). ETNA had similar annualized mortality, 2.81%, compared with ENGAGE AF-TIMI 48, 2.34%, (HR 1.49; 95% CI 0.84, 2.63; p=0.17). MB was less frequent in ETNA vs ENGAGE AF-TIMI 48 (1.10% vs 3.56%; HR 0.25; 95% CI 0.14, 0.44; p Conclusions The effectiveness of edoxaban in clinical practice from a large registry was consistent with efficacy findings from the randomized controlled trial. We observed a lower rate of bleeding events in the ETNA observational study compared with the ENGAGE AF-TIMI 48 trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Age is a risk factor for ischemic stroke and bleeding in patients with atrial fibrillation (AF). The large dataset from the global prospective, noninterventional ETNA-AF program allows for analysis of the impact of age on clinical events in AF patients treated with edoxaban. Purpose Evaluate the safety and effectiveness of edoxaban by age subgroups and the impact of age on clinical events. Methods Baseline patient characteristics, thromboembolic and bleeding events, and mortality data were collected from patients with 2-year follow-up in ETNA-AF program and analyzed in defined age subgroups. Cox regression analysis was conducted using age as a continuous variable and clinical events as outcome variables. Results A total of 27,617 patients were categorized into four age subgroups: Conclusion Two-year follow-up data from the global ETNA-AF program support the use of edoxaban as a safe and effective treatment for AF patients across all age groups, including the very elderly, in routine clinical care. The impact of age on the risk of ICH was smaller than that of ischemic stroke and major bleeding.

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.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Periprocedural management of patients on direct oral anticoagulants undergoing insertion of permanent pacemaker (PPM) and cardiac monitoring devices is mainly based on pharmacokinetic considerations, clinical experience, and expert opinion. Purpose To describe the characteristics, periprocedural management, and events of edoxaban patients undergoing implantation of PPM/monitoring devices. Methods From the global EMIT-AF/VTE registry, which includes edoxaban patients undergoing any diagnostic or therapeutic procedures, those with PPM/cardiac monitoring device implantation were observed from five days prior to 30 days post procedure. Events documented included the incidence of International Society on Thrombosis and Haemostasis defined Major Bleeding, Clinically Relevant Non-Major Bleeding (CRNMB), acute thromboembolic events (ATE) and perioperative edoxaban interruption times. Results PPM or invasive cardiac monitoring devices were implanted in 136 patients. Conformance with European Heart Rhythm Association Guidance for the interruption of anticoagulation was variable: of the cardiac monitoring patients, 62.5% had interruption of treatment, whereas in PPM procedures 23.4% had no interruption. One case of CRNMB and two cases of minor bleeding were documented. All bleedings seem non procedure-related since they occurred > three days post procedure. There were no ATE. Conclusions Relevant complications for edoxaban treated patients undergoing PPM or invasive cardiac monitoring procedures were rare. This population of patients is apparently well managed in routine practice, but further investigation of risk factors is justified. TablePatient characteristics Parameter All subjectsN = 136 All pacemakerN = 128 Insertion first pacemakerN = 89 Change pacemakerN = 39 Monitoring deviceN = 8 Age, mean (SD)Male, n (%) 75.1 (10.1)85 (62.5) 75.0 (10.3)83 (64.8) 75.7 (9.9)57 (64.0) 73.5 (11.2)26 (66.7) 76.3 (4.3)2 (25.0) BMI, mean (SD) 27.1 (5.5) 27.2 (5.6) 27.2 (6.0) 27.3 (4.5) 25.2 (4.3) AF, n (%)‡ 135 (99.3) 127 (99.2) 89 (100.0) 38 (97.4) 8 (100.0) VTE, n (%)‡ 3 (2.2) 3 (2.3) 1 (1.1) 2 (5.1) 0 CrCL, mean (SD) 63.8 (26.4) 64.1 (26.7) 62.3 (26.2) 68.3 (27.9) 58.9 (21.8) CrCL, ≤50, n (%) 43 (31.6) 41 (32.0) 33 (37.1) 8 (20.5) 2 (25.0) HAS-BLED Score, mean (SD) 2.0 (1.2) 1.9 (1.2) 1.9 (1.0) 2.1 (1.6) 2.6 (0.5) CHA2DS2-VASc Score, mean (SD) 3.7 (1.6) 3.7 (1.6) 3.7 (1.5) 3.8 (1.9) 3.1 (0.6) Edoxaban 30 mg/day, n (%) 49 (36.0) 46 (35.9) 32 (36.0) 14 (35.9) 3 (37.5) Edoxaban 60 mg/day, n (%) 86 (63.2) 81 (63.3) 56 (62.9) 25 (64.1) 5 (62.5) AF, atrial fibrillation; BMI, body mass index; CrCL, creatinine clearance; VTE, venous thromboembolism. ‡Two patients had both AF and VTE.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background The optimal periprocedural management of direct oral anticoagulants (DOAC), including edoxaban, in patients undergoing catheter-based cardiovascular procedures is unknown, and mainly based on physician opinion and experience. Purpose To assess real-world management of edoxaban in patients undergoing cardiovascular procedures, and to report their clinical events. Methods Global EMIT-AF/VTE is a prospective study of periprocedural management in edoxaban-treated patients undergoing diagnostic and therapeutic procedures. We report the data from patients undergoing cardiovascular procedures. Timing and duration of edoxaban interruption were at the treating physician’s discretion. Outcomes were collected from 5 days before until 30 days post procedure. Primary outcome was the incidence of major bleeding (MB); secondary outcomes included incidence of clinically relevant non-major bleeding (CRNMB) and acute thromboembolic events (ATE). Results Data was collected from 301 and 311 procedures with arterial or venous access, respectively. Baseline characteristics are shown in Table 1. Edoxaban was not interrupted in 36.9% of arterial and 52.7% of venous procedures. Edoxaban was interrupted pre-procedure in 41% of arterial and 32.8% of venous procedures. The median periprocedural interruption was 2 days. The overall incidence of bleeding was very low. Any bleeding was reported in 8 patients undergoing arterial and 10 patients undergoing venous procedures (2.7% and 3.2%). MB or CRNMB occurred in 2 arterial and 3 venous procedures (0.7% and 1.0%) and ATE occurred in 5 arterial and 1 venous procedure (1.7% and 0.3%, Table 1). Conclusions In this study, the periprocedural risks of bleeding and thrombotic events were low. About a third of arterial access procedures and half of venous access procedures were performed without edoxaban interruption. Arterial(n = 301) Venous(n = 311) Baseline characteristics Age, year, mean (SD)Male, n (%)Weight (kg), mean (SD) 71.9 (8.5)211 (70.1%)80.8 (16.7) 64.6 (11.1)215 (69.1%)84.1 (17.4) CrCL (mL/min), mean (SD) CHA2DS2-VASc score, mean (SD)HAS-BLED score, mean (SD) 73.5 (29.8) 3.3 (1.5)2.0 (1.0) 88.9 (35.5) 2.2 (1.5)1.3 (1.0) Edoxaban 60 mg / 30 mg, % 73% / 26% 88% / 26% Coronary heart disease, n (%) Congestive heart failure, n (%) 101 (33.6%) 58 (19.3%) 51 (16.4%) 33 (10.6%) Interruption of edoxaban, n (%) No interruption Pre-procedure only Post-procedure only Pre- and post-procedure 111 (36.9%)125 (41.5%)12 (4.0%)53 (17.6%) 164 (52.7%)102 (32.8%)8 (2.6%)37 (11.9%) Clinical events, n (%) MB or CRNMBACSStroke/Transient ischemic attackCV mortalityAll-cause mortality 2 (0.7%)2 (0.7%)3 (1.0%)1 (0.3%)2 (0.7%) 3 (1.0%) 01 (0.3%)00

Annually 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated.Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality.Of the 1442 patients, 280 (19%) were 65, 550 (38%) were 65-74, 514 (36%) 75-84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those 65, and seven in patients aged 75 years.Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed.NCT# 02950168, October 31, 2016.

Edoxaban is approved for stroke prevention in nonvalvular atrial fibrillation (AF) patients in numerous countries. Outcome data are sparse on edoxaban treatment in AF patients from routine clinical practice, especially in Asian patients. Global ETNA (Edoxaban in rouTine cliNical prActice) is a noninterventional study that integrates data from patients from multiple regional registries into one database. Here, we report the 1-year clinical events from AF patients receiving edoxaban in South Korea and Taiwan. Clinical events assessed included bleeding, strokes, systemic embolic events, transient ischemic attacks (TIAs), and all-cause and cardiovascular death. Overall, 2677 patients (mean (range) age 72 (66–78) years, male 59.7%, mean CHA2DS2-VASc score ± standard deviation 3.1 ± 1.4) were treated with 60 or 30 mg edoxaban and had 1-year follow-up data. The annualized event rates for major bleeding and clinically relevant non-major (CRNM) bleeding were 0.78% and 0.47%, respectively. Annualized event rates for ischemic stroke and hemorrhagic stroke were 0.90% and 0.19%, respectively. Event rates for major and CRNM bleeding and rates of ischemic stroke and TIA were higher in Taiwanese patients than in Korean patients. Event rates were low and similar to those found in other studies of edoxaban in Korean and Taiwanese AF patients, thus supporting the safety and effectiveness of edoxaban in this population.

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.

Background In AF patients on direct oral anticoagulants (DOAC), safety and effectiveness vary with dose. This might impact treatment decisions. Purpose To investigate the effects of dosing of the DOAC edoxaban in AF patients on safety and effectiveness during 1-year observation in a real-world setting. Methods The Global ETNA-AF NIS included 26,823 patients. Baseline data by edoxaban dosing (60mg/30mg) and their influences on the safety (major bleeding [MB], clinically relevant non-major bleeding [CRNMB]), and effectiveness (stroke, systemic embolism, myocardial infarction [MI], death) were investigated (Table). Results Figure shows the breakdown by dose (60mg vs 30mg) and recommended (rec) vs non-recommended (non-rec) dosing. Patients on non-rec 30mg vs on rec 60mg edoxaban were older (mean ± SD: 74±9 vs 70±9 y); had lower creatinine clearance (72.2±20.6 vs 85.8±26.8 mL/min); and had more comorbidities, history of MB (2.1% vs 1.1%), and strokes (11.0% vs 8.6%). Non-rec 60mg vs rec 30mg patients were younger (75±9 vs 78±9 y), had fewer comorbidities, history of MB (1.2% vs 2.6%), and strokes (10.2% vs 16.4%). In non-rec 30mg vs rec 60mg, MB was not lower and ischaemic events were not higher. In non-rec 60mg vs rec 30mg, no increase in MB, CRNMB or ischaemic events was seen. Conclusion Edoxaban was prescribed at the label recommended dose in the vast majority of patients. Non-rec 30mg patients were sicker than rec 60mg patients while non-rec 60mg patients were less sick than rec 30mg patients. Overall event rates were low, and ischaemic event rates of non-rec 30mg and bleeding event rates of non-rec 60mg were not numerically higher than that of corresponding rec dosing groups. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background Vitamin K antagonists (VKA) and non-VKA oral anticoagulants (NOACs) are used to prevent thromboembolic conditions in patients with atrial fibrillation (AF). Unlike VKA, NOACs have fixed dosage schemes, do not require regular laboratory tests, and have fewer drug and food interactions. The use of NOACs has increased substantially in recent years in Germany. However, there is limited evidence on the comparative effectiveness and safety between different NOACs and VKA in real-world settings. Purpose The objective of the study was to compare the clinical outcomes, including systemic embolism (SE), ischemic stroke (IS), and major bleeding, of edoxaban with other NOACs (apixaban, dabigatran, rivaroxaban) and VKA in AF patients in Germany. Methods Using an administrative database from our institution (Deutsche Analysedatenbank für Evaluation und Versorgungsforschung) between January 2013 and December 2017, a retrospective cohort study was conducted to compare the effectiveness (risk of SE or IS) and safety (risk of major bleeding) in NOAC-naïve AF patients who initiated anticoagulant therapy. Continuous enrolment for 12 months before anticoagulant initiation was required to assess baseline characteristics. Patients were followed up until (1) the first outcome event (SE, IS, or major bleeding), (2) disenrollment from health plans, or (3) discontinuation of the index NOAC or VKA or therapy switch, whichever occurred first. Inverse probability treatment weighting (IPTW) using propensity score was applied to control for differences in baseline characteristics. Cox proportional hazards models were used to estimate the hazard ratios (HR) for each outcome comparing edoxaban versus other NOACs and VKA. Sensitivity analyses were conducted with follow-up period cut-off at 1 year. Results A total of 1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA patients were included. Patient cohorts were well balanced after weighting. The adjusted risks of SE or IS were lower for edoxaban compared to apixaban (HR 0.83, 95% CI 0.69–0.99), dabigatran (HR 0.54, 95% CI 0.40–0.74), rivaroxaban (HR 0.72, 95% CI 0.60–0.87), and VKA (HR 0.65, 95% CI 0.53–0.78) (all p Conclusions Edoxaban was associated with a significantly lower risk of SE or IS compared to other NOACs and VKA, indicating improved effectiveness. Edoxaban also had a favourable safety profile with a significantly lower risk of major bleeding compared to dabigatran, rivaroxaban, and VKA. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Graphical Abstract Graphical Abstract, Aims Consensus is lacking regarding the best treatment for coronary in-stent restenosis (ISR). The two most effective treatments are angioplasty with paclitaxel-coated balloon (PCB) and repeat stenting with drug-eluting stent (DES) but individual trials were not statistically powered for clinical endpoints, results were heterogeneous, and evidence about comparative efficacy and safety in relevant subsets was limited. Methods and results The Difference in Anti-restenotic Effectiveness of Drug-eluting stent and drug-coated balloon AngiopLasty for the occUrrence of coronary in-Stent restenosis (DAEDALUS) study was a comprehensive, investigator-initiated, collaborative, individual patient data meta-analysis comparing angioplasty with PCB alone vs. repeat stenting with DES alone for the treatment of coronary ISR. The protocol was registered with PROSPERO (CRD42017075007). All 10 available randomized clinical trials were included with 1976 patients enrolled, 1033 assigned to PCB and 943 to DES. At 3-year follow-up, PCB was associated with a significant increase in the risk of target lesion revascularization (TLR) compared with DES [hazard ratio (HR) 1.32, 95% CI 1.02–1.70, P = 0.035; number-needed-to-harm 28.5]. There was a significant interaction between treatment effect and type of restenosed stent (P = 0.029) with a more marked difference in patients with DES-ISR and comparable effects in patients with bare-metal stent-ISR. At 3-year follow-up, the primary safety endpoint of all-cause death, myocardial infarction, or target lesion thrombosis was comparable between treatments (HR 0.80, 95% CI 0.58–1.09, P = 0.152). A pre-specified subgroup analysis indicated a significant interaction between treatment effect and type of DES used to treat ISR (P = 0.033), with a lower incidence of events associated with PCB compared with first-generation DES and similar effect between PCB and second-generation DES (HR 1.06, 95% CI 0.71–1.60, P = 0.764). Long-term all-cause mortality was similar between PCB and DES (HR 0.81, 95% CI 0.53–1.22, P = 0.310); results were consistent comparing PCB and non-paclitaxel-based DES (HR 1.42, 95% CI 0.80–2.54, P = 0.235). Myocardial infarction and target lesion thrombosis were comparable between treatments. Conclusions In patients with coronary ISR, repeat stenting with DES is moderately more effective than angioplasty with PCB at reducing the need for TLR at 3 years. The incidence of a composite of all-cause death, myocardial infarction, or target lesion thrombosis was similar between groups. The rates of individual endpoints, including all-cause mortality, were not significantly different between groups.

Non‐vitamin K dependent oral anticoagulants (NOAC) are now widely used in patients with nonvalvular atrial fibrillation (NVAF) for stroke prevention and in patients with venous thromboembolism (VTE) for the treatment and secondary prevention of the disease. Among NOAC, edoxaban demonstrated noninferiority to warfarin for stroke prevention in NVAF and for VTE treatment, with superior safety. EMIT‐AF/VTE (Edoxaban Management in Diagnostic and Therapeutic Procedures) ({"type":"clinical-trial","attrs":{"text":"NCT02950168","term_id":"NCT02950168"}}NCT02950168) is a multicenter, prospective, and noninterventional registry study designed to collect detailed information on the periprocedural management of patients with NVAF and VTE receiving edoxaban. The primary objective of EMIT‐AF/VTE is to document the periprocedural management of patients receiving edoxaban and to collect data on safety and other outcomes in these patients. The primary safety outcome is the rate of major bleeding. Other assessments include the evaluation of efficacy outcomes, periprocedural dosing, and timing of edoxaban. The observation period will start 5 days prior to the procedure and end 30 days post‐procedure. EMIT‐AF/VTE will aim to prospectively enroll up to approximately 1400 procedures from Europe. Enrollment commenced in December 2016 and will be completed in July 2018. As of July 2018, before database lock and with several procedure forms still temporarily inserted, a preliminary number of 1204 patients have been enrolled, who underwent a total of 1453 procedures. The prospective EMIT‐AF/VTE registry program will expand the knowledge of periprocedural management of patients with NVAF and VTE receiving edoxaban in clinical practice.

Introduction Periprocedural management of patients on direct oral anticoagulants (DOAC) undergoing major surgical procedures is mainly based on pharmacokinetic considerations, clinical experience as described in the Dresden Registry (Beyer-Westendorf et al. Eur Heart J. 2014;35: 1888-186.) and the PAUSE study (Douketis JD et al. JAMA Intern Med. 2019;2019;179:1469-78), and on expert opinion. The objective of this study was to describe the background characteristics, periprocedural management, and outcomes of patients taking edoxaban who underwent major surgery in routine clinical practice. Methods Patients evaluated were participants in the EMIT AF/ VTE study (Colonna P et al. Clin Cardiol. 2020 Jul;43:769-80) which analyzed data on the risks of bleeding and thromboembolic events in 1,479 patients taking edoxaban who underwent unselected diagnostic or therapeutic procedures in routine clinical practice. Patients undergoing major surgery were compared with those who underwent non-major surgery. Physicians directed management of edoxaban, especially for dosing interruption, in accordance with locally approved labelling and guidelines such as those of the European Heart Rhythm Association (EHRA). Patients were evaluated from five days before until 29 days after the procedure. The primary outcome was the incidence of major bleeding as defined by the International Society on Thrombosis and Haemostasis; secondary outcomes included the incidence of clinically relevant non-major bleeding (CRNM), acute coronary syndrome (ACS), acute thromboembolic events (ATE) as well as the perioperative interruption times and use of bridging agents. Results Of the 1,478 patients, 128 (8.7%) underwent major-surgery as defined in the Dresden registry and PAUSE study. Background characteristics are summarized in Table 1 and medical history in Table 2. Surgeries by medical specialties are listed in Table 3. Major surgery vs non-major surgery patients had more often atrial fibrillation and dyslipidemia and exhibited higher CHA 2DS 2-VASc and HAS-BLED scores. Peri-procedurally, heparin was used significantly more often in patients with major surgery vs non-major surgery (42/128 (32%) vs 142/1351 (10.5%), p Outcomes are summarized in Table 4. There were no significant differences in severe adverse outcomes between the two groups. Pre-procedural and post procedural interruption of edoxaban was longer in the major surgery group. See Table 5. Discussion The edoxaban interruption pattern was statistically different between major and non-major surgery patients. The rates of peri-procedural bleeding and acute thromboembolic events were low when patients were managed according to a clinical experience-driven management protocol. This is in line with the results in prior publications evaluating other direct oral anticoagulants. These results are important to optimize clinical management of patients undergoing elective procedures and will help to support guidelines for the peri-procedural management of edoxaban. Figure 1 Figure 1. Disclosures von Heymann: Daiichi Sankyo: Honoraria, Research Funding; Bayer AG: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; NovoNordisk Pharma: Honoraria, Research Funding; Mitsubishi Pharma: Honoraria, Research Funding; Biotest GmbH: Honoraria, Research Funding; Grunenthal GmbH: Honoraria, Research Funding; HICC GbR: Honoraria, Research Funding; German Society of Anaesthesiology and Intensive Care Medicine: Honoraria, Other: Other Mandated to write several guidelines and part of writing groups of guidelines, Research Funding; European Society of Cardiothoracic Anesthesiologists: Other: Other Mandated to write several guidelines and part of writing groups of guidelines; Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: Honoraria, Research Funding; European Society of Anaesthesiology and Intensive Care (ESAIC): Other: Mandated to write several guidelines and part of writing groups of guidelines. Unverdorben: Daiichi Sankyo: Current Employment. Colonna: Boehringer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; European Society of Cardiology: Other: Mandated to write ESC-Guidelines on AF; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Ortiz: Bayer: Consultancy; Daiichi Sankyo: Consultancy; Boehringer: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Saxena: Recor Medical Inc: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding, Speakers Bureau; The Medicines Company: Consultancy, Research Funding, Speakers Bureau; Ablative Solutions Inc: Consultancy, Research Funding, Speakers Bureau; Vascular Dynamics Inc: Consultancy, Honoraria, Speakers Bureau; Esperion Inc: Consultancy, Honoraria, Speakers Bureau; Vifor Pharma: Honoraria, Speakers Bureau. Vanassche: Bayer: Consultancy, Speakers Bureau; Boehringer Ingelheim,: Consultancy, Speakers Bureau; Pfizer/BMS: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Weitz: Daiichi Sankyo: Consultancy, Speakers Bureau. Wilkins: Daiichi Sankyo: Honoraria. Chen: Daiichi Sankyo: Current Employment.

Background: The optimal interruption schedule for NOACs in patients undergoing invasive procedures has not been determined. This analysis describes periprocedural interruption of edoxaban in real world EMIT AF/VTE study. Methods: EMIT AF/VTE was a prospective, non-interventional study conducted in 7 European countries that collected detailed information on periprocedural management of edoxaban from 5 days before to 30 days after procedure in patients with AF or VTE. Results: Among 1155 patients, pre-procedural interruption occurred in 781 (68%) patients (median 2 days, IQR 1.0-2.0) and post-procedural interruption in 308 (27%) patients (median 3 days, IQR 1.0-8.0); 279 (24.2%) patients had both pre- and post-procedural interruption. Edoxaban interruption in some patients differed from 2018 EHRA Recommendations for NOAC use in AF. Of 294 patients receiving minor risk procedures, for whom no interruption is recommended, 173 (58.8%) had preprocedural interruption (median 1 day). Of 581 patients with low bleeding risk procedures, for whom ≥24h preprocedural interruption is recommended, 188 (32.4%) had no interruption. Of 280 patients receiving high bleeding risk procedures, for whom ≥48h interruption is recommended, 46 (16.4%) had no interruption. Clinical events are shown in Table. Conclusion: Edoxaban interruption schedules in routine practice were not always consistent with EHRA guidelines; nevertheless, rates of clinically significant bleeding or acute thromboembolic events or coronary syndromes were low in the EMIT study. Table Disclosures Colonna: Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; BayerAG: Honoraria; Italian Cardiology Association: Other: Non-financial support; European Society of Cardiology: Other: Non-financial support; Pfizer/BMS: Honoraria. von Heymann:Daiichi Sankyo: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bayer AG: Honoraria; Pfizer GmBH: Honoraria; CSL Behring: Honoraria; NovoNordisk Pharma: Honoraria; EACTA and EACTS: Other; DGGG: Other; Mitsubishi Pharma: Honoraria; Ferring GmbH: Honoraria; Biotest GmbH: Honoraria; Leo Pharma GmBH: Honoraria; German Society of Anaesthesiology and Intensive Care Medicine: Other. Saxena:Daiichi Sankyo: Honoraria, Research Funding. Vanassche:Boehringer Ingelheim: Honoraria; 367 Leo Pharma: Honoraria; Bayer: Honoraria; Daiichi Sankyo: Honoraria, Research Funding. Jin:Daiichi Sankyo: Current Employment. Wilkins:Daiichi Sankyo: Honoraria. Chen:Daiichi Sankyo: Current Employment. Unverdorben:Daiichi Sankyo: Current Employment.

Background As populations age, prevalence of atrial fibrillation (AF) and ensuing need for oral anticoagulation increase. Benefits and risks of nonvitamin K antagonist oral anticoagulants such as edoxaban in the frail, elderly population with AF in regular clinical care is of special interest. Purpose Data from Global ETNA-AF capturing almost 2ehz745.1164 patients treated with edoxaban in Europe, Japan, and Korea/Taiwan, was analyzed to compare outcomes in patients Methods Global ETNA-AF is a multinational, multicentre, prospective, noninterventional program (EU: NCT02944019, Japan: UMINehz745.116417011, Korea/Taiwan: NCT02951039). Demographics, baseline characteristics, and 1-year outcome data were reported for 19416 patients classified into 3 age categories. Results At 1-year follow-up, rates of major bleeding (including intracranial haemorrhage [ICH]) and ischaemic stroke were generally low. All-cause and CV mortality increased with age; CV mortality was a minor proportion of all-cause mortality in all age groups. Rates of major bleeding and ischaemic stroke increased slightly with age, but to a lesser extent than all-cause and CV mortality. There was no increase in the rate of ICH with age. Conclusion Global data from this set of unselected patients support the use of edoxaban as a safe and effective treatment in elderly and very elderly patients with AF in regular clinical care. Acknowledgement/Funding Daiichi Sankyo

Background Randomized 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. Methods The 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. Results Globally, enrollment began in early 2015 and is ongoing. Conclusions Global 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.

Transcatheter aortic valve implantation, also called transcatheter aortic valve replacement (TAVR), is the treatment of choice for patients with severe aortic stenosis and intermediate to high operative risk. A significant portion of TAVR patients have atrial fibrillation (AF) requiring chronic oral anticoagulation. In moderate- to high-risk AF patients, the direct factor Xa inhibitor edoxaban is noninferior to vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism with less bleeding and cardiovascular deaths. ENVISAGE-TAVI AF (NCT02943785) is a multinational, multicenter, prospective, randomized, open-label, blinded end point evaluation study comparing edoxaban to VKA-based therapy in approximately 1,400 patients with an indication for chronic oral anticoagulation after successful transfemoral TAVR. The coprimary end points are to assess the differential effects of the 2 treatments (a) on net adverse clinical events (the composite of all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, and major bleeding events) and (b) on major bleeding. Twelve hours to 5 days after successful TAVR, patients will be randomized to 60 mg daily oral edoxaban or any VKA (international normalized ratio: 2.0-3.0 or 1.6-2.6 [numbers inclusive] in Japan if age ≥ 70 years). Antiplatelet therapy may be administered per physician's discretion. Randomization will be stratified by edoxaban dose reduction (per local label). Treatment duration will be up to 36 months. The study is powered (80%) to detect noninferiority (margin for the hazard ratio: 1.38) for the composite primary end points, followed by superiority testing.

Aims: Treatment of bare metal in-stent restenosis with the paclitaxel-coated balloon catheter based on the PACCOCATH® technology has yielded superior six-month angiographic and one-year clinical results compared to a paclitaxel-eluting stent. The three-year clinical follow-up is presented. Methods and results: One hundred and thirty-one patients with coronary bare metal in-stent restenosis (>70%, length

Chronic wounds present a significant societal burden in their cost of care, and they reduce patient quality of life. Key components of wound care include such measures as debridement, irrigation, and wound cleaning. Appropriate care removes necrotic tissue and reduces wound bioburden to enhance wound healing. Physical cleaning with debridement and irrigation is of documented efficacy. Wounds may be washed with water, saline, or Ringer's solution or cleaned with active ingredients, such as hydrogen peroxide, sodium hypochlorite, acetic acid, alcohol, ionized silver preparations, chlorhexidine, polyhexanide/betaine solution, or povidone-iodine--the majority of which are locally toxic and of limited or no proven efficacy in enhancing wound healing. Although the consensus opinion is that these topical cleaning agents should not be routinely used, recent clinical evidence suggests that polyhexanide/betaine may be nontoxic and effective in enhancing wound healing. Further well-designed studies are needed.

Background: Randomized trials assess the potential of a medical device in well defined indications while “all comer studies” reveal the device performance in the real clinical environment. Aims: This ‘all comers’ registry assessed the 10-month outcome of the Coroflex® Please drug-eluting stent in Europe and Asia by clinically driven major adverse cardiac events. Methods: The Coroflex® Please Registry was an international, prospective, multicenter registry enrolling patients with symptomatic ischemic heart disease. The primary endpoint was clinically driven target lesion revascularization (TLR) at 9 months. Secondary endpoints were technical success, in-hospital outcomes, definite stent thrombosis and major adverse cardiac events (death, myocardial infarction, or TLR) for subgroup analyses. Results: Of the enrolled 1230 patients (63.6 ± 11.2 years, 33.9% diabetics), 339 (27.6%) had an acute coronary syndrome, 148 (12.1%) STEMI and 191 (15.6%) NSTEMI. After 10.5 ± 3.8 months (follow-up rate 92.8%), the target lesion revascularization rate (TLR) was 7.8% overall, 8.3% in STEMI, and 11.3% in NSTEMI patients. Total MACE was 11.1% and significantly higher in ACS with either diabetes mellitus (22.9%, p = 0.017) or age ≥75 years (25.4%, p = 0.026). In European and Asian patients MI rates (5.2% vs 3.1%, p = 0.135) and cardiac death rates (1.6% vs 0.9%, p = 0.414) were similar. The MACE rate was higher in Europe (13.6% vs 4.7%, p

AIMS Coronary lesions in diabetics (DM) are associated with a high recurrence following percutaneous coronary intervention (PCI), even after drug-eluting stent (DES) deployment. Encouraging clinical data of the drug-eluting balloon catheter (DEB) SeQuent Please warrant its investigation in these patients. METHODS AND RESULTS Eighty-four diabetic patients (60.8 ± 9.1 years, 76.2% male) were randomised to either the DEB SeQuent Please or the DES Taxus Liberte to compare the 9-month clinical and angiographic outcome of PCI in native coronary arteries. Comparing the DEB vs. the DES the 9-month results (follow-up DEB 39/45 [86.7%], DES 36/39 [92.3%]) are statistically not different at the 0.05 level for the primary endpoint of in-segment (0.37 ± 0.59 mm vs. 0.35 ± 0.63 mm) and in-stent (0.51 ± 0.61 mm vs. 0.53 ± 0.67 mm) late lumen loss, overall and cardiac deaths (2/45 [4.4%] and 3/45 [6.7%] vs. 0), target lesion revascularisation (3/45 [8.9%] vs. 4/39 [10.3%]), the total MACE rate (6/45 [13.3%] vs. 6/39 [15.4%]), and the event free survival after 10.2 ± 3.8 months (Kaplan-Meier analysis, p

Previous studies indicate that cigarette smokers have a 5–30% higher white blood cell counts (WBC) compared to non-smokers and higher red blood cell counts. Methods: This study was to pool hematology data from three similar studies and analyze the data for effects on WBC, its subpopulations, platelets, red blood cell count (RBC) and hematocrit in adult cigarette smokers three days after using an electrically heated cigarette smoking system (EHCSS) as a potential reduced exposure product (PREP) or no-smoking compared to smoking a conventional cigarette. Results: Lower exposure to cigarette smoke in adult, long term smokers, by using an EHCSS or stopping smoking, leads to statistically significant decreases of up to 9% in WBC, neutrophils, lymphocytes, platelets, RBC and hematocrit within three days. Switching from CC-smoking to EHCSS-smoking or no-smoking resulted in lower WBC and vice versa within 3 days. Conclusion: This clinical model may be used as a screening tool to find new technologies that could provide insights on changes in inflammation resulting from the change in cigarette smoke.

Background and Objectives: Paclitaxel-coated stents have proven their efficacy for reducing restenosis in de novo coronary artery lesions and in-stent restenoses with superiority compared to bare metal stents. This study was performed to evaluate the procedural and 1 year results of the Paclitaxel-eluting Coroflex™ Please stent in coronary artery lesions. Methods: One-hundred and twenty-nine patients (66.2 ± 8.2 years, 31.0% diabetics, 20.2% unstable angina, 41.8% multivessel disease) were enrolled per protocol for elective single stent deployment into native de novo or post-PTCA restenotic coronary lesions.The mean reference diameter was 2.84 ± 0.43 mm, the lesion length 12.51 ± 4.6 mm, and the minimal lumen diameter 0.75 ± 0.29 mm. Follow-up was performed clinically in 129/129 (100%) after 6 and 12 months and angiographically in 120/129 (93%) patients after 6 months. Results: The success rates of the procedure and deployment were 100% and 95.3%, respectively. The in-stent late loss and the late-loss index were 0.27 ± 0.59 mm and 0.17 ± 0.40 resulting in binary in-stent restenoses in 16/120 (13.3%) subjects and in-segment restenoses in 20/120 (16.7%) subjects. Major adverse cardiac events occurred in 23/129 (17.8%) during the first 6 months of follow-up with 3/129 (2.3%) myocardial infarctions, 1/129 (0.8%) secondary to stent thrombosis. From 6 to 12 months, 2/129 (1.6%) nonlesion related PCI were performed. Conclusion: The data of the Paclitaxel-eluting Coroflex™ Please stent evaluated in PECOPS II are within the range of the other currently available Paclitaxel-eluting stent. (J Interven Cardiol 2010;23:160-166)

Genes influence smoking behavior, affect the metabolism of nicotine and specific chemicals produced during combustion, and enhance (or diminish) pathomechanistic pathways associated with the atherogenic potential of smoking, including oxidative stress, its inflammatory burden or procoagulant potential. Genome-wide association studies have revolutionized the search for new functional genetic markers with ever increasing marker density and the precision in identifying new genetic loci without the need for prior knowledge of functional pathways. Nevertheless, the statistical challenge remains to identify the few true positives, the need for replication of findings and the tedious work of identifying functional genetic variants and their mode of action. Genetic variation within a gene or in areas of the genetic code that control the expression of such a gene is far from being understood. Major advances include the detection of large-scale copy-number variants in the human genome and the demonstration of the decisive role of ‘miRNA’ in controlling gene expression. The role of the genomic methylation pattern in controlling the transcription of the underlying genetic sequence and its role in interacting with environmental influences have yet to be explored in depth. Although candidate genes and their genetic variants have been associated with atherosclerosis and cigarette smoking, a major breakthrough has still to be made.

Measurement of endothelial function using peripheral arterial tonometry (PAT) has been reported to be significantly correlated with coronary blood flow. Repetitive PAT measurements were performed in 22 healthy male subjects at test intervals of 1 hour (5 times within a day) and 0.5 hours (7 times within a day) to evaluate the variability of the reactive hyperemia index (RHI). A total of 10 subjects underwent additional repetitive PAT at 2 hour intervals (7 times within a day) for 3 consecutive days to evaluate the diurnal effects and day-to-day reproducibility. The RHI from each test was computed automatically based on a 15 minute recording of pulse wave amplitude changes of the fingers in response to reactive hyperemia induced by a 5 minute occlusion of the brachial artery. Intrasubject variability of RHI at different test intervals, defined as the coefficient of variation (CV) was 15.3% +/- 5.3%, 16.1%+/- 7.8%, and 22.6% +/- 3.9% for the tests at 0.5 hour, 1 hour, and 2 hour intervals, respectively. Reactive hyperemia indices measured at the same time points on each of the 3 days were not statistically significant. The interday reproducibility, presented as intraclass correlation coefficients (ICC) ranged from - 0.07 to 0.47. We conclude that repetitive PAT measurements have no carryover effect on RHI at 1 hour, and 2 hour intervals, and the RHI measured at 0.5 hour intervals is associated with a trend of increase. The interday reproducibility is relatively low and the intrasubject variability of RHI is similar to those observed in studies of flow-mediated dilation using brachial artery ultrasound scanning.

The normal endothelium inhibits platelet and leukocyte adhesion to the vascular surface maintaining a balance of profibrinolytic and prothrombotic activity. Endothelial function is assessed largely as endothelium-dependent vasomotion, partly based on the assumption that impaired endothelium-dependent vasodilation reflects the alteration of important endothelial functions. Atherosclerotic risk factors, such as hypercholesterolemia, hypertension, diabetes and smoking, are associated with endothelial dysfunction. In the diseased endothelium, the balance between pro- and antithrombotic, pro- and anti-inflammatory, pro- and antiadhesive or pro- and antioxidant effects shifts towards a proinflammatory, prothrombotic, pro-oxidative and proadhesive phenotype of the endothelium. A common mechanism underlying endothelial dysfunction is related to the increased vascular production of reactive oxygen species. Recent studies suggest that inflammation per se, and C-reactive protein in particular, may contribute directly to endothelial dysfunction. The loss of endothelial integrity is a hallmark of atherosclerosis and the causal possible link between each individual risk factor, the development of atherosclerosis and the subsequent clinical events, such as myocardial infarction or stroke.

CM3, a highly cross-linked cellulose in capsule form, expands in the stomach to a size several fold of its original volume. It is purported to induce a prolonged feeling of satiation and a delay in gastric emptying, thus promoting weight loss. We examined whether CM3 delays gastric emptying (using the stable isotope (13)C-octanoic breath test) and whether it influences subjective feelings of appetite sensations (using visual analog scales, VASs). We performed a double-blind randomized placebo-controlled crossover trial in 19 moderately obese but otherwise healthy subjects (mean age 55 +/- 9 years, BMI 31.1 +/- 4.6 kg/m(2)). The subjects were treated with six capsules of CM3 or matching placebo 30 min before a standardized solid meal. Breath collection and VASs were performed over 4 h every 15 min and 30 min, respectively. Half-excretion time of (13)CO(2) in breath, indicating gastric emptying half time, was the primary outcome parameter. The study was powered to detect a change in gastric emptying of 20-30 min. Mean (13)CO(2) half-excretion time changed from 2.3 +/- 0.4 to 2.4 +/- 0.33 h (mean difference +6 min, 95% confidence interval (CI) -3 to +15 min; P = 0.17). Appetite sensations (hunger, satiation, fullness, prospective food consumption, desire to eat something sweet, salty, savory, or fatty) changed over time during the course of the postprandial phase but were not influenced by CM3 (repeated measures ANOVA). In obese subjects, acute administration of the weight-loss supplement CM3 does not delay gastric emptying and does not influence subjective appetite sensations.

Dyspnea is a common symptom physiologically associated with strenuous exercise and pathologically reflecting well-known diseases and conditions that are predominantly pulmonary, cardiovascular, and weight-related in origin. Dyspnea improves with appropriate measures that enhance physical performance and treatment of the underlying diseases. Dyspnea is less commonly triggered by other causes such as the environment (e.g., ozone), drugs, and others, some of which do not seem to affect bronchopulmonary function as evidenced by normal results of comprehensive pulmonary function testing. In cardiovascular medicine, dyspnea has recently attracted attention because it has been reported that this symptom occurs more frequently with the administration of the new oral reversibly-binding platelet P2Y12 receptor inhibitors ticagrelor [1-6], cangrelor [7-10], and elinogrel [11]. This paper succinctly addresses the current understanding of the pathophysiology, clinical presentation, and diagnostics of dyspnea, associated either with bronchopulmonary function impairment, as triggered mainly by pulmonary and cardiovascular diseases, or without bronchopulmonary function impairment, as induced by endogenous or external compounds such as drugs in order to provide a context for understanding, recognizing and managing P2Y12 inhibitor-induced dyspnea.