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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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 CHA2DS2-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Geriatr Gerontol Int 2014; 14: 806-810. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BSTRACT 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (κ = 0.74) and controls (κ = 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. [ABSTRACT FROM AUTHOR]

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 β-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 β-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 β-blockers and thiazides in treatment of Japanese patients with diabetes. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Three hundred Japanese patients with benign prostatic hyperplasia (BPH) who started an α1-adrenoceptor blocker, tamsulosin, between 1993 and 1996 were followed for 3.0 ± 3.3 years (mean ± SD) to determine whether an association existed between the disease severities measured prior to the tamsulosin treatment and the timing at which the invasive therapy was implemented. Patients with a lower quality of life (QOL) index or maximum urinary flow rate (Qmax) were transferred for invasive therapy earlier than those with less severe BPH. The International Prostate Symptom Score (I-PSS) was also associated, but apparently to a lesser extent, with the timing of the invasive therapy. Finally, the overall severity evaluated using all of the above three indices, I-PSS, QOL index, and Qmax, in accordance with the ‘Severity Criteria for BPH’ issued by the Japanese Urological Association, was found to be a good measure for predicting the prognosis of patients with BPH treated with tamsulosin. [ABSTRACT FROM AUTHOR]

Purpose Five data mining methodologies for detecting a possible signal from spontaneous reports on adverse drug reactions (ADRs) were compared. Methods The five methodologies, the Bayesian method using the Gamma Poissson Shrinker (GPS), the method employed in the UK Medicines Control Agency (MCA), the Bayesian Confidence Propagation Neural Network (BCPNN), the method using the 95% confidence interval (CI) for the reporting odds ratio (RORCI) and that using the 95% CI of the proportional reporting ratio (PRRCI) were compared using Japanese data obtained between 1998 and 2000. Results There were all in all 38 731 drug-ADR combinations. The count of drug-ADR pairs was equal to 1 or 2 for 31 230 combinations and none of them were identified as a possible signal with the MCA or BCPNN. Similarly, the GPS detected a possible signal in none of the combinations where the count was equal to 1 but in 7.5% of the combinations where the count was equal to 2. The RORCI and PRRCI detected a possible signal in more than half of the combinations where the count was equal to 1 or 2. When the pairwise agreement on whether or not a drug-ADR combination satisfied the criteria for a possible signal was assessed for the 38 731 combinations, the concordance measure kappa was greater than 0.9 between the MCA and BCPNN and between the RORCI and PRRCI. Kappa was around 0.6 between the GPS and MCA and between the GPS and BCPNN. Otherwise, kappa was smaller than 0.2. Conclusions The drug-ADR combinations detected as a possible signal vary between different methodologies. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Two pilot studies for prescription-event monitoring in Japan (J-PEM) were launched in 1997 and 1998. Here we present data regarding adverse events that were reported in the second pilot J-PEM study where losartan was compared with ACE inhibitors and dihydropyridine calcium channel antagonists.Study Design: We conducted a cohort study with a concurrent control. METHODS/PATIENT GROUP: Study subjects prescribed losartan, an ACE inhibitor or a calcium channel antagonist were identified from prescriptions in hospital or community pharmacies. Events and other information were collected from doctors and pharmacists by mailed questionnaires. Events were coded and analysed using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Crude event rates were calculated and compared between patients treated with losartan and those receiving control drugs. When the difference was statistically significant, the event was further examined in several ways, including follow-up studies and by comparison with the data of the UK PEM study on losartan.Results: Pharmacists were sent 4344 questionnaires and returned 3591 (83%), while doctors were sent 3517 questionnaires and returned 1380 (39%). In the doctors' data, the adverse event rate for losartan treatment was greater than that for ACE inhibitors and/or calcium channel antagonists for the following seven events: headache, palpitations, anaemia, insomnia, feeling abnormal, increased blood pressure and asthma. Most of these are known adverse drug reactions (ADRs) of losartan except for two events: increased blood pressure and asthma. In pharmacists' data, the event rate for losartan was significantly greater than that for control drugs for the following ten events: hot flushes, abnormal hepatic function, oedema, peripheral swelling, decreased blood pressure, increased blood pressure, rhinitis, contact dermatitis, dry skin and heat rash. The first five events were known ADRs of losartan but the other five were not. When the two sets of data were combined, the rate of an additional event, increased blood creatinine phosphokinase, which is a known ADR of losartan, was significantly greater than that for the control drugs. The six events that were not documented as ADRs for losartan were not judged to be ADRs based on the results of follow-up studies and comparison with the UK PEM study on losartan. The crude rate of cough with losartan treatment was similar to that with calcium channel antagonists, but was significantly less than that with ACE inhibitors.Conclusion: No novel safety problems were found in this observational cohort study on losartan. The rates of some known ADRs differed significantly between patients treated with losartan and those in the control groups. [ABSTRACT FROM AUTHOR]

In prescription-event monitoring in Japan (J-PEM), patients are identified by prescriptions in individual pharmacies where drugs are dispensed. The methodology is somewhat different to that used by the Drug Safety Research Unit in the UK, in that two questionnaires, one to the pharmacist and the other to the doctor are sent for each patient and the method of concurrent control is employed in J-PEM. In the data analysis, the list of events reported as a suspected reaction or a reason for stopping the drug is made to generate a signal. In addition, a signal may be generated for some events with the statistically significant difference of crude rates followed by the regression analysis or a follow-up study. In J-PEM, Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for data entry and data analysis. Lowest level terms (LLTs) in MedDRA are used in data entry while a signal is generated using preferred terms (PTs). However, to generate a signal effectively, some PTs may be grouped as one term. In addition, if two terms are so similar, it may be instructed that one of those two terms is normally selected in data entry to avoid confusion. Many more PEM studies could be undertaken to determine if MedDRA can be used for effective signal generation, but the usefulness of MedDRA in J-PEM is still to be determined. [ABSTRACT FROM AUTHOR]

Objective: To examine adverse events reported in a pilot study of the prescription-event monitoring in Japan (J-PEM) scheme, comparing troglitazone with other oral hypoglycemics. Methods: We used a cohort study with a concurrent control in which information was gathered from both doctors and pharmacists. Crude event rates were calculated and compared between troglitazone (T) and alternative oral hypoglycemics (control drugs, C) using the likelihood ratio test. When the difference was statistically significant, possible confounding mechanisms were examined using Poisson regression analysis. Results: Of 3115 patient codes registered, pharmacists were sent 2078 questionnaires and returned 1814 (87%), while doctors were sent 1858 questionnaires and returned 671 (36%). The difference in crude rates was statistically significant in 11 events (seven where T>C and four where C>T) reported by pharmacists and ten events (three where T>C and seven where C>T) reported by doctors. Among those, in two events, "weight increased" (T>C) and "abnormal hepatic function" (T>C), significant differences were observed in data from both doctors and pharmacists. Regression analysis revealed that the difference in crude rates for "nausea" (T>C) was possibly due to an uneven distribution of genders and that for "weight increased" (T>C) was possibly due to an uneven distribution of compliance. Patients with hepatic function abnormalities associated with troglitazone could be divided into two subtypes: one with a slight increase in serum lactate dehydrogenase concentration only and the other with elevated serum alanine aminotransferase. Conclusions: Comparison of the event rates between troglitazone and control drugs, followed by regression analysis, revealed several features of adverse events associated with drugs, including possible confounding mechanisms. Troglitazone-induced hepatic function abnormalities may be divided into two subtypes. [ABSTRACT FROM AUTHOR]