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Background In the Japanese clinical setting, the prevalence, potential cofounders of gastrointestinal (GI) bleeding from anticoagulant therapy, including direct oral anticoagulants (DOACs) and warfarin, and prognosis after GI bleeding are unclear.Methods and Results:We examined about GI bleeding from anticoagulant therapy using data from the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 48.8% (n=1,561) were warfarin users and 51.2% (n=1,676) DOAC users. GI bleeding was identified in 68 patients (2.1%). No incidental differences in GI bleeding were observed between the DOAC and warfarin users (32 [1.9%] patients [0.67 events per 100 person-years] vs. 36 [2.3%] patients [0.75 events per 100 person-years], respectively; P=0.43). Multivariate Cox proportional hazard model analysis revealed that creatinine (hazard ratio [HR] 1.379, 95% confidence interval [CI] 1.091-1.743 P=0.007) and hemoglobin (HR 0.814, 95% CI 0.705-0.941, P=0.005) remained independent determinants of GI bleeding. Patients experiencing GI bleeding events had a higher risk of all-cause death (18%) than those without GI bleeding (6%) (P=0.045). Conclusions GI bleeding was strongly associated with anemia and renal impairment. Patients experiencing GI bleeding had higher risk for all-cause death than those without GI bleeding.

Background The burden or benefit of anticoagulation treatment affects patient satisfaction, which may in turn affect the adherence to the treatment and subsequent outcomes. Thus, we hypothesized that the patient satisfaction with direct oral anticoagulants (DOACs) may influence the clinical outcome in patients with atrial fibrillation (AF). Methods and Results We investigated the clinical outcomes among 719 DOAC users (age 71.9 ± 9.1 years, 184 females, and 449 persistent AF) enrolled in the SAKURA AF Registry who completed a satisfaction questionnaire with anticoagulation therapy by means of the Anti-Clot Treatment Scale (ACTS), which included 12-item burden and 3-item benefit scales. During a 41.8-month-follow-up, a stroke/systemic embolism (SE) occurred in 27 patients (3.8%) and major bleeding events in 25 (3.5%). A univariate Cox regression analysis revealed that an older age, persistent AF, higher CHA2DS2-VASc score, no history of AF ablation, lower creatinine clearance, and lower ACTS benefit scores were significantly associated with an increased risk of a stroke/SE, but not with major bleeding events. A low benefit score remained an independent predictor of a stroke/SE even after a multivariate adjustment. The ACTS burden scores were not associated with any clinical events. Conclusions We found a strong association between a low benefit satisfaction and increased stroke risk. We should follow patients carefully to educate them on treatment importance for patients unsatisfied with the benefits of DOACs for stroke prevention.

Atrial fibrillation (AF) and heart failure (HF) often coexist. The aims of this study were to explore the factors associated with the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the association between prognosis and a history of HF or the serum NT-proBNP level in Japanese patients with AF.The present sub-study was based on the SAKURA AF Registry, a Japanese multicenter observational registry that included 3267 AF patients (median follow-up period: 39 months). All the patients were receiving warfarin or any of four direct oral anticoagulants. Serum NT-proBNP levels were available for 2417 patients, and the median value was 508 (interquartile range 202-1095) pg/mL at the time of enrollment. Log NT-proBNP was associated with non-paroxysmal AF, creatinine clearance > 60 mL/minute, history of HF and ischemic heart disease, antiarrhythmic drug use, anemia, being elderly female, and history of AF ablation. The relative risk of adverse clinical events, except major bleeding, was significantly higher in the highest NT-proBNP quartile as compared to the lowest quartile (adjusted hazard ratios: 2.87 for death, 2.39 for stroke), but a history of HF was associated only with a higher incidence of all-cause death.Concomitant HF was associated with a higher mortality, but the high NT-proBNP was associated with higher mortality and stroke events. In Japanese AF patients receiving anticoagulant treatment, high serum NT-proBNP levels predict the risk for both stroke events and deaths, and intensive follow-up is needed in such patients.

Background Relations between characteristics and outcomes of patients in Japan with atrial fibrillation (AF) and the type of medical facility providing their outpatient care are unclear. Methods and results We compared patient characteristics and outcomes between 2 university hospitals (n = 1178), 20 general hospitals (n = 1308), and 41 private clinics (n = 751) (follow-up: 39.3 months) in the prospective SAKURA AF Registry. Private clinic patients were significantly older than university hospital and general hospital patients (73.4 ± 9.2 vs. 70.3 ± 9.8 and 72.6 ± 8.9 years; p Conclusions Adverse clinical events at small to large hospitals appear to be higher than those at private clinics, suggesting that careful attention for preventing stroke/SE and cardiovascular events should be paid to patients at a university or general hospital.

Atrial fibrillation (AF) and heart failure (HF) often coexist. The aims of this study were to explore the factors associated with the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the association between prognosis and a history of HF or the serum NT-proBNP level in Japanese patients with AF.The present sub-study was based on the SAKURA AF Registry, a Japanese multicenter observational registry that included 3267 AF patients (median follow-up period: 39 months). All the patients were receiving warfarin or any of four direct oral anticoagulants. Serum NT-proBNP levels were available for 2417 patients, and the median value was 508 (interquartile range 202-1095) pg/mL at the time of enrollment. Log NT-proBNP was associated with non-paroxysmal AF, creatinine clearance60 mL/minute, history of HF and ischemic heart disease, antiarrhythmic drug use, anemia, being elderly female, and history of AF ablation. The relative risk of adverse clinical events, except major bleeding, was significantly higher in the highest NT-proBNP quartile as compared to the lowest quartile (adjusted hazard ratios: 2.87 for death, 2.39 for stroke), but a history of HF was associated only with a higher incidence of all-cause death.Concomitant HF was associated with a higher mortality, but the high NT-proBNP was associated with higher mortality and stroke events. In Japanese AF patients receiving anticoagulant treatment, high serum NT-proBNP levels predict the risk for both stroke events and deaths, and intensive follow-up is needed in such patients.

Background: Liver diseases drive the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB4) index is a non-invasive scoring method for detecting liver fibrosis, but the prognostic impact of using it for AF patients is still unknown. Herein, we evaluated using the FIB4 index as a risk assessment tool for cardiovascular events and mortality in patients with AF. Methods: We performed a post-hoc analysis of a prospective, observational multicenter study. A total of 3067 patients enrolled in a multicenter Japanese registry were grouped as first tertile (FIB4 index &lt, 1.75, n = 1022), second tertile (1.75 &le, FIB4 index &lt, 2.51, n = 1022), and third tertile (FIB4 index &ge, 2.51, n = 1023). Results: The third tertile had statistically significant results: older age, lower body mass index, increased heart failure prevalence, and lower clearances of hemoglobin and creatinine (all p &lt, 0.05). During the follow-up period, incidences of major bleeding, cardiovascular events, and all-cause mortality were significantly higher for the third tertile (all p &lt, 0.05). After multivariate adjustment, the third tertile associated independently with cardiovascular events (HR 1.72, 95% CI 1.31&ndash, 2.25) and all-cause mortality (HR 1.43, 95% CI 1.06&ndash, 1.95). Adding the FIB4 index to a baseline model with CHA2DS2-VASc score improved the prediction of cardiovascular events and all-cause mortality, as shown by the significant increase in the C-statistic (all p &lt, 0.05), net reclassification improvement (all p &lt, 0.001), and integrated discrimination improvement (all p &lt, 0.001). A FIB4 index &ge, 2.51 most strongly associated with cardiovascular events and all-cause mortality in AF patients with high CHADS2 scores (all p &lt, 0.001). Conclusions: The FIB4 index is independently associated with risks of cardiovascular events and all-cause mortality in AF patients.

The burden of anticoagulation treatment affects patient satisfaction, which in turn affects adherence to treatment. Thus, we must thoroughly understand the advantages of direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs)/warfarin given for stroke prevention in patients with atrial fibrillation (AF). We compared satisfaction with anticoagulation therapy between 654 DOAC and 821 warfarin users enrolled in the SAKURA AF Registry. Satisfaction was assessed by means of the Anti-Clot Treatment Scale (ACTS), which includes 12-item burdens and 3-item benefits scales, and the treatment satisfaction questionnaire for medication II (TSQM II), which includes 2-item effectiveness, 3-item side effects, 3-item convenience, and 2-item global satisfaction domains. There were no significant between-group differences in TSQM II convenience (67.6 ± 14.5 versus 68.9 ± 14.5, P = 0.280), effectiveness (65.0 ± 13.3 versus 66.0 ± 15.0, P = 0.422), side effects (93.6 ± 13.7 versus 92.8 ± 14.4, P = 0.067), and global satisfaction (64.7 ± 14.9 versus 66.0 ± 14.6, P = 0.407) scores. In contrast, although there was no significant between-group difference in the ACTS benefits scores (9.8 ± 3.1 versus 10.1 ± 3.2, P = 0.051), the ACTS burdens scores (54.5 ± 6.3 versus 52.7 ± 6.9, P < 0.0001) were significantly higher in the DOAC users, independent of age, sex, and DOAC type. We can expect greater burden satisfaction with anticoagulation treatment in patients given a DOAC versus VKA/warfarin. The reduced burden of treatment will translate to greater patient adherence to their treatment plans and a positive effect on clinical outcomes.

Background: Although atrial fibrillation (AF) and coronary artery disease (CAD) are increasing in prevalence in Japan, real-world data regarding clinical outcomes in Japanese AF patients with CAD a...

Objective: To explore factors related to changing renal function and the prognostic effect of worsening renal function in patients with atrial fibrillation (AF). Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter prospective observational registry that includes 3267 AF patients from 63 institutions in the Tokyo area. Worsening renal function was defined as an estimated glomerular filtration rate (eGFR) decrease equaling more than 20% of the patient’s baseline eGFR. Results: During a median 39.3 month follow-up period, patients’ eGFR decreased annually by a mean value of 1.07 mL/min/1.73 m2. Multivariable analysis showed that age ≥75 years, body weight ≤50 kg, a history of heart failure and initially preserved renal function (creatinine clearance [CrCl] ≥ 60 mL/min) were significantly associated with a decrease in eGFR, whereas a history of AF ablation was associated with a maintain in eGFR. The 194 patients with worsening renal function were at significantly increased risk of death, stroke and major bleeding (adjusted hazard ratios [HRs]: 2.06, 1.97 and 2.23, respectively). Conclusion: Age ≥75 years, body weight ≤50 kg, a history of heart failure and initially preserved renal function appear to promote renal dysfunction in patients with AF, but a history of AF ablation seems to have a favorable effect. Worsening renal function seems to increase AF patients’ risk of adverse clinical events. Renal function can decline quickly; thus, early intervention including AF ablation is warranted.

Direct-acting oral anticoagulants (DOACs) are widely used in aged Japanese patients with atrial fibrillation (AF), but outcome data for such patients are limited. We compared outcomes between 1895 (58.5%) patients aged

Background Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan. Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081). Conclusions Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist, but the real-world data after approval of direct oral anticoagulants (DOACs) are still lacking in Japan. We investigated the association of the baseline renal function and adverse clinical events and risk of adverse clinical events with DOACs compared to warfarin for each renal functional level in Japanese AF patients. Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter observational registry (median follow-up period: 39 months). The creatinine clearance (CrCl) values were estimated by the Cockcroft–Gault formula, and divided into normal renal function, and mild and moderate-severe CKD (CrCl ≥ 80, 50–79, &lt, 50 mL/min). Results: In the SAKURA AF Registry, the baseline CrCl data were available for 3242 patients (52% for DOAC and 48% for warfarin user). The relative risk of adverse clinical events was significantly higher in the patients with a CrCl &lt, 50 mL/min as compared to those with a CrCl ≥ 80 mL/min (adjusted HRs: 2.53 for death, 2.53 for cardiovascular [CV] events, 2.13 for strokes, and 1.83 for major bleeding). Risks of all adverse clinical events were statistically even between DOAC and warfarin users for each renal function level. Conclusion: Moderate–severe CKD was associated with a higher mortality, CV events, strokes, and major bleeding than normal renal function. The safety and effectiveness of DOACs over warfarin were similar for each renal function level. By a worsening renal function, the incidence of adverse clinical events increased, especially deaths and CV events as compared to strokes and major bleeding.

The burden of anticoagulation treatment affects patient satisfaction, which in turn affects adherence to treatment. Thus, we must thoroughly understand the advantages of direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs)/warfarin given for stroke prevention in patients with atrial fibrillation (AF). We compared satisfaction with anticoagulation therapy between 654 DOAC and 821 warfarin users enrolled in the SAKURA AF Registry. Satisfaction was assessed by means of the Anti-Clot Treatment Scale (ACTS), which includes 12-item burdens and 3-item benefits scales, and the treatment satisfaction questionnaire for medication II (TSQM II), which includes 2-item effectiveness, 3-item side effects, 3-item convenience, and 2-item global satisfaction domains. There were no significant between-group differences in TSQM II convenience (67.6 ± 14.5 versus 68.9 ± 14.5, P = 0.280), effectiveness (65.0 ± 13.3 versus 66.0 ± 15.0, P = 0.422), side effects (93.6 ± 13.7 versus 92.8 ± 14.4, P = 0.067), and global satisfaction (64.7 ± 14.9 versus 66.0 ± 14.6, P = 0.407) scores. In contrast, although there was no significant between-group difference in the ACTS benefits scores (9.8 ± 3.1 versus 10.1 ± 3.2, P = 0.051), the ACTS burdens scores (54.5 ± 6.3 versus 52.7 ± 6.9, P0.0001) were significantly higher in the DOAC users, independent of age, sex, and DOAC type. We can expect greater burden satisfaction with anticoagulation treatment in patients given a DOAC versus VKA/warfarin. The reduced burden of treatment will translate to greater patient adherence to their treatment plans and a positive effect on clinical outcomes.

BACKGROUND Although direct oral anticoagulants (DOACs) are widely used in Japanese patients with atrial fibrillation (AF), large-scale investigations into their use, with suitable follow-up times and rates, are lacking. Methods and Results: The SAKURA AF Registry is a prospective multicenter registry created to investigate therapeutic outcomes of oral anticoagulant (OAC) use in Japanese AF patients. We conducted a study involving 3,237 enrollees from 63 institutions in the Tokyo area being treated with any of 4 DOACs (n=1,676) or warfarin (n=1,561) and followed-up for a median of 39.3 months (range 28.5-43.6 months). Analyses of 1- and 2-year follow-up data available for 3,157 (97.5%) and 2,952 (91.2%) patients, respectively, showed no significant differences in rates of stroke or systemic embolism (SE), major bleeding, and all-cause mortality for DOAC vs. warfarin users (1.2 vs. 1.8%/year, 0.5 vs. 1.2%/year, and 2.1 vs. 1.7%/year, respectively). Under propensity score matching, the incidence of stroke or SE (P=0.679) and all-cause death (P=0.864) remained equivalent, but the incidence of major bleeding was significantly lower (P=0.014) among DOAC than warfarin users. CONCLUSIONS A high follow-up rate allowed us to obtain reliable data on the status of OAC use and therapeutic outcomes among AF patients in Japan. Warfarin and DOACs appear to yield equivalent 3-year stroke and all-cause mortality rates, but DOACs appear to reduce the risk of major bleeding.

The incidence and causes of death among patients in Japan treated for atrial fibrillation (AF), a major determinant of strokes and death, with direct oral anticoagulants (DOACs) are unclear. This study's aim was two-fold: to compare the incidence and causes of death between DOAC and warfarin users in Japan and to identify the factors associated with vascular and nonvascular death in the Japanese AF population.The study was based on the SAKURA AF registry, in which clinical events were tracked in 3267 enrollees from 63 institutions for 2-4 years. Enrollees included warfarin users (n=1577) and users of any of 4 DOACs (n=1690). The incidence, cause, and major determinants of death were analyzed.During a median 39.3-month follow-up, 200 patients died, with most succumbing to cardiac death (25%), malignancies (21%), or respiratory infections (20%). There was no significant difference in deaths from any cause between warfarin and DOAC users (108 vs. 92 patients, p=0.34). An age ≥75 years was found to be a major determinant of death, but the relative risk (vs.75 years) was greater for nonvascular death (hazard ratio: 2.85 and 4.97 for age 75-84 and ≥85 years, respectively) than vascular death (2.14 and 2.98 for 75-84 and ≥85 years, respectively). Heart failure, renal dysfunction, and the type of institution were major determinants of vascular death, and a male sex, weight50kg, and anemia were major determinants of nonvascular death.The results of our AF registry-based study, in which two thirds of the enrolled patients succumbed to cardiac death, malignancies, or respiratory infections within 2- 4 years and use of DOACs rather than warfarin did not reduce the mortality, indicated that a management of AF that includes prophylaxis for vascular and nonvascular events in addition to strokes is warranted.

Background Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) have been shown to have a significant cardioprotective effect in high-risk patients after myocardial infarction (MI). However, there are few data on the effects of these drugs on left-ventricular (LV) remodeling after MI in Japanese patients. Methods and Results We randomly assigned 100 patients with anterior-wall MI who had received reperfusion therapy to treatment with either enalapril (n=50) or losartan (n=50), and calculated the LV ejection fraction (LVEF) and LV end-diastolic volume index (LVEDVI) in these patients at baseline and after 6 months of treatment. While a significant increase in the LVEF as compared with that at the baseline was observed in both groups, no significant difference was found in the rate of change of this parameter between the two groups. However, inverse correlations were observed between the baseline LVEF and LVEDVI and also the rates of change of the two parameters, suggesting that the greater the compromise of the LV function at baseline, the greater the preventive effect of both classes of drugs on LV remodeling. Conclusion The results of this study suggest that neither enalapril nor losartan is superior to the other in terms of the effect on LV remodeling after MI in Japanese patients. In addition, the suppressive effect of both classes of drugs on LV remodeling was greater in patients with more extensive infarction and greater compromise of LV function at baseline.

While the usefulness of measuring the plasma levels of brain natriuretic peptide (BNP) in cases with worsening heart failure and severe heart failure has already been established, the benefits of evaluation of this parameter in asymptomatic stable patients with left ventricular dysfunction is still under debate. Left ventricular function was evaluated in 141 ambulatory outpatients with a previous history of myocardial infarction not associated with symptoms of heart failure for at least one year. The plasma BNP level was also determined in these patients for comparative study. No correlation between the plasma level of BNP and EF was noted in the normal-EF group, while a negative correlation between the two parameters was observed in the low-EF group (Y = 0.439 - 0.000266X) (R2 = 0.244, P < 0.0001). The sensitivity was 91.5%, specificity 56.3%, positive predictive accuracy value 61.9%, and negative predictive accuracy value 83.8% for a plasma BNP cut-off level of 89.0 pg/mL. The results suggested that it might be meaningful to measure the plasma BNP level, especially in asymptomatic patients with a previous history of myocardial infarction having a low-EF.

We experienced a case of vasospastic angina showing resolution of vasospasm in the acetylcholine provocation test corresponding to regression of coronary atherosclerotic plaque following treatment with a combination of benidipine and pravastatin.

The outcome for facilitated percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) is known to be more favorable in cases in which TIMI-3 flow is obtained before PCI. We investigated factors that affect the acquisition of TIMI-3 flow before PCI. Facilitated PCI was performed on 178 patients divided into two groups, a group in which TIMI-3 flow was acquired before conducting PCI and another in which it was not, and their background factors and short-term outcomes were investigated. The hemoglobin concentrations, white blood cell (WBC) counts, and HbA1c values were significantly lower in the group in which TIMI-3 flow was acquired before PCI and significantly more had a history of past smoking. According to the results of logistic analysis, WBC count (odds ratio [OR], 0.865, P = 0.0077), hemoglobin concentration (OR, 0.77, P = 0.0257), and smoking history (OR, 0.266, P = 0.0021) were independent factors that predicted acquisition of TIMI-3 flow. The WBC count and hemoglobin value on arrival at the emergency room and history of smoking were shown to be independent factors for acquisition of TIMI-3 flow before PCI in facilitated PCI.

Background: We hypothesized that highly purified Eicosapentaenoic Acid (EPA) might increase the Low-Density Lipoprotein (LDL)-particles size, thereby leading to prevention of coronary artery disease. The purpose of this prospective randomized trial was to evaluate the effect of EPA in increasing the LDL-particle size, as one of the possible mechanisms by which intake of EPA may prevent coronary events. Methods: One hundred fifty hypertriglyceridemic patients who gave consent for participation in this trial were randomized with a simple sealed envelope method to EPA treatment: the EPA group (n=75) or non-EPA treatment: the control group (n=75). Subjects in the EPA group were administered a 900-mg capsule containing EPA ethyl ester of >98% purity twice a day (total daily dose, 1,800 mg). Results: In the EPA group, while the serum levels of LDL-cholesterol and high-density lipoprotein cholesterol remained changed, significant increase of LDL-particle size, as judged based on the LDL-relative mobility value measured by lipoprotein polyacrylamide-gel electrophoresis, and significant decrease of the serum levels of Triglyceride-Rich Lipoproteins (TRLs)-related markers (triglyceride, very LDL fraction, remnant-like particle cholesterol, apolipoprotein C2, and apolipoprotein C3) were noted. No such changes were observed in the control group. In multi-logistic regression analysis after adjustments for the coronary risk factors, elevation of the serum EPA-related markers (serum level of EPA at 6 months, the EPA/ arachidonic acid (AA) ratio at 6 months, absolute change from the baseline of (Δ) EPA level, and Δ EPA/AA ratio), and treatment with statins and EPA were identified as independent variables of increase in LDL-particle size. Moreover, negative correlations were found between the Δ TRLs-related markers and Δ LDL-particle size, suggesting that improvement of the triglyceride-metabolism was associated with an increase of LDL-particle size. Conclusions: This study demonstrated that EPA administration increased the LDL-particle size by improving the triglyceride-metabolism. Furthermore, the serum EPA level and EPA/AA ratio after administration of EPA might be useful markers of increased LDL-particle size.