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Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF., Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA 2 DS 2 -VASc score, 3)., Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA] 2 -B 3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores., Conclusion: Our novel risk stratification system, the HED-[EPA] 2 -B 3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

Importance: Despite the development of risk stratification schemes that have been widely used to determine the risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF), risk stratification schemes in Asian patients with NVAF remain undetermined., Objective: To determine risk factors for ischemic stroke in Japanese patients with NVAF., Design, Setting, and Participants: This cohort study analyzed individual patient data from 5 AF registries in Japan: J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) Registry, Fushimi AF Registry, Shinken Database, Keio Interhospital Cardiovascular Studies (Keio Study), and Hokuriku-Plus AF Registry. Patients with atrial fibrillation were registered from 158 institutions in the J-RHYTHM Registry, 80 in the Fushimi AF Registry, a single hospital in Shinken Database, 11 in the Keio Study, and 19 in the Hokuriku-Plus AF Registry. Patients with valvular AF or lacking data were excluded. Data were collected and integrated in March 2016, and those from the Keio Study were updated in April 2018. Data were analyzed from April 2018 to February 2020., Main Outcomes and Measures: Significant risk factors for ischemic stroke were determined by adjusted Cox proportional hazards analysis., Results: In total, 12 289 patients with NVAF (3758 [31%] female; mean [SD] age 70.2 [11] years) were analyzed with a mean (SD) follow-up period of 649 (181) days (1.8 [0.5] years). During 21 820 person-years of follow-up, 241 cases of ischemic stroke were reported. Risk factors associated with ischemic stroke after adjustment for oral anticoagulant use at enrollment were age (75-84 years: hazard ratio [HR], 1.74; 95% CI, 1.32-2.30; P < .001; and ≥85 years: HR, 2.41; 1.63-3.56; P < .001), hypertension (HR, 1.60; 95% CI, 1.15-2.23; P = .006), previous stroke (HR, 2.75; 95% CI, 2.09-3.62; P < .001), persistent or permanent AF (HR, 1.59; 95% CI, 1.21-2.10; P = .001), and body mass index less than 18.5 (HR, 1.55; 95% CI, 1.05-2.29; P = .03). Neither diabetes nor heart failure were identified as risk factors for ischemic stroke., Conclusions and Relevance: Previous stroke, advanced age, hypertension, persistent or permanent AF, and low body mass index were independent risk factors associated with ischemic stroke in Japanese patients with NVAF.

Background: To clarify the influence of hemoglobin concentration and platelet count on adverse outcomes of Japanese patients with non-valvular atrial fibrillation (NVAF), a post hoc analysis of the J-RHYTHM Registry was performed., Methods: A consecutive series of outpatients with atrial fibrillation were enrolled from 158 institutions and followed up for 2 years or until an event occurred (thromboembolism, major hemorrhage, or all-cause death). Among 7406 patients with NVAF, 6536 with complete blood count data (69.8 ± 9.9 years, 71.0% men) were divided into 4 groups according to the baseline hemoglobin level (<10.0, 10.0-11.9, 12.0-13.9, and ≥14.0 g/dL) or platelet count (<10.0, 10.0-19.9, 20.0-29.9, and ≥30.0 × 10 4 /μL)., Results: Incidence rates of major hemorrhage (p = 0.004 for trend), all-cause death (p < 0.001 for trend), and composite events (p < 0.001 for trend) increased as hemoglobin levels decreased, and composite events (p = 0.045 for trend) increased as platelet counts decreased. After adjusting for multiple confounders, the incidence of all-cause death and composite events was higher with hemoglobin levels <12.0 g/dL than a hemoglobin level ≥14.0 g/dL. In contrast, platelet count was not associated with any events. This was also true when multivariate analysis was performed using the stepwise forward method., Conclusions: A low hemoglobin level (<12.0 g/dL) was an independent risk factor for all-cause death and composite events in Japanese patients with NVAF. However, platelet count did not impact outcomes., Clinical Trial Registration: http://www.umin.ac.jp/ctr/ (unique identifier: UMIN000001569)., Competing Interests: Declaration of competing interest Dr. Kodani received remuneration from Daiichi-Sankyo, Bristol-Myers Squibb, and Ono Pharmaceutical; Dr. Inoue received remuneration from Daiichi-Sankyo, Bayer Healthcare, Boehringer Ingelheim, and Bristol-Myers Squibb; Dr. Atarashi received remuneration from Daiichi-Sankyo; Dr. Okumura received research funding from Boehringer Ingelheim and Daiichi-Sankyo and remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi-Sankyo, and Pfizer; Dr. Yamashita received research funding from Daiichi-Sankyo, Bayer Healthcare, and Bristol-Meyers Squibb and remuneration from Daiichi-Sankyo, Pfizer, Bayer Healthcare, Bristol-Myers Squibb, Toa Eiyo, and Ono Pharmaceutical; and Dr. Origasa received remuneration from Daiichi-Sankyo and Bayer Healthcare., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF). Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged ≥70 years. Target INR values were 1.6-2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13-1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37-3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41-6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56-18.18, P=0.008 and 1.60, 1.07-2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10-3.76, P=0.024 and 1.58, 1.22-2.04, P=0.001, respectively)., Conclusions: Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death.

Background: Concomitant use of vitamin K antagonist (VKA) and aspirin (ASA) is becoming increasingly prevalent among atrial fibrillation (AF) patients. We quantified the net clinical benefit of adding ASA to a VKA using nationwide prospective AF registry data., Methods: We studied 6074 patients (VKA monotherapy: 83% and VKA+ASA: 17%) between January 2009 and July 2009, and followed them for a mean follow-up period of 2years. The risk of strokes and bleeding was calculated by the CHA2DS2-VASc and HAS-BLED scores. The net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by VKAs minus intracranial hemorrhages attributable to the VKA+ASA, multiplied by an impact weight of 1.5., Results: Patients on a VKA+ASA were older with more medical comorbidities than those on VKA alone. Using VKA monotherapy as a reference, higher major bleeding rates and all-cause death were evident in those on VKA+ASA. The net clinical benefit of VKA+ASA for the overall cohort was -0.1%/year (95% confidence interval, -0.74% to 0.46%). There was a trend toward a negative net clinical benefit from VKA+ASA in patients with a CHA2DS2-VASc≥2 and HAS-BLED≤2 (-1.17%/year). The VKA+ASA yielded a positive net clinical benefit in patients with a CHA2DS2-VASc≥2 and HAS-BLED≥3 (1.16%/year). The result patterns were relatively constant using impact weight of 1.0 and 2.0., Conclusions: Our estimates of the net clinical benefit can provide a useful anchoring point for adding ASA to VKA in patients with AF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Prior ischemic stroke or transient ischemic attack (TIA) is a high risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To clarify rates of thromboembolic and hemorrhagic events, and target intensities of warfarin for secondary prevention, a subanalysis was performed using data from the J-RHYTHM Registry., Methods: Of 7937 outpatients with atrial fibrillation, 7406 with NVAF (men 70.8%, 69.8 ± 10.0 years) were followed for 2 years or until an event occurred. Event rates and effect of warfarin were compared between patients with (secondary prevention) and without (primary prevention) prior stroke/TIA., Results: Prevalence of male sex, diabetes mellitus, and mean age were higher in the secondary prevention group, showing a higher CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA) score than the primary prevention group (3.5 ± 1.0 versus 1.4 ± 1.0, P < .001). In the secondary prevention group, 93.4% of patients received warfarin and their time in therapeutic range was 62.8%. During follow-up, thromboembolism occurred more frequently in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004), especially in patients without warfarin. Major hemorrhage also occurred more frequently in the secondary prevention group (3.0% versus 1.7%, P = .006). Compared with patients not taking warfarin, combined rates of both events were lower at an international normalized ratio (INR) of 1.6-2.59 in patients taking warfarin in the secondary as well as in the primary prevention groups., Conclusions: Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior ischemic stroke/TIA. Target INR should be 1.6-2.59 for secondary as well as primary prevention of thromboembolism in Japanese NVAF patients., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The J-RHYTHM Registry 2 was a multicenter, prospective observational study that extended the follow-up period of the J-RHYTHM Registry in order to investigate long-term outcomes and effects of non-vitamin K antagonist oral anticoagulants (NOACs) in Japanese patients with atrial fibrillation (AF)., Methods and results: Among 6,616 patients with nonvalvular AF (NVAF) (men 71.0%, 69.7±9.9 years, CHADS2score 1.7±1.2), event rates were compared among patients receiving warfarin (n=3,964), NOACs (n=923), and no anticoagulation therapy (No-OAC, n=753) at the end of follow-up, except for 976 patients lacking anticoagulant data. During the 5-year follow-up period, thromboembolism occurred in 196 (4.9%), 19 (2.1%), and 45 (6.0%) patients, respectively; major hemorrhage in 233 (5.9%), 22 (2.4%), and 36 (4.8%); all-cause death in 230 (5.8%), 13 (1.4%), and 105 (13.9%), (P<0.001 for each). After adjusting for the components of the CHA2DS2-VASc score and antiplatelet drug use, the odds ratio (OR) in the Warfarin group was significantly lower for all-cause death compared with that in the No-OAC group (OR 0.30, 95% confidence interval [CI] 0.23-0.39, P<0.001), whereas ORs in the NOACs group were significantly lower for all events (OR 0.42, 95% CI 0.24-0.74, P=0.003 for thromboembolism; OR 0.53, 95% CI 0.31-0.93, P=0.027 for major hemorrhage; and OR 0.10, 95% CI 0.06-0.18, P<0.001 for all-cause death, respectively)., Conclusions: NOACs could be beneficial for reducing event rates of all types in Japanese NVAF patients.

Background: Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet., Methods and Results: We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively., Conclusions: I NR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6-2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.

Background: To clarify the effects of warfarin therapy in very old patients with non-valvular atrial fibrillation (NVAF), a post-hoc analysis was performed using the data of the J-RHYTHM Registry., Methods and results: A consecutive series of AF outpatients was enrolled from 158 institutions. Of 7,937 patients, 7,406 with NVAF (men, 70.8%; 69.8±10.0 years) were followed for 2 years or until an event occurred. Patients were divided into 3 age groups (<70, 70-84, and ≥85 years) and 5 subgroups according to international normalized ratio (INR; <1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Prevalence of female sex, permanent AF, hypertension, coronary artery disease, heart failure, and history of ischemic stroke/transient ischemic attack was higher in the older groups. In the oldest group, 79.7% of patients received warfarin and their time in therapeutic range, using the Japanese target INR of 1.6-2.6, was 67.1%. Rate of thromboembolic events was lower in the age groups <70 and 70-84 years (P=0.027 and P<0.001, respectively) for patients receiving warfarin compared with those who were not. In the oldest group, the rate of thromboembolism plus major hemorrhage was lower at INR 1.6-2.59., Conclusions: Warfarin could have beneficial effects even in very old NVAF patients if INR is kept between 1.6 and 2.59.