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Competing Interests: I declare no competing interests.

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.)

Background: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant., Conclusions: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Background: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated., Methods: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months., Results: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54)., Conclusions: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke., Clinical Trial Registration: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov., Competing Interests: I have read the journal’s policy and have the following conflicts. Dr. Koge reports no disclosures. Dr. Yamagami reports research grants from Bristol-Myers Squibb, Terumo, JIMRO, and Striker; lecturer’s fees from Stryker, Terumo, Medtronic, Medico’s Hirata, Johnson and Johnson, Bayer, Daiichi-Sankyo, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, and Otsuka Pharmaceutical; and membership of the advisory boards for Daiichi-Sankyo and Biomedical Solutions. Dr. Toyoda reports lecturer’s fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb. Dr. Yasaka reports lecturer’s fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb and CSL Behring. Dr. Hirano reports lecturer’s fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, and Medtronic. Dr. Hamasaki reports no disclosures. Dr. Nagao reports lecturer’s fee from Bayer Yakuhin. Dr. Yoshimura reports lecture fees from Boehringer, Ingelheim, Bayer, Daiichi-Sankyo, Phizer, BMS, Takeda, Sanofi, Otsuka, Tanabe-Mitsubishi, Medtronic, Stryker, and Medico’s Hirata and research support from BMS and Takeda. Dr. Fujishige reports no disclosures. Dr. Tempaku reports no disclosures. Dr. Uchiyama reports honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, AstraZeneka, and Takeda. Dr. Mori reports lecture fees from Johnson & Johnson, Otsuka, Novartis, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Sosei, Kyowahakko-Kirin, Toshiba, Medtronic, and Nihon Medi-Physics and research support from Eisai, Daiichi-Sankyo, Novartis, Fuji Film RI, General Electric, MHWL, MEXT, and JSPS. Dr. Koga reports honoraria from Bayer Yakuhin, Bristol-Myers-Squibb, Otsuka, Daiichi-Sankyo, Nippon Boehringer Ingelheim and Takeda, scientific advisory board from Ono, and research supports from Takeda, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Astellas, Pfizer and Shionogi, outside the submitted work. Dr. Minematsu reports honoraria from Bayer Yakuhin, Otsuka Pharmaceutical, Behringer Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma Corporation, Japan Stryker, Dai-ichi Sankyo, Astellas Pharma, Nippon Chemiphar, Fuji Film RI Pharma, MSD, Kyowa Hakko Kirin, Sanofi, advisory board from CSL Behring, Bayer Yakuhin, EPS, Corporation, HEALIOS K.K., T-PEC Corporation and BMS. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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).)

Introduction: Experimental models have clearly demonstrated sex differences in the pathophysiology of stroke and prognosis, however clinical evidence remains elusive. In this study, we examined sex differences as a post hoc analysis of RELAXED (Recurrent Embolism Lessened by rivaroxaban, an anti-X agent, of Early Dosing for acute IS and TIA with atrial fibrillation) Study., Methods: We stratified study participants by sex and compared baseline and clinical characteristics as well as clinical outcomes. The primary outcome measure was a good outcome defined as a modified Rankin Scale score of 0-2 at 90 days after stroke. Secondary outcomes were mortality at 90 days, intracranial hemorrhage within 90 days, and recurrence of stroke or transient ischemic attack within 90 days. We constructed a logistic regression model to estimate the adjusted odds ratio of female patients compared with male patients for the primary and secondary outcomes., Results: Of 1303 patients, most were male (57.7%) with a mean age of 74.5 years. Female patients were older with a mean age of 80.6 ± 8.9 years and had significantly less frequent anticoagulation therapy before onset of stroke and more severe NIHSS scores. Good outcome was observed in 51.2% and 63.3% of the females and males (p < 0.0001). The adjusted odds ratio of a good outcome in females was 1.12 (95% confidence interval, 0.44-2.87) (p = 0.81). There were no sex differences in secondary outcomes., Conclusion: Adjusted regression analysis found no sex difference in the treatment outcomes at 90 days after stroke with non-valvular atrial fibrillation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The study objective was to evaluate long-term safety and effectiveness of dabigatran 110 mg and 150 mg twice daily (bid) in patients with nonvalvular atrial fibrillation (NVAF) with a focus on secondary stroke prevention., Methods: In J-Dabigatran Surveillance, 6772 patients newly initiated on dabigatran to prevent ischemic stroke and systemic embolism were enrolled in Japan (1042 sites, December 2011 to November 2013). This subgroup analysis included patients with (1302) and without (5071) previous stroke/transient ischemic attack (TIA). Case report forms were reviewed to determine incidence of outcome events., Results: In patients with previous stroke/TIA, the incidence rate for recurrent stroke/TIA was 2.48/100 patient-years (ischemic stroke 2.22, hemorrhagic stroke 0.18, TIA 0.12) and for major bleeding was 1.79/100 patient-years, including intracranial bleeding (0.55). Event rates for recurrent stroke/TIA or major bleeding were 1.2% (for both) for patients who started dabigatran less than 30 days after stroke onset and 0.3% (for both) for patients who started dabigatran more than or equal to 30 days after stroke onset, and were independent of dabigatran dose. For patients with previous stroke/TIA, 17% who received 110 mg bid did not meet dose reduction recommendations (DRRs) and 28% who received 150 mg bid met at least 1 DRR, but the dabigatran dose was not reduced. Use of DRRs did not have a major impact on the incidence rates of recurrent stroke/TIA and major bleeding., Conclusion: Findings from this subgroup analysis support the real-world safety and effectiveness of long-term dabigatran in Japan, particularly for patients with NVAF in secondary prevention settings., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS 2, CHA 2 DS 2 -VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.

Aims: The Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM-II) are validated treatment satisfaction patient-reported outcome (PRO) instruments. The ACTS includes two domains: Burdens and Benefits; the TSQM-II includes four: Effectiveness, Side Effects, Convenience, and Global Satisfaction. Japanese-language versions of the ACTS and TSQM-II have been developed and linguistically validated. This study aimed to assess their psychometric properties in Japanese patients with atrial fibrillation (AF). Materials and methods: ACTS and TSQM-II data from 534 patients with AF were collected in a Japanese post-marketing surveillance study of a direct oral-anticoagulant, rivaroxaban. Four key psychometric properties, in line with best practice guidelines from the US Food and Drug Administration, were examined using traditional psychometric methods: acceptability, scaling assumptions, reliability (i.e. internal consistency reliability, test-retest reliability), and construct validity (i.e. convergent validity and known groups). Results: ACTS Burdens and Benefits and TSQM-II Effectiveness, Convenience, and Global Satisfaction scales were found to be acceptable (e.g. item-level missing data at baseline <4%), with all scales having good internal consistency (Cronbach's alpha > 0.80). test-retest reproducibility intraclass correlation coefficients for the ACTS Burdens and Benefits were 0.59 and 0.65, respectively, and between 0.54-0.61 for the TSQM-II scales. Known-groups validity for the ACTS and TSQM-II was supported by differences in scale scores by positive and negative impact ( p <  0.05). Correlations between the ACTS and TSQM-II (convergent validity) were lower than expected (range r =  0.09-0.48), but in line with the original ACTS development study. Limitations: Evaluation of test-retest reproducibility was limited by assessment period, which was longer (3 months) than recommended guidelines (usually up to 2 weeks). Conclusions: Overall, Japanese versions of ACTS and TSQM-II scales satisfied internal consistency reliability and traditional validity criteria. Our study supports the ACTS and TSQM-II as appropriate PRO instruments to measure satisfaction with anticoagulant treatment in Japanese patients with AF. Trial registration: NCT01598051, clinicaltrials.gov; registered April 20, 2012.

Background: The effectiveness and safety of dabigatran etexilate (DE) have not been elucidated thoroughly in clinical practice for Japanese patients with non-valvular atrial fibrillation (NVAF). In particular, those of DE at a reduced dose due to dose reduction recommendations (DRR) remain unknown., Methods: NVAF patients who had newly initiated DE treatment for prevention of thromboembolic events between December 2011 and November 2013 were enrolled. They were followed until August 2016. Outcome events included thromboembolism, major bleeding, and all-cause death., Results: The study group consisted of 6443 patients (mean age, 70.9 years; male, 66.9%; and mean CHADS 2 score, 1.8). During a follow-up period of 610 days (median), stroke, transient ischemic attack (TIA), and systemic embolism (SE) occurred at 1.4%/year for DE 110mg twice daily (BID) (DE220, n=4759) and 0.8% for dabigatran 150mg BID (DE300, n=1571, unadjusted p=0.0317). Major bleeding occurred at 1.3 and 0.6%/year for DE220 and DE300, respectively (unadjusted p=0.0097). All-cause death occurred at 1.5 and 0.5%/year for DE220 and DE300, respectively (unadjusted p=0.0005). When patients were divided into four groups based on DRR and DE doses (DE300 groups meeting and not meeting DRR, and DE220 groups meeting and not meeting DRR), incidence rates of stroke/TIA/SE and major bleeding differed among the four groups (unadjusted p=0.0026 and 0.0194 for trend, respectively); DE220 group meeting DRR had the highest rates (1.7% and 1.4%/year, respectively). However, in multivariate analysis, no differences between doses were observed regarding any outcomes., Conclusions: The present results are indicative of the favorable benefit-risk profile of dabigatran in Japanese clinical practice. Dabigatran dose was not independently associated with thromboembolic and bleeding events in Japanese NVAF patients., (Copyright © 2019. Published by Elsevier Ltd.)

The efficacy of early anticoagulation in acute stroke with nonvalvular atrial fibrillation (NVAF) remains unclear. We performed a study to evaluate the risk of recurrent ischemic stroke (IS) and major bleeding in acute IS patients with NVAF who started rivaroxaban. This observational study evaluated patients with NVAF and acute IS/transient ischemic attack (TIA) in the middle cerebral arterial territory who started rivaroxaban within 30 days after the index IS/TIA. The primary endpoints were recurrent IS and major bleeding within 90 days after the index IS/TIA. The relationship between the endpoints and the time to start rivaroxaban was evaluated by correlation analysis using cerebral infarct volume, determined by diffusion-weighted magnetic resonance images within 48 hours of onset of the index IS/TIA. Of 1309 patients analyzed, recurrent IS occurred in 30 (2.3%) and major bleeding in 11 (0.8%) patients. Among patients with known infarct size (N = 1207), those with small (<4.0 cm3), medium (≥4.0 and <22.5 cm3), and large (≥22.5 cm3) infarcts started rivaroxaban a median of 2.9, 2.9, and 5.8 days, respectively, after the index IS/TIA. Recurrent IS was significantly less frequent when starting rivaroxaban ≤14 days versus ≥15 days after IS (2.0% versus 6.8%, P = 0.0034). Incidences of recurrent IS and major bleeding in whom rivaroxaban was started <3 days (N = 584) after IS were also low: 1.5% and 0.7%, respectively. Initiation of rivaroxaban administration in acute IS or TIA was associated with a low recurrence of IS (2.3%), and a low incidence of major bleeding events (0.8%) for 90 days after the index stroke. For the prevention of recurrent attacks in acute IS patients with NVAF, it is feasible to start the administration of rivaroxaban within 14 days of onset. Rivaroxaban started within 3 days of onset may be a feasible treatment option for patients with a small or medium-sized infarction., Competing Interests: I have read the journal's policy and have the following conflicts. Yasaka M received lecture fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Pfizer, BMS, Takeda, Sumitomo-Dainippon, Sanofi, Otsuka, CSL Behring, Ezai, Tanabe-Mitsubishi, Medtronic, Boston Scientific, and Sekisui Medical and research support from Sanofi, Boehringer Ingelheim, and Daiichi-Sankyo. Minematsu K received lecture fees from Bayer Healthcare, Otsuka Pharmaceutical, Boehringer-Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma Cooperation, Japan Stryker, Kowa, Nihon Medi-Physics Co, BMS, Sawai Pharmaceutical Co., Sumitomo Dainippon Pharma Co Ltd, Medico’s Hirata, Daiichi Sankyo, Astellas Pharma, Kyowa Hakko Kirin Pharma, Inc, Sanofi, MSD, Eisai Co., Nippon Chemiphar, and Towa Pharmaceutical Co. Toyoda K received lecture fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Pfizer, BMS, Takeda, Sumitomo-Dainippon, Sanofi, Otsuka, CSL Behring, Tanabe-Mitsubishi, and Kyowa-Kirin and research support from Bayer, Daiichi-Sankyo, Pfizer, Takeda, and Japan Agency for Medical Research and Development (AMED: 17ek0210091h0001, 15ek0210055h0001). Mori E received lecture fees from Johnson & Johnson, Otsuka, Novartis, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Sosei, Kyowahakko-Kirin, Toshiba, Medtronic, and Nihon Medi-Physics and research support from Eisai, Daiichi-Sankyo, Novartis, Fuji Film RI, General Electric, MHWL, MEXT, and JSPS. Hirano T received lecture fees from Astellas, Bayer, Boehringer Ingelheim, BMS, CSL Behring, Daiichi-Sankyo, Eisai, Medtronic, Otsuka, Pfizer, Sumitomo-Dainippon, Sanofi, Takeda, and Tanabe-Mitsubishi and research support from Astellas, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, MSD, Otsuka, Tanabe-Mitsubishi, and JSPS KAKENHI (Grant Number 25461320, PI, 2014-2016; Grant Number 16K09731, PI, 2016-2017). Hamasaki T received lecture fees from Johnson & Johnson and research support from Teikoku Pharmaceuticals. Yamagami H received lecture fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Pfizer, BMS, Takeda, Sanofi, Otsuka, Tanabe-Mitsubishi, Medtronic, Striker, and Medico’s Hirata and research support from Boehringer Ingelheim and BMS. Nagao T received lecture fees from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi, Sankyo, Sumitomo Dainippon, Eisai, FP, Kyowa Hakko Kirin, Medtronic, Mochida, Nippon Boehringer Ingelheim, Novartis, Otsuka, Pfizer, Sanofi, Takeda, and Mitsubishi Tanabe. Yoshimura S received lecture fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Pfizer, BMS, Takeda, Sanofi, Otsuka, Tanabe-Mitsubishi, Medtronic, Stryker, and Medico’s Hirata and research support from BMS and Takeda. Uchiyama S received lecture fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Takeda, Sumitomo Dainippon, Sanofi, Otsuka, Mitsubishi Tanabe, AstraZeneca, Shionogi, and Astellas Amgen and research support from the Japan Cardiovascular Research Foundation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The EXPAND Study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). In this sub-analysis, we compared the differences in efficacy and safety between patients with and those without history of stroke or transient ischemic attack (TIA). This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients aged ≥ 20 years [mean age 71.6 ± 9.4 (SD) years] who were being or planned to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for a mean period of 897.1 ± 206.8 days with a high follow-up rate (99.7%). The primary prevention group comprised patients without history of ischemic stroke or TIA (n = 5546, 77.7%), and the secondary prevention group comprised those with history of ischemic stroke or TIA (n = 1595, 22.3%). In the primary and secondary prevention groups, the incidence rate of stroke or SE (primary efficacy endpoint) was 0.7 and 2.2%/year, respectively (P < 0.001), and the incidence rate of major bleeding (primary safety endpoint) was 1.2 and 1.5%/year, respectively (P = 0.132). For major bleeding events, the incidence rate of intracranial bleeding was 0.4 and 0.8%/year (P = 0.002) in the primary and secondary prevention groups, respectively. This sub-analysis of the EXPAND Study showed that the Japan-specific dosages of rivaroxaban were effective and safe in Japanese NVAF patients with and those without ischemic stroke or TIA in routine clinical practice.

Objectives: Rivaroxaban has previously been shown to be as efficacious and safe as warfarin for the prevention of stroke in non-valvular atrial fibrillation (NVAF). Therefore, treatment satisfaction becomes an important consideration. Here we examine treatment satisfaction in Japanese NVAF patients who were switched from warfarin to rivaroxaban., Methods: Patient-reported outcome (PRO) data were collected as part of a prospective, multi-center, post-marketing surveillance (PMS) of a direct oral-anticoagulant, rivaroxaban, in Japan. The Anti-Clot Treatment Scale (ACTS) and the Treatment Satisfaction Questionnaire for Medication version II (TSQM-II) were collected at baseline, month 3, and month 6. Change in scores from baseline to month 3 and month 6 were assessed. Exploratory analyses included change in scores by patient characteristics. Safety and effectiveness of rivaroxaban were also assessed., Results: ACTS Burdens scores significantly improved at month 3 (54.6 ± 6.3) and month 6 (54.5 ± 6.5) compared to baseline (51.0 ± 7.6) (p < .001). ACTS Benefits score remained stable over time (baseline = 10.1 ± 2.8, month 3 = 10.2 ± 3.1, month 6 = 10.1 ± 3.1). Mean TSQM-II sub-scale scores significantly improved at month 3 and month 6 compared to baseline for all four domains (all p < .001)., Conclusions: Findings suggest treatment satisfaction may improve in Japanese NVAF patients after a switch from warfarin to rivaroxaban. Higher treatment satisfaction may translate into improved treatment adherence, which is critical for the long-term prevention of stroke.

Aims: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF)., Methods and Results: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS 2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS 2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS 2 ), as shown for warfarin in the XANTUS international prospective post-marketing study., Conclusions: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS 2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Since stroke patients with nonvalvular atrial fibrillation (NVAF) have poor outcomes in general, the prediction of outcomes following discharge is of utmost concern for these patients. We previously reported that brain natriuretic peptide (BNP) levels were significantly higher in NVAF patients with larger infarcts, higher modified Rankin Scale (mRS) score, and higher CHADS2 score. In the present study, we evaluated an array of variables, including BNP, in order to determine significant predictors for functional outcome in patients with NVAF after acute ischemic stroke (AIS)., Methods: A total of 615 consecutive patients with AIS within 48 h of symptom onset, admitted to our hospital between April 2010 and October 2015, were retrospectively searched. Among these patients, we enrolled consecutive patients with NVAF. We evaluated the mRS score 3 months after onset of stroke and investigated associations between mRS score and the following clinical and echocardiographic variables. Categorical variables included male sex, current smoking, alcohol intake, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, peripheral artery disease, use of antiplatelet drugs, anticoagulants, or tissue plasminogen activator (tPA), and infarct size. Continuous variables included age, systolic blood pressure (SBP), diastolic blood pressure, hemoglobin, creatinine, D-dimer, brain natriuretic peptide (BNP), left atrial diameter, left ventricular ejection fraction (EF), and early mitral inflow velocity/diastolic mitral annular velocity (E/e'). We also analyzed the association of prestroke CHADS2, CHA2DS2-VASc, and R2CHADS2 scores, and National Institutes of Health Stroke Scale (NIHSS) score on admission with mRS score 3 months after the onset of stroke. Patients were classified into 2 groups according to mRS score: an mRS score ≤2 was defined as good outcome, an mRS score ≥3 was defined as poor outcome. To clarify the correlations between categorical or continuous variables and mRS score, uni- and multivariate logistic regression models using the stepwise variable selection method were applied., Results: Among 157 patients with NVAF after AIS, 63.7% were male and the mean age was 75.9 years. In univariate regression analysis, poor outcome (mRS score ≥3) was associated with use of tPA, infarct size, age, SBP, BNP, EF, and NIHSS score. In multivariate regression analysis, BNP levels (odds ratio [OR] 6.40; 95% confidence interval [CI] 1.26-32.43; p = 0.0235) and NIHSS score (OR 2.87; 95% CI 1.84-4.47; p < 0.001) were significantly associated with poor outcome (mRS score ≥3) after adjusting for use of tPA, infarct size, age, BNP, EF, and NIHSS score., Conclusions: Apart from NIHSS score, BNP was a very useful predictor for long-term outcomes of patients with NVAF after AIS.
., (© 2017 The Author(s)
. Published by S. Karger AG, Basel.)

Background: Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups., Methods: The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups., Results: The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment., Conclusions: Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS 2 score ≤ 1 and a CHA 2 DS 2 -VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.

Background: Atrial fibrillation (AF) is an important risk factor for transient ischemic attack (TIA). However, little is known about the characteristics of TIA patients with AF. This study investigated the characteristics of such patients, using data from a retrospective, observational, multicenter study., Methods: TIA patients admitted to 13 stroke centers in Japan within 7 days of onset between January 2008 and December 2009 were included. The present analyses compared baseline characteristics, clinical symptoms, findings from diffusion-weighted imaging (DWI), and clinical outcomes between patients with and without AF (AF and non-AF groups)., Results: A total of 464 patients (292 men; mean age 68.5 ± 13.2 years) were registered. Of these, 79 patients (17%) had AF. Patients in the AF group were older (73.9 ± 9.1 vs. 67.4 ± 13.6 years, p < 0.001) and more likely to show disturbance of consciousness (13 vs. 6%, p = 0.046) and aphasia (9 vs. 3%, p = 0.007) than patients in the non-AF group. Although no difference in the overall DWI-positive rate was seen between the groups (28 vs. 20%, p = 0.102), a single lesion (23 vs. 10%, p < 0.001), a lesion ≥15 mm (11 vs. 4%, p = 0.006), and a single lesion ≥15 mm (11 vs. 2%, p < 0.001) on DWI were more frequent in the AF group. Multivariate logistic regression analysis identified increased age [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.02-1.07] and DWI single lesion ≥15 mm (OR 5.67; 95% CI 1.92-16.7) as independently associated with the presence of AF., Conclusions: In this study, 17% of our TIA patients had AF. We found an association between the acute ischemic lesion pattern on DWI of a single lesion ≥15 mm and AF in TIA patients. These results might lead to a better diagnosis of TIA patients with AF.

Background and Purpose: Paroxysmal atrial fibrillation (PAF) is often difficult to detect in patients with acute ischemic stroke. We aimed to assess the predictive value of a prolonged QT interval corrected for heart rate (QTc) in PAF detection after acute ischemic stroke., Methods: We enrolled 972 patients with acute ischemic stroke consecutively extracted from our observational stroke registry system. Exclusion criteria were as follows: (1) AF on the initial 12-lead ECG (n=171); (2) previously diagnosed PAF (n=47); and (3) the use of a cardiac pacemaker (n=10). Of the 972 patients, 744 (mean age, 67.6 years; men, 62.6%) were eligible for analysis. The clinical characteristics and 12-lead ECG findings of the patients with and without PAF were compared, and multiple logistic regression analysis was performed to identify predictors of poststroke PAF., Results: The poststroke cardiac work-up yielded 69 (9.3%) de novo PAF cases among the 744 patients. The QTc interval was significantly longer in patients with PAF than in those without PAF (436 versus 417 ms; P<0.001). Each 10-ms increase in the QTc interval was associated with an increased risk of PAF after multivariate adjustments (odds ratio, 1.41; 95% confidence interval, 1.24-1.61; P<0.001). The optimal threshold value of QTc interval calculated by a receiver-operating characteristic curve was 438 ms, and the area under the curve was 0.73 in this data set., Conclusions: The QTc interval prolongation is potentially a strong and useful predictor for poststroke PAF., (© 2014 American Heart Association, Inc.)

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84-1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66-1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03-2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25-1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.

The CHADS2 and CHA2DS2-VASc scores, that is, ischemic stroke risk indices for patients having atrial fibrillation (AF), may also be useful as bleeding risk indices. Japanese patients with AF, who routinely took oral antithrombotic agents were enrolled from a prospective, multicenter study. The CHADS2 and CHA2DS2-VASc scores were assessed based on information at entry. Scores of 0, 1 and ⩾2 were defined as the low, intermediate and high ischemic risk categories, respectively, for each index. Of 1221 patients, 873 took warfarin, 114 took antiplatelet agents and 234 took both. The annual incidence of ischemic stroke was 0.76% in the low-risk category, 1.46% in the intermediate-risk category and 2.90% in the high-risk category by CHADS2 scores, and 1.44, 0.42 and 2.50%, respectively, by CHA2DS2-VASc scores. The annual incidence of major bleeding in each category was 1.52, 2.19 and 2.25% by CHADS2, and 1.44, 1.69 and 2.24% by CHA2DS2-VASc. After multivariate adjustment, the CHADS2 was associated with ischemia (odds ratio 1.76, 95% confidence interval 1.03-3.38 per 1-category increase) and the CHA2DS2-VASc tended to be associated with ischemia (2.18, 0.89-8.43). On the other hand, associations of the indices with bleeding were weak. In conclusion, bleeding risk increased gradually as the CHADS2 and CHA2DS2-VASc scores increased in Japanese antithrombotic users, although the statistical impact was rather weak compared with their predictive power for ischemic stroke.

Background: The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF., Methods: Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed., Results: The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate -2.13; 95% confidence interval [CI]: -.26 to -3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: -1.14; 95% CI: -3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function., Conclusion: Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Results from a trial of rivaroxaban versus warfarin in 1280 Japanese patients with atrial fibrillation (J-ROCKET AF) revealed that rivaroxaban was noninferior to warfarin with respect to the principal safety outcome. In this subanalysis, we investigated the safety and efficacy of rivaroxaban and warfarin in relation to patients' CHADS2 scores., Results: The mean CHADS2 score was 3.25, and the most frequent scores were 3 and 4. No statistically significant interactions were observed between principal safety outcome event rates and CHADS2 scores with respect to treatment groups (P value for interaction = .700). Irrespective of stratification into moderate- and high-risk groups based on CHADS2 scores of 2 and 3 or more, respectively, no differences in principal safety outcome event rates were observed between rivaroxaban- and warfarin-treated patients (moderate-risk group: hazard ratio [HR], 1.06; 95% confidence interval [CI], .58-1.95; high-risk group: HR, 1.11; 95% CI, .86-1.45; P value for interaction = .488). The primary efficacy end point rate in the rivaroxaban-treated group was numerically lower than in the warfarin-treated group, regardless of risk group stratification (moderate-risk group: HR, .46; 95% CI, .09-2.37; high-risk group: HR, .49; 95% CI, .22-1.11; P value for interaction = .935)., Conclusion: This subanalysis indicated that the safety and efficacy of rivaroxaban compared with warfarin were similar, regardless of CHADS2 score., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The J-ROCKET AF study found that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcome in patients with atrial fibrillation (AF). The aim of this subgroup analysis was to assess the safety and efficacy of rivaroxaban and warfarin in relation to patient age., Methods and Results: A total of 39.0% were elderly (aged ≥75 years). In elderly patients, the principal safety outcome occurred at 25.05%/year with rivaroxaban vs. 16.95%/year on warfarin (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.02-2.16), whereas the primary efficacy endpoint occurred at 2.18%/year vs. 4.25%/year (HR, 0.51; 95% CI: 0.20-1.27), respectively. There were significant interactions in the principal safety outcomes of rivaroxaban compared with warfarin between the elderly and non-elderly groups, but not in the primary efficacy endpoints (P=0.04 and 0.82 for both interactions, respectively). Furthermore, in elderly patients, in the rivaroxaban group there was a trend to increase the principal safety outcome regardless of renal function. In elderly patients with preserved renal function, however, patients on rivaroxaban had a marginally favorable trend in the primary efficacy endpoint incidence rate compared with patients on warfarin., Conclusions: There is a need to carefully consider the risks and benefits of therapy with rivaroxaban in elderly patients with non-valvular AF.

Background: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin., Methods: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group)., Results: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively)., Conclusions: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Paroxysmal atrial fibrillation (PAF) is a strong independent risk factor for ischemic stroke and is also associated with stroke severity and mortality. However, the detection rate of PAF in patients with ischemic stroke is limited because they are often asymptomatic or present with sinus rhythm on electrocardiograms (ECGs). In the present study, we aimed to identify predictors of PAF in stroke patients by continuous ECG monitoring of the heart rate in sinus rhythm., Methods: We enrolled 741 consecutive patients with acute symptomatic ischemic stroke who were admitted to our hospital. Exclusion criteria were the following: (1) patients with persistent AF, (2) cardiac pacemaker users and (3) incomplete clinical investigations. Each patient was subject to 24-hour Holter ECG, cardiac monitoring by inpatient telemetry and routine transthoracic echocardiography. The minimum and mean sinus heart rates (SHRs) on 24-hour Holter ECGs were recorded. The presence of PAF was judged on the basis of previous history and cardiac studies during hospitalization. Clinical characteristics of the patients with and without PAF were compared, and multiple logistic regression analysis was performed to identify the predictors of PAF., Results: Of all enrolled patients, 606 (mean age 68.2 years, 63.4% male) were eligible for analysis, and the presence of PAF was confirmed in 116 subjects (19.1%). In the univariate analysis, the patients with and without PAF showed significant differences in age (74.3 vs. 66.7 years, p < 0.001), dyslipidemia (32.8 vs. 50.4%, p = 0.001), chronic heart failure (16.4 vs. 4.7%, p < 0.001), admission National Institute of Health Stroke Scale score (8.5 vs. 6, p < 0.001) and absence of vascular etiology (80.2 vs. 54.1%, p < 0.001). Furthermore, the minimum and mean SHRs were slower in the patients with than in those without PAF (46.5 vs. 54.0 bpm, p < 0.001 and 70.7 vs. 73.8 bpm, p = 0.009, respectively). In 501 (82.7%) out of 606 patients, minimum SHRs were detected at night (from 9:00 p.m. to 7:00 a.m.). A minimum SHR was an independent predictive factor of PAF in the multivariate analysis (odds ratio 1.08, 95% confidence interval 1.05 - 1.12, p < 0.001)., Conclusions: A slow SHR on monitoring ECG is a potential predictive factor of PAF in patients with ischemic stroke., (Copyright © 2013 S. Karger AG, Basel.)

Background: In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15 mg once daily was given to patients with creatinine clearance (CrCl) ≥ 50 ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30-49 ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment., Methods and Results: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78-1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25-2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively)., Conclusions: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function.

Coagulation necrosis is a peculiar type of ischemic necrosis that is characterized by firm, eosinophilic parenchyma with recognizable cell outlines without massive glial reactions. This is an autopsy report of coagulation necrosis 6 months after thrombolytic tissue plasminogen activator therapy against massive cerebral embolism in an 84-year-old man with atrial fibrillation., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Nonvalvular atrial fibrillation (NVAF) is a well-known strong risk factor for stroke, although few studies have examined silent cerebral ischemic lesions in patients with NVAF. We investigated silent cerebral infarcts (SCIs) and cerebral white matter lesions and risk factors for stroke in NVAF patients., Methods: Subjects included 71 consecutive patients with NVAF and 71 sex-and age-matched controls with sinus rhythm who had undergone MRI. Number, size, and localization of SCIs and severity of periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH) on magnetic resonance imaging were analyzed. The risk factors and CHADS2 score for stroke were also investigated., Results: The number of SCIs was significantly larger and the rates of SCIs in the cortex/subcortex and deep white matter were higher in the NVAF group than in the control group. The DSWMH grade was also significantly higher in the NVAF group. NVAF was an independent risk factor for SCIs and DSWMH. The number of cortical and subcortical SCIs was significantly correlated with CHADS2 score., Conclusions: Cortical/subcortical and deep white matter SCIs were more frequent and DSWMH grades were higher in NVAF patients compared with control subjects. CHADS2 score was an effective scheme not only in stroke risk but also in risk of SCI., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Stroke is a major health problem worldwide, and is often fatal or associated with poor long-term outcomes. Atrial fibrillation (AF) is responsible for up to 20% of all strokes; and the risk of stroke in patients with AF increases with age. Although warfarin is well established for the prevention of stroke in patients with AF, it has some limitations, particularly a narrow therapeutic window, variable/unpredictable pharmacokinetic/pharmacodynamic properties, the restriction of vitamin K intake, and the need for regular coagulation monitoring. Therefore, warfarin is underused for stroke prevention in patients with AF. Several anticoagulants that inhibit thrombin or factor Xa have been developed. Dabigatran is a direct thrombin (factor IIa) inhibitor that overcomes many of the limitations associated with warfarin. The recent Randomized Evaluation of Long Term Anticoagulant Therapy study showed the noninferiority of 110 mg and 150 mg dabigatran twice daily, and the superiority of 150 mg dabigatran twice daily versus adjusted-dose warfarin in the prevention of stroke or systemic embolism in patients with nonvalvular AF. In addition, the rate of intracranial hemorrhage was much lower with both doses of dabigatran than with warfarin. Dabigatran was recently approved in Japan for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular AF. Therefore, in this review, we discuss the properties of dabigatran and its clinical efficacy, safety, and positioning in the prevention of stroke. We also discuss precautions for the use of dabigatran and future perspectives with a view to reducing the risk of stroke with new oral anticoagulants, including factor Xa inhibitors in AF patients., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Edoxaban is a once-daily (QD) oral, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF., Methods and Results: A total of 536 NVAF patients (CHADS2 ≥1) were randomized to receive double-blinded edoxaban 30, 45, or 60 mg QD or open-label warfarin (international normalized ratio [INR] 2.0-3.0 for age <70 years; 1.6-2.6 for age ≥70 years) for 12 weeks. The primary endpoint was the incidence of all bleeding events (major, clinically relevant non-major, and minor bleeds). Patients underwent CT and/or MRI to assess asymptomatic intracranial hemorrhage (ICH). Secondary endpoints included thromboembolic events and pharmacodynamic indices. The mean incidence of all bleeding events for edoxaban 30, 45, and 60mg, and warfarin was 18.5%, 22.4%, 27.7%, and 20.0%, respectively. There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group. There were no asymptomatic ICH events in any group. One episode of cerebral infarction was observed in the edoxaban 45-mg group. Subgroup analysis suggested low body weight (≤60kg) was associated with higher bleeding risk., Conclusions: Edoxaban 30, 45, and 60mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range, but this was not statistically significant, nor was any dose compared with warfarin.

Background: The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation (AF). A separate trial, J-ROCKET AF, compared the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF., Methods and Results: J-ROCKET AF was a prospective, randomized, double-blind, phase III trial. Patients (n=1,280) with non-valvular AF at increased risk for stroke were randomized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines. The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinically relevant bleeding, in the on-treatment safety population. The primary efficacy endpoint was the composite of stroke and systemic embolism. Non-inferiority of rivaroxaban to warfarin was confirmed; the rate of the principal safety outcome was 18.04% per year in rivaroxaban-treated patients and 16.42% per year in warfarin-treated patients (hazard ratio [HR] 1.11; 95% confidence interval 0.87-1.42; P<0.001 [non-inferiority]). Intracranial hemorrhage rates were 0.8% with rivaroxaban and 1.6% with warfarin. There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin (HR, 0.49; P=0.050)., Conclusions: J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice.

Dabigatran is a direct thrombin inhibitor, does not require blood coagulation monitoring and limitation of vitamin K intake as well as very few drug interactions, and thus expected to be an oral anticoagulant alternative to warfarin. Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) was conducted to determine non-inferiority of dabigatran against warfarin as an international multicenter-cooperative randomized trial in patients with non-valvular atrial fibrillation (NVAF). The results showed not only non-inferiority of dabigatran but also superiority of high-dose dabigatran in efficacy and of low-dose dabigatran in safety. In a sub-analysis of RE-LY in NVAF patients with history of stroke or TIA, who are at high risk of intracranial hemorrhage with anticoagulants, hemorrhagic stroke was much less frequent in patients on either dose of dabigatran than in those on warfarin. In a sub-analysis of RE-LY in Japanese patients with NVAF, the results showed a consistency of the efficacy and safety profiles of dabigatran with the results of the global RE-LY trial. Use of dabigatran should be contraindicated in NVAF patients with renal insufficiency because some cases with fatal bleeding have been reported in a post marketing survey.

Background: There remains uncertainty about the risk of cardiovascular events in stable outpatients with a history of myocardial infarction (MI), stroke, and atrial fibrillation in Japan., Methods and Results: In the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE), a nationwide prospective cohort of stable outpatients with a history of MI (n=2,291), stroke (n=3,554), and/or atrial fibrillation (n=2,242), 1-year follow-up data were available for 7,513 of 8,087 patients (follow-up rate: 92.9%). The primary endpoint (death/MI/stroke) was reported in 3.53 events per 100 person-years (95% confidence interval [CI]: 3.11-3.99) within 1 year. The rates of all-cause death, death from stroke, and death from MI within 1 year were 1.35 (95%CI: 1.10-1.65), 0.15 (95%CI: 0.08-0.27), and 0.06 (95%CI: 0.02-0.14) per 100 person-years, respectively. The rate of non-fatal stroke was 1.85 (95%CI: 1.55-2.19), while that of non-fatal MI was 0.33 (95%CI: 0.21-0.49). The rate of non-fatal stroke was highest among stroke patients (2.95; 95%CI: 2.39-3.60 per 100 person-years), while that of non-fatal MI was similar across all disease categories. Investigator-decided serious non-fatal bleeding events occurred in 0.21 events (95%CI: 0.12-0.34) per 100 person-years., Conclusions: In this large, nationwide Japanese registry, the highest stroke event rate was seen in patients with a history of stroke.

Objective: We sought to clarify risk factor profiles and current treatment of Japanese patients with stroke, myocardial infarction (MI), and nonvalvular atrial fibrillation (NVAF) using the database of the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE)., Methods: J-TRACE is a nationwide multicenter cooperative cohort of Japanese patients with MI, stroke, and NVAF. Baseline characteristics of 8087 Japanese patients (5804 male, average age 68.7 years) with history of stroke (n=3554), MI (n=2291), or NVAF (n=2242) were analyzed., Results: History of stroke (14.7%) was more frequent than history of MI (2.6%) in patients with stroke, whereas history of stroke (6.6%) was less frequent than history of MI (7.6%) in patients with MI. In patients with NVAF, history of stroke (14.3%) was far more frequent than history of MI (3.4%). Hypertension was more frequent in stroke (74.4%) than MI (62.0%) or NVAF (57.7%), whereas hypercholesterolemia, diabetes mellitus, and cigarette smoking were more prevalent in patients with MI (56.1%, 35.1%, and 33.3%, respectively) than in those with stroke (35.7%, 22.4%, and 19.7%, respectively) or NVAF (26.9%, 17.2%, and 16.1%, respectively). Alcohol consumption (34.9%) and obesity (body mass index>25) (32.8%) were most common in patients with NVAF. In all patients, nonmedication rates were higher in patients with hypercholesterolemia (29.8%) or diabetes (36.9%) than in those with hypertension (9.5%). Warfarin was used in 58.9% of patients with low-risk and 75.4% with high-risk NVAF., Conclusion: Risk factor profiles and their modification were not similar among patients in Japan with MI, stroke, and NVAF, although they share a high risk of thrombotic events., (Copyright (c) 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Clinical characteristics, including risk factors for thromboembolism, and medications differ between men and women with atrial fibrillation (AF) in Western countries. Whether such a difference exists for Japanese patients with AF is unclear, so data from J-TRACE were used to investigate this issue., Methods and Results: A total of 2,892 patients (2,028 men, 864 women; 70.3 years old) with AF were analyzed for the respective prevalences of risk factors and medications. CHADS2 score was calculated to determine thromboembolic risk level. Women were older (P<0.001), and more frequently had heart failure (P<0.001), and hypertension (P=0.051) than men. The proportion of subjects aged 75 years or older was higher among women than among men (P<0.001). CHADS2 score was therefore significantly higher in women than in men (2.05+/-1.29 vs 1.88+/-1.33, P<0.001). Sex-related differences were not observed for the prevalence of diabetes mellitus, myocardial infarction or ischemic stroke, nor did warfarin usage differ between men and women., Conclusions: Sex-related differences were observed in the risk factor profile and medications of Japanese patients with AF. CHADS2 score was higher in women than in men.

Background: Atrial fibrillation (AF) is a major risk factor (RF) for ischemic stroke. Its prevalence and prognostic impact in patients with atherothrombosis are unclear., Methods: Risk factors, drug usage, and 1-year cardiovascular (CV) outcomes (CV death, myocardial infarction [MI], and stroke) were compared in AF and non-AF patients from the REduction of Atherothrombosis for Continued Health (REACH) Registry, an international, prospective cohort of 68,236 stable outpatients with established atherothrombosis or>or=3 atherothrombotic RFs., Results: Atrial fibrillation and 1-year follow-up data are available for 63,589 patients. The prevalence of AF was, 12.5%, 13.7%, 11.5%, and 6.2% among coronary artery disease, CV disease, peripheral artery disease, and RF-only patients, respectively. Of the 6,814 patients with AF, 6.7% experienced CV death, nonfatal MI, or nonfatal stroke within a year. The annual incidence of nonfatal stroke (2.4% vs 1.6%, P<.0001) and unstable angina (6.0% vs 4.0%, P<.00001) was higher, and CV death was more than double (3.2% vs 1.4%, P<.0001), in AF versus non-AF patients. In these patients with or at high risk of atherothrombosis, most patients with AF received antiplatelet agents, but only 53.1% were treated with oral anticoagulants. Even with high CHADS2 (congestive heart failure, hypertension, aging, diabetes mellitus, and stroke) scores, anticoagulant use did not exceed (59%). The rate of bleeding requiring hospitalization was higher in AF versus non-AF patients (1.5% vs 0.8%, P<.0001), possibly related to the more frequent use of anticoagulants (53.1% vs 7.1%)., Conclusions: Atrial fibrillation is common in patients with atherothrombosis, associated with more frequent fatal and nonfatal CV outcomes, and underuse of oral anticoagulants.

Background: A previous history of myocardial infarction (MI), stroke, and the presence of atrial fibrillation (AF) are known risk factors for the onset of arterial thromboembolic events such as MI and ischemic stroke. To clarify the rate of incidence of such events for these high-risk patients in Japan, a nation-wide cohort study was conducted that was named the 'Japan Thrombosis Registry of Atrial Fibrillation, Coronary and Cerebrovascular Events' (ie, J-TRACE) [UMIN Registered ID C000000189]., Methods and Results: In the J-TRACE registry, a total of 8,093 Japanese patients with either a history of stroke and/or MI or patients with non-valvular AF were registered. This registry was developed by specialists in cardiology and neurology, physicians working at general hospitals, as well as general practice physicians, from whole regions of Japan, possibly reflecting the real-world medical practice. Recruited patients will be followed up for 2-3 years. Medical history, accompanying risk factors, demographic characteristics, and information regarding the use of medications were collected for these patients at baseline. Cardiovascular ischemic events and serious adverse experiences, including cerebral bleedings, which occur during the follow-up period will be recorded over a maximum of 3 years., Conclusion: The J-TRACE offers an opportunity to provide fundamental information regarding the incidence of cardiovascular ischemic events by a stratum of the risk factor profile and current medical treatment for Japanese patients at high risk for thromboembolic diseases.

Background and Purpose: Although the efficacy of anticoagulant therapy for primary prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) has been established, efficacy of antiplatelet therapy for low-risk patients is disputable in Japanese patients because of the frequent hemorrhagic complications. We examined the efficacy and safety of aspirin therapy in Japanese patients with NVAF in a prospective randomized multicenter trial., Methods: Patients with NVAF were randomized to an aspirin group (aspirin at 150 to 200 mg per day) or a control group without antiplatelet or anticoagulant therapy. Primary end points included cardiovascular death, symptomatic brain infarction, or transient ischemic attack., Results: A total of 426 patients were randomized to aspirin group and 445 to no treatment. The trial was stopped earlier because there were 27 primary end point events (3.1% per year; 95% CI, 2.1% to 4.6% per year) in the aspirin group versus 23 (2.4% per year; 95% CI, 1.5% to 3.5% per year) in the control group, suggesting a low possibility of superiority of the aspirin treatment for prevention of the primary end point. In addition, treatment with aspirin caused a marginally increased risk of major bleeding (7 patients; 1.6%) compared with the control group (2 patients; 0.4%; Fisher exact test P=0.101)., Conclusions: For prevention of stroke in patients with NVAF, aspirin at 150 to 200 mg per day does not seem to be either effective or safe. Further prospective studies are needed to determine the best preventive therapy for cerebrovascular events in Japanese patients with NVAF.

Aspirin should be used for the prevention of cardiovascular (CV) events by the risk–benefit balance. This study was conducted to clarify CV and bleeding events in Japanese aspirin users with a history of CV diseases. This study was a prospective, nationwide, multicenter cooperative registry of Japanese patients with CV diseases at risk of thromboembolism who were taking aspirin (75–325 mg) for at least 1 year. We observed major CV and bleeding events during follow-up. Patients with history of ischemic stroke (IS), transient ischemic attack (TIA), coronary artery disease (CAD), atrial fibrillation (AF), and venous thromboembolism (VTE) were included and analyzed in this sutdy. CV events included IS, TIA, CAD, CV death, angioplasty or stenting, and hospitalization because of CV disease. Bleeding events included major bleeding requiring hospitalization and/or blood transfusion. A total of 1506 patients were categorized into IS/TIA (N = 540), CAD (N = 632), and AF/VTE (N = 232). Among them, 101 patients had two or more categories. CV and bleeding events occurred in 61 (3.82%/year) and 15 patients (0.93%/year), respectively. The annual rates of CV and bleeding events were 2.81% and 0.93% in IS/TIA, 5.32% and 0.75% in CAD, 1.15% and 1.15% in AF/VTE, and 6.44% and 0.91% in two or more disease categories, respectively. The Management of Aspirin-induced Gastrointestinal Complications (MAGIC) study clarified the rates of major CV and bleeding events with long-term use of aspirin in patients with prior CV diseases in real-world clinical practice. The risk–benefit balance of aspirin was acceptable in patients with IS/TIA, CAD, and multiple CV diseases but not in those with AF/VTE. Trial Registration: The MAGIC Study is registered at UMIN Clinical Trial Registry (www.umin.ac.jp/ctr/index-j.htm), number UMIN000000750. [ABSTRACT FROM AUTHOR]

In the original publication of the article, the Figure 2b and the Tables 2 and 3 were published incorrectly. The corrected figure and tables are provided below. [ABSTRACT FROM AUTHOR]

Introduction: Following approval of dabigatran and other antithrombotics in Japan, few studies have specifically evaluated the clinical characteristics of patients prescribed these antithrombotics for nonvalvular atrial fibrillation (NVAF) in real-world practice. Methods: We conducted a descriptive analysis of data from two real-world studies [J-dabigatran surveillance and Japanese study on current Anticoagulation therapies for Patients with nonvalvular Atrial Fibrillation (JAPAF); conducted at sites common to both studies] to determine the characteristics of patients with NVAF initiated on dabigatran etexilate [110 mg twice daily (BID; DE110) or 150 mg BID (DE150)], warfarin, rivaroxaban, or antiplatelets as their first antithrombotic treatment. Inferential statistical analyses were not performed, and no statistical hypothesis was tested. Results: Data for 1270 and 3011 eligible patients from the J-dabigatran surveillance (DE110, 976; DE150, 273) and JAPAF study (warfarin, 82.5%; rivaroxaban, 10.3%; antiplatelets, 21%), respectively, were extracted. In the J-dabigatran surveillance, 31.8% (full cohort, 28.1%) of patients had been switched from warfarin to dabigatran. Among patients prescribed DE110/DE150, 41.4%/57.5% and 41.5%/18.7% of patients had low-to-intermediate risk for ischemic stroke (CHADS2 score of 0 or 1) and high risk for bleeding (HAS-BLED score ≥ 3), respectively. Similarly, 33.7%/41.3%/40.2% and 48.7%/42.6%/75.7% of patients taking warfarin/rivaroxaban/antiplatelets had a CHADS2 score of 0 or 1 and HAS-BLED score ≥ 3, respectively. Dabigatran was favored in patients with creatinine clearance > 50 ml/min. Conclusions: In Japan, physicians who attempt stroke prevention in patients with atrial fibrillation choose appropriate anticoagulant treatment, taking into consideration the individual patient backgrounds as well as the features of each antithrombotic agent. Trial Registration: ClinicalTrials.gov Identifier, NCT01491178 and University Hospital Medical Information Network (UMIN) Clinical Trial Registry Identifier, UMIN000009644. Funding: Nippon Boehringer Ingelheim Co., Ltd. Plain Language Summary: Plain language summary available for this article. [ABSTRACT FROM AUTHOR]

Background/aim A post-marketing surveillance (PMS) study is being conducted to investigate the safety and effectiveness of the long-term use of dabigatran etexilate (dabigatran) in Japanese patients with nonvalvular atrial fibrillation (NVAF). Results of an interim analysis of this prospective cohort study including patient characteristics and adverse drug reactions (ADRs) collected up to September 17, 2014 are reported here. Methods Patients with NVAF who began to receive dabigatran for the first time from December 2011 to November 2013 were enrolled at 1042 study sites in Japan. Clinical parameters included patient characteristics, dabigatran dose strength, concomitant medications and outcome events. All outcome events were collected as serious and non-serious adverse events (AEs). ADRs were evaluated in this report. Pre-defined safety events of special interest for intensive survey were serious and non-serious outcome events such as myocardial infarction, as well as the total number of hemorrhage and gastrointestinal disorders. Results A total of 6772 patients were registered. The safety analysis set included 6148 patients; mean age was 70.8±9.9 (SD) years: 2323 patients (37.8%) were aged 75 years or older. Males accounted for 66.8% of the patients. Mean CHADS 2 score was 1.8±1.3; the CHADS 2 score was 0 in 13.6%, 1 in 31.3%, 2 in 25.9%, 3 in 14.9%, and 4 to 6 in 11.1% of the patients. Of the 6148 patients, 1701 patients (27.7%) were switchers from warfarin and 4407 patients (71.7%) were non-switchers (OAC naïve patients). Treatment adherence was assessed for the first 3 months from the start of treatment for this analysis. Total 5656 patients (92.0%) reported taking dabigatran twice daily (bid) every day according to the label recommendation. During the follow up period [mean duration of follow up: 498±259 days (corresponding to 8386 patient-years)], pre-defined safety events of special interest for intensive survey (reported as serious ADRs) were: myocardial infarction, reported in 5 patients (0.06 per 100 patient-years); serious hemorrhage, reported in 46 patients (0.55 per 100 patient-years); and gastrointestinal disorders (non-hemorrhagic), reported in 11 patients (0.13 per 100 patient-years). Fifteen patients had ADRs with fatal outcome. Conclusions The interim findings from this 6148 patient PMS study further corroborate the favorable safety profile of dabigatran as demonstrated previously in controlled clinical trials. (ClinicalTrials.gov number, NCT01491178.) [ABSTRACT FROM AUTHOR]

Elevated serum brain natriuretic peptide (BNP) levels are associated with cardioembolic stroke mainly because of atrial fibrillation (AF). However, the mechanisms of increased serum BNP levels are hitherto unclear. We aimed to identify the factors associated with increased BNP levels in patients with acute ischemic stroke. We measured serum BNP levels in consecutive patients aged 18 years or older. Stroke subtypes were classified using the Trial of ORG 10172 in Acute Stroke Treatment criteria. Categorical variables included age, sex, smoking status, alcohol consumption status, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease (CAD), AF, antiplatelet therapy, and anticoagulant therapy. Continuous variables included hemoglobin, creatinine (Cr), β-thromboglobulin, platelet factor 4, thrombin–antithrombin complex, and d-dimer levels. We further determined the relationship between serum BNP and intima–media thickness, left ventricular ejection fraction, size of infarction, National Institutes of Health Stroke Scale score on admission, and modified Rankin Scale (mRS) score at discharge. Of the 231 patients (mean age, 71 ± 12 years) with acute ischemic stroke (AIS), 36% were women. Serum BNP levels significantly correlated with CAD, AF, Cr, mRS, and cardioembolism (CE) (Dunnett method, P = .004). BNP levels were significantly higher in patients with larger infarcts, higher mRS scores, and higher CHADS2 scores. The levels were higher in patients with larger infarcts, higher mRS scores at discharge, and higher CHADS2 scores among AF patients. [Copyright &y& Elsevier]