Search

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]

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]

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]

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]

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]

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]

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]

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. [ABSTRACT FROM AUTHOR]

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.)

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: 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.

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.

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.)

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.)

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.

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.)

Purpose: To examine the relationship of the use of calcium channel blockers (CCBs) in hypertensive patients to myocardial infarction in Japan, where CCBs are prescribed much more frequently than in Europe and America., Design: We conducted a nested case-control study using a hospital information system in Japan., Subjects: Cases were hypertensive patients who were repeat visitors to Tokyo University Hospital as of April 1996 and had an incidence of fatal or non-fatal myocardial infarction between 1996 and 1999. Controls were hypertensive patients individually matched to cases by sex, age and history of angina pectoris., Results: The study consisted of 16 cases, who were matched to 80 controls. Of the 80 control patients, 54 (68%) received CCBs. On the other hand, all but one of 16 cases received CCBs and the crude odds ratio of myocardial infarction associated with the use of calcium channel blockers was as high as 7.0 (0.9-55.3). The odds ratio was reduced to 4.9 (0.6-42.4) when adjusted by diabetes and diastolic blood pressure., Conclusions: Although the crude odds ratio of myocardial infarction associated with CCBs was high, the ratio was reduced when adjusted by known confounding factors, suggesting a mechanism of confounding by indication. In addition, the results obtained in this study using records from a single hospital should not be generalized.