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Purpose: This retrospective study aimed to analyze anti-seizure medication (ASM) prescription trends in Japan, particularly among older adults and women of childbearing age, to inform future treatment strategies and optimize ASM selection criteria., Methods: Data were extracted from the National Database Open Data Japan for fiscal years (FY) 2018-2021, covering prescriptions across sex and 5-year age groups. We conducted data imputation for prescriptions under 1,000 units to maintain anonymity, calculated the estimated number of patients using standard adult maintenance doses, and adjusted for pediatric dosing using Augsberger's formula., Results: Our analysis revealed a 7.6% increase in ASM usage, with a notable shift from older to newer ASMs, such as levetiracetam (LEV) and lamotrigine (LTG). LEV and LTG prescriptions increased by 26.7% and 15.0% from FY 2018 to FY 2021, respectively, whereas older ASMs such as phenytoin, declined. Sex-specific analysis showed a higher LTG prescription rate among women, especially in adolescent and young adult cohorts, where the female-to-male prescription ratio increased from 1.65 to 1.85. Valproate (VPA) and LEV accounted for 57.0% of ASM prescriptions in older adults. The number of inpatient LTG prescriptions was notably lower than that of outpatient LTG prescriptions across age groups. Pediatric use of generics was lower than that in other age groups., Conclusion: This study revealed that newer ASMs are being used increasingly, with a significant proportion of VPA continuously prescribed among women of childbearing age. In older adults, VPA and LEV accounted for more than half of the ASM prescriptions. These findings are crucial for developing future treatment strategies and improving the ASM selection criteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

While the coronavirus disease 2019 (COVID-19) pandemic has impacted medication adherence and consultation patterns, its effects on the medical practice and dispensary separation system of Japan remain unclear. Thus, the utilization of the medication record handbook (MRH) in both medical and dental areas remains uncertain. This study uses the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB); we analyzed the separation of medication prescription and dispensing in both medicine and dentistry, as well as estimated how much drug information is shared by utilizing a patient-carried MRH. The external prescription (EP) rate was used as the main indicator. We then analyzed the MRH utilization rate during outpatient medication guidance. During the pandemic, there was no distinctive change in the rate of EPs in both medicine and dentistry. Furthermore, an analysis between EPs, medical internal prescriptions (IPs), and dental IPs relative to the MRH utilization rate revealed significant correlations between EPs and medical IPs as well as medical and dental IPs. Conversely, no significant correlation was found between EPs and dental IPs. Therefore, our results suggest that active MRH implementation within healthcare facilities may lead to an increase in its utilization in dentistry., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ura et al.)

The case-crossover study design has been proposed as a suitable design for use when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the condition of "brief exposure" is rarely satisfied because medication use is often chronic or successive, which may result in bias due to within-subject exposure dependency. Here we describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios ranging up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by using the case-time-control study design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and we demonstrate how to detect and remove them., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8-95.4) in Brazil to 315.9 (95% CI 314.0-317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Press-through packaging (PTP) is the most common type of drug packaging in Japan, and a production procedure for PTP has been established at an acceptable cost. However, unknown problems and new needs with regard to safety among users of various age-groups still need to be examined. Considering accident reports involving children and older adults, the safety and quality of PTP and new forms of PTP, such as child-resistant and senior-friendly (CRSF) packaging, should be evaluated. We conducted an ergonomic study on children and older adults to compare types of commonly used PTP and new varieties of PTP. Opening tests were attempted by children and older adults using a common type of PTP (Type A) and child-resistant (CR) PTP (Types B1 and B2) made from soft aluminum foil. The same opening test was conducted on older patients with rheumatoid arthritis (RA). The results showed that CR PTP was difficult for children to open: only 1 out of 18 children could open Type B1. On the other hand, all eight of the older adults could open Type B1, and eight patients with RA could easily open Types B1 and B2. These findings suggest that the quality of CRSF PTP can be improved with the use of new materials.

Purpose: To compare the effectiveness and safety of reduced or standard daily doses of direct oral anticoagulants (DOACs) with warfarin in Japanese patients with nonvalvular atrial fibrillation (NVAF). We used post-hoc analyses to identify patient groups that could benefit from reduced-dose DOACs., Patients and Methods: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, we identified 944,776 patients with NVAF who had started an oral anticoagulant after at least one year of non-use between April 2011 and March 2016. We matched patients taking any, reduced, or standard doses of DOACs 1:1 with those taking warfarin. We measured treatment effectiveness based on admission due to stroke or systemic embolism (S/SE) and safety based on admission due to any bleeding (defined as major bleeding, MB). We compared both outcomes between DOACs and warfarin using the Cox proportional hazards model. We used post-hoc analysis to match patients receiving reduced-dose DOACs to those receiving standard-dose DOACs and compared treatment effectiveness and safety., Results: More than half of patients receiving DOACs used a reduced dose. The occurrences of S/SE and MB in patients receiving any, reduced, or standard doses of DOACs were equal to or lower than those receiving warfarin. In the post-hoc analysis, the risk of S/SE and MB was similar between reduced and standard doses of DOACs except for those with a history of cerebral infarction and CHA 2 DS 2 -VASc score ≥3, where the risk of S/SE was lower for reduced doses of any and individual DOACs., Conclusion: Findings from the current study are consistent with recent Asian and global studies but different from most studies conducted in North America and Europe, where patients receiving a reduced dose of DOACs had an increased risk of S/SE. Future studies should test the reproducibility of results from the current study., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Kubota and Ooba.)

Background: Blister packs with paperboard backing, which is useful for displaying instructions and information, are the most popular type of packaging for osteoporosis drugs in Japan. However, the main users of drugs are the aged, who often find blister packs difficult to open or drop their pills during opening. In this study, we compared different types of blister packs in terms of usability and handling., Methods: We conducted a subjective and objective study to compare commonly used blister packs with newly designed ones that have a jagged notch designed to hold a pill temporarily and a perforated line that enables the pack to be held easily in one hand. Regarding subjective data, packaging and sensory tests were performed. The participants in the sensory test were healthy older adults and patients with rheumatoid arthritis (RA). We also measured the pinch power of all participants., Results: A comparison of several items, including opening status, prevention of pill dropping, and understanding of the instructions, using a numerical rating scale revealed no significant differences between ordinary (type A) and newly designed (type B) packaging. However, the scores for type B were the same or better than those for type A for every evaluation item. In addition, more than 85% of the participants reported preferring to use type B. More than 80% of the participants in both groups reported dropping pills using type A, which seemed to be related to their preference for type B. In the evaluation by the examiner (objective study), all participants could successfully remove their pills without dropping using type B, including those in the RA group who had difficulty handling packages., Conclusion: These findings suggest that the new type of blister pack assessed in this study (type B) is preferable among older and shows promise for a universal design., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Sadamoto et al.)

It is known that younger patients treated with antipsychotics are at increased risk of metabolic events; however, it is unknown how this risk varies according to ethnicity, the class of antipsychotic and the specific product used, and by age group. We conducted a multinational sequence symmetry study in Asian populations (Hong Kong, Japan, Korea, Taiwan and Thailand) and non-Asian populations (Australia and Denmark) to evaluate the metabolic events associated with antipsychotics in both Asian and non-Asian populations, for typical and atypical antipsychotics, and by the subgroups of children and adolescents, and young adults. Patients aged 6-30 years newly initiating oral antipsychotic drugs were included. We defined a composite outcome for metabolic events which included dyslipidemia, hypertension and hyperglycemia. We calculated the sequence ratio (SR) by dividing the number of people for whom a medicine for one of the outcome events was initiated within a 12-month period after antipsychotic initiation by the number before antipsychotic initiation. This study included 346,904 antipsychotic initiators across seven countries. Antipsychotic use was associated with an increased risk of composite metabolic events with a pooled adjusted SR (ASR) of 1.22 (95% CI 1.00-1.50). Pooled ASRs were similar between Asian (ASR, 1.22; 95% CI 0.88-1.70) and non-Asian populations (ASR, 1.22; 95% CI 1.04-1.43). The pooled ASR for typical and atypical antipsychotics was 0.98 (95% CI 0.85-1.12) and 1.24 (95% CI 0.97-1.59), respectively. No difference was observed in the relative effect in children and adolescents compared to young adults. The risk of metabolic events associated with antipsychotics use was similar in magnitude in Asian and non-Asian populations despite the marked difference in drug utilization patterns., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency exists, conditional logistic regression can be biased. However, this bias has not been well studied., Methods: We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia., Results: When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression., Conclusion: Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders., (© 2021. The Author(s).)

Introduction: Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records., Methods and Analysis: This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported., Ethics and Dissemination: Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences., Competing Interests: Competing interests: ICKW, SW, KMCV, A-MT, HTS, J-YS, DP-A, MMdA, EC-CL, KK, CD-P, MC, AHYC, and JSB had financial support from Amgen Inc. for the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An administrative database covering a whole population such as the national database in Japan may be used to estimate the nationwide prevalence of diseases including rheumatoid arthritis (RA) when a well-validated definition of the disease is available. In Japan, the record linkage between the administrative database and medical charts in hospitals is strictly prohibited. A "hospital-based" validation study is one of few possible validation studies where claims kept inside the study hospital are rearranged into the database structure., Methods: We selected random samples of 19,734 patients from approximately 1.6 million patients who received medical care between February 2018 and January 2019 in one of the 64 hospitals of the Tokushukai Medical Group. We excluded patients whose observation period was less than 365 days and identified 334 patients who met the definition of "possible cases of RA" whose medical charts were then independently evaluated by two rheumatologists. In a sensitivity analysis, we assessed bias due to misclassifying some patients with RA who did not meet the definition of "possible cases of RA" as a patient with no RA., Results: The kappa coefficient between the two rheumatologists was 0.80. The prevalence of RA in the study population was estimated to be 0.56%. We found that [condition code of RA] and ([any disease-modifying antirheumatic drug] or [oral corticosteroid with no systemic autoimmune diseases (other than RA) and no polymyalgia rheumatica]) had a relatively high sensitivity (approximately 73%) and a high positive predictive value (approximately 80%). In a sensitivity analysis, we found that when some patients with RA who did not meet the definition of "possible cases of RA" were misclassified as a patient with no RA, then this would lead to underestimation of the prevalence of the definition-positive patients and the adjusted prevalence., Conclusions: We recommend using the claims-based definition of RA (found in the current validation study) to estimate the prevalence of RA in Japan. We also suggest estimating the adjusted prevalence using the quantitative bias analysis method, since the prevalence of the disease in the "hospital-based" validation study is different from that in the administrative database., Trial Registration: The current study is not a clinical trial and hence not subject to trial registration.

The use of antipsychotic medications (APMs) could be different among countries due to availability, approved indications, characteristics and clinical practice. However, there is limited literature providing comparisons of APMs use among countries. To examine trends in antipsychotic prescribing in Taiwan, Hong Kong, Japan, and the United States, we conducted a cross-national study from 2002 to 2014 b y using the distributed network approach with common data model. We included all patients who had at least a record of antipsychotic prescription in this study, and defined patients without previous exposure of antipsychotics for 6 months before the index date as new users for incidence estimation. We calculated the incidence, prevalence, and prescription rate of each medication by calendar year. Among older patients, sulpiride was the most incident [incidence rate (IR) 11.0-23.3) and prevalent [prevalence rate (PR) 11.9-14.3) APM in Taiwan, and most prevalent (PR 2.5-3.9) in Japan. Quetiapine and haloperidol were most common in the United States (IR 8.1-9.5; PR 18.0-18.4) and Hong Kong (PR 8.8-13.7; PR 10.6-12.7), respectively. The trend of quetiapine use was increasing in Taiwan, Hong Kong and the United States. As compared to older patients, the younger patients had more propensity to be prescribed second-generation APM for treatment in four countries. Trends in antipsychotic prescribing varied among countries. Quetiapine use was most prevalent in the United States and increasing in Taiwan and Hong Kong. The increasing use of quetiapine in the elderly patients might be due to its safety profile compared to other APMs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The number of patients with diabetes is increasing particularly in Asia-Pacific region. Many of them are treated with antidiabetics. As the basis of the studies on the benefit and harm of antidiabetic drugs in the region, the information on patterns of market penetration of new classes of antidiabetic medications is important in providing context for subsequent research and analyzing and interpreting results., Methods: We compared penetration patterns of dipeptidyl peptidase-4 (DPP-4) inhibitors in Taiwan, Hong Kong, Japan, and the United States. We used the Taiwan National Health Insurance Research Database, a random sample of the Hong Kong Clinical Data Analysis and Reporting System, the Japan Medical Data Center database, and a 5% random sample of the US Medicare database converted to the Observational Medical Outcomes Partnership's Common Data Model to identify new users of oral antidiabetic medications. We standardized prevalence and incidence rates of medication use by age and sex to those in the 2010 Taiwanese population. We compared age, sex, comorbid conditions, and concurrent medications between new users of DPP-4 inhibitors and biguanides., Results: Use of DPP-4 inhibitors 1 year after market entry was highest in Japan and lowest in Hong Kong. New users had more heart failure, hyperlipidemia, and renal failure than biguanide users in Taiwan, Hong Kong, and the United States while the proportions were similar in Japan. In a country with low penetration of DPP-4 inhibitors (eg, Hong Kong), users had diabetes with multiple comorbid conditions compared with biguanidine users. In a country with high penetration (eg, Japan), the proportion of users with comorbid conditions was similar to that of biguanide users., Conclusions: We observed a marked difference of the penetration patterns of newly marketed antidiabetics in different countries in Asia. Those results will provide the basic information useful in the future studies., Competing Interests: This work was supported by a research agreement between Duke University and Janssen Research & Development, LLC. Among authors, P Ryan, M Schuemie, and P Stang are employees of Janssen, a company that developed canagliflozin for treatment of Type 2 diabetes. This does not alter our adherence to PLOS ONE policies on sharing data and material.

Background: In Japan, several large healthcare databases have become available for research since the early 2000's. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims., Methods: We selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI., Results: In a random sample of 200 patients, the average age was 67.7 years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%., Conclusion: The PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke.

Purpose: The safety of nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in Asia-Pacific countries has had limited study. We assessed the risk of hospitalization for gastrointestinal events with loxoprofen and mefenamic acid compared with other NSAIDs in Asia-Pacific populations., Methods: We conducted a cohort study using a distributed network with a common data model in Australia, Hong Kong, Japan, Korea, and Taiwan. We included patients who initiated diclofenac, loxoprofen, mefenamic acid, or celecoxib and followed them until their first gastrointestinal hospitalization, switch or discontinuation of medication, disenrollment, or end of database coverage. We used Cox proportional hazards models to assess hospitalization risk., Results: We identified 9879 patients in Japan, 70 492 in Taiwan, 263 741 in Korea, and 246 in Hong Kong who initiated an NSAID, and 44 013 patients in Australia, a predominantly Caucasian population. The incidence of gastrointestinal hospitalization was 25.6 per 1000 person-years in Japan, 32.8 in Taiwan, 11.5 in Korea, 484.5 in Hong Kong, and 35.6 in Australia. Compared with diclofenac, the risk of gastrointestinal events with loxoprofen was significantly lower in Korea (hazards ratio, 0.37; 95% CI, 0.25-0.54) but not in Japan (1.65; 95% CI, 0.47-5.78). The risk of gastrointestinal events with mefenamic acid was significantly lower in Taiwan (0.45; 95% CI, 0.26-0.78) and Korea (0.11; 95% CI, 0.05-0.27) but not Hong Kong (2.16; 95% CI, 0.28-16.87), compared with diclofenac., Conclusions: Compared with diclofenac, loxoprofen was associated with a lower risk of gastrointestinal hospitalizations in Korea and mefenamic acid with a lower risk in Taiwan and Korea., (© 2018 John Wiley & Sons, Ltd.)

Background: The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence., Methods: We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends., Findings: 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries., Interpretation: Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Anticoagulant therapy is recommended in patients with atrial fibrillation (AF) but remains underused. The proper use of anticoagulants has been encouraged in guidelines frequently published over the past two decades., Materials and Methods: In this study, we used insurance claims data collected from 2005 to 2014 to investigate the prevalence and incidence of non-valvular AF (NVAF) patients aged 20 to 74 years standardized to the Japanese population in 2012 and subdivided by stroke prevention drug type. We estimated the frequency of coagulation monitoring in patients with incident NVAF undergoing warfarin therapy in 2011 and later., Results: From 2005 to 2014, the standardized prevalence of NVAF increased from 117/100,000 to 278/100,000 and the proportion of anticoagulant users increased from 38.4% to 58.0%, while that of antiplatelet monotherapy decreased from 32.3% to 12.0%. The standardized incidence of NVAF was stable at ~40/100,000 patient-years. The proportion of those patients who started anticoagulant soon after the initial diagnosis increased from 19.9% to 49.1% from 2006 to 2013. Among patients who started warfarin, switchers to DOAC had more frequent coagulation monitoring than non-switchers., Conclusion: The use of anticoagulant therapy has gradually increased in patients with NVAF in Japan during the study period from 2005 to 2014., Competing Interests: The authors have declared that no competing interests exist.

Objective: The goal of the Asian Pharmacoepidemiology Network is to study the effectiveness and safety of medications commonly used in Asia using databases from individual Asian countries. An efficient infrastructure to support multinational pharmacoepidemiologic studies is critical to this effort., Study Design and Setting: We converted data from the Japan Medical Data Center database, Taiwan's National Health Insurance Research Database, Hong Kong's Clinical Data Analysis and Reporting System, South Korea's Ajou University School of Medicine database, and the US Medicare 5% sample to the Observational Medical Outcome Partnership common data model (CDM)., Results: We completed and documented the process for the CDM conversion. The coordinating center and participating sites reviewed the documents and refined the conversions based on the comments. The time required to convert data to the CDM varied widely across sites and included conversion to standard terminology codes and refinements of the conversion based on reviews. We mapped 97.2%, 86.7%, 92.6%, and 80.1% of domestic drug codes from the USA, Taiwan, Hong Kong, and Korea to RxNorm, respectively. The mapping rate from Japanese domestic drug codes to RxNorm (70.7%) was lower than from other countries, and we mapped remaining unmapped drugs to Anatomical Therapeutic Chemical Classification System codes. Because the native databases used international procedure coding systems for which mapping tables have been established, we were able to map >90% of diagnosis and procedure codes to standard terminology codes., Conclusion: The CDM established the foundation and reinforced collaboration for multinational pharmacoepidemiologic studies in Asia. Mapping of terminology codes was the greatest challenge, because of differences in health systems, cultures, and coding systems., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Therapeutic drug monitoring (TDM) for lithium is recommended in guidelines; however, the prevalence of TDM for lithium is seldom reported. We have therefore investigated the prevalence of TDM for lithium and evaluated the impact of the regulatory warnings requiring routine TDM for lithium., Methods: Monthly claims data covering around 1.7 million persons aged 20-74 years old during the period January 1, 2005, and March 31, 2015, were evaluated. All patients who had at least one prescription for lithium were selected and included to calculate the annual prevalence of TDM for lithium. Also we assessed whether the 2 regulatory warnings requiring routine TDM for lithium and issued in April 2012 and September 2012 had an impact on TDM for lithium, using segmented regression analysis., Results: Between 2005 and 2014, 136,956 prescriptions of lithium were issued to 5823 patients, and the annual prevalence of TDM for lithium was 14.9% (95% confidence interval, 14.7%-15.1%). The analysis revealed that the mean prevalence increased abruptly by 6.9% (P = 0.001) after the regulatory warning in April 2012, whereas that the warning in September 2012 decreased by 1.2% (P = 0.47). There was no significant change in trends of period prevalence after the warning in April 2012 (April 2012-August 2012) compared with prevalence before the warning (April 2010-March 2012). Similarly, no significant change was observed in the trends before (April 2012-August 2012) and after (September 2012-March 2014) the subsequent warning in September 2012., Conclusions: Results showed that the prevalence of TDM for lithium was low, although TDM for lithium was strongly recommended by the guidelines. Regulatory warnings requiring compliance with the measurement of blood levels during treatment with lithium, issued twice during the five-month period, were associated with an increase in the prevalence of TDM for lithium. However, the impact of the second warning was not remarkable compared with the first warning.

Objective: To investigate whether lipid-lowering drugs are associated with new-onset diabetes after adjusting for baseline clinical risk factors for diabetes., Design: A retrospective cohort study., Setting: Japanese employees of large corporations and their dependents using health insurance claims data linked to clinical and laboratory data for annual health screenings., Participants: All persons aged 20 to 74 years with dyslipidaemia between 1 January 2005 and 31 March 2011. We defined the index date as the first date when the person met the criteria for dyslipidaemia. Persons were excluded if they had lipid-lowering drugs, or had a diagnosis, a treatment or a laboratory test result (haemoglobin A1c ≥6.5% or fasting blood glucose ≥126 mg/dL) indicating diabetes during the 6-month period before the index date., Main Outcome Measures: New-onset diabetes., Results: We identified 68 620 persons with dyslipidaemia. During the mean follow-up period of 1.96 years, 3674 persons started treatment with a lipid-lowering drug: 979 with a low potency statin, 2208 with a high potency statin and 487 with a fibrate. Of 3674 new users of a lipid-lowering drug, 3621 had a period of non-use of any lipid-lowering drugs before starting a lipid-lowering drug. Among statin users, the incidence rate of new-onset diabetes was 124.6 per 1000 person-years compared with 22.6 per 1000 person-years in non-users. After adjusting for confounding factors including clinical data in health screening using Cox proportional hazards models, the HR was 1.91 (95% CI 1.38 to 2.64) for low potency statins and 2.61 (2.11 to 3.23) for high potency statins., Conclusion: The use of statins was associated with a 1.9-fold to 2.6-fold increase in the risk of new-onset diabetes in a Japanese population of working age, despite adjusting for clinical risk factors for diabetes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficile infections across multiple countries Method: National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest., Results: 54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation., Conclusion: Our study confirms the association between PPI initiation and C. difficile infections across countries in the Asia-Pacific region.

Introduction: A postmarketing study without a comparator group has been recognized as a problem as it provides no measure of association. Nevertheless, the design is sometimes used in company postmarketing studies particularly when the study involves the primary data collection. In this report, the "Symmetry Analysis Cohort Design" without a comparator group but with a control period is proposed., Methods and Results: In the proposed design, the rate ratio is estimated using the method of prescription sequence symmetry analysis with slight modification so that the rate ratio can be estimated using data on subjects who have started the drug during the study period but no data on other subjects., Discussion: The proposed design has an advantage that it can provide the measure of association. Another advantage common to all self-controlled methods is that the effect of the measured and unmeasured confounders is automatically canceled out when the effect is stable over the study period. Compared with the standard design with a comparator group, the proposed design also has weaknesses. For example, adjustment of confounding by the indication may be difficult when the indication is an acute condition. In addition, the rate ratio is not valid when the probability of the prescription of the drug is dependent on the occurrence of the outcome in the unexposed (pre-dose) period. The design may be used to evaluate the need for further studies although its real usefulness is to be determined in the future., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: This study describes the availability and characteristics of databases in Asian-Pacific countries and assesses the feasibility of a distributed network approach in the region., Methods: A web-based survey was conducted among investigators using healthcare databases in the Asia-Pacific countries. Potential survey participants were identified through the Asian Pharmacoepidemiology Network., Results: Investigators from a total of 11 databases participated in the survey. Database sources included four nationwide claims databases from Japan, South Korea, and Taiwan; two nationwide electronic health records from Hong Kong and Singapore; a regional electronic health record from western China; two electronic health records from Thailand; and cancer and stroke registries from Taiwan., Conclusions: We identified 11 databases with capabilities for distributed network approaches. Many country-specific coding systems and terminologies have been already converted to international coding systems. The harmonization of health expenditure data is a major obstacle for future investigations attempting to evaluate issues related to medical costs.

Introduction: The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of adverse drug events., Objective: The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan., Methods: Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates., Results: Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone [adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14-1.91] and rosiglitazone (ASR 1.65; 95 % CI 1.58-1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93-1.32 and ASR 1.21; 95 % CI 1.01-1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01-3.5 and ASR 1.25; 95 % CI 0.76-2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations., Conclusion: The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use.

Background: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings., Methods: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method., Results: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively., Conclusion: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events., (© 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

Background: Patients have been allowed to report adverse drug reactions (ADRs) directly to the government in some countries, which would contribute to pharmacovigilance., Objective: We started a pilot study to determine whether web-based patient ADR reporting would work in Japan. This article aims to describe the characteristics of the patient reporters, and to clarify patient views and experiences of reporting., Methods: Patients who submitted online ADR reports were contacted to respond to an ADR reporting questionnaire; only consenting reporters were included. Subjects with multiple responses were excluded from analysis. The questionnaire consisted of both closed and open questions. Questionnaire responses were examined using Pearson's chi-squared test., Results: A total of 220 web-based ADR reports were collected from January to December 2011; questionnaires were sent to 190 reporters, excluding those who gave multiple reports and those that refused to be contacted. Responses were obtained from 94 individuals (effective response rate: 49.5%). The median respondent age was 46.0 years. Sixty-three respondents found out about this pilot study on the Internet (67.0%). The numbers of respondents claiming that they had difficulty recalling the time/date of ADR occurrence were 16 patient reporters and three non-patient reporters. The number of reporters who found it difficult to complete the online reporting form was 22 patients (26.2%) and one non-patient (10%). Fifty-seven respondents (60.6%) expected feedback after reporting and many respondents wanted to know the process of ADR data collection and related information. Seventy-three respondents (77.7%) stated that they would report ADRs again in future., Conclusion: Throughout the entire questionnaire, online patient ADR reporting was received with a forward-looking, positive approach. To facilitate smoother web-based reporting experiences in future, some improvements may be required in online ADR reporting forms, particularly with regard to respondent feedback.

Objective: The primary objective was to estimate the national prevalence of psoriasis and palmoplantar pustulosis (PPP) in Japan. Secondary objectives were to determine (1) whether psoriasis and PPP disease activity varies by season, and (2) whether disease severity is associated with concurrent diabetes mellitus, hyperlipidaemia and hypertension., Settings: Patients with a psoriasis or PPP diagnosis code between April 2010 and March 2011 were identified using a Japanese national database., Participants: 565 903 patients with psoriasis or PPP were identified. No patient was excluded., Primary and Secondary Outcome Measures: National prevalence was calculated using census data. We estimated the difference in the proportion of patients who used healthcare services, as a proxy for disease activity, between the hot and cold seasons and the difference in the standardised prevalence of comorbidities between severe and mild disease. The measures were estimated separately for the two broad disease categories of psoriasis and PPP but not in all patients as planned because the two disease categories had major differences., Results: The national prevalence of psoriasis and PPP was 0.34% (95% CI 0.34% to 0.34%) and 0.12% (0.12% to 0.12%), respectively. The difference in the proportion of patients who used healthcare services in the hot compared to the cold season was -0.3% (-0.5% to -0.1%) for psoriasis and 10.0% (9.8% to 10.3%) for PPP. The difference in the standardised prevalence between severe and mild psoriasis was 3.1% (2.7% to 3.4%), 3.2% (2.8% to 3.6%) and 5.1% (4.7% to 5.6%) for concurrent diabetes mellitus, hyperlipidaemia and hypertension, respectively. No significant difference in the prevalence of comorbidity was observed for PPP., Conclusions: The national prevalence, seasonal variation in disease activity and prevalence of comorbidities in Japanese patients with psoriasis and PPP estimated in this descriptive study may be used as basic information for future studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background/objectives: HMG-CoA reductase inhibitors (statins) reduce ischemic heart disease (IHD) in middle-aged diabetic individuals, and LDL-cholesterol (LDL-C) is a risk factor. However, their preventive effects on cerebrovascular attack (CVA) have not been identified in elderly, especially in elderly ≥ 75 years (late elderly), who account for approximately 30% of diabetic individuals in Japan. Randomized controlled studies of statins for late elderly are difficult to carry out, because many co-morbidities in elderly disrupt randomized controlled conditions., Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up since 2004. A total of 4014 type 2 diabetic patients without previous IHD or CVA (n=1936 women; age = 67.4 ± 9.5 years; ≥ 75 years: n = 1016) were enrolled, while 405 patients were registered as sub-cohort patients. We recorded detailed information on medications and laboratory data after every change in medication in patients of sub-cohort and suffered from IHD or CVA. We subdivided statin-users into prevalent, new and non-users., Results: A total of 104 CVAs occurred during 5.5-years. Plasma HDL-C level was inversely correlated with CVA in patients ≥ 65 years. In case-control study, among patients who were not prescribed statins, CVA increased in age-dependent manner. CVA incidence was lower in prevalent and new statin-users than in non-users (hazard ratio [HR]:0.46, 0.523), especially in late elderly (HR: 0.51, 0.21). Statins reduced CVAs mainly due to a direct effect and partially due to the effects of HDL-C and glucose metabolism. No significant differences were observed between statins., Conclusion: Statins prevented CVA in middle-aged, elderly and late elderly diabetic patients via a direct effect. This study is the first to demonstrate the usefulness of observational studies for statistically analyzing agents' effects on late elderly., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aim: The risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia., Method: The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia., Results: The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged <65 years, 65-74 years and >75 years (n=168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years, and HDL-C and diastolic blood pressure was significantly associated with cardiovascular events in patients aged 65-74 years. Non-HDL-C was not significantly associated with the risk of cardiovascular events. Multiple regression analysis showed that lower HDL-C was significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <65 years and 65-74 years., Conclusions: Lower HDL-C was an important risk factor for cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged <75 years., (© 2013 Japan Geriatrics Society.)

Purpose: To assess the association between statins and diverse adverse events in Japanese population., Methods: New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009., Results: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009)., Conclusions: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.

Purpose: To undertake a multi-country study to investigate the risk of acute hyperglycaemia with antipsychotic use., Methods: Using a distributed network model with a common minimal data set, we performed a prescription sequence symmetry analysis (PSSA) to investigate the risk of acute hyperglycaemia associated with antipsychotic initiation. Incident insulin prescriptions were used as a proxy indicator of acute hyperglycaemia. Participating countries and population datasets included Australia (300,000 persons), Japan I (300,000 persons), Japan II (200,000 persons), Korea (53 million persons) Taiwan (1 million persons), Sweden (9 million persons), USA-Public (87 million persons) and USA-Private (47 million persons)., Results: Olanzapine showed a trend towards increased risk in most databases, with a significant association observed in the USA-Public database (Adjusted sequence ratio (ASR) = 1.14; 95% Confidence Interval (CI) 1.10-1.17) and Sweden (ASR = 1.53; 95% CI 1.13-2.06). Null or negative associations were observed for haloperidol, quetiapine and risperidone., Conclusion: Acute hyperglycaemia appears to be associated with olanzapine use, however, this effect was only observed in two large databases. Despite different patterns of utilization of both antipsychotics and insulin, PSSA analysis results for individual antipsychotic medicines were qualitatively similar across most countries. PSSA, used in conjunction with existing methods, may provide a simple and timely method further supporting multi-national drug safety monitoring., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: For the pending National Claims Database in Japan, researchers will not have access to death information in the enrollment files. We developed and evaluated a claims-based definition of death., Methodology/principal Findings: We used healthcare claims and enrollment data between January 2005 and August 2009 for 195,193 beneficiaries aged 20 to 74 in 3 private health insurance unions. We developed claims-based definitions of death using discharge or disease status and Charlson comorbidity index (CCI). We calculated sensitivity, specificity and positive predictive values (PPVs) using the enrollment data as a gold standard in the overall population and subgroups divided by demographic and other factors. We also assessed bias and precision in two example studies where an outcome was death. The definition based on the combination of discharge/disease status and CCI provided moderate sensitivity (around 60%) and high specificity (99.99%) and high PPVs (94.8%). In most subgroups, sensitivity of the preferred definition was also around 60% but varied from 28 to 91%. In an example study comparing death rates between two anticancer drug classes, the claims-based definition provided valid and precise hazard ratios (HRs). In another example study comparing two classes of anti-depressants, the HR with the claims-based definition was biased and had lower precision than that with the gold standard definition., Conclusions/significance: The claims-based definitions of death developed in this study had high specificity and PPVs while sensitivity was around 60%. The definitions will be useful in future studies when used with attention to the possible fluctuation of sensitivity in some subpopulations.

Background: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age., Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model., Results: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels., Conclusions: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease., Trial Registration: UMIN-CTR, UMIN00000516.

Background: We analyzed the effects of insulin therapy, age and gender on the risk of ischemic heart disease (IHD) and cerebrovascular accident (CVA) according to glycemic control., Methods and Results: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) of type 2 diabetes patients (n = 4014) for 2 years. The primary endpoint was the onset of fatal/non-fatal IHD and/or CVA, which occurred at rates of 7.9 and 7.2 per 1000 person-years, respectively. We divided diabetic patients into four groups based on age (≤ 70 and > 70) and hemoglobin A1C levels (≤ 7.0 and > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure and low HDL-C in patients under 70 years of age with fair glycemic control and was associated with low diastolic blood pressure in the older/fair group. Interestingly, insulin use was associated with IHD in the older/poor group (OR = 2.27, 95% CI = 1.11-5.89; p = 0.026) and was associated with CVA in the older/fair group (OR = 2.09, 95% CI = 1.06-4.25; p = 0.028). CVA was associated with lower HDL-C and longer duration of diabetes in younger/poor glycemic control group. Results by stepwise analysis were similar. Next, patients were divided into four groups based on gender and diabetic control(hemoglobinA1C < or > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure in male/fair glycemic control group, age in male/poor control group, and short duration of diabetic history in females in both glycemic control groups. Interestingly, insulin use was associated with IHD in the male/poor group(OR = 4.11, 95% CI = 1.22-8.12; p = 0.018) and with CVA in the female/poor group(OR = 3.26, 95% CI = 1.12-6.24; p = 0.02). CVA was associated with short duration of diabetes in both female groups., Conclusions: IHD and CVA risks are affected by specific factors in diabetics, such as treatment, gender and age. Specifically, insulin use has a potential role in preventing IHD but may also be a risk factor for CVA among the diabetic elderly, thus revealing a need to develop improved treatment strategies for diabetes in elderly patients. The Japan Cholesterol and Diabetes Mellitus Study was formulated to evaluate them(Umin Clinical Trials Registry, clinical trial reg. no. UMIN00000516; http://www.umin.ac.jp/ctr/index.htm).

Purpose: In order to evaluate the incidence of an adverse event encountered when using a new therapeutic intervention, it is essential to know the background rate of this adverse event in the same patient population. Interstitial lung disease (ILD) often develops in Japanese patients receiving treatment with anti-neoplastic agents or other drugs. In our study, we estimated the background rate of ILD in patients with malignant mesothelioma (MM)., Methods: We conducted a retrospective cohort study of 328 Japanese patients diagnosed with MM during the period between 1996 and 2006., Results: After the diagnosis of MM had been made, 21 (15 new and 6 exacerbation) of the 328 patients developed ILD. The crude baseline rate of ILD was estimated to be 0.023 (95%CI, 0.009-0.054) per patient-year, and the baseline rate using the Poisson regression model was estimated to be 0.032 (95%CI, 0.017-0.059) per patient-year where major therapeutic interventions were incorporated in the model. The risk of ILD was increased by surgical excision (rate ratio, 8.87; 95%CI, 2.39-33.0), pleurodesis with picibanil (rate ratio, 5.14; 95%CI, 1.63-16.3), and systemic chemotherapy using vinorelbine (rate ratio, 5.95; 95%CI, 1.22-29.0)., Conclusions: Our results have implications for evaluating the safety outcomes of future studies in patients receiving treatment for MM. The development of ILD in such studies at an incidence rate higher than 0.02-0.03 per patient-year might indicate an excess occurrence as a result of a therapeutic intervention., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions., Objective: The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG., Methods: Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs., Results: Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively., Conclusions: Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function.

Objective: The objective in our study was to examine baseline and other characteristics associated with survival in patients with malignant pleural mesothelioma in Japan., Methods: Three hundred and fourteen patients with an adjudicated diagnosis of mesothelioma were examined. Survival was evaluated by the Kaplan-Meier method with the log-rank test. The Cox model was used to estimate the hazard ratio for the possible prognostic factors., Results: Of 314 patients, 223 (71%) died and only 40 (13%) were still alive at the end of the observation period starting from the day of diagnosis, while 51 (16%) were transferred to other hospitals or had the last health service contact before the end of the study period yielding the median survival of 308 days. In the multivariate analysis, age older than 70 years (hazard ratio = 2.17; 95% confidence interval, 1.36-3.46), non-epithelioid type (hazard ratio = 1.58; 95% confidence interval, 1.15-2.18), poor performance status (hazard ratio = 3.22; 95% confidence interval, 1.19-8.74), high white blood cell count (hazard ratio = 1.49; 95% confidence interval, 0.99-2.26) and high C-reactive protein level (hazard ratio = 1.80; 95% confidence interval, 1.06-3.06) were negatively associated with survival, after adjustment for other factors., Conclusions: Some baseline conditions including old age, poor performance status, non-epithelioid type, high white blood cell count and high C-reactive protein level were determinants of poor survival of patients with malignant mesothelioma.

Purpose: To know whether the reporting odds ratio (ROR) using "control events" can detect signals hidden behind striking reports on one or more particular events., Methods: We used data of 956 drug use investigations (DUIs) conducted between 1970 and 1998 in Japan and domestic spontaneous reports (SRs) between 1998 and 2008. The event terms in DUIs were converted to the preferred terms in Medical Dictionary for Regulatory Activities (MedDRA). We calculated the incidence proportion for various events and selected 20 "control events" with a relatively constant incidence proportion across DUIs and also reported regularly to the spontaneous reporting system. A "signal" was generated for the drug-event combination when the lower limit of 95% confidence interval of the ROR exceeded 1. We also compared the ROR in SRs with the RR in DUIs., Results: The "control events" accounted for 18.2% of all reports. The ROR using "control events" may detect some hidden signals for a drug with the proportion of "control events" lower than the average. The median of the ratios of the ROR using "control events" to RR was around the unity indicating that "control events" roughly represented the exposure distribution though the range of the ratios was so diverse that the individual ROR might not be regarded as the estimate of RR., Conclusions: The use of the ROR with "control events" may give an adjunctive to the traditional signal detection methods to find a signal hidden behind some major events., (Copyright © 2010 John Wiley & Sons, Ltd.)

Although inhibitors of the renin-angiotensin system are effective as first-line antihypertensive drugs in hypertensive patients with chronic kidney disease, they cannot completely prevent the progression of renal injury. Many animal studies, including our own, and a few human studies suggest that mineralocorticoid receptor blockade could inhibit the ongoing renal damage in chronic kidney disease. Thus, we designed this double-blinded, randomized, placebo-controlled trial to evaluate the antialbuminuric effect of a low dose (50 mg day(-1)) of the mineralocorticoid receptor antagonist eplerenone. The study subjects will include 340 hypertensive patients (blood pressure: 130-180/80-100 mm Hg) with albuminuria (urinary albumin/creatinine ratio: 30-600 mg g(-1) in the first morning void urine), who are treated with an inhibitor of the renin-angiotensin system. Other classes of antihypertensive drugs may be added as needed to achieve the target blood pressure (<130/80 mm Hg). The primary study end point is the change in the urinary albumin/creatinine ratio after a 1-year study period. This trial is expected to show whether a low dose of mineralocorticoid receptor antagonists can exert an antialbuminuric effect in patients with chronic kidney disease.

Thalidomide, once withdrawn because of its teratogenicity, has now been re-launched worldwide. In Japan, thalidomide has been imported by individual doctors since around the year 2000. In October 2008, it was approved for the treatment of multiple myeloma (MM) by the Ministry of Health, Labour and Welfare (MHLW) on the condition that the manufacturer implemented a risk management programme termed the Thalidomide Education and Risk Management System (TERMS). It is likely that the imports of thalidomide will be used off-label to treat diseases other than MM. Thus, the MHLW is also planning to introduce a web-based registration system, referred to as the Safety Management System for Unapproved Drugs (SMUD), for thalidomide imported by individual doctors. To evaluate the difference between TERMS and SMUD and establish a way to resolve the 'double standard' for risk management of thalidomide treatment in Japan. The fraction of patients with disorders other than MM was estimated by the volume of annual imports obtained from the MHLW and records of the imports for patients with MM, other oncological diseases (ODs) and non-ODs in 2007 through a major supplier covering 63% of the total imported thalidomide. The information for TERMS was obtained from web pages of the manufacturer and the MHLW. The components of TERMS were compared with those in SMUD. Provided that the distribution of the indication for thalidomide (MM) in 2007, estimated from the records of imports through the major supplier, is representative of the entire nation, it is estimated that on average 866 patients, including 851 (98.3%) with MM, are using thalidomide on any one day. However, if the major supplier's imports, which account for 63% of the total imports, are not representative of the nation as a whole, possibly only half of the patients treated with thalidomide in Japan have MM. This would be the case in a scenario where the remaining 37% of imports are exclusively used to treat disorders other than MM. TERMS consists of tools for education and registration of patients, and has the potential for real-time intervention. SMUD is a system for registration of patients and exchange of safety information between health professionals, but has some mandatory components that encourage patient registration. TERMS and SMUD are different in nature, and they impose different criteria that doctors and patients should satisfy in order to use thalidomide. To eliminate this double standard, implementation of a single system would be desirable. However, improvement of SMUD may be the second best option by developing tools for patient education, enhancing the potential for real-time intervention and monitoring thalidomide usage by each patient. On average, a total of about 1000 patients are estimated to be using thalidomide on any one day in Japan. It is likely that those patients are placed under one of two different risk management programmes. SMUD should be improved so that all patients are monitored in a way that results in a similar level of risk management.

In our recent case-control study on the association between non-steroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB), the risk of UGIB was higher in non-drinkers than in heavy-drinkers. To explore this unexpected finding, we re-analyzed the data to test whether non-drinking represented risk factors for UGIB and also conducted an additional survey to find any disagreement with the original study that might suggest information bias. In the re-analysis, we estimated odds ratios (ORs) of UGIB by classifying 183 non-drinkers in the original study into 39 ex- and 144 never-drinkers. We also measured the prevalence of potential risk factors of UGIB in controls. In the new survey, we sent a self-administered questionnaire on previous alcohol consumption. In the re-analysis, the OR for ex-drinking (5.4) was higher and the OR for never-drinking (2.6) was lower than the OR for non- (ex- plus never-) drinking (3.2) in the original study. Ex-drinkers had higher prevalence of H. pylori infection, history of previous ulcer and use of GI drugs than other types of drinkers. The answers on their previous alcohol consumption were consistent between the original and new surveys both in cases (kappa = 0.74) and controls (kappa = 0.73). Ex-drinking may represent unmeasured risk factors for UGIB such as undiagnosed ulcer. In an observational study of UGIB, ex-drinking may be distinguished from never-drinking as a potential surrogate for UGIB risk. When prescribing an NSAID to an ex-drinker in clinical practice, one may make sure to explore whether an ex-drinker has a history of ulcer.

Purpose: In hypertensive patients with diabetes, antihypertensive therapy is important in reducing the risk of macro- and microvascular complications. In contrast to the guidelines issued by the American Diabetes Association (ADA) in and after 2002, the guidelines issued by the Japanese Society of Hypertension (JSH) in 2000 and 2004 maintained the traditional view that beta-blockers and thiazides should be rated as second-line drugs. However, both sets of guidelines recommended angiotensin converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as first-line agents for such patients., Methods: We examined the use of antihypertensives in hypertensive patients with and without diabetes using the prescription data for 1999, 2002 and 2005 from three Japanese university hospitals., Results: When compared with 1999, the proportion of patients with and without diabetes using ARBs was dramatically increased in 2005 from 1.5 to 55% and from 1.5 to 40%, while that of angiotensin converting enzyme inhibitors decreased from 52 to 32% and 35 to 23%, respectively. A relatively stable proportion of patients (around 10% with and without diabetes) used beta-blockers and around 60% of patients with and without diabetes used calcium channel blockers (CCBs) and very few (<5%) used thiazides., Conclusions: The rapid increase in use of ARBs and under-use of thiazides may be explained by the fee schedule in the Japanese health insurance system. The paucity of large-scale clinical trials may also hinder evaluation of the traditional view of the role of beta-blockers and thiazides in treatment of Japanese patients with diabetes.

Background: The respective incidences of ischemic heart and cerebrovascular disease (IHD, CVD) are high in diabetic individuals. Complications of dyslipidemia increase the risk, but direct evidence is limited, so a cohort prospective study (Japan-CDM) was conducted., Methods and Results: The study group comprised 4,014 subjects with type 2 diabetes (1,936 women, 2,078 men; mean age 67.4+/-9.5 years) who were divided into dyslipidemic patients (79.1%) with or without medication (medicated, 50.9%; not medicated, 28.2%) and normo-lipidemic patients (20.9%). The incidence of IHD, CVD, arteriosclerosis obliterans (ASO), congestive heart failure (CHF) and death was assessed. IHD and CVD occurred in 0.82 and 0.67%, respectively, during the first year following registration. CHF, ASO and sudden death occurred in 0.27%, 0.12% and 0.12%, respectively. There was a significant statistical difference in the relation of elevated levels of high-density lipoprotein-cholesterol to lower rates of IHD and CVD. IHD and CVD in males were dependent on the level of low-density lipoprotein-cholesterol (LDL-C): 0.45%, 1.56%, 1.78%, 1.91% and 2.34% were observed in less than 2.11, 2.11-2.62, 2.63-3.15, 3.16-3.67, and more than 3.68 mol/L of LDL-C. In the lowest LDL-C group, death other than from vascular diseases was increased. Age, sex (male) and complicated hypertension increased the risk of events. Patients who were prescribed antihyperlipidemic agents suffered less events than patients who were not being treated, which suggests direct effects of therapy., Conclusion: Strict lipid control may be effective for reducing the incidence of vascular events in Japanese diabetic individuals.

Hemoglobin A1c (HbA1c) has been widely used as a measure of glycemic control in patients with diabetes mellitus. However, the role of HbA1c in the prediabetic stage has received little attention, although the effectiveness of early intensive intervention for the prediabetic patients defined by plasma glucose is well documented. In this study, routine clinical data in a Japanese university hospital were used to address whether the level of HbA1c predicted drug treatment for diabetes mellitus. The study population consisted of 38,628 adolescent and adult patients (>or=15 years old) who used routine medical care services provided by the hospital and who were prescribed no anti-diabetic drugs in the 12 months before the 3-year study period. The rates of starting anti-diabetic drugs during the study period were calculated for subgroups divided by the level of HbA1c followed by Kaplan-Meier survival analysis and Cox proportional-hazard regression. In addition, the medical records of middle-aged patients with borderline (5.6-6.4%) and high (>or=6.5%) levels of HbA1c were examined to estimate the rates of initial drug treatment for type 2 diabetes mellitus. The rate (95% confidence interval; CI) of beginning anti-diabetic drug therapy was 1.5 (0.9-2.5)/1000 patient-years in patients with a normal level of HbA1c (<5.6%), which is similar to 2.1 (1.8-2.5)/1000 patient-years in patients with no HbA1c data, but lower than the value of 23.0 (18.6-28.6) and 161.8 (144.8-180.7)/1000 patient-years in those with borderline and high levels of HbA1c, respectively (P < 0.001). In a small group of 513 middle-aged patients, the rates of initial drug treatment for type 2 diabetes mellitus were 39.4 (28.1-55.1)/1000 patient-years and 270.4 (209.4-349.0)/1000 patient-years in those with borderline and high levels of HbA1c, respectively. A borderline (5.6-6.4%) or high (>or=6.5%) level of HbA1c was found to strongly predict future drug treatment for diabetes mellitus.

Objective: Studies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics., Methods: Cases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls., Results: The odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe 'prodrug', was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: -5.8-8.1)., Conclusion: NSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.