Gastrointestinal bleeding in elderly patients with atrial fibrillation: prespecified All Nippon Atrial Fibrillation in the Elderly (ANAFIE) Registry subgroup analysis.

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88-1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Coronary events in elderly patients with non-valvular atrial fibrillation: a prespecified sub-analysis of the ANAFIE registry.

Real-world data on coronary events (CE) in elderly patients with atrial fibrillation (AF) are lacking in the direct oral anticoagulant era. This prespecified sub-analysis of the ANAFIE Registry, a prospective observational study in > 30,000 Japanese patients aged ≥ 75 years with non-valvular AF (NVAF), investigated CE incidence and risk factors. The incidence and risk factors for new-onset CE (a composite of myocardial infarction [MI] and cardiac intervention for coronary heart diseases other than MI), MI, and cardiac intervention for coronary heart diseases other than MI during the 2-year follow-up were assessed. Bleeding events in CE patients were also examined. Among 32,275 patients, the incidence rate per 100 patient-years was 0.48 (95% confidence interval (CI): 0.42-0.53) for CE during the 2-year follow-up, 0.20 (0.16-0.23) for MI, and 0.29 (0.25-0.33) for cardiac intervention for coronary heart diseases other than MI; that of stroke/systemic embolism was 1.62 (1.52-1.73). Patients with CE (n = 287) likely had lower creatinine clearance (CrCL) and higher CHADS2 and HAS-BLED scores than patients without CE (n = 31,988). Significant risk factors associated with new-onset CE were male sex, systolic blood pressure of ≥ 130 mmHg, diabetes mellitus (glycated hemoglobin ≥ 6.0%), CE history, antiplatelet agent use, and CrCL < 50 mL/min. Major bleeding incidence was significantly higher in patients with new-onset CE vs without CE (odds ratio [95% CI], 3.35 [2.06-5.43]). In elderly patients with NVAF, CE incidence was lower than stroke/systemic embolism incidence. New-onset CE (vs no CE) was associated with a higher incidence of major bleeding.Trial registration: UMIN000024006.

Renal Function and Clinical Outcomes Among Elderly Patients With Nonvalvular Atrial Fibrillation From ANAFIE.

Background: Advancing age, decreasing renal function, and atrial fibrillation are strongly associated. Real-world evidence of direct oral anticoagulant (DOAC) use among elderly patients ≥75 years of age with nonvalvular atrial fibrillation and renal dysfunction is limited. Objectives: This study sought to assess 2-year outcomes and anticoagulant treatment, stratified by renal function. Methods: Enrolled patients were divided into 4 subgroups by creatinine clearance (CrCl) to determine the impact of renal dysfunction on clinical outcomes. Results: Of 32,275 patients, 26,202 with CrCl data were analyzed (median follow-up 2.00 [IQR: 1.92-2.00] years); 1.3% of patients had CrCl <15 mL/min, 10.7% had CrCl 15 to <30 mL/min, 33.4% had CrCl 30 to <50 mL/min, 35.8% had CrCl ≥50 mL/min, and 18.9% had unknown CrCl. Cumulative incidences of stroke/systemic embolic events, major bleeding, major plus clinically relevant nonmajor bleeding, cardiovascular death, all-cause death, and net clinical outcomes increased with decreasing CrCl. In multivariable Cox regression analysis, lower CrCl emerged as an independent risk factor for these clinical outcomes, except for major bleeding, compared with CrCl ≥50 mL/min. The effectiveness and safety of DOACs over warfarin were similar or better across 3 CrCl subgroups with CrCl 15 mL/min or more. DOAC use was associated with a lower risk of stroke/systemic embolic events, major bleeding, cardiovascular death, all-cause death, and net clinical outcome compared with warfarin in patients with CrCl 30 to <50 mL/min. Conclusions: Incidences of major clinical outcomes increased with decreasing renal function in elderly nonvalvular atrial fibrillation patients. DOACs were effective and safe even in patients with renal dysfunction (CrCl 15-<50 mL/min). (Prospective Observational Study in Late-Stage Elderly Patients with Non-Valvular Atrial Fibrillation: All Nippon AF In Elderly Registry [ANAFIE Registry]; UMIN000024006).

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.

Oral Anticoagulants in Very Elderly Nonvalvular Atrial Fibrillation Patients With High Bleeding Risks: ANAFIE Registry.

Background: Data on the effectiveness and safety of oral anticoagulant (OAC) agents in very elderly nonvalvular atrial fibrillation patients with high bleeding risk are lacking. Objectives: This study examined 2-year outcomes and effects of OAC agents among these patients using the ANAFIE (All Nippon Atrial Fibrillation in the Elderly) registry (N = 32,275) data. Methods: Patients were classified into high-risk (age: ≥80 years; CHADS2 score: ≥2; and presence of ≥1 bleeding risk factor: creatinine clearance of 15-30 mL/minute, prior bleeding at critical sites, body weight of ≤45 kg, or continuous antiplatelet use) and reference groups. Results: In the high-risk (n = 7,104) and reference (n = 25,171) group patients, 89.0% and 93.4%, respectively, used OAC agents. Of these, respectively, 30.1% and 24.2% used warfarin, and 58.9% and 69.1% used direct-acting OAC (DOAC) agents. Compared with the reference group, the high-risk group had higher incidences of stroke/systemic embolism, major bleeding, intracranial hemorrhage, gastrointestinal bleeding, cardiovascular events, and all-cause death. In the high-risk group, DOAC agent use vs nonuse of OAC agents was associated with reduced incidences of stroke/systemic embolism (HR: 0.53; 95% CI: 0.36-0.79) and all-cause death (HR: 0.65; 95% CI: 0.52-0.81) but not with major bleeding (HR: 1.09; 95% CI: 0.63-1.89). DOAC agents were superior to warfarin in effectiveness and safety. For high-risk patients, history of major bleeding, severe liver dysfunction, and falls within 1 year were independent risk factors for major bleeding. Conclusions: High-risk elderly nonvalvular atrial fibrillation patients had higher event incidences. DOAC agents were associated with reduced risk of stroke/systemic embolism and all-cause death vs nonuse of OAC agents or warfarin. (Prospective Observational Study in Late-Stage Elderly Patients With Nonvalvular Atrial Fibrillation [ANAFIE registry]; UMIN000024006).

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.

Background characteristics and anticoagulant usage patterns of elderly non-valvular atrial fibrillation patients in the ANAFIE registry: a prospective, multicentre, observational cohort study in Japan.

OBJECTIVE: To explore anticoagulant usage patterns stratified by stroke and bleeding risk in elderly patients with non-valvular atrial fibrillation (NVAF). DESIGN: Prospective, multicentre, observational cohort study. SETTING: The real-world All Nippon AF In the Elderly (ANAFIE) registry. PARTICIPANTS: Japanese patients aged ≥75 years with NVAF (n=32 726). OUTCOME MEASURES: The distribution of stroke and bleeding risk scores, and the selection of anticoagulant regimen for patients at high stroke and bleeding risk. RESULTS: Overall, 18 185 (55.6%) patients had a high risk of stroke (CHADS2 score ≥3). Of these, 12 561 (38.4% of the total ANAFIE population) had a low bleeding risk (HAS-BLED ≤2) and 5624 (17.2%) had a high bleeding risk (HAS-BLED ≥3). Significant differences were noted between the high versus low bleeding risk groups in sex, height, weight, systolic blood pressure and rates of abnormality of lipid metabolism, gastrointestinal disease, cerebrovascular disorders, chronic kidney disease, angina pectoris, respiratory disease, primary malignant tumour, dementia and fall history within the past year (all p<0.0001). Patients with high stroke and bleeding risks had a lower anticoagulant usage rate versus the low bleeding risk group, and 8.7% and 5.8%, respectively, were not receiving any anticoagulant (p<0.0001). Patients in the high bleeding risk group had a higher usage of warfarin versus the low bleeding risk group (p<0.0001); more patients (14.0%) in the high bleeding risk group receiving warfarin had time in the therapeutic range <40%, versus those in the low bleeding risk group (11.6%, p=0.0146). Direct-acting oral anticoagulants (DOACs) were used less in the high bleeding risk group, without notable differences in the DOAC dose distribution between the two groups. CONCLUSIONS: In elderly NVAF patients at high stroke risk, significant demographic and clinical differences were observed according to bleeding risk. Administration of low-dose DOACs was frequent, but the dose distribution was unaffected by bleeding risk. TRIAL REGISTRATION NUMBER: UMIN000024006 (http://www.umin.ac.jp/).

Safety and effectiveness of edoxaban in Japanese patients with nonvalvular atrial fibrillation: Final report of a two-year postmarketing surveillance study (ETNA-AF-Japan).

BACKGROUND: Direct oral anticoagulants (DOACs) are the recommended first-line therapy for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of edoxaban for this indication requires monitoring over the long term in real-world settings. METHODS: ETNA-AF-Japan (trial no. UMIN000017011) was a prospective, multicenter observational study (part of postmarketing surveillance in Japan). NVAF patients due to receive edoxaban to prevent ischemic stroke were enrolled between 13 April 2015 and 30 September 2017. RESULTS: A total of 11 569 patients were enrolled. For the 11 111 patients (female, 40.6%) whose data comprised the safety analysis set, age, body weight, creatinine clearance (CLcr), and CHADS2 score were 74.2 ± 10.0 years, 60.0 ± 12.7 kg, 63.9 ± 25.8 mL/min, and 2.2 ± 1.3, respectively (mean ± SD). The majority (86.3%) received edoxaban in accordance with package insert information. The mean duration of treatment was 561.9 ± 261.2 days. The annual incidence (95% confidence interval) of all bleeding events and major bleeding events was 5.60% (5.25%-5.98%) and 1.02% (0.88%-1.18%), respectively. The annual incidence of ischemic stroke (excluding transient ischemic attack, TIA) or systemic embolism was 1.08% (0.93%-1.25%). Multivariate analysis showed low body weight, low CLcr, history of gastrointestinal bleeding, anemia, and use of an antiplatelet agent to be associated with major bleeding, and history of ischemic stroke or TIA, vascular disease, and antiplatelet agent use to be associated with ischemic stroke (excluding TIA) or systemic embolism. CONCLUSIONS: These results provide real-world evidence for the long-term good safety and effectiveness profile of edoxaban in Japanese NVAF patients under clinical practice.

Clinical and Angiographic Features of Patients With Out-of-Hospital Cardiac Arrest and Acute Myocardial Infarction.

BACKGROUND: Sudden cardiac arrest is a serious complication of acute myocardial infarction (MI). Although in-hospital mortality from MI has decreased, the mortality of MI patients complicated with out-of-hospital cardiac arrest (OHCA) remains high. However, the features of acute MI patients with OHCA have not been well known. OBJECTIVES: We sought to characterize the clinical and angiographic features of acute MI patients with OHCA comparing with those without OHCA. METHODS: We retrospectively analyzed 480 consecutive patients with acute MI undergoing percutaneous coronary intervention. Patients complicated with OHCA were compared with patients without OHCA. RESULTS: Of the patients, 141 (29%) were complicated with OHCA. Multivariate analysis revealed that age (odds ratio [OR]: 0.8; 95% confidence interval [CI]: 0.7 to 0.9 per 5 years; p < 0.001), estimated glomerular filtration rate (OR: 0.8; 95% CI: 0.7 to 0.8 per 10 ml/min/1.73 m2; p < 0.001), peak creatine kinase-myocardial band (OR: 1.3; 95% CI: 1.2 to 1.4 per 102 U/l; p < 0.001), calcium-channel antagonists use (OR: 0.4; 95% CI: 0.2 to 0.7; p = 0.002), the culprit lesion at the left main coronary artery (OR: 5.3; 95% CI: 1.9 to 15.1; p = 0.002), and the presence of chronic total occlusion (OR: 2.9; 95% CI: 1.5 to 5.7; p = 0.001) were significantly associated with OHCA. CONCLUSIONS: Younger age, no use of calcium-channel antagonists, worse renal function, larger infarct size, culprit lesion in the left main coronary artery, and having chronic total occlusion were associated with OHCA.

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA-AF-Japan): One-year safety and effectiveness analyses.

BACKGROUND: The safety and effectiveness of edoxaban in real-world clinical settings have not yet been elucidated thoroughly among Japanese patients with nonvalvular atrial fibrillation (NVAF). We report the one-year interim results of ETNA-AF-Japan (Edoxaban Treatment in routiNe clinical prActice in patients with nonvalvular Atrial Fibrillation: UMIN000017011), an ongoing two-year study. METHODS: ETNA-AF-Japan is a prospective, real-world multicenter observational study that analyzes the long-term safety and effectiveness of edoxaban. Physicians recorded clinical characteristics, bleeding events, and clinical events of ischemic stroke and systemic embolism, among others. RESULTS: In total, 11 569 patients with NVAF were enrolled. The demographic and clinical characteristics of the patients in the safety analysis set (n = 11 107) were a mean age of 74.2 ± 10.0 years; female sex, 40.6%; age ≥75 years, 52.4%; body weight ≤60 kg, 54.3%; creatinine clearance ≤50 mL/min, 31.2%; mean CHADS2 score of 2.2 ± 1.3. The mean treatment period was 311.2 days (median; 366.0 days), and ~80% of patients continued edoxaban treatment. In the safety analysis, the incidence of all bleeding events was 6.32% [95% CI: 5.87, 6.79] (n = 702), and for major bleeding, it was 1.08% [0.90, 1.29] (n = 120). In the effectiveness analysis set (n = 11 059), the incidence of ischemic stroke (excluding TIA) or systemic embolism was 1.10% [0.92, 1.32] (n = 122). CONCLUSIONS: At one-year follow-up, the results showed no major concerns about the safety and effectiveness of edoxaban in Japanese patients with NVAF in a real-world clinical setting.

Characteristics of Japanese Patients with Nonvalvular Atrial Fibrillation on Anticoagulant Treatment: A Descriptive Analysis of J-dabigatran Surveillance and JAPAF Study.

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

Postmarketing surveillance on clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA-AF-Japan): Three-month interim analysis results.

BACKGROUND: Direct oral anticoagulants are the first-line drugs for anticoagulation therapy in nonvalvular atrial fibrillation (NVAF). However, a real-world, large-scale, clinical study on edoxaban has not been performed. Our ongoing postmarketing surveillance, ETNA-AF-Japan (Edoxaban Treatment in routiNe clinical prActice in patients with non-valvular Atrial Fibrillation; UMIN000017011), was designed to collect such data. METHODS: Enrollment started on 13 April 2015 and ended on 30 September 2017. Eligible patients were those diagnosed with NVAF who were to receive edoxaban for the first time and provided written consent for study participation. Baseline patient characteristics and adverse events (AEs) were collected. RESULTS: A total of 11 569 patients were enrolled. Data for 8157 patients in the first 3 months were analyzed. Mean age, body weight, creatinine clearance (CLcr), and CHADS 2 score were 74.2 ± 10.0 years, 60.0 ± 12.6 kg, 64.0 ± 25.6 mL/min, and 2.2 ± 1.3, respectively. Female patients, and patients with age ≥75 years, body weight ≤60 kg, and CLcr <30 mL/min constituted 40.7%, 52.4%, 54.6%, and 4.7%, respectively. Patients with paroxysmal, persistent, and permanent AF constituted 46.1%, 38.7%, and 15.1%, respectively. Most patients (85.3%) received dosages according to the prescribing information, and 90.8% continued the medication for 3 months. Bleeding AEs occurred in 3.29%, including major bleeding in 0.29%. CONCLUSIONS: The majority (90.8%) of patients continued medication and no significant safety concerns related to edoxaban were reported during the first 3 months of treatment. Clearer safety and efficacy profiles of edoxaban await data analyses after the 2-year follow-up period.

Three-dimensional image-based high-dose-rate interstitial brachytherapy for mobile tongue cancer.

To investigate the influence of a 3D image-based treatment-planning method for high-dose-rate interstitial brachytherapy (HDR-ISBT) for mobile tongue cancer, we analyzed dose-volume histogram results for the clinical target volume (CTV) and the mandible. Between October 2010 and November 2011, one and four patients having T2 and T3 tumors, respectively, were treated with HDR-ISBT. Multiplane implantation using 9-15 treatment applicators was performed. Lugol's iodine staining, metal markers, ultrasonography, and magnetic resonance imaging were used to identify the contours of the gross tumor volume (defined as the CTV). The results of the image-based treatment plan were compared with those of the conventional simulated plan on the basis of a reference point 5 mm from the applicator position. The mean D90(CTV) and V100(CTV) were 112% of the prescribed dose (PD) and 98.1%PD, respectively, for the image-based plan, and 113%PD and 97.2%PD, respectively, for the conventional plan. The median CTVref/Vref was 0.23 for the image-based plan and 0.16 for the conventional plan (P = 0.01). The mean D0.1 cm(3) (mandible), D1 cm(3) (mandible), and D2 cm(3) (mandible) were 80.1%PD, 62.5%PD, and 55.7%PD, respectively, for the image-based plan, and 109.1%PD (P = 0.02), 82.4%PD (P = 0.005), and 74%PD (P = 0.004), respectively, for the conventional plan). Image-based treatment planning may achieve high-conformity radiotherapy for the CTV and decrease irradiated doses to the mandible.

Daily CT measurement of needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy for postoperative recurrent uterine cancer.

We investigated daily needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy (HDR-ISBT) for postoperative recurrent uterine cancer. Eight patients with postoperative recurrent uterine cancer received HDR-ISBT with or without external beam radiotherapy using our unique ambulatory technique. To analyze displacement, we obtained daily computed tomography (CT) images for 122 flexible needle applicators at 21, 45, 69, and 93 hours after implantation. Displacement was defined as the length between the center of gravity of titanium markers and the needle applicator tips along the daily CT axis. For cases in which displacement was not corrected, we also calculated the dose that covered 90% of the clinical target volume (D90(CTV)) using a dose-volume histogram (DVH). Median caudal needle applicator displacement at 21, 45, 69, and 93 hours was 3, 2, 4, and 5 mm, respectively. More than 15 mm displacement was observed for 2% (2 of 122) and 17% (10 of 60) of needle applicators at 21 and 93 hours, respectively. Cases in which dwell positions were not changed to correct the treatment plan, 2 of 8 patients showed more than 10% reduction in D90(CTV) values compared with the initial treatment plan. Correction of dwell positions of the treatment source improves treatment DVH for multifractionated HDR-ISBT.

Antithrombotic therapy in atrial fibrillation: evaluation and positioning of new oral anticoagulant agents.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for stroke. For more than 60 years, warfarin has been the only approved anticoagulant for prevention of stroke in patients with AF. Although highly effective, it has many limitations that make its use difficult. Therefore, several novel anticoagulants are under development to overcome the limitations of warfarin, and some of these have entered phase III clinical trials. Dabigatran is an oral, reversible direct thrombin inhibitor approved in Europe and in several other countries for the prevention of venous thromboembolism after elective knee and hip replacement surgery. It has also been approved in the United States and Japan for the prevention of stroke and systemic embolism in patients with nonvalvular AF. In this review, the mechanism of action and pharmacological properties of new anticoagulants are described in detail, and the correct use of dabigatran in clinical practice is discussed.

Long-term oral administration of dipyridamole improves both cardiac and physical status in patients with mild to moderate chronic heart failure: a prospective open-randomized study.

Adenosine is known as an endogenous cardioprotectant. We previously reported that plasma adenosine levels increase in patients with chronic heart failure (CHF), and that a treatment that further elevates plasma adenosine levels may improve the pathophysiology of CHF. Therefore, we performed a prospective, open-randomized clinical trial to determine whether or not exposure to dipyridamole for 1 year improves CHF pathophysiology compared with conventional treatments. The study enrolled 28 patients (mean+/-SEM: 66+/-4 years of age) attending specialized CHF outpatient clinics with New York Heart Association (NYHA) class II or III, no major complications, and stable CHF status during the most recent 6 months under fixed medications. They were randomized into three groups with or without dipyridamole (Control: n=9; 75 mg/day: n=9; 300 mg/day: n=10) in addition to their original medications and were followed up for 1 year. The other drugs were not altered. Among the enrolled patients, 100%, 4%, 100%, and 79% received angiotensin-converting enzyme inhibitors, aldosterone analogue, loop diuretics, and beta-adrenoceptor blocker, respectively. Fifteen patients suffered from dilated cardiomyopathy, and 7/3/3 patients suffered from ischemic/valvular/hypertensive heart diseases, respectively. Mean blood pressure was comparable among the groups. While the baseline conditions were comparable, we found that echocardiographic ejection fraction (p<0.01 vs. baseline, p<0.01 vs. Control), left ventricular systolic diameter (p<0.05, p<0.05), Specific Activity Scale (SAS) score (p<0.05, p<0.01), maximal oxygen consumption (p<0.05, p<0.05) and plasma B-type natriuretic peptide level (p<0.01, p<0.01) were significantly improved in patients with dipyridamole after 1 year, generally in a dose-dependent manner. Therefore, we suggest that an additional administration of dipyridamole further improves CHF pathophysiology.

Clinical impact of metabolic syndrome and its additive effect with smoking on subsequent cardiac events after acute myocardial infarction.

Little information is available regarding the clinical effect of metabolic syndrome (MS) or its combined effect with smoking on subsequent cardiac events after acute myocardial infarction (AMI). To examine whether MS independently predicts cardiac events (cardiac death and nonfatal reinfarction) and to assess the combined effect of MS and smoking on cardiac events after AMI, we studied 3,858 survivors of AMI registered in the Osaka Acute Coronary Insufficiency Study (OACIS). During a median follow-up of 725 days, the incidence of cardiac events was higher in patients with MS than in those without MS (p=0.021). After adjustment for baseline characteristics, MS was an independent predictor of cardiac events after AMI (hazard ratio [HR] 1.480, 95% confidence interval [CI] 1.128 to 1.942, p=0.005). Compared with patients who did not have MS and were nonsmokers, the adjusted HR for cardiac events was 2.868 (95% CI 1.573 to 5.227, p=0.001) in patients with MS who continued smoking after AMI. Cessation of smoking after AMI was associated with a significantly lower risk of cardiac events in patients with MS (HR 0.485, 95% CI 0.281 to 0.837, p=0.009) but not in patients without MS (HR 0.618, 95% CI 0.330 to 1.157, p=0.132). In conclusion, MS is independently associated with an increased risk of cardiac events after AMI. Smoking has an additive adverse effect on cardiac events after AMI, and cessation of smoking is beneficial and strongly recommended for AMI, especially in patients with MS.