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Although prescription review is an important role for pharmacists in anticancer drug therapy, there are no guidelines in Japan that specify what pharmacists should check for in chemotherapy regimens. This prospective multicenter survey aimed to investigate the implementation of chemotherapy regimen checks by pharmacists in general hospitals by focusing on 19 recommended confirmation items designed to enhance chemotherapy safety. This study involved 14 hospitals within the National Hospital Organization in different regions of Japan. The top five cancers in Japan (gastric, colorectal, lung, breast, and gynecological) were targeted and specific chemotherapy regimens were analyzed. This study assessed the amount of time required for regimen checks, the number of confirmation items completed, the number and the content of inquiries raised regarding prescriptions, and the pharmacists' opinions using a questionnaire that had a maximum score of 10 points. Pharmacists checked 345 and 375 chemotherapies of patients in the control group (CG) and recommended items group (RIG), respectively. The mean time periods required for completing a chemotherapy regimen check were 4 min and 14 s (SD ±1 min and 50 s) and 6 min and 18 s (SD, ±1 min and 7 s) in the CG and RIG, respectively. The mean of the recommended items for the CG = 12.4 and for the RIG = 18.6. The items that the pharmacists did not confirm included urine protein (sixty-nine cases, 18.4%), allergy history (four cases, 1%), previous history (two cases, 0.5%), and a previous history of hepatitis B virus (sixty-nine cases, 18.4%). The number of inquiries for a doctor's prescription order was higher in the RIG than in the CG (41 vs. 27 cases). This multicenter survey demonstrated the potential effectiveness of implementing 19 recommended confirmation items in the regimen checks by pharmacists in general hospitals other than cancer treatment collaborative base hospitals. [ABSTRACT FROM AUTHOR]

Hypersensitivity reactions induced by nonionic iodine contrast media sometimes occur and can be life threatening. However, independent factors affecting their occurrence remain to be fully established. Therefore, the purpose of this study was to clarify independent factors affecting the occurrence of hypersensitivity reactions induced by nonionic iodine contrast media. Patients who received nonionic iodine contrast media at Keiyu Hospital from April 2014 to December 2019 were included. The adjusted odds ratio (OR) and 95% confidence interval (CI) for factors affecting hypersensitivity reactions induced by contrast media were calculated by logistic regression analysis. The multiple imputation method was used to impute missing data. Hypersensitivity reactions occurred in 0.72% (163 cases) of 22,695 cases enrolled in this study. In univariate analysis, 10 variables met the criteria of P <.05 and proportion of missing data <50%. In multivariate analysis, age (OR, 0.98; 95% CI, 0.97–0.99), outpatient status (OR, 2.08; 95% CI, 1.20–3.60), contrast medium iodine content (OR, 1.02; 95% CI, 1.01–1.04), history of drug allergy (OR, 2.41; 95% CI, 1.50–3.88), and asthma (OR, 17.4; 95% CI, 7.53–40.1) were identified as independent factors affecting contrast media–induced hypersensitivity reactions. Among these factors, history of drug allergy and asthma appear to be clinically relevant and reliable due to their high OR and plausible biological mechanisms, but the other three factors require further validation. [ABSTRACT FROM AUTHOR]

Glasgow prognostic score (GPS) has been used to evaluate inflammatory response and nutritional status. This study aimed to investigate the impact of nutritional status on cardiac prognosis by using GPS in patients after undergoing percutaneous coronary intervention (PCI). We included 862 patients who underwent PCI for stable angina pectoris between 2015 and 2018. We used the original cutoff values, which were an albumin (Alb) level of 3.5 g/dl and a C-reactive protein (CRP) level of 0.3 mg/dl. We categorized them into the three groups: originally defined GPS (od-GPS) 0 (high Alb and low CRP), 1 (low Alb or high CRP), and 2 (low Alb and high CRP). Major adverse clinical events (MACEs) included all-cause death, nonfatal myocardial infarction, revascularization, and hospitalization for heart failure. The median follow-up period was 398.5 days. During the follow-up, MACEs occurred in 136 patients. Od-GPS 2 had higher prevalence rates in terms of chronic kidney disease (CKD; 31.7% [229/722] vs. 44.9% [53/118] vs. 63.6% [14/22], p < 0.001), hemodialysis (6.4% [46/722] vs. 14.4% [17/118] vs. 31.8% [7/22], p < 0.001), and heart failure cases (HF; 9.1% [66/722] vs. 14.4% [17/118] vs. 27.3% [6/22], p = 0.007), with higher creatinine (1.17 ± 1.37 mg/dl vs. 1.89 ± 2.60 mg/dl vs. 3.49 ± 4.01 mg/dl, p < 0.001) and brain natriuretic peptide levels (104.1 ± 304.6 pg/ml vs. 242.4 ± 565.9 pg/ml vs. 668.1 ± 872.2 pg/ml, p < 0.001) and lower low-density lipoprotein cholesterol (101.5 ± 32.9 mg/dl vs. 98.2 ± 28.8 mg/dl vs. 77.1 ± 24.3 mg/dl, p = 0.002) than od-GPS 0 and 1.Od-GPS 2 (HR 2.42; 95% CI 1.16–5.02; p = 0.018), od-GPS 1 (HR 2.09; 95% CI 1.40–3.13; p < 0.001), diabetes (HR 1.41; 95% CI 1.00–1.99; p = 0.048), CKD (HR 2.10; 95% CI 1.49–2.96; p < 0.001), and HF (HR 1.64; 95% CI 1.05–2.56; p = 0.029) were independent predictors of MACEs. A scoring system using CRP and Alb levels with a milder definition than GPS suitably predicted the risk of MACEs in the patients who underwent PCI. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to clarify the practical clinical treatment for acute carbon monoxide (CO) poisoning in Japan and to investigate the efficacy of hyperbaric oxygen (HBO2) therapy in preventing delayed neurological sequelae (DNS) in the acute phase of CO poisoning. Methods: We conducted a multicenter, prospective, observational study of acute CO poisoning in Japan. Patients with acute CO poisoning were enrolled and their treatment details were recorded. The primary endpoint was the onset of DNS within 2 months of CO exposure. Factors associated with DNS were assessed with logistic regression analysis. Results: A total of 311 patients from 57 institutions were registered and 255 were analyzed: 171 received HBO2 therapy (HBO2 group) and 84 did not (normobaric oxygen [NBO2] group). HBO2 therapy was performed zero, once, twice, or three times within the first 24 h in 1.8%, 55.9%, 30.9%, and 11.3% of the HBO2 group, respectively. The treatment pressure in the first HBO2 session was 2.8 ATA (47.9% of the HBO2 group), 2.0 ATA (41.8%), 2.5 ATA (7.9%), or another pressure (2.4%). The incidence of DNS was 13/171 (7.6%) in the HBO2 group and 3/84 (3.6%) in the NBO2 group (P = 0.212). The number of HBO2 sessions in the first 24 h was one of the factors associated with the incidence of DNS (odds ratio, 2.082; 95% confidence interval, 1.101–3.937; P = 0.024). Conclusions: The practical clinical treatment for acute CO poisoning, including HBO2 therapy, varied among the institutions participating in Japan. HBO2 therapy with inconsistent protocols showed no advantage over NBO2 therapy in preventing DNS. Multiple HBO2 sessions was associated with the incidence of DNS. [ABSTRACT FROM AUTHOR]

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC–MS/MS was 194.3 (49.4–345.3) and 17.0 (4.8–40.7) ng/mL at peak (2–4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT–N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492). [ABSTRACT FROM AUTHOR]

Background: Development of acute kidney injury (AKI) depends on the severity of renal dysfunction, clinical setting, comorbid factors, and geographical location. Gastric cancer is one of the deadliest malignancies worldwide, and its incidence is significantly high in Japan. Objective: We analyzed the rank-order of the association of anticancer agents for gastric cancer with AKI using a spontaneous reporting system database, the Japanese Adverse Drug Event Report database. Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and March 2017. Results: Anticancer drug-related AKI was common in patients in their 60s and 70s (39.2% and 43.2%, respectively). AKI occurred most frequently within 1 month after anticancer drug administration. The signals of AKI were reported after treatment with S-1 (tegafur/gimeracil/oteracil), cisplatin (CDDP), and capecitabine, with significant adjusted reporting odds ratios (95% CI) of 1.50 (1.09-2.07), 3.43 (2.48-4.74), and 1.82 (1.15-2.90), respectively. CDDP-induced AKI was more likely to occur in patients who were male, hypertension, or diabetes mellitus. Conclusion and Relevance: This study showed that most AKI cases were related to S-1 and/or CDDP adjuvant chemotherapy for gastric cancer treatment. The data also clarified that AKIs occurred within 1 month and that their clinical outcomes were more severe than previous reports of drug-induced AKI in general medicine. Our study provides useful information to minimize the risks of administration to patients at high risk for S-1 and/or CDDP containing chemotherapy-induced AKI. [ABSTRACT FROM AUTHOR]

Background: Collaboration between pharmacists, doctors, and nurses in outpatient treatment is beneficial; however, such services are limited in Japan due to the lack of a healthcare reimbursement fee for outpatient pharmacy services at outpatient clinic. Objective: We evaluated the impact of a service in which clinical pharmacists collaborated with an oncologist at an outpatient clinic in the treatment of adverse drug reactions in outpatient cancer chemotherapy. Methods: We performed a retrospective cohort study using patients' medical records and treatment diaries. Subjects were patients who received outpatient chemotherapy via a clinical pharmacist collaboration service provided by six outpatient pharmacists and an oncologist at an outpatient clinic between June and August 2016. Results: During the study period, the total number of outpatient services was 2508, with 2055 (81%) related to chemotherapy. The six outpatient pharmacists provided interventions to 498 of the 2055 cases (24%). Of the 498 interventions, 103 (20%), in addition to oncologist's prescription, were suggested treatments for adverse drug reactions due to cancer chemotherapy. Oncologists approved a total of 82 prescription suggestions from pharmacists (79%) to 63 patients. Fifty-seven percent (n = 47) of the adverse drug reactions were improved following the pharmacists' suggested prescriptions. Conclusions: This is the first study to clarify the benefits of outpatient pharmacy services in which pharmacists collaborate with oncologists at an outpatient clinic for the management of adverse drug reactions in cancer patients in Japan. [ABSTRACT FROM AUTHOR]

Despite the increasing incidence of acute coronary syndrome (ACS) in Japan, its prognosis has improved. However, there is a paucity of longitudinal registry data providing trends of in-hospital care and prognosis of ACS in Japan. ACS patients undergoing percutaneous coronary intervention (PCI) included in the Shinken Database 2004-2014 were divided into two groups according to admission year (2004-2009, n = 390; 2010-2014, n = 328). Patient characteristics, lesion/procedure characteristics, medications at discharge, all-cause mortality, cardiovascular death, acute myocardial infarction (AMI), target lesion revascularization (TLR), re-PCI to new lesion, and coronary artery bypass graft (CABG) within 2 years after discharge were compared between the groups. Prevalence of hypertension, dyslipidemia, and dual antiplatelet/statin prescription increased significantly between periods. Usage of second-generation drug-eluting stents (DES) increased markedly between the two periods (2.6, 66.8%), while those of bare metal stents (64.4, 26.5%) and first-generation DES (25.6, 1.5%) decreased (all, p < 0.01). Two-year event-free survival rate increased for all-cause mortality (94.6-98.3%, p = 0.01), TLR (79.4-96.1%, p < 0.01), and re-PCI to new lesion (87.3-95.1%, p < 0.01). There were no significant differences in cardiovascular death, AMI, or CABG between the two periods. The event-free rates for TLR and re-PCI to new lesion in ACS patients have increased over the last decade in Japan. These observations should be confirmed in larger, longitudinal, multicenter registries. [ABSTRACT FROM AUTHOR]

The article focuses on decline of estimated glomerular filtration rate has triphasic changes according to age. Topics include estimating glomerular filtration rate (eGFR) has primarily developed as a simple method for estimating renal function, the number of reports suggested that eGFR has associated with cardiovascular morbidities and mortality, and promoting it as one of the useful biomarkers representing the systemic cardiovascular status.

To date construction materials that contain engineered nanomaterials (ENMs) are available at the markets, but at the same time very little is known about their environmental fate. Therefore, this study aimed at modeling the potential fate of ENMs by using the example of the Japanese construction sector and by conducting a dynamic material flow analysis. Expert interviews and national reports revealed that about 3920–4660 tons of ENMs are annually used for construction materials in Japan. Nanoscale TiO 2 , SiO 2 , Al 2 O 3 and carbon black have already been applied for decades to wall paints, road markings or concrete. The dynamic material flow model indicates that in 2016 about 95% of ENMs, which have been used since their year of market penetration, remained in buildings, whereas only 5% ended up in the Japanese waste management system or were diffusely released into the environment. Considering the current Japanese waste management system, ENMs were predicted to end up in recycled materials (40–47%) or in landfills (36–41%). It was estimated that only a small proportion was used in agriculture (5–7%, as ENM-containing sewage sludges) or was diffusely released into soils, surface waters or the atmosphere (5–19%). The results indicate that ENM release predominantly depend on their specific applications and characteristics. The model also highlights the importance of adequate collection and treatment of ENM-containing wastes. In future, similar dynamic flow models for other countries should consider, inasmuch as available, historical data on ENM production (e.g. like declaration reports that are annually published by relevant public authorities or associations), as such input data is very important regarding data reliability in order to decrease uncertainties and to continuously improve model accuracy. In addition, more environmental monitoring studies that aim at the quantification of ENM release and inadvertent transfer, particularly triggered by waste treatment processes, would be needed in order to validate such models. [ABSTRACT FROM AUTHOR]

Background Computerized provider order entry (CPOE) has been developed and implemented within cancer center hospitals nationwide in Japan. To ensure that high-quality services are routinely provided by oncology pharmacists, this study was designed to evaluate the interventions through reviewing the orders that are generated by CPOE. Methods The objective of this retrospective chart review was to evaluate how pharmacists contributed to safe cancer treatment using paper-based pharmacy records. Data were collected from a total of 35,062 chemotherapy regimens for 18,515 outpatients between January and December 2013. Results Of these 35,062 chemotherapy regimens, the rate of pharmacists’ interventions was 1.1% (n = 408). Among them, 53.1% (217/408) of the chemotherapy prescriptions were modified due to pharmacist interventions. The reasons for interventions included “changes in the chemotherapy regimen were unclear” in 49.5%, “physicians’ prescription errors” (22.0%), “pharmacist suggestions to improve chemotherapy” (15.1%), and “finding differences between physicians’ chemotherapy records and their chemotherapy prescriptions” (13.2%). The top three reasons for the 217 prescription modifications due to pharmacist interventions were “finding prescription errors” (34.5%), “reasons for change in the chemotherapy regimen were unclear” (32.7%), and “finding differences between physicians’ chemotherapy records and their chemotherapy prescriptions” (28.5%). Conclusion The computer could not evaluate chemotherapy protocols or adjust doses of anticancer medicines according to patients’ conditions. Therefore, oncology pharmacists should continue to ensure safe and appropriate administration of cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Background In the Japanese healthcare system, board certification not only maintains the quality of daily practice but is also required for hospitals to receive healthcare reimbursement. To date, no data on the effects of the board certification system in Japanese hospitals have been reported. Objective We performed a survey to clarify the impact of pharmacist certification on the quality of chemotherapy. Setting A nationwide mailing survey was conducted in Japan. Method We surveyed oncology pharmacists from 388 cancer designated hospitals (DHs) and 984 randomly selected general hospitals (GHs). Main outcome measure Multivariate analysis of factors for compliance with standard cancer chemotherapy to clarify the impact of pharmacist certification on the quality of chemotherapy. Results The response rate was 70.6 % (274/388) at the DHs and 43.4 % (428/984) at the GHs. Of the 13 different regimens, 66.1 % (181/274) of DHs and 64.7 % (277/428) of GHs reported having experienced either improper doses or intervals of drug administration. The median number of improper regimens was 1 at both the DHs (range 0-15) and GHs (range 0-22). We identified two groups of hospitals, those with two or more improper regimens and those with one improper regimen or less. Univariate analysis showed significant differences in the number of DHs (p < 0.01), performance of more than 10 chemotherapies per day (p < 0.05), presence of more than 400 beds (p < 0.01) and the professional qualifications of oncology pharmacists or medical oncologists. From multivariate analysis, significant differences were observed in certifications from the Japanese Society of Pharmacy Healthcare and Sciences certified Senior Oncology Pharmacist (odds ratio 0.29, p < 0.01) and the Japanese Society of Medical Oncology certified oncologist (odds ratio 0.48, p < 0.01). Conclusion Board certification was more prevalent in the designated (cancer specialist) hospitals than general hospitals and adherence to appropriate therapy was better when the DH was involved. Board certification was shown to be beneficial in terms of adherence to adequate chemotherapy. [ABSTRACT FROM AUTHOR]

The article focuses on the predictors for a high trough apixaban level in older patients with atrial fibrillation prescribed with reduced dose of the drug based on an analysis of a registry of patients in Japan. The analysis discovered the relation between reduced dose and bleeding that required hospitalization. Among the independent predictors are female gender, creatinine clearance and heart failure. Also noted is the anti-Xa assay needs of patients with three or more risk factors.

• Frailty was assessed in patients with non-valvular atrial fibrillation in ANAFIE. • Patients were classified as robust, pre-frail or frail based on the kihon checklist. • Warfarin was more commonly used in frail patients than direct oral anticoagulants. • Frail patients (36.2%) had the highest incidence rates of most clinical outcomes. • Frailty was significantly associated with cardiovascular and all-cause death. We aimed to determine the proportion of frail patients among older adults with non-valvular atrial fibrillation (NVAF), characterize them and their use of anticoagulant therapy, and examine the association between frailty and clinical outcomes in a real-world setting using the ANAFIE Registry dataset. The target population consisted of more than 30,000 adults aged ≥75 years definitively diagnosed with NVAF by electrocardiogram. For this sub-cohort study, patients who answered the Kihon Checklist were registered prospectively. Patients were classified into robust, pre-frail, and frail groups based on the Kihon Checklist score. Of the 32,275 patients in the ANAFIE Registry, 2951 were enrolled in this subanalysis and responded to the Kihon Checklist: 959 (32.5%) patients were robust; 924 (31.3%), pre-frail; and 1068 (36.2%), frail. In the robust, pre-frail, and frail groups, respectively, the 2-year cumulative incidence rates of stroke/systemic embolic events were 2.4%, 3.3%, and 4.5%, (P =.025); all-cause death, 2.9%, 5.1%, and 13.7%, (P <.001); major bleeding, 1.5%, 1.2%, and 2.9%, (P =.029); and net clinical outcomes, 5.5%, 8.2%, and 17.1% (P <.001). Results were similar when comparing the robust+pre-frail vs frail groups. In multivariate analyses, cardiovascular death, all-cause death, and net clinical outcomes were significantly associated with frailty. In the robust+pre-frail vs frail groups, major bleeding was also associated with frailty. Frailty was associated with cardiovascular and all-cause death, net clinical outcomes, and major bleeding but not stroke or intracranial hemorrhage in older Japanese adults with NVAF. [ABSTRACT FROM AUTHOR]

Between September 2009 and January 2010, 6 members of the Japanese Eastern Army, who had completed the same training program, were diagnosed with active tuberculosis (TB) on different occasions. The Ministry of Defense conducted a contact investigation of all members who had come into contact with the infected members. The purpose of this study was to verify the efficacy of the TB screening protocol used in this investigation. A total of 884 subjects underwent interferon-gamma release assay (IGRA) and chest X-ray. The 132 subjects who were IGRA positive or with X-ray findings suggestive of TB subsequently underwent chest computer tomography (CT). Chest CT was performed for 132 subjects. Based on CT findings, 24 (2.7%) subjects were classified into the active TB group, 107 (12.1%) into the latent tuberculosis infection (LTBI) group, and 753 (85.2%) into the non-TB group. The first 2 groups underwent anti-TB therapy, and all 3 groups were followed for 2 years after treatment. Although one subject in the active TB group experienced relapse during the follow-up period, no patient in the LTBI or non-TB groups developed TB. IGRA and chest X-ray, followed by chest CT for those IGRA positive or with suspicious X-ray findings, appears to be an effective means of TB contact screening and infection prevention. [ABSTRACT FROM AUTHOR]

• The effect of recycling bin designs on PET bottle collection performance was studied. • Round insert slot is an effective design to reduce recycling contamination. • Signage and all-in-one design promoted cap removal when set with other bins. • Signage is effective on waste separation at single setting of the bin. • Design effect on waste separation depends on setting condition. Many municipalities in Japan have collected PET bottles as recyclable waste since 1980s. When caps are removed from bottles, it reduces collection and transportation costs because bottles can be easily compressed by collection trucks. However, PET bottles collected from recycling bins are usually capped and include other materials. This study designed 10 recycling bins for PET bottle to investigate the effect of design on cap removal efficiency and recycling contamination (foreign waste mixture). Recycling bins for PET bottle were designed focusing on four design items. They are (1) individual recycling bins specifically for bottles and caps or all-in-one recycling bin for both bottle and cap collections, (2) inside-visibility (see-through), (3) signage (wording like "Bottle" and "Cap") near insert slot and (4) insert slot shape. PET bottle collection performance of designed recycling bins was monitored in Suzukakedai campus of Tokyo Tech. Perceptive preferences of recycling bin designs and insert slot shapes were measured by online surveys. Experimental results indicate that insert slot with round shape contributed to significantly lower recycling contamination than bottle-like shape although perceptive preference of insert slots with bottle-like shape was higher than that of the round shape. Signage and all-in-one design is significantly effective to promote cap removal only when it was set with other recycling bins. On the other hand, signage is effective to decrease recycling contamination in a single setting. This study found that design effect depended on the setting condition of recycling bins in terms of cap removal and foreign waste disposal. [ABSTRACT FROM AUTHOR]

Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF., Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA 2 DS 2 -VASc score, 3)., Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA] 2 -B 3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores., Conclusion: Our novel risk stratification system, the HED-[EPA] 2 -B 3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

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/m 2 , 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/m 2 (n=656) vs. ≤48.0 mL/m 2 (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/m 2 were at higher risk of all-cause death.

Pericardial effusion (PE) presentation varies from an incidental finding to a life-threatening situation; thus, its etiology and clinical course remain unknown. The aim of the present study was to retrospectively investigate these factors.We analyzed 171 patients (0.4%) who presented with PE among 34,873 patients who underwent echocardiography between 2011 and 2021 at our hospital. Clinical and prognostic information was retrieved from electronic medical records. The primary endpoints were all-cause death, hospitalization due to heart failure (HF), and other cardiovascular events such as cardiovascular death, acute coronary syndrome, elective percutaneous coronary intervention, and stroke.The etiologies of PE were as follows: idiopathic (32%), HF-related (18%), iatrogenic (11%), cardiac surgery-related (10%), radiation therapy-related (9%), malignancy (8%), pericarditis/myocarditis (8%), myocardial infarction-related (2%), and acute aortic dissection (2%). Patients with idiopathic/HF etiology were more likely to be older than the others.During a mean follow-up period of 2.5 years, all-cause death occurred in 21 patients (12.3%), cardiovascular events in 10 patients (5.8%), and hospitalization for HF in 24 patients (14.0%). All-cause death was frequently observed in patients with malignancy (44% per person-year). Cardiovascular events were mostly observed in patients with radiation therapy-related and malignancy (8.6% and 7.3% per person-year, respectively).The annual incidence of hospitalization for HF was the highest in patients with HF-related (25.1% per person-year), followed by radiation therapy-related (10.4% per person-year).This retrospective study is the first, to the best of our knowledge, to reveal the contemporary prevalence of PE, its cause, and outcome in patients who visited a cardiovascular hospital in an urban area of Japan.

Dispensing errors pose a significant health risk, with drug name similarity being a potential contributory factor. To determine the impact of drug name similarity on dispensing errors within clinical settings, we analyzed 563 dispensing errors at an acute hospital in Japan from April 2015 to June 2018. Drug name similarity between two drugs was classified into Name-Similar and Name-Dissimilar groups using the m2-vwhtfrag index, the value of the drug name similarity. Drug efficacy similarity was categorized into Efficacy-Same, Efficacy-Close, and Efficacy-Far. The drug name similarity and drug efficacy similarity of all possible pair combinations were obtained and similarly classified. The proportion of the number of pairs with dispensing errors per the total number of drug pairs in the hospital's drug formulary in each category was calculated. The highest proportion of the number of pairs with dispensing errors was 36% for the Efficacy-Same and Name-Similar group, and the lowest proportion was 0.022% for the Efficacy-Far and Name-Dissimilar group. The proportion of the number of pairs with dispensing errors was significantly higher in the Name-Similar category than in the Name-Dissimilar category for all drug efficacy categories. Our results indicate that drug name similarity increases the risk of dispensing errors, and that m2-vwhtfrag is a useful indicator to assess dispensing errors in clinical practice. Such drug name and efficacy similarity evaluations can help identify factors causing dispensing errors, and predict the risk of dispensing errors for newly adopted drugs, considering the relationship with the whole drug formulary in the hospital dispensary.

Background: Opioid-induced respiratory depression (RD) is a potentially life-threatening adverse drug event. This study used the Japanese Adverse Drug Event Report (JADER) database to investigate the profile of opioid-related RD in non-cancer patients., Methods: We analyzed data recorded in the JADER database between April 2004 and February 2020, which were downloaded from the Pharmaceutical and Medical Devices Agency website. Reporting odds ratios for RD were calculated for the 20 opioids approved in Japan, and daily dose and onset time were further analyzed for opioids used in chronic non-cancer pain (CNCP)., Results: Among the opioids, RD adverse event signals were detected for 22 combinations of opioids and administration routes in non-cancer patients. Of these combinations, transdermal buprenorphine and oral tramadol/acetaminophen were approved for CNCP and tended to be reported more frequently in elderly patients. The median daily doses of transdermal buprenorphine and oral tramadol/acetaminophen were 10.0 and 22.5 mg of daily oral morphine equivalent doses, respectively, which are within the standard range for starting dosage. The median time-to-onset of transdermal buprenorphine and oral tramadol/acetaminophen was 6.5 and 4.0 days, respectively, and 75% of cases were reported within 20 to 40 days after the start of treatment. The hazard type for both opioids was classified as early failure., Conclusions: Our findings suggest that elderly CNCP patients should be closely monitored after the start of opioid treatment, especially during the first week and, if possible, for 1 month, even if starting doses are within ranges recommended by the manufacturer and guidelines.

Catheter ablation for atrial fibrillation (AF) has been an established and frequently utilized approach in a variety of clinical settings. Nevertheless, real-world data about the clinical course of AF patients after initial catheter ablation remain limited, and these are mainly derived from particular registries or selected high-volume centers.In this study, we used health check-ups and insurance claims database from a Japanese insurance organization. The study population was comprised of 1777 patients who underwent catheter ablation for AF before June 2016. During the 3-year follow-up period, 396 (22.3%) patients underwent at least one repeated AF ablation, while 74 (4.2%) underwent two or more repeated ablations. In multivariate Cox regression analysis, longer time after AF diagnosis (7-11 months and ≥12 months versus 1-6 months) (HR, 1.05; 95% CI, 1.01-1.08 and HR, 1.04; 95% CI 1.02-1.07) was independently associated with repeated ablation. The discontinuation rates of OACs and AADs after the first ablation were 26.7% and 63.0% at 3 months and 75.2% and 89.1% at 1 year after the initial ablation, respectively. The former was independently associated with shorter time after AF diagnosis and lower diastolic blood pressure, whereas the latter was independently associated with older age, smaller CHADS 2 score, and shorter time after AF diagnosis.We presented real-world data regarding the clinical course of young Japanese AF patients after initial catheter ablation based on a claims database in Japan.

Background Increasing age predisposes patients with atrial fibrillation to both thromboembolic and bleeding events; however, data on outcomes of very elderly patients (aged ≥85 years) receiving appropriate antithrombotic therapy are still limited. Methods and Results The J-ELD AF (Multicenter Prospective Cohort Study to Investigate the Effectiveness and Safety of Apixaban in Japanese Elderly Atrial Fibrillation Patients) Registry is a multicenter prospective observational study of Japanese patients with nonvalvular atrial fibrillation aged ≥75 years taking on-label doses (standard dose of 5 mg BID or reduced dose of 2.5 mg BID) of apixaban. The entire cohort (3031 patients from 110 institutions) was divided into 3 age groups: 75 to 79 years (n=1068, 35.2%), 80 to 84 years (n=1120, 37.0%), and ≥85 years (n=843, 27.8%). The event incidence rates (/100 person-years) were 1.40, 1.55, and 1.95 for stroke or systemic embolism (log-rank P =0.65); 1.70, 1.55, and 2.61 for bleeding requiring hospitalization (log-rank P =0.33); 2.09, 2.60, and 5.29 for total deaths (log-rank P <0.001); and 0.40, 1.06, and 1.55 for cardiovascular deaths (log-rank P =0.045), respectively. After adjusting for confounders using a Cox regression analysis, age ≥85 years was identified as an independent risk of total death (hazard ratio, 1.89; 95% CI, 1.10-3.26 [ P =0.022]), but not of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death. Conclusions Although mortality increased with age, age ≥85 years was not a significant risk of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death in Japanese patients with nonvalvular atrial fibrillation taking on-label doses of apixaban. Registration URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000017895.

Background: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). We investigated the adherence of DOACs for years known to be associated with the effectiveness in Japanese NVAF patients, using a claim database., Method: We performed a retrospective evaluation of NVAF patients in a claims database in Japan, who initiated dabigatran, rivaroxaban, and apixaban between April 2011 and June 2016. Drug persistence was assessed by Kaplan-Meier method for the initially-prescribed DOAC and all DOACs including switched ones. Proportion of days covered (PDC) was also evaluated in patients with persistent prescription and compared among DOACs., Results: In the total of 671 patients, rivaroxaban (47%) was more prescribed than dabigatran (28%) and apixaban (25%). Drug persistence at 3 years was higher in rivaroxaban (69%) than dabigatran (57%) and apixaban (67%). Including switching to other DOACs, persistence of DOACs was 72% at 3 years without significant differences between index-DOACs. In multivariate Cox regression analysis, absence of hypertension, and prior history of cancer were significantly associated with the drug discontinuation of all DOACs. The mean PDC was ~ 95% and the frequency of high-adherent patients (PDC ≥0.80) was more than 90%, which similarly persisted at 3 years and showed no significant differences between index DOACs., Conclusion: In a real-world Japanese claim data analysis, about 70% of patients under DOAC showed persistence with anticoagulation therapy at 3 years. High adherence to DOACs assessed by PDC (over 90%) persisted to 3 years regardless of the types of DOACs., Competing Interests: Declaration of Competing Interest Dr Suzuki received research fund from Daiichi Sankyo and Mitsubishi Tanabe Pharm and lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. Dr Yamashita has received research funds and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Ono Pharmaceutical, and Toa Eiyo., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry., Methods and results: The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m 2 (L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E 2 S 2 score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS 2 (0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA 2 DS 2 -VASc scores (0.641; 95% CI=0.608-0.673, P=0.008)., Conclusions: The HELT-E 2 S 2 score may be useful for identifying Japanese NVAF patients at risk of ischemic stroke.

Dose reduction of apixaban is applied in atrial fibrillation (AF) patients fulfilling ≥ 2 of the following criteria: (1) age ≥ 80 years, (2) body weight ≤ 60 kg and (3) serum creatinine ≥ 1.5 mg/dL. However, the clinical significance of each criterion remains unclear. The J-ELD AF Registry is a prospective observational study of elderly (≥ 75 years) Japanese AF patients receiving on-label dose of apixaban. In patients receiving the standard dose (5 mg bid, n = 1243), the incidence rates (% per patient-year) of stroke or systemic embolism in those fulfilling none [n = 516] or one of the above criteria (1) [n = 328], (2) [n = 378] and (3) [n = 21] were 1.24, 2.32, 1.41 and 4.93 (log-rank P = 0.422), respectively, and those of bleeding requiring hospitalization were 1.03, 0.99, 1.98 and 4.93 (P = 0.318), respectively. In patients receiving a reduced dose (2.5 mg bid, n = 1,515), the incidences of stroke or systemic embolism in those fulfilling (1)/(2) [n = 1,331], (1)/(3) [n = 65], (2)/(3) [n = 23] and all three criteria [n = 96] were 1.38, 1.64, 4.67 and 3.51 (P = 0.295), respectively, and those of bleeding requiring hospitalization were 2.04, 1.64, 0.00 and 4.71 (P = 0.318), respectively. Univariate analysis demonstrated that the types or combinations of each criterion was not significantly associated with the incidence of thromboembolic or bleeding events. The types or combinations of the three apixaban dose reduction criteria did not have significant impact on effectiveness and safety in Japanese elderly AF patients receiving on-label dose of apixaban, although the impact of the creatinine criterion remains uncertain due to the few number of the patients.

Background: Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice., Research Design and Methods: The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time., Results: Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype., Conclusions: Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice., Clinical Trial Registration: NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta).

Whether ablation for atrial fibrillation (AF) is, in terms of clinical outcomes, beneficial for Japanese patients has not been clarified. Drawing data from 2 Japanese AF registries (AF Frontier Ablation Registry and SAKURA AF Registry), we compared the incidence of clinically relevant events (CREs), including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular events, and death, between patients who underwent ablation (n = 3451) and those who did not (n = 2930). We also compared propensity-score matched patients (n = 1414 in each group). In propensity-scored patients who underwent ablation and those who did not, mean follow-up times were 27.2 and 35.8 months, respectively. Annualized rates for stroke/TIA (1.04 vs. 1.06%), major bleeding (1.44 vs. 1.20%), cardiovascular events (2.15 vs. 2.49%) were similar (P = 0.96, 0.39, and 0.35, respectively), but annualized death rates were lower in the ablation group than in the non-ablation group (0.75 vs.1.28%, P = 0.028). After multivariate adjustment, the risk of CREs was statistically equivalent between the ablation and non-ablation groups (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.71-1.11), but it was significantly low among patients who underwent ablation for paroxysmal AF (HR 0.68 [vs. persistent AF], 95% CI 0.49-0.94) and had a CHA 2 DS 2 -VASc score  < 3 (HR 0.66 [vs. CHA 2 DS 2 -VASc score ≥ 3], 95% CI 0.43-0.98]). The 2-year risk reduction achieved by ablation may be small among Japanese patients, but AF ablation may benefit those with paroxysmal AF and a CHA 2 DS 2 -VASc score < 3.

Purpose: Incorporation of patient-generated health data (PGHD) into clinical research requires an investigation of the validity of outcomes and feasibility of implementation. This single-arm pilot trial investigated the feasibility of using a commercially available activity tracking wearable device in cancer patients to assess adherence to the device and real-time PGHD collection in a clinical research setting., Methods: From July to November 2017, enrolled adult patients were asked to wear a wristband-style device. Brief Fatigue Inventory (BFI) and MD Anderson Symptom Inventory (MDASI) were assessed at baseline and on day 29. Furthermore, 29-day Pittsburgh Sleep Quality Index, global impression of the devices, and NCI CTCAE v4 were evaluated., Results: Of 30 patients (mean age, 58.6 years; male, 21 [70%]), 15 (50%) and 11 (36.7%) had gastrointestinal and lung cancer, respectively, and 27 (90%, 95% CI: 0.74-0.98) were well adhered (> 70%) to the device for 28 days. The mean adherence was 84.9% (range: 41.7-95.2%). More frequent PGHD synchronization tended to show better device adherence, with moderate correlation (r = 0.62, 95% CI: 0.33-0.80, p < 000.1)., Conclusions: The feasibility of using a wearable activity tracker was confirmed in cancer patients receiving chemotherapy for a month. For future implementation in clinical trials, there is a need for further comprehensive assessment of the validity and reliability of wearable activity trackers., Trial Registration: This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN: UMIN000027575.

Direct oral anticoagulants (DOACs) are sometimes prescribed at off-label under-doses for patients who have undergone ablation for atrial fibrillation (AF). This practice may be an attempt to balance the risk of bleeding against that of stroke or AF recurrence.We examined outcomes of 1163 patients who continued use of a DOAC after ablation. The patients were enrolled in a large (3530 patients) multicenter registry in Japan. The study patients were classified as 749 (64.4%) appropriate standard-dose DOAC users, 216 (18.6%) off-label under-dose DOAC users, and 198 (17.0%) appropriate low-dose DOAC users.Age and CHA 2 DS 2 -VASc scores differed significantly between DOAC dosing regimens, with patients given an appropriate standard-dose being significantly younger (63.3 ± 9.4 versus 64.8 ± 9.5 versus 73.2 ± 6.8 years, P < 0.0001) and lower (2.1 ± 1.5 versus 2.4 ± 1.6 versus 3.4 ± 1.4, P < 0.0001) than those given an off-label under-dose or an appropriate low-dose. During the median 19.0-month follow-up period, the AF recurrence rate was similar between the appropriate standard-dose and off-label under-dose groups but relatively low in the appropriate low-dose group (42.5% versus 41.2% versus 35.4%, P = 0.08). Annualized rates of thromboembolic events, major bleeding, and death from any cause were 0.47%, 0.70%, and 0.23% in the off-label under-dose group, while those rates were 0.74%, 0.73%, and 0.65% in the appropriate standard-dose, and 1.58%, 2.12%, and 1.57% in the appropriate low-dose groups.In conclusion, the clinical adverse event rates for patients on an off-label under-dose DOAC regimen after ablation, predicated on careful patient evaluations, was not high as seen with that of patients on a standard DOAC dosing regimen.

Initial screening for proteinuria by urine dipstick test (UDT) may be useful for predicting clinical outcomes. The Shinken Database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. Patients for whom UDT was performed at their initial visit between 2004 and 2010 (n = 7131) were divided into three groups according to the test results: negative, trace, and positive (1+ to 4+) proteinuria. During the mean follow-up period of 3.4 years, 233 (3.1%) deaths, 255 (3.6%) heart failure (HF) events, and 106 (1.5%) ischemic stroke (IS) events occurred. Prevalence of atherothrombotic risks increased with an increase in the amounts of proteinuria. The incidence of all-cause death, HF and IS events increased significantly from negative to trace to positive proteinuria groups (log rank test, P for trend < 0.001). Multivariate analysis revealed independent association between proteinuria and all-cause death [hazard ratio (HR): 1.50, 95% confidence interval (CI) 1.07-2.10], HF (HR: 1.55, 95% CI 1.14-2.12), and IS (HR: 2.08, 95% CI 1.26-3.45). Even trace proteinuria was independently associated with HF (HR: 1.64, 95% CI 1.07-2.53) and IS (HR: 2.17, 95% CI 1.14-4.11) and with all-cause death (HR: 1.56, 95% CI 0.99-2.47). In conclusions, dipstick proteinuria was independently associated with cardiovascular events and death, suggesting that the UDT is a useful tool for evaluating patients' risk for such adverse events.

Treatment and prognosis of elderly patients with atrial fibrillation (AF) may differ by the experience of fall or bone fracture. However, their current status is still unclear. From our institute database between 2010 and 2015, 674 AF patients with age ≥ 70 years were selected and were divided into those who experienced fall or fracture during the observation period (F/F group; n = 49) and those who did not (non-F/F group; n = 625). We compared the treatment and prognosis between the 2 groups. Patients in the F/F group were older (79 vs 76 years, P < 0.001) and had more comorbidities compared with those in the non-F/F group. The prescription rate of oral anticoagulant was similar between the two groups (77.6% vs 68.2%, P = 0.201), where warfarin was predominant. The F/F group was not associated with higher incidence of ischemic stroke. The F/F group was associated with a higher incidence of heart failure events (adjusted odds ratio (OR) 3.88; 95% confidence intervals (Cl) 1.70-8.85; P = 0.001), and cardiovascular events (OR 3.43; 95% Cl 1.71-6.85; P < 0.001). In elderly AF patients in a cardiovascular hospital, the experience of fall or fracture did not affect the prescription of oral anticoagulants and the incidence of ischemic stroke, but it was significantly associated with increase of heart failure.

Purpose: To investigate the distribution of plasma apixaban levels and their relationships with clinical outcomes in elderly patients with atrial fibrillation (AF)., Method: The J-ELD AF Registry is a multicenter prospective observational study of Japanese non-valvular AF patients aged ≥75 years taking an on-label dose of apixaban (3015 patients from 110 institutions). Among them, plasma apixaban levels at trough were estimated by anti-Xa assay (Api-AXA) in 943 patients. Patients with standard (5 mg bid; n = 431) and reduced (2.5 mg bid; n = 512) dose were further divided into two groups with low and high Api-AXA levels (boundary: median value)., Results: The incidence rates (per 100 person-years) of events in the low- and high-Api-AXA groups were as follows: 1.48 and 1.99 (log-rank test, P = 0.695) for stroke or systemic embolism, 0.98 and 1.49 (P = 0.652) for bleeding requiring hospitalization, and 0.49 and 0.99 (P = 0.565) for total deaths in patients with standard dose, versus 0.84 and 1.68 (P = 0.414), 0.42 and 4.64 (P = 0.004), and 2.52 and 6.65 (P = 0.035) in patients with a reduced dose, respectively. In multivariate Cox regression analysis among patients with a reduced dose, a high Api-AXA level was independently associated with bleeding requiring hospitalization (HR 12.12, 95% CI: 1.56-94.22) and nonsignificantly with total deaths., Conclusions: A high trough apixaban level in patients indicated for standard dose was not associated with adverse events, while a high apixaban level in patients indicated for a reduced dose was associated with bleeding requiring hospitalization.

Importance: Despite the development of risk stratification schemes that have been widely used to determine the risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF), risk stratification schemes in Asian patients with NVAF remain undetermined., Objective: To determine risk factors for ischemic stroke in Japanese patients with NVAF., Design, Setting, and Participants: This cohort study analyzed individual patient data from 5 AF registries in Japan: J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) Registry, Fushimi AF Registry, Shinken Database, Keio Interhospital Cardiovascular Studies (Keio Study), and Hokuriku-Plus AF Registry. Patients with atrial fibrillation were registered from 158 institutions in the J-RHYTHM Registry, 80 in the Fushimi AF Registry, a single hospital in Shinken Database, 11 in the Keio Study, and 19 in the Hokuriku-Plus AF Registry. Patients with valvular AF or lacking data were excluded. Data were collected and integrated in March 2016, and those from the Keio Study were updated in April 2018. Data were analyzed from April 2018 to February 2020., Main Outcomes and Measures: Significant risk factors for ischemic stroke were determined by adjusted Cox proportional hazards analysis., Results: In total, 12 289 patients with NVAF (3758 [31%] female; mean [SD] age 70.2 [11] years) were analyzed with a mean (SD) follow-up period of 649 (181) days (1.8 [0.5] years). During 21 820 person-years of follow-up, 241 cases of ischemic stroke were reported. Risk factors associated with ischemic stroke after adjustment for oral anticoagulant use at enrollment were age (75-84 years: hazard ratio [HR], 1.74; 95% CI, 1.32-2.30; P < .001; and ≥85 years: HR, 2.41; 1.63-3.56; P < .001), hypertension (HR, 1.60; 95% CI, 1.15-2.23; P = .006), previous stroke (HR, 2.75; 95% CI, 2.09-3.62; P < .001), persistent or permanent AF (HR, 1.59; 95% CI, 1.21-2.10; P = .001), and body mass index less than 18.5 (HR, 1.55; 95% CI, 1.05-2.29; P = .03). Neither diabetes nor heart failure were identified as risk factors for ischemic stroke., Conclusions and Relevance: Previous stroke, advanced age, hypertension, persistent or permanent AF, and low body mass index were independent risk factors associated with ischemic stroke in Japanese patients with NVAF.

Direct oral anticoagulants, including edoxaban, primarily do not need routine monitoring of the anticoagulant effect. However, extremely high/low plasma concentrations of edoxaban (PC-Ed) should be properly evaluated, especially when patients under anticoagulation therapy are at an emergency state. For this purpose, PC-Ed determined by an anti-Xa assay (indirect PC-Ed) is more convenient and, therefore, more useful compared with PC-Ed determined by an LC-MS/MS (direct PC-Ed) in daily clinical practice. Consecutive 97 patients with non-valvular atrial fibrillation (NVAF) under edoxaban therapy were evaluated, in whom edoxaban 60/30 mg doses were prescribed for 48/49 patients, 71 (73.2%) were men, and the average age was 69 years. CHADS 2 score 0, 1, and ≥ 2 were 26.8%, 44.3%, and 28.9%, while CHA 2 DS 2 -VASc score 0, 1, and ≥ 2 were 14.4%, 16.5%, and 69.1%, respectively. Median values of direct and indirect PC-Ed by LC-MS/MS and anti-Xa assay were 187.1 and 176.1 ng/mL at peak (2-4 h post-dose) and 14.4 and 17.5 ng/mL at trough (pre-dose), respectively. The PC-Ed at peak and trough by two methods were significantly correlated, and the correlation coefficients were r = 0.973 and 0.963 (both, p < 0.0001), respectively. By a Bland-Altman plot, mean differences between the direct and indirect PC-Ed [lower to upper percent limit of agreement] were - 4.87 [- 46.71 to 36.98] and 4.66 [- 1.37 to 10.69] ng/mL at peak and trough, respectively. Moreover, mean % error for difference between the direct and indirect PC-Ed [lower to upper percent limit of agreement] was - 1.22 [- 20.59 to 18.14] and 31.75 [- 14.03 to 77.53] % at peak and trough, respectively, where the % error extremely increased around the lower limit of detection (LLOD) in the anti-Xa assay. Strong similarity was observed between the direct and indirect PC-Ed, especially at peak. The indirect PC-Ed was higher than the direct PC-Ed, especially around the LLOD, suggesting the need for caution when we use the anti-Xa assay for measurement of trough PC-Ed (UMIN 000032492).

Background: A global, randomized clinical trial indicated the efficacy and safety of apixaban in stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, data in the elderly NVAF patients ≥75 years, especially those on reduced dose, are limited., Hypothesis: To confirm the current dose reduction criteria of apixaban in elderly NVAF patients., Method: With a large-scale, multicenter prospective observational study, one-year outcomes after administration of on-label doses of apixaban were analyzed in Japanese NVAF patients aged ≥75 years. Endpoints were stroke or systemic embolism, bleeding requiring hospitalization, total death, and cardiovascular death., Results: A total of 3031 patients (average age, 81.7 years; female, 48.2%) taking standard (5 mg bid) or reduced dose (2.5 mg bid) of apixaban were enrolled from 110 facilities. Standard and reduced apixaban doses were administered in 1284 (42.4%) and 1747 (57.6%) patients, respectively. Event rates (/100 person-years) in standard and reduced dose groups were 1.67 and 1.56, respectively, for stroke or systemic embolism, 1.42 and 2.25 for bleeding requiring hospitalization, 1.41 and 4.46 for total death, and 0.41 and 1.36 for cardiovascular death. Reduced apixaban dose was not significantly associated with stroke or systemic embolism and bleeding requiring hospitalization, but was independently associated with total and cardiovascular death., Conclusions: Incidences of stroke or systemic embolism and bleeding requiring hospitalization were similar between standard and reduced apixaban doses in the elderly NVAF patients. The incidences of total and cardiovascular death were significantly higher in the reduced dose group due to the coexisting higher risks in this group., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

In Japanese surveillance in an early phase after the approval of rivaroxaban, inappropriate underdose was frequently utilized. The aim of this study was to describe the prevalence and predictors of the inappropriate usage of rivaroxaban in a single-center, cardiovascular-specialized hospital. Consecutive 661 non-valvular atrial fibrillation (NVAF) patients treated with rivaroxaban between 2012 and 2017 were recruited. After excluding 30 patients without assessment of creatinine clearance (CCr), the proportion and predictors of inappropriate underdose were analyzed. Additionally, patient outcomes, including thromboembolism (ischemic stroke or systemic embolism) and major bleeding, were determined. In patients with CCr ≥ 50 mL/min (n = 532) and < 50 mL/min (n = 98), inappropriate underdose and overdose were used in 123 (23%) and 8 (8%), respectively. The predictors of inappropriate underdose (in patients with CCr ≥ 50 mL/min) were CCr [50-63 mL/min (the lowest tertile) compared to ≥ 64 mL/min], age ( ≥ 75 years), female gender, prescription of antiplatelet, and coexistence of heart failure. Although PT under rivaroxaban was lower in patients with inappropriate underdose than in those with an appropriate dose, no significant increase in the incidence of thromboembolism or major bleeding was observed within the mean follow-up of 683 days. Inappropriate underdose of rivaroxaban was frequently observed for NVAF patents even in a cardiovascular hospital, particularly in patients with CCr adjacent to the dose reduction criteria. The responses of PT and the incidence of adverse outcomes under an inappropriate dose of rivaroxaban should be further investigated.

Background: The safety of discontinuing oral anticoagulant (OAC) after ablation for atrial fibrillation (AF) in Japanese patients has not been clarified., Methods and results: A study based on the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) was conducted. Data were collected from 3,451 consecutive patients (74.1% men; age, 63.3±10.3 years) who had undergone AF ablation at any of 24 cardiovascular centers in Japan between August 2011 and July 2017. During a 20.7-month follow-up period, OAC therapy was discontinued in 1,836 (53.2%) patients; 51 patients (1.5%) suffered a stroke/transient ischemic attack (TIA), 71 (2.1%) suffered major bleeding, and 36 (1.0%) died. Patients in whom OAC therapy was discontinued were significantly younger than those in whom OACs were continued, and their CHA 2 DS 2 -VASc scores were significantly lower. The incidences of stroke/TIA, major bleeding, and death were significantly lower among these patients. Upon multivariate adjustment, stroke events were independently associated with relatively high baseline CHA 2 DS 2 -VASc scores but not with OAC status., Conclusions: Although the incidences of stroke/TIA, major bleeding, and death were relatively low among patients for whom OAC therapy was discontinued, stroke/TIA occurrence was strongly associated with a high baseline stroke risk rather than with OAC status. Thus, discontinuation of OAC therapy requires careful consideration, especially in patients with a high baseline stroke risk.

No nationwide study on polypharmacy in palliative care among Japanese community pharmacies has yet been conducted. We conducted an online questionnaire survey for community pharmacist members of The Japanese Society for Pharmaceutical Palliative Care and Sciences regarding their contributions to cancer patients who regularly used six or more drugs, including opioids, in service during the two-month period from October to November 2017. Of 579 community pharmacists, 83 responded to the survey (14.3%). Among them, 47.0 and 27.7% of respondents replied that more than 40% of opioid-using and non-using cancer patients were prescribed six or more regular medications, respectively. The proportion of patients with polypharmacy was marginally higher among opioid-using than non-using patients. Additionally, 31.3 and 22.9% of respondents replied that a low or moderate rate of opioid-using and non-using patients with polypharmacy received inappropriate prescriptions, respectively, including "unnecessary medications," "adverse drug reactions" and "duplication of pharmacological effect." The proportion of patients who received inappropriate prescriptions was significantly higher among opioid-using than non-using patients. Furthermore, 37.3 and 19.3% of respondents replied that pharmacist's recommendations contributed to drug reduction in opioid-using and non-using patients with polypharmacy who received inappropriate prescriptions, respectively. The responders with higher confidence in palliative care showed more success rate for reducing inappropriate medications. Our findings suggest that opioid use can be associated with an increased risk of polypharmacy in cancer patients, and that recommendations by a population of community pharmacists can reduce inappropriate medications and improve adverse drug reactions in both opioid-using and non-using cancer patients with polypharmacy.

Objectives: Several studies have suggested a possible relationship between atrial fibrillation (AF) and falls. However, whether the relationship depends on AF types is unclear. We investigated the relationship between sustaining AF and falls., Design: Single hospital-based cohort study with a follow-up of falls within 3 years after baseline., Setting and Participants: A total of 14,056 patients from our cohort between February 2010 and March 2016., Measures: Incidence of falls within 3 years by baseline cardiac rhythm was measured, and we investigated the effects of AF types on incidence of falls., Results: The study population was divided into younger (<75 years old; n = 11,808) and older (≥75 years old; n = 2248) groups, and then divided into 3 groups according to the baseline cardiac rhythm: sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PeAF). There were more male patients in the PeAF group; these patients had more comorbidities both in the younger and older groups. The cumulative incidence rates of falls at 1 year in patients with SR, PAF, and PeAF were similar in the younger group (0.4%, 0.4%, and 0.6%, respectively; P = .496), whereas those were significantly different in the older group (2.3%, 2.7%, and 5.0%, respectively; P = .024). In multivariate analysis, both PAF [hazard ratio (HR) 1.179; 95% confidence interval (CI) 0.553-2.511, reference SR] and PeAF (HR 1.502; 95% CI 0.635-3.556) were not associated with falls in the younger group. In the older group, PeAF was independently associated with incidence of falls (HR 2.257; 95% CI 1.262-4.037), but PAF was not (HR 1.317; 95% CI 0.673-2.574)., Conclusions/implications: PeAF, not PAF, was associated independently with falls in older patients, suggesting the possible effect of irregular beats on physical frailty in the older population., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.

Opioid analgesics have greatly contributed to the advancement of pain management. However, although opioids have been appropriately used in Japan, they rarely induce serious adverse events, such as respiratory depression. The present study aimed to investigate the temporal changes in the occurrence of opioid-related adverse events and deaths between 2004 and 2017 in Japan using the Japanese Adverse Drug Event Report (JADER) database. We analyzed the following points using data extracted from JADER website: 1) temporal changes in the number and proportion of opioid-related adverse event reports; 2) temporal changes in the number of morphine-, oxycodone-, and fentanyl-related adverse event reports per annual consumption; and 3) cases in which the reported outcome following opioid-related adverse events was death. Our results showed no dramatic changes in the overall incidence of opioid-related adverse events, despite the temporal changes in the annual consumption and shared component of each opioid during the survey period. However, the number and rate of fentanyl-related adverse events and their outcome "death" increased since 2010, being the highest among all adverse event including those related to morphine and oxycodone. Outcome "death" by fentanyl-related adverse events was caused mainly due to respiratory depression. These findings suggest that, although opioid-related adverse events can be controlled through proper monitoring and management by medical personnel in Japan, extra caution should be continuously paid for the rare but serious fentanyl-induced adverse events.

Background: The predictive role of E/e' on ischemic stroke (IS) and atrial fibrillation (AF) in Japanese patients without AF are unclear., Methods and Results: Shinken database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. E/e' has been routinely measured since 2007. Patients without AF for whom E/e' was measured at the initial visit between 2007 and 2014 (n=11 477, mean age 57.2 years old, men 59.5%) were divided into E/e' tertiles (<8.04, 8.04-11.00, >11.00). During the mean follow-up period of 1.8 years, 58 IS and 140 new appearances of AF were observed. High E/e' tertile was associated with more prevalence of atherothrombotic risks. The cumulative incidence of IS events and new appearance of AF at 6 years in low, middle, and high E/e' tertiles were 0.5%, 1.4%, and 3.0%/year (log-rank test, p<0.001), and 2.5%, 2.9%, and 4.2%/year (log-rank test, p=0.007), respectively. In multivariate analysis, high E/e' tertile was independently associated with IS (HR, 2.857, 95%CI 1.257-6.495, p=0.012). Although high E/e' tertile was independently associated with new appearance of AF when adjusted for coexistence of atherothrombotic risk factors (HR, 1.694, 95%CI, 1.097-2.616, p=0.017), the association was attenuated after adjustment for left atrial dimension., Conclusions: E/e' was significantly associated with incidence of IS and new appearance of AF in non-AF patients., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn's method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510-6.292), older age (≥75 years old; OR 2.984, 95% CI 1.844-4.826) and severe renal dysfunction (eGFR <30 mL/min/1.73 m 2 ; OR 3.918, 95% CI 1.742-8.813) were identified as independent predictors of high INR variability on multivariate logistic regression analysis., Conclusions: The determinants of INR variability in AF patients under warfarin therapy could assist Japanese clinicians in identifying patients likely to show unstable warfarin control irrespective of the definition of the target INR range.

Background: We previously reported a cross-sectional analysis regarding the relationship between smoking and atrial fibrillation (AF) in a single hospital-based cohort with Japanese patients, but the effect of cessation of smoking and/or total tobacco consumption were unclear., Methods and Results: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. After excluding those previously diagnosed with AF (n=2296), 15,221 patients (men/women, n=9016/6205) were analyzed. During the follow-up period of 2.0±2.1 years (range 0.0-8.1), the incidence rates of new AF in smokers and non-smokers were 9.0 and 5.0 per 1000 patient-years, respectively. In adjusted models with Cox regression analysis, smokers were independently associated with new AF [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.09-2.00]. Also, current smokers (HR 1.81, 95% CI 1.17-2.79) and smokers with Brinkman index ≥800 (HR 1.69, 95% CI 1.05-2.70) were independently associated with new AF. However, in current smokers, the HRs were not different by Brinkman index (Brinkman index <800/≥800; HR 1.81/1.82, 95% CI 1.07-3.05/0.94-3.51, respectively)., Conclusions: Smoking was independently associated with the first-appearance of AF in patients in sinus rhythm, especially when the patients continued their smoking habit. However, in patients who continued smoking, difference by total tobacco consumption was not observed, suggesting the significance of cessation of smoking for preventing AF. Our data are limited because of a single hospital-based nature and a relatively short observation period., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Repeated hospitalization due to acute decompensated heart failure (HF) is a pandemic health problem in Japan. However, it is difficult to predict rehospitalization after discharge for acute decompensated HF. We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 282 patients discharged after their first acute HF admission were included in the analysis. The median follow-up period was 908 ± 865 days. Of these patients, rehospitalization due to worsening HF occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. Patients with rehospitalization were older than those without rehospitalization. Prevalence of diabetes mellitus (DM) was more common in patients with rehospitalization. Average heart rate (HR) tended to be higher in patients with rehospitalization. Loop diuretics were more commonly used at hospital discharge in patients with rehospitalization. Multivariate Cox regression analysis revealed that age ≥ 75 years, DM, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for rehospitalization. The number of these independent risk factors could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk patients. HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HR, and loop diuretics use at discharge were independently associated with HF rehospitalization. By simply counting these risk factors, we might be able to predict the risk of HF rehospitalization after discharge.

Background: The incidence rate of ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients without anticoagulation therapy remains unclear., Methods and Results: We performed a pooled analysis of 3,588 patients from the Shinken Database (n=1,099), J-RHYTHM Registry (n=1,002), and Fushimi AF Registry (n=1,487) to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Average patient age was 68.1 years. During the follow-up period (total, 5,188 person-years; average, 1.4 years), 69 patients suffered from ischemic stroke (13.3 per 1,000 person-years; 95% confidence intervals [CI]: 10.5-16.8). The incidence rates of ischemic stroke were 5.4, 9.3, and 24.7 per 1,000 person-years and 5.3, 5.5, and 18.4 per 1,000 person-years in patients with low (0), intermediate (1), and high (≥ 2) CHADS2 and CHA2DS2-VASc scores, respectively. History of ischemic stroke or transient ischemic attack (hazard ratio [HR], 3.25; 95% CI: 1.86-5.67), age ≥ 75 years (HR, 2.31; 95% CI: 1.18-4.52), and hypertension (HR, 1.69; 95% CI: 1.01-2.86) were independent risk factors for ischemic stroke., Conclusions: A low incidence rate of ischemic stroke was observed in Japanese NVAF patients except for those with CHADS2 score ≥ 2. In this pooled analysis, history of ischemic stroke or transient ischemic attack, advanced age, and hypertension were identified as independent risk factors for ischemic stroke.

Functional mitral regurgitation (MR) is frequently associated with left ventricular systolic dysfunction (LVSD). Ventricular volume overload that occurs in patients with MR may lead to a progression of myocardial dysfunction. However, the prevalence and clinical outcomes of functional MR in Japanese patients with LVSD remain unclear. The aim of the present study is to clarify the prevalence and prognosis of functional MR in Japanese LVSD patients in the contemporary era. We followed patients with LVSD (LV ejection fraction (LVEF) ⩽ 40%) who were listed within a single, hospital-based cohort in the Shinken Database from 2004 to 2011, which was composed of all new patients (n = 17,517) who visited the Cardiovascular Institute. A total of 506 patients were included: 86 FMR (moderate-to-severe functional MR) patients and 420 non-FMR (none or mild functional MR) patients. FMR patients were older, had lower rates of hypertension and ischemic heart disease but had higher rates of chronic kidney disease, dilated cardiomyopathy and New York Heart Association III/IV classification. FMR patients had higher brain natriuretic peptide levels and lower LVEF. The Kaplan-Meier curves revealed that the incidence of all-cause death, cardiovascular death and heart failure (HF) admission was significantly higher in FMR patients. The presence of FMR was independently associated with a significantly higher risk of composite end point, including all-cause death and/or HF admission (hazard ratio 1.551, 95% confidence interval 1.045-2.303, P = 0.029). FMR was common in Japanese patients with LVSD and was associated with adverse long-term outcomes. Future study is warranted to establish the optimal therapeutic strategy for FMR and LVSD.