Gastrointestinal Bleeding From Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA Atrial Fibrillation Registry.

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.

Prognostic Value of Serum N-Terminal Pro-Brain Natriuretic Peptide Level over Heart Failure for Stroke Events and Deaths in Patients with Atrial Fibrillation.

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.

Clinical Outcomes of Off-Label Dosing of Direct Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA AF Registry.

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.

Oral anticoagulant use and clinical outcomes in elderly Japanese patients: findings from the SAKURA AF Registry.

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 < 75 years (non-elderly), 1078 (33.3%) 75-84 years (elderly) and 264 (8.2%) ≥ 85 years (very elderly) enrolled in a prospective multicenter registry. Kaplan-Meier analysis (median follow-up: 39.3 months) revealed a significantly high incidence of stroke/systemic embolism (SE) among the very elderly relative to that among the non-elderly or elderly (3.2 vs. 1.2 and 1.5 events per 100 patient-years, p < 0.001). Major bleeding in the non-elderly group was significantly infrequent relative to that among the elderly or very elderly group (1.1 vs. 1.6 vs. 1.8 events, p = 0.033). After multivariate adjustment, the stroke/SE incidence was comparable between DOAC and warfarin users, regardless of age, but major bleeding decreased significantly among very elderly DOAC users (adjusted HR 0.220, 95% CI 0.042-0.920). The greater increasing incidence of stroke/SE than major bleeding as patients age suggests that stroke prevention should outweigh the bleeding risk when anticoagulants are being considered for aged patients. Our data indicated that DOACs can be a therapeutic option for stroke prevention in very elderly patients.

Three-Year Clinical Outcomes Associated With Warfarin vs. Direct Oral Anticoagulant Use Among Japanese Patients With Atrial Fibrillation　- Findings From the SAKURA AF Registry.

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.

Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia.

BACKGROUND: Hyperglycemia, a risk factor for development of cardiovascular disease, causes endothelial dysfunction. Alpha-glucosidase inhibitors (α-GIs) improve postprandial hyperglycemia (PPHG) and may have favorable effects on associated cardiovascular disease. Effects of α-GIs in patients with acute coronary syndrome (ACS) and PPHG remain unclear; thus, we assessed the effect of α-GI miglitol on endothelial function in such patients by digital reactive hyperemia peripheral arterial tonometry (RH-PAT). METHODS: Fifty-four patients with ACS who underwent primary percutaneous coronary intervention were enrolled in the study: 36 with new-onset PPHG and 18 with normal glucose tolerance. Eighteen PPHG patients were given 50 mg of miglitol with each meal for 1 week. Endothelial function was assessed on the basis of the RH-PAT index (RHI) before and after the 1-week miglitol treatment. The other 18 PPHG patients and the 18 NGT patients were not given any anti-diabetic agent for 1 week, and endothelial function was assessed. RESULTS: Postprandial RHI decreased significantly in patients with PPHG. Miglitol improved PPHG significantly; postprandial RHI also improved (p = 0.007). Significant inverse correlation was found between the postprandial change in RHI and postprandial fasting-to-60-minutes surge in glucose (r = -0.382, p = 0.009). Moreover, the improvement in endothelial function correlated with the reduced postprandial glucose surge achieved with miglitol (r = -0.462, p = 0.001). CONCLUSIONS: Postprandial changes in glucose are related to endothelial dysfunction in ACS. Miglitol-based improvement in PPHG appears to improve endothelial function. The effect of miglitol on glucose-dependent endothelial function might improve outcomes of ACS.

Magnetic Resonance Imaging Scan of the Brain After Mild COVID-19 Infection.

PURPOSE: There have been several reports of central nervous system impairments associated with severe coronavirus disease 2019 (COVID-19) infection on head magnetic resonance imaging and angiography (MRI/A). However, head MRI/A is rarely performed in mild cases, and there have been few reports on intracranial changes after COVID-19 infection in these cases. Here, we report a comparative examination of the findings seen in common head MRI/A sequences in mild cases of COVID-19. METHODS: Of the 15,376 patients who underwent head MRI/A examination called "Brain Dock" between June 2020 and June 2021, 746 patients who received a COVID-19 antibody test were evaluated. Positive and negative patients were comparatively examined for head MRI/A findings such as cerebral white matter lesions, ischemic changes, cerebral microbleeds, cerebral aneurysms, arterial stenosis, sinusitis, and other abnormal findings. RESULTS: Overall, 31 (4.2%) patients were COVID-19 positive, and all of them had mild infections not requiring hospitalization. There was no significant difference in patient characteristics and head MRI/A findings between positive and negative patients. All positive patients showed no particular abnormalities in the nasal findings such as olfactory bulb atrophy or thickening of the olfactory mucosa. CONCLUSION: Intracranial lesions in mild patients do not show a clear difference from those in negative patients. This indicates that findings seen in common MRI/A sequences of severe patients are not likely in mild patients, supporting that there is relatively no damage to the central nervous system in mild patients.

Effectiveness of tuning an artificial intelligence algorithm for cerebral aneurysm diagnosis: a study of 10,000 consecutive cases.

Diagnostic image analysis for unruptured cerebral aneurysms using artificial intelligence has a very high sensitivity. However, further improvement is needed because of a relatively high number of false positives. This study aimed to confirm the clinical utility of tuning an artificial intelligence algorithm for cerebral aneurysm diagnosis. We extracted 10,000 magnetic resonance imaging scans of participants who underwent brain screening using the "Brain Dock" system. The sensitivity and false positives/case for aneurysm detection were compared before and after tuning the algorithm. The initial diagnosis included only cases for which feedback to the algorithm was provided. In the primary analysis, the sensitivity of aneurysm diagnosis decreased from 96.5 to 90% and the false positives/case improved from 2.06 to 0.99 after tuning the algorithm (P < 0.001). In the secondary analysis, the sensitivity of aneurysm diagnosis decreased from 98.8 to 94.6% and the false positives/case improved from 1.99 to 1.03 after tuning the algorithm (P < 0.001). The false positives/case reduced without a significant decrease in sensitivity. Using large clinical datasets, we demonstrated that by tuning the algorithm, we could significantly reduce false positives with a minimal decline in sensitivity.

Factors associated with the location of perivascular space enlargement in middle-aged individuals undergoing brain screening in Japan.

OBJECTIVE: In elderly populations, the enlargement of the perivascular space is related to small vessel disease and the glymphatic system. Enlarged perivascular spaces (EPVS) in the basal ganglia (EPVS-BG) and EPVS in the centrum semiovale (EPVS-CSO) are associated with different pathophysiological processes. However, the prevalence of EPVS and the factors associated with EPVS location in healthy middle-aged individuals are still unclear. We aimed to determine the prevalence of EPVS and the factors associated with EPVS location among healthy individuals in their 40 s METHODS: This study included 5000 consecutive healthy individuals who underwent screening for brain diseases in Japan from August to December 2018. Of them, the data of individuals in their 40 s were extracted and analyzed. The associations of age, sex, body mass index, smoking and drinking history, and medical history with EPVS location were investigated. Similar analyses were performed for the other age groups. A literature review on the factors associated with EPVS location was also performed. RESULTS: A total of 1720 individuals in their 40 s were finally included. The prevalence of EPVS-BG and EPVS-CSO was 7.7% and 9.2%, respectively. Age (years), smoking history, and hypertension were associated with EPVS-BG; none of the studied factors were found to be associated with EPVS-CSO. In the elderly, the factors previously reported to be associated with EPVS-BG included atherosclerosis change, while the factors associated with EPVS-CSO were cerebral amyloid angiopathy-related formation. CONCLUSION: Both EPVS-BG and EPVS-CSO occurred among healthy individuals in their 40 s, but they did so rarely, and less prevalently than in older age groups. EPVS-BG and EPVS-CSO may represent early imaging signs of the atherosclerotic and cerebral amyloid angiopathy processes, respectively. DATA AVAILABILITY: The anonymized data for this study will be shared upon any qualified investigator's request to the corresponding author. Primary data from this study will be made available upon reasonable request in accordance with the review board of the research institute.

Prevalence and risk factors for brain white matter changes in young and middle-aged participants with Brain Dock (brain screening): a registry database study and literature review.

This study aimed to determine the prevalence and risk factors for brain white matter changes in normal young and middle-aged participants who underwent Brain Dock (brain screening). We analyzed 5,000 consecutive healthy participants from the Brain Dock registry between August to December 2018. Age, sex, body mass index (BMI), medical history, deep subcortical white matter high intensity (DSWMH), periventricular high intensity (PVH), and enlargement of perivascular space (EPVS) were investigated in relation to age. The prevalence of DSWMH, PVH, and EPVS were 35.3%, 14.0%, and 17.8%, respectively. Multivariate logistic regression analyses for brain white matter changes were conducted. The significant risk factors in participants aged < 50 years were: age (OR:1.09, 95% CI:1.07-1.12), the female sex (1.29, 1.03-1.60), BMI obesity (1.86, 1.12-3.08), and hypertension (1.67, 1.18-2.35) for DSWMH; age (1.08, 1.04-1.13) and the female sex (1.56, 1.03-2.36) for PVH; and age (1.07, 1.05-1.10) and the female sex (0.77, 0.60-1.00) for EPVS. In conclusion, age was consistently identified as a significant risk factor in young and middle-aged participants. Some risk factors for brain white matter changes were identified even in young and middle-aged participants in this study. Further longitudinal studies should be done in the future.

Relationship between the Renal Function and Adverse Clinical Events in Patients with Atrial Fibrillation: A Japanese Multicenter Registry Substudy.

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, <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 < 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.

University hospitals, general hospitals, private clinics: Place-based differences in patient characteristics and outcomes of AF-A SAKURA AF Registry Substudy.

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<0.001), and these patients' CHADS2 scores were significantly lower than general hospital, but higher than university hospital patients (1.8±1.1 vs. 2.0±1.2 and 1.6±1.1; p<0.001). The Kaplan-Meier incidences of stroke/systemic embolism (SE) (1.72 vs. 1.58 vs. 0.84 events per 100 patient-years; p=0.120), a cardiovascular event (4.09 vs. 2.44 vs. 1.40; p<0.001), and death were higher (2.39 vs. 2.21 vs. 1.24; p=0.015) for university and general hospital patients than for private clinic patients; the incidences of major bleeding were equivalent (1.78 vs. 1.33 vs. 1.16; p=0.273). After multivariate adjustments, this trend persisted. 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.

Detection of coronary artery disease by free-breathing, whole heart coronary magnetic resonance angiography: our initial experience.

Free-breathing, whole heart coronary magnetic resonance angiography (MRA) has gained great attention as a totally noninvasive diagnostic modality for the detection of coronary artery disease. We examined the accuracy of coronary MRA to identify the presence or absence of coronary artery stenosis in comparison with conventional coronary angiography. Free-breathing, whole heart coronary MRA was performed in 43 consecutive patients undergoing conventional coronary angiography. A total of 172 coronary arteries and 344 coronary artery segments were analyzed. In the coronary artery segment-based analysis, the sensitivity to detect coronary stenosis >/=50% was 82% and specificity was 100%. The accuracy, positive predictive value, and negative predictive value was 97%, 98%, and 96%, respectively. In the vessel-based analysis the sensitivity was 86%, specificity 99%, accuracy 95%, positive predictive value 98%, and negative predictive value 94%. In the patient-based analysis, the sensitivity to detect coronary stenosis <50% was 97% and the specificity to define luminal narrowing <50% was 90%. The accuracy, positive predictive value, and negative predictive value was 95%, 97%, and 90%, respectively. Free-breathing, whole heart coronary MRA yields excellent diagnostic accuracy to detect significant coronary artery disease and has the potential to become the routine diagnostic modality for patients with suspected coronary artery disease.

Influence of genetic polymorphisms in oxidative stress related genes and smoking on plasma MDA-LDL, soluble CD40 ligand, E-selectin and soluble ICAM1 levels in patients with coronary artery disease.

BACKGROUND: Previous studies have shown that oxidative stress plays an important role in coronary heart disease. Polymorphisms in key enzymes that regulate oxidative stress may play a role in atherogenicity and were investigated in this study. MATERIAL/METHODS: One hundred and forty-three patients with angiographically proven coronary artery disease were studied. The effect of the C242T polymorphism of the p22phox gene, an essential component of the NADH/NADPH oxidase, and glutathione-S-transferase T1, M1 and P1 polymorphisms on plasma MDA-LDL, soluble CD40 ligand, E-selectin and soluble ICAM1 levels was determined. Genotyping of the p22 phox C242T polymorphism was performed by RFLP analysis, and GSTT1, GSTM1 and GSTP1 genotypes were determined using a multiplex PCR assay. The MDA-LDL, sCD40L, E-selectin and sICAM1 levels were determined using ELISA. RESULTS: Patients with the TT or TC genotype of the p22 phox C242T polymorphism had significantly higher plasma MDA-LDL levels compared to those of the CC genotype. Plasma E-selectin and soluble ICAM1 levels were significantly higher in the TT or TC genotype compared to that of the CC genotype. In GSTT1+ patients, plasma MDA-LDL levels were significantly higher than those of GSTT1- patients. CONCLUSIONS: Genetic polymorphism of the p22 phox gene had a significant effect on plasma lipid peroxidation and endothelial function through oxidative stress. The results of this study confirm the effect of NADH/NADPH oxidase on atherogenecity.

Adverse clinical events in Japanese atrial fibrillation patients with and without coronary artery disease-findings from the SAKURA AF Registry.

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 are limited.Methods: The SAKURA AF Registry is a prospective multi-center registry created to investigate outcomes of oral anticoagulant (OAC) use in Japanese AF patients. A study was conducted involving 3237 enrollees from 63 Tokyo-area institutions who were followed up for a median of 39.3 months. Clinical adverse events were compared between the patients accompanied with (n = 312) and without CAD (n = 2925).Results: The incidence of cardiovascular events and all-cause mortality rates were significantly higher among patients with CAD than among those without CAD (5.98 vs 2.52 events per 100 patient-years, respectively, p < 0.001; 3.27 vs 1.94 deaths per 100 patient-years, respectively, p = 0.012), but there was no difference in strokes/transient ischemic attacks or systemic embolisms (1.70 vs 1.34). After a multivariate adjustment, CAD remained a risk factor for cardiovascular events (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.08-2.25, p = 0.018). Among CAD patients, the propensity score-adjusted risk for major bleeding was significantly decreased among direct oral anticoagulant (DOAC) users in comparison to that among warfarin users (HR = 0.29, 95% CI = 0.07-0.94, p = 0.04), but other adverse clinical events did not differ significantly between these two groups.Conclusions: CAD did not appear to be a major determinant of strokes/TIAs, major bleeding, or all-cause mortality, but appeared to increase the risk of cardiovascular events in Japanese AF patients. The risk of major bleeding in CAD patients appeared to decrease when a DOAC rather than warfarin was administered. The data suggested that patients with AF and concomitant CAD require careful management and follow-up to reduce cardiovascular risks, and DOACs may be a better choice over warfarin when considering the risk of major bleeding.

Different determinants of vascular and nonvascular deaths in patients with atrial fibrillation: A SAKURA AF Registry substudy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, weight <50kg, and anemia were major determinants of nonvascular death. CONCLUSIONS: 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.

Worsening renal function, adverse clinical events and major determinants for changes of renal function in patients with atrial fibrillation: a Japanese multicenter registry substudy.

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.

Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans.

BACKGROUND: The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans. METHODS AND RESULTS: Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684+/-549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1+/-0.7 to 1.5+/-1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year. CONCLUSIONS: In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.

Current use of direct oral anticoagulants for atrial fibrillation in Japan: Findings from the SAKURA AF Registry.

BACKGROUND: Large-scale investigations on the use of oral anticoagulants including direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) have not included Japanese patients. METHODS: We established the multicenter SAKURA AF Registry to support prospective observational research on the status of anticoagulation treatment, especially with DOAC, for AF in Japan. We enrolled 3266 AF patients treated with warfarin (n=1577) or any of 4 DOACs (n=1689) from 63 institutions (2 cardiovascular centers, 13 affiliated hospitals or community hospitals, and 48 private clinics) in the Tokyo area. RESULTS: We conducted our first analysis of the registry data, and although we found equivalent mean age between the DOAC and warfarin users (71.8±9.5 vs. 72.3±9.4 years, p=0.2117), we found a slightly lower risk of stroke (CHADS2 score of 0 or 1 [46.9% vs. 39.4%, p<0.0001]) and significantly better creatinine clearance in DOAC users (70.4±27 vs. 65.6±25.7 mL/min, p<0.0001). Importantly, we documented under-dosing in 32% of warfarin users and inappropriate-low-dosing in 19.7-27.6% of DOAC users. CONCLUSIONS: Our initial analysis of the SAKURA AF Registry data clarified the real-world use of anticoagulants, which includes DOACs and warfarin in Japan. The DOAC users were at a lower risk for stroke than the warfarin users. In 20-30% of DOAC users, the dose was inappropriately reduced.