Characteristics and outcomes in elderly patients with non-valvular atrial fibrillation and high bleeding risk: subanalysis of the J-RHYTHM Registry.

Recently, a once-daily dose of edoxaban (15-mg) has been approved for stroke prevention in non-valvular atrial fibrillation (NVAF) patients aged ≥ 80 years, in whom standard oral anticoagulants are not recommended because of high bleeding risk (HBR), based on the ELDERCARE-AF trial. However, information regarding the characteristics and clinical outcomes among such patients is limited. Thus, this study aimed to clarify the characteristics and event rates in elderly patients with NVAF and HBR defined by the ELDERCARE-AF criteria. Of the 7406 NVAF outpatients included in the J-RHYTHM Registry, 60 patients with creatinine clearance (CrCl) < 15 mL/min were excluded. The remaining 7346 patients (age, 69.7 ± 9.9 years; men, 70.9%; warfarin use, 78.7%) were divided into three groups: Group 1, aged < 80 years (n = 6165); Group 2, aged ≥ 80 years without HBR (n = 584); and Group 3, aged ≥ 80 years with HBR (at least one of the followings; CrCl, 15-30 mL/min, history of bleeding, body weight ≤ 45 kg, and antiplatelet use) (n = 597, eligible for 15-mg edoxaban). Patients in Group 3 had a higher prevalence of comorbidities, and therefore, both higher thromboembolic and bleeding risk scores than in the other groups. During the 2-year follow-up period, the incidence rates (per 100 person-years) of thromboembolism in Groups 1, 2, and 3 were 0.7, 1.5, and 2.1 (P < 0.001), major hemorrhage, 0.8, 1.2, and 2.0 (P < 0.001), and all-cause death, 0.8, 2.6, and 4.6 (P < 0.001), respectively. Adjusted hazard ratios of Group 3 were 1.64 (95% confidence interval 0.89-3.04, P = 0.116) for thromboembolism, 1.53 (0.85-2.72, P = 0.154) for major hemorrhage, and 1.84 (1.19-2.85, P = 0.006) for all-cause death compared with Group 1. The NVAF Patients aged ≥ 80 years with HBR defined by the ELDERCARE-AF criteria were certainly at a higher adverse event risk, especially for all-cause death. Clinical trial registration: The J-RHYTHM Registry is registered in the University Hospital Medicine Information Network (UMIN) Clinical Trials Registry (unique identifier: UMIN000001569) http://www.umin.ac.jp/ctr/ .

Prolonged exposure to hypergravity increases number and size of cells and enhances lignin deposition in the stem of Arabidopsis thaliana.

We have performed a lab-based hypergravity cultivation experiment using a centrifuge equipped with a lighting system and examined long-term effects of hypergravity on the development of the main axis of the Arabidopsis (Arabidopsis thaliana (L.) Heynh.) primary inflorescence, which comprises the rachis and peduncle, collectively referred to as the main stem for simplicity. Plants grown under 1 × g (gravitational acceleration on Earth) conditions for 20-23 days and having the first visible flower bud were exposed to hypergravity at 8 × g for 10 days. We analyzed the effect of prolonged hypergravity conditions on growth, lignin deposition, and tissue anatomy of the main stem. As a result, the length of the main stem decreased and cross-sectional area, dry mass per unit length, cell number, and lignin content of the main stem significantly increased under hypergravity. Lignin content in the rosette leaves also increased when they were exposed to hypergravity during their development. Except for interfascicular fibers, cross-sectional areas of the tissues composing the internode significantly increased under hypergravity in most types of the tissues in the basal part than the apical part of the main stem, indicating that the effect of hypergravity is more pronounced in the basal part than the apical part. The number of cells in the fascicular cambium and xylem significantly increased under hypergravity both in the apical and basal internodes of the main stem, indicating a possibility that hypergravity stimulates procambium activity to produce xylem element more than phloem element. The main stem was suggested to be strengthened through changes in its morphological characteristics as well as lignin deposition under prolonged hypergravity conditions.

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.

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.

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.

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.

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.

Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy.

BACKGROUND AND AIMS: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. APPROACH AND RESULTS: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)ß inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/ß phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. CONCLUSIONS: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.

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.

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.

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.

Ischemic stroke, hemorrhage, and mortality in patients with non-valvular atrial fibrillation and renal dysfunction treated with rivaroxaban: sub-analysis of the EXPAND study.

The EXPAND Study demonstrated the effectiveness and safety of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) in routine clinical practice in Japan. This sub-analysis was conducted to reveal the effectiveness and safety of rivaroxaban in Japanese NVAF patients according to baseline creatinine clearance (CrCl) levels and rivaroxaban doses in the EXPAND Study. We examined 6806 patients whose baseline CrCl data were available and classified them into 2 groups: normal renal function group with CrCl ≥ 50 mL/min (n = 5326, 78%) and renal dysfunction group with CrCl < 50 mL/min (n = 1480, 22%). In the normal renal function group, 1609 (30%) received 10 mg/day (under-dose), while in the renal dysfunction group, 108 (7%) received 15 mg/day (over-dose). In the normal renal function group, under-dose of rivaroxaban was associated with higher all-cause mortality, while in the renal dysfunction group, over-dose was associated with higher incidence of major bleeding. In contrast, the incidence of stroke or systemic embolism was not different between the 2 groups regardless of the dose of rivaroxaban. In the propensity score matched analysis to adjust the difference in characteristics according to doses of rivaroxaban, the incidences of clinical outcomes were comparable between the 2 dose groups in both renal function groups. These results indicate that the dose of rivaroxaban should be reduced depending on the renal function, considering the balance between risks of bleeding and ischemia.

Nicotinamide Mononucleotide Potentiates Resistance to Biotrophic Invasion of Fungal Pathogens in Barley.

Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), induces disease resistance to the Fusarium head blight fungus Fusarium graminearum in Arabidopsis and barley, but it is unknown at which stage of the infection it acts. Since the rate of haustorial formation of an obligate biotrophic barley powdery mildew fungus Blumeria graminis f. sp. hordei (Bgh) was significantly reduced in NMN-treated coleoptile epidermal cells, the possibility that NMN induces resistance to the biotrophic stage of F. graminearum was investigated. The results show that NMN treatment caused the wandering of hyphal growth and suppressed the formation of appressoria-like structures. Furthermore, we developed an experimental system to monitor the early stage of infection in real-time and analyzed the infection behavior. We observed that the hyphae elongated windingly by NMN treatment. These results suggest that NMN potentiates resistance to the biotrophic invasion of F. graminearum as well as Bgh.

Baseline Characteristics of Elderly Japanese Patients Aged ≥75 Years With Non-Valvular Atrial Fibrillation and a History of Stroke　- ANAFIE Registry.

BACKGROUND: Despite the well-established benefits in patients with non-valvular atrial fibrillation (NVAF), oral anticoagulants (OAC) have been underused in elderly patients. We investigated the characteristics and status of anti-thrombotic therapy in elderly NVAF patients in Japan according to a history of stroke or of transient ischemic attack (TIA).Methods and Results:In a multicenter, prospective, observational study, 32,726 Japanese patients aged ≥75 years with NVAF were enrolled, and divided into 3 groups for the present analysis: 6,543 patients with previous ischemic stroke (IS) or TIA (2,410 women), 275 with previous hemorrhagic stroke (HS; 113 women), and the other 25,908 without previous stroke or TIA (11,470 women). Median CHADS2score was 5 in patients with IS/TIA, 2 in those with HS and 2 in those without stroke/TIA (P<0.05). Anti-thrombotic agents were used in 97.1% of patients with IS/TIA (OAC alone in 73.0%; antiplatelets alone in 3.7%; and both in 23.4%), 90.2% of those with HS (84.7%, 3.2%, and 12.1%, respectively), and 94.1% of those without stroke/TIA (83.4%, 2.7%, and 13.9%, respectively; P<0.05 for any anti-thrombotic choice). Of patients taking OAC, 72.2% received direct OAC (DOAC). CONCLUSIONS: In this unique nationwide NVAF registry of >30,000 elderly patients, >90% of patients, even those with HS, received anti-thrombotic therapy, nearly always with OAC. DOAC were the major choice of OAC.

Age-Related Differences in the Clinical Characteristics and Treatment of Elderly Patients With Atrial Fibrillation in Japan　- Insight From the ANAFIE (All Nippon AF In Elderly) Registry.

BACKGROUND: Atrial fibrillation (AF) is increasing as the global population ages. Elderly AF patients (≥75 years) have a worse prognosis than younger patients, and effective management is often difficult due to multiple comorbidities. This analysis examined the age-related differences in clinical characteristics and treatment in real-world elderly Japanese AF patients.Methods and Results:The ANAFIE Registry is a multicenter, prospective, observational registry of 32,726 non-valvular AF patients aged ≥75 years. The present study assessed the age-related differences in baseline clinical status and anticoagulant therapy between age groups 75-<80, 80-<85, 85-<90, and ≥90 years. The prevalence of persistent or permanent AF increased, and that of paroxysmal AF decreased, with increasing age (trend P<0.0001). The risk of stroke, based on CHADS2and CHA2DS2-VASc scores, and bleeding, based on HAS-BLED score, increased with age. Both warfarin and apixaban were used more often as age increased (trend P<0.0001, for each), while other anticoagulants were used less. Anticoagulant doses were significantly lower in older patients. CONCLUSIONS: Permanent/persistent AF, comorbidities, and cardiovascular and bleeding risk all increased significantly with age. Furthermore, use of warfarin and apixaban increased with age, accompanied by a decrease in other oral anticoagulant usage.

Secondary stroke prevention with apixaban in nonvalvular atrial fibrillation: A subgroup analysis of the STANDARD study.

BACKGROUND: Data on independent risk factors for stroke recurrence in Japanese patients with nonvalvular atrial fibrillation are limited. METHODS: We performed a subgroup analysis of a postmarketing surveillance study of apixaban (STroke prevention ANticoagulant Drug Apixaban Real-world Data study) in Japanese patients with nonvalvular atrial fibrillation receiving oral apixaban (5 mg/2.5 mg twice daily) in routine clinical practice. Patients were categorized into primary and secondary prevention groups based on the absence or presence of a history of ischemic stroke/transient ischemic attack, respectively. RESULTS: Patients in the secondary prevention group (1101 of 6306 patients [17.5%] analyzed; mean observation period, 15.7 months) had a higher risk of ischemic stroke or hemorrhage than those in the primary prevention group. The incidence rates of major (3.92%/year vs 2.06%/year), intracranial (1.87%/year vs 0.55%/year), and cerebral (1.14%/year vs 0.37%/year) hemorrhage and effectiveness outcomes (ischemic stroke/systemic embolism/transient ischemic attack, 3.25%/year vs 0.57%/year) were significantly higher (all P < 0.001) in the secondary prevention group than in the primary prevention group. Multivariate analysis identified no independent risk factors in the secondary prevention group, while prior major bleeding, alcohol abuse, advanced age, male sex, lower body weight, higher serum creatinine, and antiplatelet drug use were identified as risk factors for major hemorrhage, and advanced age and antiplatelet drug use for effectiveness outcomes in the primary prevention group. CONCLUSIONS: Among Japanese patients with nonvalvular atrial fibrillation who received apixaban, presence of a history of ischemic stroke/transient ischemic attack was associated with higher incidence rates of hemorrhage and thromboembolic events.

Dabigatran for Japanese Patients with Atrial Fibrillation and Prior Stroke: A Subgroup Analysis of the J-Dabigatran Surveillance Program.

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

Impact of Digitalis Use on Mortality in Japanese Patients With Non-Valvular Atrial Fibrillation　- A Subanalysis of the J-RHYTHM Registry.

BACKGROUND: Because the influence of digitalis use on the death of patients with non-valvular atrial fibrillation (NVAF) remains controversial, a subanalysis of the J-RHYTHM Registry was performed.Methods and Results:A consecutive series of outpatients with AF from 158 institutions was enrolled and followed for 2 years or until the occurrence of an event. Among 7,406 patients with NVAF, 7,018 (age, 69.7±10.0 years; men, 71.1%) with information on antiarrhythmic drug and digitalis use at baseline were divided into 2 groups based on digitalis use. The influence of digitalis on death was investigated using a propensity score-matching model. In 802 patients treated with digitalis, all-cause death was significantly higher than in 6,216 patients with no digitalis use during the 2-year follow-up period (4.4% vs. 2.4%, unadjusted P<0.001). Digitalis use was significantly associated with all-cause death in the crude model (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.28-2.68, P=0.001). However, after propensity score-matching, the association was not significant (HR 1.31, 95% CI 0.70-2.46, P=0.405). Older age, male sex, heart failure, coronary artery disease, and lower body mass index were significantly associated with all-cause death in NVAF patients treated with digitalis. CONCLUSIONS: Digitalis use was not independently associated with all-cause death, and several clinical confounding factors might contribute to increased mortality in NVAF patients treated with digitalis.

Baseline Demographics and Clinical Characteristics in the All Nippon AF in the Elderly (ANAFIE) Registry.

BACKGROUND: Despite the well-established benefits in patients with nonvalvular atrial fibrillation (NVAF), anticoagulants have been underused in elderly patients. The All Nippon AF In the Elderly (ANAFIE) Registry is a multicenter, prospective, observational study with 2-year follow-up of Japanese patients aged ≥75 years with a definitive diagnosis of NVAF, aiming to collect detailed information on clinical status and therapeutic challenges in this patient population.Methods and Results:Patients were enrolled from October 2016 to January 2018. A total of 32,726 patients (57.2% male) were included. The average age, CHADS2score, and creatinine clearance were 81.5±4.8 years (26.2% of patients were aged ≥85 years), 2.9±1.2, and 48.4±21.8 mL/min, respectively. Paroxysmal AF was the most common clinical AF type (42.0%), and most patients (97.2%) had comorbidities. Most patients (91.9%) were receiving anticoagulant therapy; of these, 27.8% and 72.2% were treated with warfarin and direct oral anticoagulants, respectively. The average number of concomitant drugs used was 6.6±3.2, including anticoagulants. CONCLUSIONS: The ANAFIE Registry is the largest prospective registry study of elderly Japanese patients with NVAF to date. Baseline data indicate that patients in this age group are treated in a manner similar to their younger counterparts.

Primary and secondary prevention of stroke and systemic embolism with rivaroxaban in patients with non-valvular atrial fibrillation : Sub-analysis of the EXPAND Study.

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