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Background:  We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk., Methods:  This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies., Results:  The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 ( n  = 427) and 93.3 ± 57.8 ng/mL ( n  = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 ( n  = 79; 12.4 ± 12.1 and n  = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group ( n  = 83; 25.1 ± 36.6 and n  = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study ( n  = 39; 18.4 ± 11.2 and n  = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not., Conclusion:  PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight., Competing Interests: T.Y. received personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; grants and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and Bristol Myers Squibb K.K.; personal fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Toa Eiyo Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. outside the submitted work. Y.I., M.F., and T.H. are employees of Daiichi Sankyo Co., Ltd. S.H. is an employee of Certara, Inc. K.O. received grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; personal fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson and Johnson K.K., and Bayer Yakuhin, Ltd. outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: This prospective ANAFIE Registry substudy investigated the relationship between the echocardiographic parameters of left atrial (LA) structure and function and clinical outcomes at 2 years among atrial fibrillation (AF) patients aged ≥75 years., Methods and results: Outcomes of 1,474 elderly non-valvular AF (NVAF) patients who underwent transthoracic echocardiography at baseline were analyzed by categories of maximum LA volume index (max. LAVi) and LA emptying fraction (LAEF) total. Baseline mean±standard deviation LAEF total and max. LAVi were 28.2±14.9% and 54.2±25.9 mL/m 2 , respectively. Proportions of oral anticoagulant (OAC), direct OAC, and warfarin use were 92.7%, 68.7%, and 24.0%, respectively. Patients with LAEF total ≤45.0% (n=1,213) vs. >45.0% (n=224) were at higher risk of cardiovascular events (hazard ratio [HR]: 2.19, P=0.021) and heart failure (HF) hospitalization (HR: 2.25, P=0.045). Risk of all-cause death was higher with max. LAVi >48.0 mL/m 2 (n=656) vs. ≤48.0 mL/m 2 (n=621) (HR: 1.69, P=0.048). Subgroups with abnormal LA function and structure had increased incidence of cardiac/cardiovascular events and HF hospitalization. No significant interaction was observed between echocardiographic parameters and OAC type., Conclusions: Elderly Japanese patients with NVAF and LAEF total ≤45.0% were at higher risk of cardiovascular events and HF hospitalization, and those with max. LAVi >48.0 mL/m 2 were at higher risk of all-cause death.

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m 2 , prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88-1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding., (© 2024. The Author(s).)

Recently, a once-daily dose of edoxaban (15-mg) has been approved for stroke prevention in non-valvular atrial fibrillation (NVAF) patients aged ≥ 80 years, in whom standard oral anticoagulants are not recommended because of high bleeding risk (HBR), based on the ELDERCARE-AF trial. However, information regarding the characteristics and clinical outcomes among such patients is limited. Thus, this study aimed to clarify the characteristics and event rates in elderly patients with NVAF and HBR defined by the ELDERCARE-AF criteria. Of the 7406 NVAF outpatients included in the J-RHYTHM Registry, 60 patients with creatinine clearance (CrCl) < 15 mL/min were excluded. The remaining 7346 patients (age, 69.7 ± 9.9 years; men, 70.9%; warfarin use, 78.7%) were divided into three groups: Group 1, aged < 80 years (n = 6165); Group 2, aged ≥ 80 years without HBR (n = 584); and Group 3, aged ≥ 80 years with HBR (at least one of the followings; CrCl, 15-30 mL/min, history of bleeding, body weight ≤ 45 kg, and antiplatelet use) (n = 597, eligible for 15-mg edoxaban). Patients in Group 3 had a higher prevalence of comorbidities, and therefore, both higher thromboembolic and bleeding risk scores than in the other groups. During the 2-year follow-up period, the incidence rates (per 100 person-years) of thromboembolism in Groups 1, 2, and 3 were 0.7, 1.5, and 2.1 (P < 0.001), major hemorrhage, 0.8, 1.2, and 2.0 (P < 0.001), and all-cause death, 0.8, 2.6, and 4.6 (P < 0.001), respectively. Adjusted hazard ratios of Group 3 were 1.64 (95% confidence interval 0.89-3.04, P = 0.116) for thromboembolism, 1.53 (0.85-2.72, P = 0.154) for major hemorrhage, and 1.84 (1.19-2.85, P = 0.006) for all-cause death compared with Group 1. The NVAF Patients aged ≥ 80 years with HBR defined by the ELDERCARE-AF criteria were certainly at a higher adverse event risk, especially for all-cause death. Clinical trial registration: The J-RHYTHM Registry is registered in the University Hospital Medicine Information Network (UMIN) Clinical Trials Registry (unique identifier: UMIN000001569) http://www.umin.ac.jp/ctr/ ., (© 2023. The Author(s).)

Aims: Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF., Methods and Results: The ANAFIE Registry is a multicentre, prospective observational study following elderly non-valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P < 0.001), cardiovascular events (HR 1.59, P < 0.001), cardiovascular death (HR 1.49, P < 0.001), all-cause death (HR 1.32, P < 0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all-cause death (HR 1.23, P < 0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P = 0.56) and major bleeding (HR 1.14, P = 0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P = 0.19 in HF; HR 0.79, P = 0.016 in non-HF; P for interaction = 0.56), major bleeding (HR 0.71, P = 0.008 in HF; HR 0.75, P = 0.016 in non-HF; P for interaction = 0.74), HF hospitalization or cardiovascular death (HR 0.81, P < 0.001 in HF; HR 0.78, P < 0.001 in non-HF; P for interaction = 0.26), cardiovascular events (HR 0.83, P < 0.001 in HF; HR 0.82, P = 0.001 in non-HF; P for interaction = 0.65), cardiovascular death (HR 0.84, P = 0.12 in HF; HR 0.75, P = 0.035 in non-HF; P for interaction = 0.18), all-cause death (HR 0.89, P = 0.082 in HF; HR 0.80, P = 0.001 in non-HF; P for interaction = 0.091), and net clinical outcome (HR 0.88, P = 0.019 in HF; HR 0.81, P < 0.001 in non-HF; P for interaction = 0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations., Conclusions: Non-valvular AF patients aged ≥75 years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non-valvular AF with or without HF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Real-world data on coronary events (CE) in elderly patients with atrial fibrillation (AF) are lacking in the direct oral anticoagulant era. This prespecified sub-analysis of the ANAFIE Registry, a prospective observational study in > 30,000 Japanese patients aged ≥ 75 years with non-valvular AF (NVAF), investigated CE incidence and risk factors. The incidence and risk factors for new-onset CE (a composite of myocardial infarction [MI] and cardiac intervention for coronary heart diseases other than MI), MI, and cardiac intervention for coronary heart diseases other than MI during the 2-year follow-up were assessed. Bleeding events in CE patients were also examined. Among 32,275 patients, the incidence rate per 100 patient-years was 0.48 (95% confidence interval (CI): 0.42-0.53) for CE during the 2-year follow-up, 0.20 (0.16-0.23) for MI, and 0.29 (0.25-0.33) for cardiac intervention for coronary heart diseases other than MI; that of stroke/systemic embolism was 1.62 (1.52-1.73). Patients with CE (n = 287) likely had lower creatinine clearance (CrCL) and higher CHADS 2 and HAS-BLED scores than patients without CE (n = 31,988). Significant risk factors associated with new-onset CE were male sex, systolic blood pressure of ≥ 130 mmHg, diabetes mellitus (glycated hemoglobin ≥ 6.0%), CE history, antiplatelet agent use, and CrCL < 50 mL/min. Major bleeding incidence was significantly higher in patients with new-onset CE vs without CE (odds ratio [95% CI], 3.35 [2.06-5.43]). In elderly patients with NVAF, CE incidence was lower than stroke/systemic embolism incidence. New-onset CE (vs no CE) was associated with a higher incidence of major bleeding.Trial registration: UMIN000024006., (© 2024. The Author(s).)

Background: The ELDERCARE-AF trial showed that low-dose edoxaban benefits elderly patients with nonvalvular atrial fibrillation considered ineligible for standard oral anticoagulants due to high bleeding risk, but whether this applied to patients with extremely low body weight was unclear., Methods and Results: This was a prespecified subanalysis by body weight (≤45, >45 kg) of the phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven ELDERCARE-AF trial, which compared low-dose edoxaban (15 mg once daily) with placebo in Japanese patients considered ineligible for oral anticoagulants at the recommended therapeutic strength or the approved doses. The primary efficacy and safety end points were stroke or systemic embolism and major bleeding (International Society on Thrombosis and Hemostasis definition), respectively. The ≤45-kg weight group included 374/984 patients (38.0%), and the >45-kg group included 610/984 patients (62.0%). The stroke or systemic embolism rate was lower with edoxaban than placebo in both weight groups (≤45 kg: hazard ratio [HR], 0.36 [95% CI, 0.16-0.80]; >45 kg: HR, 0.31 [95% CI, 0.13-0.73]; interaction P =0.82). Major bleeding incidence was numerically higher with edoxaban than placebo (≤45 kg: HR, 3.05 [95% CI, 0.84-11.11]; >45 kg: HR, 1.40 [95% CI, 0.56-3.48), with no interaction with body weight (interaction P =0.33). All-cause mortality was higher in the ≤45-kg group, with no significant difference between treatment groups., Conclusions: The benefit of edoxaban 15 mg was consistent in elderly patients with atrial fibrillation and extremely low body weight, though clinicians must remain vigilant about the risk of major bleeding, especially gastrointestinal bleeding., Registration Information: ClinicalTrials.gov. Identifier: NCT02801669.

The benefits of direct oral anticoagulants (DOACs) and warfarin in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) and high home systolic blood pressure (H-SBP) are unclear. This sub-cohort study of the ANAFIE Registry estimated the incidence of clinical outcomes in patients receiving anticoagulant therapy (warfarin and DOACs) stratified by H-SBP levels (<125 mmHg, ≥125-<135 mmHg, ≥135-<145 mmHg and ≥145 mmHg). Of the overall ANAFIE population, 4933 patients who underwent home blood pressure (H-BP) measurements were analyzed; 93% received OACs (DOACs: 3494, 70.8%; warfarin: 1092, 22.1%). In the warfarin group, at <125 mmHg and ≥145 mmHg, the respective incidence rates (per 100 person-years) were 1.91 and 5.89 for net cardiovascular outcome (a composite of stroke/systemic embolic events (SEE) and major bleeding), 1.31 and 3.39 for stroke/SEE, 0.59 and 3.91 for major bleeding, 0.59 and 3.43 for intracranial hemorrhage (ICH), and 4.01 and 6.24 for all-cause death. Corresponding incidence rates in the DOACs group were 1.64 and 2.65, 1.00 and 1.88, 0.78 and 1.69, 0.55 and 1.31, and 3.43 and 3.51. In warfarin-treated patients, the incidence rates of net cardiovascular outcome, stroke/SEE, major bleeding, and ICH were significantly increased at H-SBP ≥ 145 mmHg versus <125 mmHg. In the DOAC group, although there was no significant difference between H-SBP < 125 mmHg and ≥145 mmHg, the incidence rates of these events tended to increase at ≥145 mmHg. These results suggest that strict BP control guided by H-BP is required in elderly NVAF patients receiving anticoagulant therapy., (© 2023. The Author(s).)

Background: This sub-analysis of the ANAFIE Registry, a prospective, observational study of >30,000 Japanese non-valvular atrial fibrillation (NVAF) patients aged ≥75 years, assessed the prevalence of direct oral anticoagulant (DOAC) under-dose prevalence, identified the factors of under-dose prescriptions, and examined the relationship between DOAC dose and clinical outcomes., Methods and results: Patients, divided into 5 groups by DOAC dose (standard, over-, reduced, under-, and off-label), were analyzed for background factors, cumulative incidences, and clinical outcome risk. Endpoints were stroke/systemic embolic events (SEE), major bleeding, and all-cause death during the 2-year follow-up. Of 18,497 patients taking DOACs, 20.7%, 3.8%, 51.6%, 19.6%, and 4.3%, were prescribed standard, over-, reduced, under-, and off-label doses. Factors associated with under-dose use were female sex, age ≥85 years, reduced creatinine clearance, history of major bleeding, polypharmacy, antiplatelet agents, heart failure, dementia, and no history of catheter ablation or cerebrovascular disease. After confounder adjustment, under-dose vs. standard dose was not associated with the incidence of stroke/SEE or major bleeding but was associated with a higher mortality rate. Patients receiving an off-label dose showed similar tendencies to those receiving an under-dose; that is, they showed the highest mortality rates for stroke/SEE, major bleeding, and all-cause death., Conclusions: Inappropriate low DOAC doses (under- or off-label dose) were not associated with stroke/SEE or major bleeding but were associated with all-cause death.

Background and Aims: Elderly patients with nonvalvular atrial fibrillation (NVAF) might have a higher risk of intracerebral hemorrhage. To investigate this, we compared the incidence of intracranial hemorrhage (ICH) and its subtypes, as well as ischemic stroke, in patients taking direct oral anticoagulants (DOACs) compared with warfarin in a real-world setting. We also determined the baseline characteristics associated with both ICH and ischemic stroke., Methods: Patients aged ⩾ 75 years with documented NVAF enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were evaluated. The co-primary endpoints were the incidence of ischemic stroke and ICH. Secondary endpoints included subtypes of ICH., Results: Of 32,275 patients (13,793 women; median age, 81.0 years) analyzed, 21,585 (66.9%) were taking DOACs and 8233 (25.5%) were taking warfarin. During the median 1.88-year follow-up, 743 patients (1.24/100 person-years) developed ischemic stroke and 453 (0.75/100 person-years) developed ICH (intracerebral hemorrhage, 189; subarachnoid hemorrhage, 72; subdural/epidural hemorrhage, 190; unknown subtype, 2). The incidence of ischemic stroke (adjusted hazard ratio (aHR) 0.82, 95% confidence interval (CI) 0.70-0.97), ICH (aHR 0.68, 95% CI 0.55-0.83), and subdural/epidural hemorrhage (aHR 0.53, 95% CI 0.39-0.72) was lower in DOAC users versus warfarin users. The incidence of fatal ICH and fatal subarachnoid hemorrhage was also lower in DOAC users versus warfarin users. Several baseline characteristics other than anticoagulants were also associated with the incidence of the endpoints. Of these, history of cerebrovascular disease (aHR 2.39, 95% CI 2.05-2.78), persistent NVAF, (aHR 1.90, 95% CI 1.53-2.36), and long-standing persistent/permanent NVAF (aHR 1.92, 95% CI 1.60-2.30) was strongly associated with ischemic stroke; severe hepatic disease (aHR 2.67, 95% CI 1.46-4.88) was strongly associated with overall ICH; and history of fall within 1 year was strongly associated with both overall ICH (aHR 2.29, 95% CI 1.76-2.97) and subdural/epidural hemorrhage (aHR 2.90, 95% CI 1.99-4.23)., Conclusion: Patients aged ⩾ 75 years with NVAF taking DOACs had lower risks of ischemic stroke, ICH, and subdural/epidural hemorrhage than those taking warfarin. Fall was strongly associated with the risks of intracranial and subdural/epidural hemorrhage., Data Access Statement: The individual de-identified participant data and study protocol will be shared for up to 36 months after the publication of the article. Access criteria for data sharing (including requests) will be decided on by a committee led by Daiichi Sankyo. To gain access, those requesting data access will need to sign a data access agreement. Requests should be directed to yamt-tky@umin.ac.jp.

In this subcohort study of the ANAFIE (All Nippon Atrial Fibrillation In the Elderly) Registry enrolling >30,000 Japanese elderly (aged ≥75 years) patients with nonvalvular atrial fibrillation (NVAF), we assessed the association between patient comprehension of NVAF and adherence to anticoagulant therapy with clinical outcomes. Data from 1,968 patients evaluated for NVAF comprehension by a questionnaire consisting of 4 key questions, and 2,362 patients who completed the Morisky Medication Adherence Scale-8 questionnaire were analyzed. Overall, NVAF comprehension was low (81.9% had <3 points), and compared with high comprehension (score ≥3), low comprehension (0 points: 42.1%) was associated with poor prognosis, nonsignificantly higher risk of stroke or systemic embolic event (adjusted hazard ratio [aHR] 2.60 [95% confidence interval 0.97 to 6.94, p = 0.057]), all-cause death (aHR 1.71 [0.96 to 3.04, p = 0.069]), and significantly higher risk of net clinical outcome (composite of stroke/systemic embolic events, major bleeding, and all-cause death) (aHR 1.63 [1.04 to 2.54, p = 0.032]). Adherence to anticoagulant therapy assessed by Morisky Medication Adherence Scale-8 was high (64.9% had high adherence; 29.2%, had medium adherence), but compared with high adherence (score 8), low adherence (score <6: 5.9%) was associated with poor prognosis, significantly higher risk of ischemic stroke (aHR 2.95 [1.08 to 8.04, p = 0.035]), all-cause death (aHR 1.93 [1.16 to 3.21, p = 0.011]), and net clinical outcome (aHR 1.75 [1.12 to 2.75, p = 0.015]). Overall, NVAF comprehension and adherence showed a weak correlation to anticoagulant therapy at baseline (correlation coefficient 0.049). In conclusion, low NVAF comprehension and low anticoagulant adherence were associated with poor clinical outcomes in elderly patients with NVAF., Competing Interests: Declaration of Competing Interest Dr. Akao received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Dr. Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. Dr. Atarashi received remuneration from Daiichi Sankyo. Dr. Ikeda received research funding from Daiichi Sankyo and Bayer, and remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Koretsune received remuneration from Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. Dr. Okumura received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. Dr. Shimizu received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim, and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer (Bristol), and Nippon Boehringer Ingelheim (Ingelheim, Germany). Dr. Suzuki received remuneration from Bristol-Myers Squibb and Daiichi Sankyo. Dr. Tsutsui received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan, scholarship funding from Daiichi Sankyo, and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. Dr. Toyoda received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Otsuka, Novartis, and Abbott Medical. Dr. Hirayama participated in a course endowed by Boston Scientific Japan, has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. Dr. Yasaka received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer Japan. Dr. Yamaguchi acted as an Advisory Board member of Daiichi Sankyo and received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. Dr. Teramukai received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. Drs. Kimura, Morishima, and Takita are employees of Daiichi Sankyo. Dr. Inoue received remuneration from Daiichi Sankyo and Nippon Boehringer Ingelheim, and consultancy fees from Daiichi Sankyo., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Catheter ablation (CA) for atrial fibrillation (AF) is preferred for paroxysmal AF (PAF) but selectively performed in patients with persistent AF (PersAF). This study aimed to investigate the prognostic differences and consequences of CA based on the AF type. Methods and Results Data from a multicenter AF cohort study were analyzed, categorizing patients as PAF or PersAF according to AF duration (≤7 or >7 days, respectively). A composite of all-cause death, heart failure hospitalization, stroke, and bleeding events during 2-year follow-up and changes in the Atrial Fibrillation Effect on Quality-of-life score were compared. Additionally, propensity score matching was performed to compare clinical outcomes of patients with and without CA in both AF types. Among 2788 patients, 51.6% and 48.4% had PAF and PersAF, respectively. Patients with PersAF had a higher incidence of the composite outcome (12.8% versus 7.2%; P <0.001) and smaller improvements in Atrial Fibrillation Effect on Quality-of-life scores than those with PAF. After adjusting for baseline characteristics, PersAF was an independent predictor of adverse outcomes (adjusted hazard ratio, 1.35 [95% CI, 1.30-1.78], P =0.031) and was associated with poor improvements in Atrial Fibrillation Effect on Quality-of-life scores. Propensity score matching analysis showed that the CA group had significantly fewer adverse events than the medication group among patients with PAF (odds ratio, 0.31 [95% CI, 0.18-0.68]; P =0.002). Patients with PersAF showed a similar but nonsignificant trend. Conclusions PersAF is a risk factor for worse clinical outcomes, including patients' health status. CA is associated with fewer adverse events, although careful consideration is required based on the AF type.

Background: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM)., Methods: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%)., Results: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA 2 DS 2 -VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11-1.93]) and net clinical outcome (aHR 1.33 [1.05-1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs., Conclusions: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level., Trial Registration: UMIN000024006; date of registration: September 12, 2016., (© 2023. The Author(s).)

Aims: Linear lesions are routinely created by radiofrequency catheter ablation. Unwanted electrical conduction gaps can be produced and are often difficult to ablate. This study aimed to clarify the characteristics of conduction gaps during atrial fibrillation ablation by analysing bidirectional activation maps using a high-density mapping system (RHYTHMIA)., Methods and Results: This retrospective study included 31 patients who had conduction gaps along pulmonary vein (PV) isolation or box ablation lesions. Activation maps were sequentially created during pacing from the coronary sinus and PV to reveal the earliest activation site, defined by the entrance and exit. The locations, length between the entrance and exit (gap length), and direction were analysed. Thirty-four bidirectional activation maps were drawn: 21 were box isolation lesions (box group), and 13 were PV isolation lesions (PVI group). Among the box group, nine conduction gaps were present in the roof region and 12 in the bottom region, while nine in right PV and four in left PV among the PVI group. Gap lengths in the roof region were longer than those in the bottom region (26.8 ± 11.8 vs. 14.5 ± 9.8 mm; P = 0.022), while those in right PV tended to longer than those in left PV (28.0 ± 15.3 vs. 16.8 ± 8.0 mm, P = 0.201)., Conclusion: The entrances and exits of electrical conduction gaps were separated, especially in the roof region, indicating that epicardial conduction might contribute to gap formation. Identifying the bidirectional conduction gap might indicate the location and direction of epicardial conduction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era., Methods and results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease., Conclusions: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

Background: Elderly patients with atrial fibrillation (AF) are at a higher risk for all-cause mortality and heart failure. Rate control is an essential component in AF management. This exploratory study assessed the relationship between resting heart rate during AF at baseline and clinical outcomes in Japanese elderly non-valvular AF (NVAF) patients, using the All Nippon AF In the Elderly Registry (ANAFIE) dataset., Methods: This sub-cohort included patients who agreed to participate and presented with AF at enrollment in the ANAFIE study. They were categorized into six groups according to the resting heart rate during AF. Outcomes included 2-year cumulative incidences of stroke/systemic embolic events (SEE), ischemic stroke, major bleeding, cardiovascular (CV) events, CV death, all-cause death, and net clinical outcome, a composite of stroke/SEE, major bleeding, and all-cause death., Results: Of the 8292 patients included in this sub-cohort (paroxysmal, 1496; non-paroxysmal, 6796), 90 % of patients were using anticoagulants. Higher heart rate was more frequently reported in women and in patients with paroxysmal AF and was associated with increased use of direct oral anticoagulants (DOACs) and antiarrhythmic drugs. Heart rate ≥110 beats per minute (bpm) was associated with a significantly higher incidence of cardiac events and numerically higher incidences of CV death and all-cause death compared with a heart rate of 60 to <80 bpm, all of which were driven by an increased risk in patients with non-paroxysmal AF. Hazard ratios by the type of anticoagulant for each clinical outcome were comparable across all heart rate categories, indicating no significant interactions., Conclusions: Elderly Japanese patients with non-paroxysmal NVAF and a heart rate ≥110 bpm have an increased risk of cardiac events. There was no interaction between heart rate category and the relative risk of adverse clinical events in patients taking DOACs compared with those taking warfarin., Competing Interests: Declaration of competing interest Takanori Ikeda received research grants from Daiichi Sankyo, Medtronic Japan, and Japan Lifeline and honoraria from Ono Pharma, Bayer Yakuhin, Daiichi Sankyo, Bristol-Myers Squibb, and Pfizer. Additionally, Takanori Ikeda was a member of the advisory board for Bayer Yakuhin, Bristol-Myers Squibb, and Daiichi Sankyo. Takeshi Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo, and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, Bristol-Myers Squibb, and Ono Pharmaceutical. Masaharu Akao received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Hirotsugu Atarashi received remuneration from Daiichi Sankyo. Yukihiro Koretsune received remuneration from Daiichi Sankyo, Bayer, and Nippon Boehringer Ingelheim. Ken Okumura received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. Wataru Shimizu received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim, and patent royalties/licensing fees from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. Hiroyuki Tsutsui received research funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, and IQVA services Japan, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, Pfizer Japan, Otsuka Pharmaceutical, and Mitsubishi Tanabe Pharma, scholarship funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Teijin Pharma, and consultancy fees from Novartis Pharma, Pfizer Japan, Bayer, Nippon Boehringer Ingelheim, and Ono Pharmaceutical. Kazunori Toyoda received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Takeda, and Nippon Boehringer Ingelheim. Atsushi Hirayama participated in a course endowed by Boston Scientific Japan, and has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Sanofi, Astellas Pharma, Sumitomo Dainippon Pharma, Amgen Astellas BioPharma, and AstraZeneca, and patent royalties/licensing fees from Toa Eiyo M. Masahiro Yasaka received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Pfizer Japan, and CSL Behring. Takenori Yamaguchi acted as an advisory board member of Daiichi Sankyo, and received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. Satoshi Teramukai received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. Tetsuya Kimura has stock and is an employee of Daiichi Sankyo. Yoshiyuki Morishima and Atsushi Takita are employees of Daiichi Sankyo. Hiroshi Inoue received remuneration from Daiichi Sankyo, Bayer, and Bristol-Myers Squibb, and consultancy fees from Daiichi Sankyo., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although anticoagulants are indicated for many elderly patients with non-valvular atrial fibrillation (NVAF), some patients do not receive anticoagulant therapy, whose characteristics and outcomes are diverse., Methods and Results: In this sub-analysis of the All Nippon AF In the Elderly (ANAFIE) Registry, the phenotypes of patients who were not receiving anticoagulants at baseline were evaluated by cluster analysis using Ward's linkage hierarchical algorithm. Of 32,275 enrolled patients, 2445 (7.6%) were not receiving anticoagulants. Two clusters were identified: (1) elderly paroxysmal AF (PAF) patients with a high proportion of catheter ablation history (57%) and (2) very elderly patients with a high prevalence of previous major bleeding (43%). Respective mean ages were 80.9 and 84.2 years, mean CHA2DS2-VASc scores were 3.8 and 4.9, PAF prevalences were 100.0% and 31.4%, proportions of patients with catheter ablation history were 21.0% and 7.9%, and proportions of patients with a history of major bleeding were 4.0% and 10.8%. Annual incidence rates were 2.72% and 8.81% for all-cause death, 1.66% and 5.85% for major adverse cardiovascular or neurological events, 1.08% and 3.30% for stroke or systemic embolism, and 0.69% and 1.19% for major bleeding, respectively., Conclusions: In this cohort of elderly NVAF patients from the ANAFIE Registry who were not receiving anticoagulants, over half had PAF with a high proportion of catheter ablation history and a low incidence of adverse outcomes; for them, non-prescription of anticoagulants may be partially understandable, but they should be carefully monitored regarding AF burden or atrial cardiomyopathy and be adequately anticoagulated when adverse findings are detected. The remaining were very elderly patients with a high prevalence of previous major bleeding and a high incidence of adverse outcomes; for them, non-prescription of anticoagulants is inappropriate because of the high thromboembolic risk., Trial Registration: Registration: http://www.umin.ac.jp/; Unique identifier: UMIN000024006., Competing Interests: S.S. received research funding from Daiichi Sankyo, and remuneration from Bristol-Myers Squibb and Daiichi Sankyo. T. Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. M.A. received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.A. received remuneration from Daiichi Sankyo. T.I. received research funding from Daiichi Sankyo, and remuneration from Daiichi Sankyo, Pfizer Japan, and Bayer. Y.K. received remuneration from Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. W.S. received research funding from Daiichi Sankyo, and Nippon Boehringer Ingelheim, and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. H.T. received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan, scholarship funding from Daiichi Sankyo, and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. K.T. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Otsuka, Novartis, and Abbott. A.H. participated in a course endowed by Boston Scientific Japan, has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. M.Y. received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer Japan. T. Yamaguchi acted as an advisory board member for Daiichi Sankyo and has received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. S.T. received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. T.K., Y.M., and A.T. are employees of Daiichi Sankyo. H.I. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and consultancy fee from Daiichi Sankyo. This disclosure does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

High alkaline phosphatase (ALP) levels are reported to be associated with an increased risk of cardiovascular events in patients with chronic kidney disease (CKD). Given the pathological link with CKD, a similar relationship may exist in patients with atrial fibrillation (AF). We retrospectively evaluated 1,719 patients with AF and normal hepatic function who were registered in the Shinken Database between November 2011 and March 2017. Study patients were divided into three groups according to ALP value tertiles with cut-offs of 175 and 227 IU/L (normal range: 95-350 IU/L). Each group's incidence rate was recorded, and the risks of cardiovascular events and each component for patients in the middle and high ALP tertiles were compared with those in the low tertile and evaluated using Cox regression models. The additional predictive value of the high ALP tertile over the existing risk scores for the components of cardiovascular events was evaluated via receiver operating characteristic (ROC) curve analysis. During the median follow-up of 731 days (IQR: 444-1095 days), 137 cardiovascular events occurred, with incidence rates of 2.94%, 3.44%, and 6.19%/person-year for the low, middle, and high ALP tertiles, respectively. Of these cardiovascular events, heart failure had the highest incidence rates (1.34%, 1.89%, and 4.29%/person-year for the low, middle, and high ALP tertiles, respectively) and the incidence rates of the other components of cardiovascular event were similar in each ALP groups. Multivariate Cox regression analysis yielded hazard ratios of 1.22 (95% confidence interval [CI] 0.70-1.96) and 1.62 (95% CI 1.06-2.48) for cardiovascular events and 1.66 (95% CI 0.87-3.15) and 2.50 (95% CI 1.39-4.48) for heart failure admission in the middle and high ALP tertiles, respectively. By ROC curve analysis for heart failure admission showed that the high ALP tertile lacked significant additive predictive value over the existing risk scores. High serum ALP levels, even those in the normal range, were significantly associated with an increased risk of cardiovascular events, especially heart failure admission in patients with AF., (© 2022. Springer Japan KK, part of Springer Nature.)

Background: Early detection of atrial fibrillation (AF) is important. Japan has a universal screening system, and regular health screening (HS) is available to support AF detection without a hospital visit. However, health-related outcomes and other characteristics of HS-detected and conventionally diagnosed AF remain unknown., Hypothesis: That the characteristics and health-related outcomes of patients with HS-detected AF may differ from those of patients whose AF was detected by other procedures., Methods: In total, 3318 consecutive newly referred AF cases were enrolled; demographic characteristics and health-related and clinical outcomes were compared between two groups created based on the mode of AF detection (the HS and non-HS groups). Health-related outcomes were assessed using the AF Effect on QualiTy-of-life (AFEQT) questionnaire at baseline and after 1 year of follow-up., Results: AF was detected by HS in 25.0% of patients; these patients had lower CHADS 2 scores (1.01 vs. 1.50, p < .001), higher prevalence of persistent AF (odds ratio, 95% confidence interval; 2.21, 1.88-2.60) and asymptomatic presentation (3.19, 2.71-3.76), and better baseline QoL scores (83.6 vs. 75.0; p < .001). Catheter ablation was more frequently performed in the HS group at follow-up (44.4% vs. 34.1%; p < .001). At 1-year follow-up, the AFEQT scores of the HS group were significantly better in most subdomains., Conclusions: In the Japanese registry, AF was detected via HS in 25% of patients referred to specialty centers for management. Notably, the overall health status of patients with HS-detected AF improved after medical interventions, including catheter ablations., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Background: This All Nippon AF in the Elderly (ANAFIE) Registry sub-analysis evaluated the impact of polypharmacy on 2-year outcomes in a large, elderly (aged ≥75 years) Japanese population with non-valvular atrial fibrillation (NVAF)., Methods and results: The ANAFIE Registry was a multicenter, prospective, observational study with a 24-month follow-up period. Of 32,275 enrolled NVAF patients, 31,419 were grouped by the number of prescribed concomitant medications (other than oral anticoagulants [OACs]): 0-4 [38.8%], 5-8 [43.3%], and ≥9 [17.9%]). Patients receiving more concomitant medications were older, had poor renal function, and suffered more comorbidities than those receiving fewer concomitant medications. Several patient background factors, including diabetes mellitus, myocardial infarction, and chronic kidney disease, were significantly correlated with an increased number of concomitant medications. With increasing medications, OAC prescription rates decreased, but the warfarin prescription rate increased, and the cumulative incidence rates of stroke/systemic embolic events (SEE), major bleeding, gastrointestinal bleeding, fracture/falls, cardiovascular events, cardiovascular death, and all-cause death significantly increased (each, P<0.05). In multivariate analysis, increasing medications was independently associated with increases in these events, except for stroke/SEE. There were no significant interactions between the number of medications and anticoagulant treatment with direct OAC or warfarin concerning the incidence of these events., Conclusions: Polypharmacy was frequent among elderly patients with NVAF who were older with more comorbidities, and was independently associated with a higher incidence of extracranial events.

Background: Blood pressure (BP) fluctuates significantly in patients with atrial fibrillation (AF); office BP measurements seem insufficient to assess AF patient risk accurately. We hypothesized that home BP could better predict the risk of stroke/systemic embolic events (SEE) and major bleeding in patients with AF than office BP., Methods: In this prespecified subcohort study of the ANAFIE (All Nippon AF in the Elderly) Registry, we evaluated the impact of home BP on the risk of stroke/SEE, major bleeding, intracranial hemorrhage, all-cause death, and net cardiovascular outcome (a composite of stroke/SEE and major bleeding). At enrollment, home BP was measured twice in the morning and evening for 7 days., Results: In total, 4933 elderly patients (aged ≥75 years) with nonvalvular AF participated. Incidences of net cardiovascular outcome, stroke/SEE, major bleeding, and intracranial hemorrhage increased significantly with increasing home systolic BP (H-SBP). Compared with H-SBP <125 mm Hg, ≥145 mm Hg was associated with increased risk of these events. The association between H-SBP and the events was observed only in patients with ≥20 H-SBP measurements., Conclusions: In elderly patients with nonvalvular AF, high H-SBP (≥145 mm Hg) was a significant predictor of stroke/SEE, major bleeding, and intracranial hemorrhage risk. Strict BP control guided by the increasing number of home BP measurements may provide an accurate clinical outcome risk assessment., Registration: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000024006.

Although time in target range (TTR) of systolic blood pressure (BP), an index of consistency of BP control, is reportedly associated with major cardiovascular outcomes, the impact of BP-TTR on adverse events in patients with nonvalvular atrial fibrillation (NVAF) has not been thoroughly investigated. Thus, we performed a post hoc analysis to clarify it in patients with NVAF using data of the J-RHYTHM registry. Of 7,406 outpatients with NVAF, 7,226 (age, 70 ± 10 years; men, 71%), in whom BP was measured 4 times or more (15 ± 5 times) during the 2-year follow-up period or until occurrence of an event, constituted the study group. Systolic BP-TTR, with a target range of 110 to 130 mm Hg, was calculated by Rosendaal linear interpolation method. Overall systolic BP-TTR was 50 ± 28%. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 110 (1.5%), 121 (1.7%), 168 (2.3%), and 60 patients (0.8%), respectively. Each 1% increase in systolic BP-TTR was significantly associated with a decreased incidence of all adverse events in the unadjusted model; whereas, significant association was observed only for cardiovascular death (adjusted hazard ratio 0.983, 95% confidence interval 0.971 to 0.995, p = 0.006) after adjusting for known confounders and systolic BP at the time closest to an event. In contrast, each 1% increase in systolic BP time in subtarget range of &lt;110 mm Hg was significantly associated with an increased risk of thromboembolism (hazard ratio 1.014, 95% confidence interval 1.005 to 1.024, p = 0.002). In conclusion, systolic BP-TTR and BP time in subtarget range would be useful for risk evaluation of cardiovascular death and thromboembolism, respectively, in patients with NVAF., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background We investigated the predictors related to major bleeding events during treatment with edoxaban 15 mg in patients aged ≥80 years with nonvalvular atrial fibrillation and high bleeding risk, for whom standard oral anticoagulants are inappropriate, focusing on standard laboratory tests related to bleeding. Methods and Results This was a prespecified subanalysis of the on-treatment analysis set of the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Major bleeding was the primary safety end point. The event rates were calculated according to prespecified characteristics at baseline. A total of 984 Japanese patients were randomly assigned to edoxaban 15 mg or placebo (n=492, each). During the study period, 20 and 11 major bleeding events occurred in the edoxaban and placebo groups, respectively. The adjusted analysis revealed that hemoglobin <12.3 g/dL (adjusted hazard ratio [aHR], 3.57 [95% CI, 1.10-11.55]) and prothrombin time ≥12.7 seconds; (aHR, 2.89 [95% CI, 1.05-8.02]) independently predicted major bleeding, while creatinine clearance <30 mL/min showed a tendency towards an increase in major bleeding (aHR, 2.68; 95% CI, 0.96-7.46). In patients treated with edoxaban lacking these 3 risk factors, no major bleeding occurred; major bleeding event rates increased with each risk factor. Patients with 3 risk factors were significantly more likely to have a major bleeding event at 11.05%/year (HR, 7.15 [95% CI, 1.92-26.71]). Conclusions In elderly patients with nonvalvular atrial fibrillation with high bleeding risk, baseline hemoglobin <12.3 g/dL, prothrombin time ≥12.7 seconds, and creatinine clearance <30 mL/min may predict major bleeding during treatment with edoxaban 15 mg. Registration URL: ELDERCARE-AF https://www.clinicaltrials.gov; Unique number: NCT02801669.

Background: Idarucizumab, a dabigatran-specific reversal agent, was launched in Japan in 2016. The J-Dabigatran Surveillance 2 study was designed to assess the characteristics and outcomes of dabigatran-treated patients after the launch of idarucizumab., Methods: Patient characteristics and outcomes, including thromboembolic and bleeding events, of dabigatran-naïve patients with non-valvular atrial fibrillation (NVAF) who received dabigatran etexilate [110 mg or 150 mg twice-daily (b.i.d.)] for the prevention of ischemic stroke and systemic embolism were investigated and presented descriptively. Absolute standardized differences (ASD) in baseline characteristics compared with the first J-Dabigatran Surveillance (J-Dabi1; 2011-2013) study were included., Results: In total, 5660 patients were enrolled and 5436 were analyzed in this study; 3516 and 1898 received 110 mg b.i.d. and 150 mg b.i.d. dabigatran, respectively; 22 received other doses. The overall duration of follow-up (mean ± standard deviation) was 287 ± 179 days. Baseline characteristics, including stroke/bleeding-risk scores, were typical of this patient population. Overall, paroxysmal, persistent, permanent, and symptomatic atrial fibrillation were observed for 53.2%, 27.1%, 13.7%, and 53.9% of patients, respectively (J-Dabi1 ASD: 0.2, 0.0, 0.3, and 0.2, respectively). Catheter ablation was selected in 27.9% of patients (J-Dabi1 ASD: 0.6). Rates of clinical outcomes were low in the study (mostly <2%/year). The incidence rate of major bleeding was 1.1%/year (n = 46) and stroke/transient ischemic attack/systemic embolism was 1.7%/year (n = 71). Twelve (0.2%) patients received idarucizumab, commonly for serious bleeding events, and most recovered., Conclusions: Dabigatran continues to be safe and well tolerated in patients with NVAF for stroke and systemic embolism prevention and continues to be prescribed appropriately. Treatment outcomes have not changed since the availability of idarucizumab. Since the J-Dabi1 study, treatment guidelines for anticoagulation use in NVAF have been updated based on emerging clinical evidence, accounting for differences in patient characteristics, and making dabigatran a preference for distinct patient populations., Competing Interests: Declaration of competing interest Takeshi Yamashita has received remuneration from Boehringer Ingelheim, Daiichi Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Novartis, Otsuka Pharmaceutical, Ono Pharmaceutical, and Toa Eiyo, and research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Bayer Healthcare, and Daiichi Sankyo; Shinichiro Uchiyama has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Sanofi; Hirotsugu Atarashi has received remuneration from Boehringer Ingelheim and Daiichi Sankyo; Ken Okumura has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Pfizer; Yukihiro Koretsune has received remuneration from Daiichi Sankyo, Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb, and Pfizer; Masahiro Yasaka has received remuneration from Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo, and research funding from Boehringer Ingelheim; Junichi Wakayama is an employee of EPS Corporation; Taku Fukaya is an employee of Nippon Boehringer Ingelheim; Hiroshi Inoue has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Bristol-Myers Squibb., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Although direct oral anticoagulants are effective and safe in preventing stroke in atrial fibrillation (AF) patients with low body weight, data remain limited in AF patients with extremely low body weight (<50 kg). We aimed to investigate the association of this body weight category with clinical outcomes in elderly AF patients receiving apixaban., Methods: The J-ELD AF Registry is a large-scale, multicenter prospective observational study of Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban. The entire cohort (3025 patients from 110 institutions) was divided into three body weight subgroups: >60 kg (n = 1019, 33.7%), 50-60 kg (n = 1126, 37.2%), and <50 kg (n = 880, 29.1%)., Results: The event incidence rates (/100 person years) were 1.69, 1.82, and 1.23 for stroke or systemic embolism (P = 0.60); 1.37, 1.73, and 2.73 for bleeding requiring hospitalization (P = 0.154); 2.02, 2.67, and 4.92 for total death (P = 0.003); and 0.73, 0.95, and 1.23 for cardiovascular death (P = 0.57), respectively. After adjusting for confounders by Cox regression analysis, body weight <50 kg was not an independent risk for stroke or systemic embolism, bleeding requiring hospitalization, total death, or cardiovascular death., Conclusions: The incidence of events in each body weight group was comparable for stroke or systemic embolism and bleeding requiring hospitalization, and body weight <50 kg might not be an independent risk for death in Japanese non-valvular AF patients aged ≥ 75 years taking on-label doses of apixaban., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: The prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment., Objective: To compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial., Design, Setting, and Participants: This is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022., Exposure: Edoxaban (15 mg) once daily or placebo., Main Outcomes and Measures: The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding., Results: A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups., Conclusions and Relevance: Regardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

Background: We determined the long-term event incidence among elderly patients with nonvalvular atrial fibrillation in terms of history of stroke/transient ischemic attack (TIA) and oral anticoagulation., Methods: Patients aged ≥75 years with documented nonvalvular atrial fibrillation enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were divided into 2 groups according to history of stroke/TIA. The primary end point was the occurrence of stroke/systemic embolism within 2 years, and secondary end points were major bleeding and all-cause death within 2 years. Cox models were used to determine whether there was a difference in the hazard of each end point in patients with/without history of stroke/TIA, and in ischemic stroke/TIA survivors taking direct oral anticoagulants versus those taking warfarin., Results: Of 32 275 evaluable patients (13 793 women [42.7%]; median age, 81.0 years), 7304 (22.6%) had a history of stroke/TIA. The patients with previous stroke/TIA were more likely to be male and older and had higher hazard rates of stroke/systemic embolism (adjusted hazard ratio, 2.25 [95% CI, 1.97-2.58]), major bleeding (1.25, 1.05-1.49), and all-cause death (1.13, 1.02-1.24) than the other groups. Of 6446 patients with prior ischemic stroke/TIA, 4393 (68.2%) were taking direct oral anticoagulants and 1668 (25.9%) were taking warfarin at enrollment. The risk of stroke/systemic embolism was comparable between these 2 groups (adjusted hazard ratio, 0.90 [95% CI, 0.71-1.14]), while the risk of major bleeding (0.67, 0.48-0.94), intracranial hemorrhage (0.57, 0.39-0.85), and cardiovascular death (0.71, 0.51-0.99) was lower among those taking direct oral anticoagulants., Conclusions: Patients aged ≥75 years with nonvalvular atrial fibrillation and previous stroke/TIA more commonly had subsequent ischemic and hemorrhagic events than those without previous stroke/TIA. Among patients with previous ischemic stroke/TIA, the risk of hemorrhagic events was lower in patients taking direct oral anticoagulants compared with warfarin., Registration: URL: https://www., Clinicaltrials: gov; Unique Identifier: UMIN000024006.

Background: B-type natriuretic peptide (BNP) is a risk factor for stroke and cardiac death in patients with atrial fibrillation. We hypothesized the prognostic outcomes of very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment would vary according to BNP stratification., Methods: In this subanalysis of the ELDERCARE-AF trial, patients were stratified by BNP levels at enrollment, and clinical outcomes compared among BNP subgroups. Hazard ratios were adjusted for age, atrial fibrillation type, body mass index, creatine clearance, congestive heart failure, and D-dimer. BNP levels were measured using chemiluminescence enzyme immunoassays., Results: In total, 984 patients (average age: 86.6 years) not considered eligible for oral anticoagulant therapy at approved doses for stroke prevention were included. The BNP levels at enrollment were <200 (low), 200 to <400 (moderate), and ≥400 (high) pg/mL in 428, 300, and 256 patients, respectively. The number (%) of patients with stroke or systemic embolism (SSE) was 7 (1.2%), 24 (5.9%), and 28 (8.6%) in the low, moderate, and high BNP subgroups, respectively (adjusted hazard ratio 3.82, P = .0025 for low vs moderate BNP and 4.76, P = .0007 for low vs high BNP). There was no significant difference in major bleeding incidence between the BNP subgroups. Edoxaban 15 mg was associated with a consistent reduction in SSE vs placebo in all BNP subgroups., Conclusions: Stratification by BNP level was associated with the incidence of SSE for very elderly non-valvular atrial fibrillation patients ineligible for standard anticoagulation treatment, and the effect of edoxaban 15 mg was consistent across BNP levels., (Copyright © 2022. Published by Elsevier Inc.)

Background: Catheter ablation is widely used as first-line therapy for patients with impaired quality of life; however, whether catheter ablation improves survival and other outcomes in atrial fibrillation (AF) cases remains unclear., Objective: The purpose of this study was to evaluate whether catheter ablation reduces adverse clinical outcomes and improves patients' quality of life using data from a contemporary Japanese multicenter registry of patients with early-stage AF., Methods: The Keio Interhospital Cardiovascular Studies-Atrial Fibrillation registered 3318 patients with AF newly diagnosed at or referred to participating hospitals between 2014 and 2018. Propensity score matching based on 47 demographic variables was performed. We extracted 823 pairs who underwent catheter ablation or medical therapy alone. The primary outcome was the composite of all-cause death, stroke, bleeding events, and heart failure hospitalization during a 2-year follow-up period. Additionally, the Atrial Fibrillation Effect on QualiΤy-of-Life scores at baseline and 1-year follow-up were evaluated., Results: Within the matched cohort, the median time since AF diagnosis was 0.3 years (interquartile range [IQR] 0.1‒2.3 years), age was 67.0 years (IQR 59.0‒73.0 years), and the CHA 2 DS 2 -VASc score was 2.0 (IQR 1.0‒2.0). During a median follow-up period of 730 days (IQR 366‒731 days), patients who underwent catheter ablation had a lower risk of primary outcomes (hazard ratio 0.49; 95% confidence interval 0.30‒0.79; P = .004), with a significantly lower risk of heart failure hospitalization (hazard ratio 0.33; 95% confidence interval 0.14-0.77; P = .010) and improved Atrial Fibrillation Effect on QualiΤy-of-Life scores, than did those who received medical therapy., Conclusion: In patients with propensity score-matched, early-stage, real-world AF, catheter ablation was associated with a lower risk of adverse clinical events and improved quality of life as compared with medical therapy., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to determine the proportion of frail patients among older adults with non-valvular atrial fibrillation (NVAF), characterize them and their use of anticoagulant therapy, and examine the association between frailty and clinical outcomes in a real-world setting using the ANAFIE Registry dataset., Methods: The target population consisted of more than 30,000 adults aged ≥75 years definitively diagnosed with NVAF by electrocardiogram. For this sub-cohort study, patients who answered the Kihon Checklist were registered prospectively. Patients were classified into robust, pre-frail, and frail groups based on the Kihon Checklist score., Results: Of the 32,275 patients in the ANAFIE Registry, 2951 were enrolled in this subanalysis and responded to the Kihon Checklist: 959 (32.5%) patients were robust; 924 (31.3%), pre-frail; and 1068 (36.2%), frail. In the robust, pre-frail, and frail groups, respectively, the 2-year cumulative incidence rates of stroke/systemic embolic events were 2.4%, 3.3%, and 4.5%, (P = .025); all-cause death, 2.9%, 5.1%, and 13.7%, (P < .001); major bleeding, 1.5%, 1.2%, and 2.9%, (P = .029); and net clinical outcomes, 5.5%, 8.2%, and 17.1% (P < .001). Results were similar when comparing the robust+pre-frail vs frail groups. In multivariate analyses, cardiovascular death, all-cause death, and net clinical outcomes were significantly associated with frailty. In the robust+pre-frail vs frail groups, major bleeding was also associated with frailty., Conclusions: Frailty was associated with cardiovascular and all-cause death, net clinical outcomes, and major bleeding but not stroke or intracranial hemorrhage in older Japanese adults with NVAF., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated., Objective: To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial., Design, Setting, and Participants: This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo., Interventions: Edoxaban (15 mg once daily) or placebo., Main Outcomes and Measures: The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis-defined major bleeding., Results: A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n = 181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n = 184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n = 127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P = .13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata., Conclusions and Relevance: Results of this subanalysis of the ELDERCARE-AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding., Trial Registration: ClinicalTrials.gov Identifier: NCT02801669.

Aims: To clarify the real-world clinical status and prognosis of elderly and very elderly non-valvular atrial fibrillation (NVAF) patients, more than 30 000 elderly patients with NVAF aged ≥75 years were enrolled in the ANAFIE Registry., Methods and Results: This multicentre, prospective, observational study followed elderly NVAF patients in Japan for ∼2 years. Among 32 275 patients (mean age, 81.5 years; men, 57.3%; mean CHA2DS2-VASc score, 4.5), 2445 (7.6%) were not receiving oral anticoagulants (OACs) and 29 830 (92.4%) were given OACs. Of these, 21 585 (66.9%) were receiving direct OACs (DOACs) and 8233 (25.5%), warfarin (mean time in therapeutic range: ∼75%). In total, the 2-year incidence rate was 3.01% for stroke/systemic embolic events (SEE); 2.00%, major bleeding; and 6.95%, all-cause death. When compared with the warfarin group, the DOAC group had a lower hazard ratio (HR) for stroke/SEE, major bleeding, and all-cause death after adjusting for confounders. The group without OACs had a higher HR for stroke/SEE and all-cause death, with a lower HR for major bleeding. History of falls within 1 year at enrolment and of catheter ablation were positive and negative independent risk factors, respectively, for stroke/SEE, major bleeding, and all-cause death., Conclusion: In Japan, a large proportion of elderly and very elderly NVAF patients were receiving DOACs, which was significantly associated with lower rates of stroke/SEE, major bleeding, and all-cause death vs. well-controlled warfarin. History of falls and of catheter ablation were independently associated with stroke/SEE, major bleeding, and all-cause death., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Echocardiographic data on the cardiac structure and function in elderly patients with atrial fibrillation (AF) and heart failure (HF) are limited. This subcohort study of the ANAFIE Registry analyzed echocardiographic parameters to identify cardiac structural and functional characteristics.Methods and Results:Of 32,726 subjects in the ANAFIE population, 1,494 (4.6%) were entered as the echocardiography subcohort. Half of the patients, including those with persistent and permanent AF, older age (≥80 years), and CHADS 2 score ≥2, had left atrial (LA) volume index ≥48 mL/m 2 , indicating severe LA enlargement. LA enlargement significantly correlated with impaired LA reservoir function, regardless of age and CHADS 2 score. Types of AF and rhythm were strongly related to LA volume and reservoir function (P<0.0001). Moderate-to-severe mitral and tricuspid regurgitation were significantly more common, and the early diastolic mitral inflow velocity to mitral annulus velocity ratio was significantly higher among patients with than without HF history (all, P<0.0001)., Conclusions: In this subcohort, LA enlargement correlated with impaired LA reservoir function. Elderly patients with non-valvular AF and a history of HF had LA enlargement and dysfunction, increased LV mass index, low LV ejection fraction, and high heart rate.

Background: Data on outcomes for patients with atrial fibrillation (AF) and active cancer are scarce. The effect of active cancer on thrombosis and bleeding risks in elderly (≥75 years) patients with non-valvular AF (NVAF) enrolled in the All Nippon AF In the Elderly (ANAFIE) Registry were prospectively analyzed.Methods and Results:In this subanalysis of the ANAFIE Registry, a prospective, multicenter, observational study conducted in Japan, we compared the incidence rates of clinical outcomes between active cancer and non-cancer groups. Relationships between primary outcomes and anticoagulation status were evaluated. Of the 32,725 patients enrolled in the Registry, 3,569 had active cancer at baseline; 92.0% of active cancer patients received anticoagulants (23.7%, warfarin; 68.2%, direct oral anticoagulants [DOACs]). Two-year probabilities of stroke/systemic embolic events (SEE) were similar in the cancer (3.33%) and non-cancer (3.16%) groups. Patients with cancer had greater incidences of major bleeding (2.86% vs. 2.04%), all-cause death (10.95% vs. 6.77%), and net clinical outcomes (14.63% vs. 10.00%) than those without cancer. In patients without cancer, DOACs were associated with a decreased risk of stroke/SEE, major bleeding, all-cause death, and net clinical outcome compared with warfarin. No between-treatment differences were observed in patients with active cancer., Conclusions: Active cancer had no effect on stroke/SEE incidence in elderly NVAF patients, but those with cancer had higher incidences of major bleeding events and all-cause death than those without cancer.

We have previously reported that atrial endocardial remodeling is induced by atrial fibrillation (AF), and the endocardial dysfunction may be partly responsible for the thrombus formation in the left atrium associated with AF. However, the relationship between the endocardial dysfunction and the epidemiologically determined risk factors of AF-related strokes, including aging, hypertension, and diabetes mellitus, is yet to be elucidated.To test the hypothesis that aging, hypertension, and diabetes mellitus individually impair the atrial endocardial function in conjunction with AF, we have analyzed the expression of the tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) in the atrial endocardium in 30-week-old Wister-Kyoto (WKY), 60-week-old WKY, 30-week-old spontaneously hypertensive rats (SHR), and 30-week Goto-Kakizaki (GK) rats during normal sinus rhythm and after rapid atrial pacing at 1200 bpm for 8 hours, using Western blotting and immunohistochemical analysis. Even during sinus rhythm, the TFPI and TM expressions were noted to be remarkably downregulated in the atrial endocardium among 60-week-old WKY rats. In contrast, in SHR rats, only the TFPI expression has significantly decreased, while TM was preserved to the same level of control 30-week-old WKY rats. Rapid atrial pacing significantly reduced the TM and TFPI expression similarly in each model, thereby augmenting the endocardial dysfunction during normal sinus rhythm individually induced by the risk factors themselves prior to AF.Aging and hypertension, both of which are epidemiologically well-known risk factors for strokes in AF, have been associated with a specific atrial endocardial impairment prior to AF that could additionally disturb the antithrombotic function of the atrial endocardium.

The incidence of ischemic stroke (IS) increases in patients with enlarged left atrium (LA) irrespective of whether or not the existence of atrial fibrillation (AF). In such situation, it is unclear whether the impact of LA on incidence of IS still significant in young, non-AF patients with enlarged LA who are primarily unconcerned on anticoagulation therapy. The study population consisted of 18,511 consecutive patients not receiving oral anticoagulants and undergoing echocardiography with measurement of LAD at baseline. The incidence rate of ischemic stroke was calculated in 3 groups according to left atrial dimension (LAD; < 30, 30-45 and ≥ 45 mm) in AF and non-AF patients. Further subgroup analysis was performed in stratification by elderly and young (aged ≥ 65 and < 65 years, respectively). The incidences of IS (per 100 patient-years) were 0.11 and 0.71 in non-AF and AF patients with LAD < 30 mm, respectively, which increased to 0.58 and 1.35 in LAD ≥ 45 mm (adjusted hazard ratios [HRs]; 1.95 [95% confidence intervals, CIs: 0.76-5.01] and 1.22 [95% CIs: 0.27-5.58], interaction P was 0.246). In non-AF patients, the incidences of IS were 0.30 and 0.04 in elderly and young patients with LAD < 30 mm, which increased to 0.67 and 0.48 in LAD ≥ 45 mm (adjusted HRs; 1.34 [95% CIs: 0.43-4.15] and 4.21 [95% CIs: 0.77-23.12], interaction P was 0.158). The incidence of IS significantly increased with increase of LAD in non-AF, especially in non-AF and young patients, although the difference was not independent of other clinical factors. The impact of LAD on IS was numerically larger in non-AF than in AF, and larger in young and non-AF than in elderly counterpart, although a significant interaction was not observed in this small population. Further studies with large population are necessary to judge whether these population with enlarged LA need antithrombotic therapy., (© 2021. Springer Japan KK, part of Springer Nature.)

The prognostic impact of anemia, especially mild anemia, in atrial fibrillation (AF) remains unclear. We examined clinical burdens of mild anemia on the quality of life (QoL) and clinical outcomes of 1,677 AF patients. Patients were divided into a non-anemia (hemoglobin [Hb] ≥13 g/dl for men and Hb ≥12 g/dl for women) and a mild anemia group (10≤ Hb <13 g/dl for men and 10≤ Hb <12 g/dl for women). At baseline, 22.5% of patients (n = 378) had anemia; patients in the mild anemia group had higher CHA 2 DS 2 -VASc scores (3.7 vs 2.7; p <0.01) and brain natriuretic peptide levels (253.5 vs 159.6 pg/ml; p <0.01) and were more likely to develop chronic kidney disease (64.2 vs 42.9%; p <0.01) than those in the non-anemia group. During follow-up (mean 1.7 ± 0.4 years), patients with mild anemia had a higher risk of heart failure hospitalization and major bleeding events than those without (12.2 vs 3.8%; p <0.01 and 5.6 vs 2.5%; p <0.01, respectively). Mild anemia was an independent risk factor for heart failure hospitalization (adjusted hazard ratio: 1.67, 95% confidence interval 1.06 to 2.62, p = 0.03) but not for major bleeding (adjusted hazard ratio: 1.44, 95% confidence interval 0.80 to 2.62, p = 0.23). QoL improvement was less likely in the mild anemia group during follow-up, despite the lack of significant differences at baseline. In conclusion, the presence of even mild anemia was associated with increased risks of heart failure hospitalization and poor QoL improvement., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Catheter ablation for atrial fibrillation (AF) has been an established and frequently utilized approach in a variety of clinical settings. Nevertheless, real-world data about the clinical course of AF patients after initial catheter ablation remain limited, and these are mainly derived from particular registries or selected high-volume centers.In this study, we used health check-ups and insurance claims database from a Japanese insurance organization. The study population was comprised of 1777 patients who underwent catheter ablation for AF before June 2016. During the 3-year follow-up period, 396 (22.3%) patients underwent at least one repeated AF ablation, while 74 (4.2%) underwent two or more repeated ablations. In multivariate Cox regression analysis, longer time after AF diagnosis (7-11 months and ≥12 months versus 1-6 months) (HR, 1.05; 95% CI, 1.01-1.08 and HR, 1.04; 95% CI 1.02-1.07) was independently associated with repeated ablation. The discontinuation rates of OACs and AADs after the first ablation were 26.7% and 63.0% at 3 months and 75.2% and 89.1% at 1 year after the initial ablation, respectively. The former was independently associated with shorter time after AF diagnosis and lower diastolic blood pressure, whereas the latter was independently associated with older age, smaller CHADS 2 score, and shorter time after AF diagnosis.We presented real-world data regarding the clinical course of young Japanese AF patients after initial catheter ablation based on a claims database in Japan.

Aim: Polypharmacy is known to be a risk factor for falls or bone fracture (F/F) in elderly patients. However, this relationship is not fully described in patients with non-valvular atrial fibrillation (NVAF), for which F/F may lead to serious clinical outcomes, including major bleeding., Methods: We analyzed 509 elderly (aged ≥75 years) patients with NVAF who had recently visited a hospital specializing in cardiology, of which 272 patients had paroxysmal atrial fibrillation (PAF) and 237 had persistent/permanent atrial fibrillation (PeAF). Patients were divided into four groups according to the number of medications: ≤3, 4-6, 7-9, and ≥10. The relationship between the number of medications and incidence rate of F/F in AF patients was analyzed. In addition, this relationship was analyzed in patients with each AF type., Results: Cumulative incidence of F/F at 3 years in the respective categories was 3.7%, 5.4%, 4.3% and 5.7% for PAF, and 5.2%, 7.5%, 7.8% and 25.0% for PeAF (log-rank test, P = 0.930 and 0.003, respectively). In a multivariable model, patients with ≥10 medications showed a significantly higher risk for F/F compared with those with ≤3 medications as reference only in PeAF (adjusted hazard ratio 4.82, 95%CI 1.42-16.33), without significant interaction (P = 0.081)., Conclusions: Elderly NVAF patients using ≥10 medications showed a higher risk for F/F. In subgroup analysis, this association was observed only in patients with PeAF, although there was no significant interaction between number of medications and AF type. Geriatr Gerontol Int 2021; 21: 802-809., (© 2021 Japan Geriatrics Society.)

Background: Machine learning (ML) has emerged as a promising tool for risk stratification. However, few studies have applied ML to risk assessment of patients with atrial fibrillation (AF)., Hypothesis: We aimed to compare the performance of random forest (RF), logistic regression (LR), and conventional risk schemes in predicting the outcomes of AF., Methods: We analyzed data from 7406 nonvalvular AF patients (median age 71 years, female 29.2%) enrolled in a nationwide AF registry (J-RHYTHM Registry) and who were followed for 2 years. The endpoints were thromboembolisms, major bleeding, and all-cause mortality. Models were generated from potential predictors using an RF model, stepwise LR model, and the thromboembolism (CHADS 2 and CHA 2 DS 2 -VASc) and major bleeding (HAS-BLED, ORBIT, and ATRIA) scores., Results: For thromboembolisms, the C-statistic of the RF model was significantly higher than that of the LR model (0.66 vs. 0.59, p = .03) or CHA 2 DS 2 -VASc score (0.61, p < .01). For major bleeding, the C-statistic of RF was comparable to the LR (0.69 vs. 0.66, p = .07) and outperformed the HAS-BLED (0.61, p < .01) and ATRIA (0.62, p < .01) but not the ORBIT (0.67, p = .07). The C-statistic of RF for all-cause mortality was comparable to the LR (0.78 vs. 0.79, p = .21). The calibration plot for the RF model was more aligned with the observed events for major bleeding and all-cause mortality., Conclusions: The RF model performed as well as or better than the LR model or existing clinical risk scores for predicting clinical outcomes of AF., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

The EXPAND Study demonstrated the effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) in routine clinical practice in Japan. This sub-analysis was conducted to reveal the effectiveness and safety of rivaroxaban in Japanese NVAF patients according to baseline creatinine clearance (CrCl) levels and rivaroxaban doses in the EXPAND Study. We examined 6806 patients whose baseline CrCl data were available and classified them into 2 groups: normal renal function group with CrCl ≥ 50 mL/min (n = 5326, 78%) and renal dysfunction group with CrCl < 50 mL/min (n = 1480, 22%). In the normal renal function group, 1609 (30%) received 10 mg/day (under-dose), while in the renal dysfunction group, 108 (7%) received 15 mg/day (over-dose). In the normal renal function group, under-dose of rivaroxaban was associated with higher all-cause mortality, while in the renal dysfunction group, over-dose was associated with higher incidence of major bleeding. In contrast, the incidence of stroke or systemic embolism was not different between the 2 groups regardless of the dose of rivaroxaban. In the propensity score matched analysis to adjust the difference in characteristics according to doses of rivaroxaban, the incidences of clinical outcomes were comparable between the 2 dose groups in both renal function groups. These results indicate that the dose of rivaroxaban should be reduced depending on the renal function, considering the balance between risks of bleeding and ischemia., (© 2021. The Author(s).)

Background Increasing age predisposes patients with atrial fibrillation to both thromboembolic and bleeding events; however, data on outcomes of very elderly patients (aged ≥85 years) receiving appropriate antithrombotic therapy are still limited. Methods and Results The J-ELD AF (Multicenter Prospective Cohort Study to Investigate the Effectiveness and Safety of Apixaban in Japanese Elderly Atrial Fibrillation Patients) Registry is a multicenter prospective observational study of Japanese patients with nonvalvular atrial fibrillation aged ≥75 years taking on-label doses (standard dose of 5 mg BID or reduced dose of 2.5 mg BID) of apixaban. The entire cohort (3031 patients from 110 institutions) was divided into 3 age groups: 75 to 79 years (n=1068, 35.2%), 80 to 84 years (n=1120, 37.0%), and ≥85 years (n=843, 27.8%). The event incidence rates (/100 person-years) were 1.40, 1.55, and 1.95 for stroke or systemic embolism (log-rank P =0.65); 1.70, 1.55, and 2.61 for bleeding requiring hospitalization (log-rank P =0.33); 2.09, 2.60, and 5.29 for total deaths (log-rank P <0.001); and 0.40, 1.06, and 1.55 for cardiovascular deaths (log-rank P =0.045), respectively. After adjusting for confounders using a Cox regression analysis, age ≥85 years was identified as an independent risk of total death (hazard ratio, 1.89; 95% CI, 1.10-3.26 [ P =0.022]), but not of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death. Conclusions Although mortality increased with age, age ≥85 years was not a significant risk of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death in Japanese patients with nonvalvular atrial fibrillation taking on-label doses of apixaban. Registration URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000017895.

Background: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). We investigated the adherence of DOACs for years known to be associated with the effectiveness in Japanese NVAF patients, using a claim database., Method: We performed a retrospective evaluation of NVAF patients in a claims database in Japan, who initiated dabigatran, rivaroxaban, and apixaban between April 2011 and June 2016. Drug persistence was assessed by Kaplan-Meier method for the initially-prescribed DOAC and all DOACs including switched ones. Proportion of days covered (PDC) was also evaluated in patients with persistent prescription and compared among DOACs., Results: In the total of 671 patients, rivaroxaban (47%) was more prescribed than dabigatran (28%) and apixaban (25%). Drug persistence at 3 years was higher in rivaroxaban (69%) than dabigatran (57%) and apixaban (67%). Including switching to other DOACs, persistence of DOACs was 72% at 3 years without significant differences between index-DOACs. In multivariate Cox regression analysis, absence of hypertension, and prior history of cancer were significantly associated with the drug discontinuation of all DOACs. The mean PDC was ~ 95% and the frequency of high-adherent patients (PDC ≥0.80) was more than 90%, which similarly persisted at 3 years and showed no significant differences between index DOACs., Conclusion: In a real-world Japanese claim data analysis, about 70% of patients under DOAC showed persistence with anticoagulation therapy at 3 years. High adherence to DOACs assessed by PDC (over 90%) persisted to 3 years regardless of the types of DOACs., Competing Interests: Declaration of Competing Interest Dr Suzuki received research fund from Daiichi Sankyo and Mitsubishi Tanabe Pharm and lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. Dr Yamashita has received research funds and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Ono Pharmaceutical, and Toa Eiyo., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry.Methods and Results:The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m 2 (L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E 2 S 2 score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS 2 (0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA 2 DS 2 -VASc scores (0.641; 95% CI=0.608-0.673, P=0.008)., Conclusions: The HELT-E 2 S 2 score may be useful for identifying Japanese NVAF patients at risk of ischemic stroke.

Dose reduction of apixaban is applied in atrial fibrillation (AF) patients fulfilling ≥ 2 of the following criteria: (1) age ≥ 80 years, (2) body weight ≤ 60 kg and (3) serum creatinine ≥ 1.5 mg/dL. However, the clinical significance of each criterion remains unclear. The J-ELD AF Registry is a prospective observational study of elderly (≥ 75 years) Japanese AF patients receiving on-label dose of apixaban. In patients receiving the standard dose (5 mg bid, n = 1243), the incidence rates (% per patient-year) of stroke or systemic embolism in those fulfilling none [n = 516] or one of the above criteria (1) [n = 328], (2) [n = 378] and (3) [n = 21] were 1.24, 2.32, 1.41 and 4.93 (log-rank P = 0.422), respectively, and those of bleeding requiring hospitalization were 1.03, 0.99, 1.98 and 4.93 (P = 0.318), respectively. In patients receiving a reduced dose (2.5 mg bid, n = 1,515), the incidences of stroke or systemic embolism in those fulfilling (1)/(2) [n = 1,331], (1)/(3) [n = 65], (2)/(3) [n = 23] and all three criteria [n = 96] were 1.38, 1.64, 4.67 and 3.51 (P = 0.295), respectively, and those of bleeding requiring hospitalization were 2.04, 1.64, 0.00 and 4.71 (P = 0.318), respectively. Univariate analysis demonstrated that the types or combinations of each criterion was not significantly associated with the incidence of thromboembolic or bleeding events. The types or combinations of the three apixaban dose reduction criteria did not have significant impact on effectiveness and safety in Japanese elderly AF patients receiving on-label dose of apixaban, although the impact of the creatinine criterion remains uncertain due to the few number of the patients.

Objectives: This study sought to investigate whether symptom under-recognition is associated with the application of catheter ablation., Background: Atrial fibrillation (AF) symptom burden is frequently under-recognized and may affect the choice of treatment strategies., Methods: A total of 3,276 patients with AF consecutively registered in a Japanese multicenter database from 2012 to 2017 were analyzed. All patients underwent AF symptom burden assessment via the symptom and daily activities domain within the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. For the present analysis, 1,173 symptomatic patients (AFEQT score ≤80) with a clinical indication for catheter ablation were included. Under-recognition of symptom burden was defined as no subjective complaints checked by physicians despite self-reported AFEQT scores ≤80. Logistic regression analysis identified the predictors associated with receiving catheter ablation., Results: Of the 1,173 patients (age: 68 ± 12 years, men: 61%) analyzed, 459 underwent catheter ablation (ablation group); they had lower overall AFEQT scores (p < 0.01 for all domains) compared with the nonablation group. At the 1-year follow-up, greater improvement in the AFEQT scores was noted in the ablation group, even after adjusting for clinically relevant factors (+20.0 ± 1.2, +14.2 ± 0.9, respectively; p < 0.001). Notably, 306 (28%) patients met the criteria for symptom under-recognition, which was associated with the nonuse of catheter ablation during follow-up (odds ratio: 0.41; 95% confidence interval: 0.28 to 0.60; p < 0.001)., Conclusions: Under-recognition of AF symptom burden was frequently noted and was associated with less use of catheter ablation. Standardized recognition of symptoms using the application of validated questionnaires may facilitate outcome improvement., Competing Interests: Funding Support and Author Disclosures This study was funded by the Grant-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development (Pooled analysis for identifying RISK factors for Atrial Fibrillation and cardioembolic stroke, in Japanese: ID 924988), Japan Society for the Promotion of Science (Grant No. 20H03915, 16KK0186, and 16H05215), and by an unrestricted research grant from Bayer Yakuhin Ltd. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation, such as that associated with intermediate CD14 ++ CD16 + monocytes and atrial structural remodeling (SRM), may be important in the recurrence of atrial fibrillation (AF) after catheter ablation. However, the relationship between the intermediate CD14 ++ CD16 + monocytes, SRM, and AF recurrence is unclear., Methods: Twenty-four patients with AF were enrolled. The proportion of intermediate monocytes (PIM) was assessed before ablation by flow cytometry. As a surrogate marker of SRM, the volume ratio (VR) of signal intensity greater than 1 standard deviation on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) was calculated. We investigated whether PIM correlated with SRM on LGE-MRI and determined the optimal cutoff value for predicting AF recurrence., Results: Univariate analysis revealed positive correlations between PIM and BNP with SRM (PIM: r = .593, p = .002; BNP: r = .567, p = .004). Multivariable analysis revealed that PIM was independently associated with VR on LGE-MRI (β = .522; p = .033). The finding of an area under the receiver operating characteristic curve of 0.750 revealed that a VR ≥ 13.3% on LGE-MRI as the optimal cutoff value to predict AF recurrence with 80% sensitivity and 71% specificity, which was associated with PIM ≥ 10.0%., Conclusion: Intermediate monocytes were significantly positively correlated with SRM. PIM ≥ 10% was associated with a VR ≥ 13.3% on LGE-MRI, which predicted AF recurrence after catheter ablation., (© 2021 Wiley Periodicals LLC.)