Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization.

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.

Unique behavioral patterns of wandering colonies of Brevibacillus thermoruber on agar plates.

Brevibacillus thermoruber strain Nabari cells grow as widely spreading dendritic colonies on reasoner's 2A-agar (1.5%) plates at around 55°C but as small motile colonies at 37°C. Motile colonies can be divided into colonies that move in straight or curved lines over long distances (wandering colonies), and colonies that rotate at a fixed location (rotating colonies). The addition of surfactant to the agar medium greatly increased the frequency of wandering colonies and facilitated the study of such colonies. The morphology of the wandering colonies varied: circular at the tip and pointed at the back, lemon-shaped with pointed ends, crescent-shaped, bullet-shaped, fish-like, and so on. A single colony may split into multiple colonies as it moves, or multiple colonies may merge into a single colony. The most surprising aspect of the movement of wandering colonies was that when a moving colony collides with another colony, it sometimes does not make a U-turn, but instead retreats straight back, as if bouncing back. The migration mechanisms of wandering colonies are discussed based on optical microscopic observations of swimming patterns of single cells in water and scanning electron microscopy of the arrangement of bacterial cells in wandering colonies.

The Ragulator complex serves as a substrate-specific mTORC1 scaffold in regulating the nuclear translocation of transcription factor EB.

The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is activated by intracellular nutritional sufficiency and extracellular growth signals. It has been reported that mTORC1 acts as a hub that integrates these inputs to orchestrate a number of cellular responses, including translation, nucleotide synthesis, lipid synthesis, and lysosome biogenesis. However, little is known about specific control of mTORC1 signaling downstream of this complex. Here, we demonstrate that Ragulator, a heteropentameric protein complex required for mTORC1 activation in response to amino acids, is critical for inhibiting the nuclear translocation of transcription factor EB (TFEB). We established a unique RAW264.7 clone that lacked Ragulator but retained total mTORC1 activity. In a nutrition-sufficient state, the nuclear translocation of TFEB was markedly enhanced in the clone despite total mTORC1 kinase activity. In addition, as a cellular phenotype, the number of lysosomes was increased by tenfold in the Ragulator-deficient clone compared with that of control cells. These findings indicate that mTORC1 essentially requires the Ragulator complex for regulating the subcellular distribution of TFEB. Our findings also suggest that other scaffold proteins may be associated with mTORC1 for the specific regulation of downstream signaling.

Impact of glycated hemoglobin on 2-year clinical outcomes in elderly patients with atrial fibrillation: sub-analysis of ANAFIE Registry, a large observational study.

BACKGROUND: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). METHODS: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). RESULTS: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11-1.93]) and net clinical outcome (aHR 1.33 [1.05-1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. CONCLUSIONS: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. TRIAL REGISTRATION: UMIN000024006; date of registration: September 12, 2016.

11C-Labeling of acyclic retinoid peretinoin by rapid C-[11C]methylation to disclose novel brain permeability and central nervous system activities hidden in antitumor agent.

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [11C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[11C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the 11C-labeled ester produced [11C]peretinoin in 13 ± 8% RCY (n = 3). After pharmaceutical formulation, the resulting [11C]benzyl ester and [11C]peretinoin had high radiochemical purity (>99% each) and molar activities of 144 and 118 ± 49 GBq µmol-1 at total synthesis times of 31 min and 40 ± 3 min, respectively. Rat brain PET imaging for the [11C]ester revealed a unique time-radioactivity curve, suggesting the participation of the acid [11C]peretinoin for the brain permeability. However, the curve of the [11C]peretinoin rose steadily after a shorter time lag to reach 1.4 standardized uptake value (SUV) at 60 min. These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of > 3.0 at 90 min). With the opportunity to identify high brain uptake of [11C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages.

Incidence and risk factors for venous thromboembolism in the Cancer-VTE Registry stomach cancer subcohort.

BACKGROUND: The Cancer-VTE Registry was a large-scale, multicenter, prospective registry designed to investigate real-world data on venous thromboembolism (VTE) incidence and risk factors in adult Japanese patients with solid tumors. This pre-specified subgroup analysis aimed to estimate the incidence of VTE, including VTE types other than symptomatic VTE, and identify risk factors of VTE in stomach cancer from the Cancer-VTE Registry. METHODS: Stage II-IV stomach cancer patients who planned to initiate cancer therapy and underwent VTE screening within 2 months before registration were enrolled. RESULTS: Of 1,896 patients enrolled, 131 (6.9%) had VTE at baseline, but 96.2% were asymptomatic. Female sex, age ≥ 65 years, VTE history, and D-dimer > 1.2 µg/mL were independent risk factors of VTE at baseline. Notably, patients with D-dimer > 1.2 µg/mL at the time of cancer diagnosis had an approximately 20-fold risk of VTE. During follow-up, event incidences were symptomatic VTE, 0.3%; incidental VTE requiring treatment, 1.1%; composite VTE, 1.4%; bleeding, 1.6%; cerebral infarction/transient ischemic attack/systemic embolic events, 0.7%; and all-cause death, 15.0%. The incidence of all-cause death was higher in patients with VTE vs without VTE at baseline (adjusted hazard ratio 1.67; 95% confidence interval 1.21-2.32; p = 0.002). CONCLUSIONS: VTE prevalence at the time of cancer diagnosis was not negligible and was extremely high when the patients had high D-dimer. VTE screening by D-dimer before starting cancer treatment is advisable, even for asymptomatic patients, regardless of whether the patient is undergoing surgery or chemotherapy. TRIAL REGISTRATION: UMIN000024942.

Relationship Between Direct Oral Anticoagulant Doses and Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　- ANAFIE Registry Sub-Analysis.

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

Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　- Results From the ANAFIE Registry.

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

Echocardiographic Parameters of Left Atrial Structure and Function and Clinical Outcomes at 2 Years in Elderly Patients With Atrial Fibrillation　- The ANAFIE Echocardiographic Substudy.

BACKGROUND: This prospective ANAFIE Registry substudy investigated the relationship between the echocardiographic parameters of left atrial (LA) structure and function and clinical outcomes at 2 years among atrial fibrillation (AF) patients aged ≥75 years.Methods and Results: Outcomes of 1,474 elderly non-valvular AF (NVAF) patients who underwent transthoracic echocardiography at baseline were analyzed by categories of maximum LA volume index (max. LAVi) and LA emptying fraction (LAEF) total. Baseline mean±standard deviation LAEF total and max. LAVi were 28.2±14.9% and 54.2±25.9 mL/m2, respectively. Proportions of oral anticoagulant (OAC), direct OAC, and warfarin use were 92.7%, 68.7%, and 24.0%, respectively. Patients with LAEF total ≤45.0% (n=1,213) vs. >45.0% (n=224) were at higher risk of cardiovascular events (hazard ratio [HR]: 2.19, P=0.021) and heart failure (HF) hospitalization (HR: 2.25, P=0.045). Risk of all-cause death was higher with max. LAVi >48.0 mL/m2(n=656) vs. ≤48.0 mL/m2(n=621) (HR: 1.69, P=0.048). Subgroups with abnormal LA function and structure had increased incidence of cardiac/cardiovascular events and HF hospitalization. No significant interaction was observed between echocardiographic parameters and OAC type. CONCLUSIONS: Elderly Japanese patients with NVAF and LAEF total ≤45.0% were at higher risk of cardiovascular events and HF hospitalization, and those with max. LAVi >48.0 mL/m2were at higher risk of all-cause death.

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). METHODS: An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. RESULTS: Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. CONCLUSIONS: RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.

Impact of Previous Stroke on Clinical Outcome in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Registry.

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

Incidence and risk factors for venous thromboembolism, bleeding, and death in colorectal cancer (Cancer-VTE Registry).

The impact of venous thromboembolism in Japanese colorectal cancer patients has not been elucidated. This prespecified subanalysis of the Cancer-VTE Registry aimed to report venous thromboembolism and event data after 1 year of follow-up in 2477 patients with colorectal cancer and investigate risk factors of venous thromboembolism. Of 2477 patients, 158 (6.4%) had venous thromboembolism in venous thromboembolism screening at enrollment. Asymptomatic distal deep-vein thrombosis accounted for 123/158 (77.8%) of venous thromboembolism cases. During the follow-up period, symptomatic, incidental events requiring treatment and composite venous thromboembolism incidences were 0.3%, 0.8%, and 1.0%, respectively. The incidence of bleeding events, cerebral infarction/transient ischemic attack/systemic embolic event, and all-cause death were 1.0%, 0.3%, and 4.8%, respectively. These results were consistent with the main study results. In multivariable analysis, venous thromboembolism at baseline was a risk factor of composite venous thromboembolism during the follow-up period. Japanese patients with colorectal cancer and advancing cancer stage before treatment had more frequent venous thromboembolism complications at baseline, higher incidence of venous thromboembolism events during cancer treatment, and higher mortality.

Catheter Ablation Energy Sources and Myocardial Injury and Coagulation Biomarkers During Uninterrupted Periprocedural Edoxaban Use　- A Subanalysis of KYU-RABLE.

BACKGROUND: The effects of catheter ablation (CA) energy sources on myocardial injury and coagulation biomarkers among Japanese non-valvular atrial fibrillation patients receiving uninterrupted periprocedural edoxaban are unclear. This KYU-RABLE exploratory subanalysis compared the effects of CA using radiofrequency energy vs. cryoballoon on: (1) myocardial injury; and (2) plasma edoxaban and coagulation biomarker concentrations measured before and after CA.Methods and Results:Plasma creatine kinase (CK), edoxaban, D-dimer, and prothrombin fragment 1+2 (F1+2) concentrations within 1 h before CA were compared with concentrations the day after. All biomarkers increased after CA, regardless of the energy source, but especially with cryoballoon. Significantly higher increases in CK concentrations from before to the day after CA were seen with cryoballoon compared with radiofrequency energy (P<0.0001). Edoxaban concentrations were similar in both groups. Concentrations of D-dimer and F1+2 increased in both groups, but were significantly higher in the cryoballoon group (P<0.0001 and P=0.006, respectively). There were no significant between-group differences in the incidence of thrombotic or bleeding events. CONCLUSIONS: Uninterrupted edoxaban concentrations were similar in both groups. Both myocardial injury and coagulation biomarkers increased after CA, especially with cryoballoon, but there was no difference in the incidence of thrombotic or bleeding events. These findings suggest the efficacy of uninterrupted edoxaban, regardless of the CA energy source. Periprocedural anticoagulation, particularly with cryoballoon, should be undertaken with care.

Real-World Investigation on Anticoagulation Management Before and After Catheter Ablation for Atrial Fibrillation in Japan　- Periprocedural and Long-Term Outcomes.

BACKGROUND: Optimal periprocedural oral anticoagulant (OAC) therapy before catheter ablation (CA) for atrial fibrillation (AF) and the safety profile of OAC discontinuation during the remote period (from 31 days and up to 1 year after CA) have not been well defined.Methods and Results: The RYOUMA registry is a prospective multicenter observational study of Japanese patients who underwent CA for AF in 2017-2018. Of the 3,072 patients, 82.3% received minimally interrupted direct-acting OACs (DOACs) and 10.2% received uninterrupted DOACs. Both uninterrupted and minimally interrupted DOACs were associated with an extremely low thromboembolic event rate. Female, long-standing persistent AF, low creatinine clearance, hepatic disorder, and high intraprocedural heparin dose were independent factors associated with periprocedural major bleeding. At 1 year after CA, DOAC was continued in 55.9% of patients and warfarin in 56.4%. The incidence of thromboembolic and major bleeding events for 1 year was 0.3% and 1.2%, respectively. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding events. Univariate analyses revealed that warfarin continuation and off-label overdose of DOACs were risk factors for major bleeding after CA. CONCLUSIONS: High intraprocedural dose of heparin was associated with periprocedural major bleeding events. At 1 year after CA, over half of the patients had continued OAC therapy. Thromboembolic events were extremely low; however, major bleeding occurred in 1.2%. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding after CA.

Effect of Polypharmacy on Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　- A Sub-Analysis of the ANAFIE Registry.

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

Effect of Cancer on Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　- Substudy of the ANAFIE Registry.

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

Antithrombotic Therapy for Patients With Atrial Fibrillation and Bioprosthetic Valves　- Real-World Data From the Multicenter, Prospective, Observational BPV-AF Registry.

BACKGROUND: Although bioprosthetic valve (BPV) replacements are becoming more common within our aging society, there are limited prospective data on the appropriate antithrombotic therapy for East Asian patients with atrial fibrillation (AF) and BPV replacement. Antithrombotic therapy and thrombotic and hemorrhagic event rates in Japanese patients with AF and BPV replacement are investigated.Methods and Results:This multicenter, prospective, observational study enrolled patients with BPV replacement and AF. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. Of the 894 patients analyzed, 54.7%, 29.4%, and 9.6%, were treated with warfarin-based therapy, direct oral anticoagulant (DOAC)-based therapy, or antiplatelet therapy without anticoagulants, respectively; 6.3% did not receive any antithrombotic drugs. The mean observation period was 15.3±4.0 months. The event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively. The multivariate adjusted hazard ratios for DOAC vs. warfarin were 1.02 (95% confidence intervals [CI], 0.30-3.41 [P=0.979]) for systemic embolic events and 0.96 (95% CI, 0.29-3.16 [P=0.945]) for major bleeding. CONCLUSIONS: Approximately 30% of patients with AF and BPV replacement were treated with DOAC. The risks of major bleeding and stroke or systemic embolism were similar between warfarin- and DOAC-treated patients with AF who had BPV replacement. Treatment with DOACs could be an alternative to warfarin in this population.

Echocardiographic Structure and Function in Elderly Patients With Atrial Fibrillation in Japan　- The ANAFIE Echocardiographic Substudy.

BACKGROUND: Echocardiographic data on the cardiac structure and function in elderly patients with atrial fibrillation (AF) and heart failure (HF) are limited. This subcohort study of the ANAFIE Registry analyzed echocardiographic parameters to identify cardiac structural and functional characteristics.Methods and Results:Of 32,726 subjects in the ANAFIE population, 1,494 (4.6%) were entered as the echocardiography subcohort. Half of the patients, including those with persistent and permanent AF, older age (≥80 years), and CHADS2score ≥2, had left atrial (LA) volume index ≥48 mL/m2, indicating severe LA enlargement. LA enlargement significantly correlated with impaired LA reservoir function, regardless of age and CHADS2score. Types of AF and rhythm were strongly related to LA volume and reservoir function (P<0.0001). Moderate-to-severe mitral and tricuspid regurgitation were significantly more common, and the early diastolic mitral inflow velocity to mitral annulus velocity ratio was significantly higher among patients with than without HF history (all, P<0.0001). CONCLUSIONS: In this subcohort, LA enlargement correlated with impaired LA reservoir function. Elderly patients with non-valvular AF and a history of HF had LA enlargement and dysfunction, increased LV mass index, low LV ejection fraction, and high heart rate.

Edoxaban vs. Vitamin K Antagonist for Atrial Fibrillation After Transcatheter Aortic Valve Replacement in Japanese Patients　- A Subanalysis of the ENVISAGE-TAVI AF Trial.

BACKGROUND: Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38-1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45-3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT. CONCLUSIONS: In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.

Comparison of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and an Aortic Bioprosthetic Valve.

BACKGROUND: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV.Methods and Results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577). CONCLUSIONS: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.