Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality.

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).

Pharmacokinetic/pharmacodynamic analysis of vancomycin in patients with Enterococcus faecium bacteraemia: a retrospective cohort study.

OBJECTIVES: The trough concentration of vancomycin and the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio are crucial in determining vancomycin efficacy against methicillin-resistant Staphylococcus aureus. However, the use of similar pharmacokinetic principles in determining antibiotic efficacy against other gram-positive cocci is lacking. We performed a pharmacokinetic/pharmacodynamic analysis (association of target trough concentration values and AUC/MIC with therapeutic outcome) of vancomycin in patients with Enterococcus faecium bacteraemia. METHODS: Between January 2014 and December 2021 we performed a retrospective cohort study of patients with E. faecium bacteraemia treated with vancomycin. Patients who received renal replacement therapy or had chronic kidney disease were excluded. Clinical failure, the primary outcome, was defined as a composite of 30-day all-cause mortality, vancomycin-susceptible infection requiring change of treatment, and/or recurrence. AUC24 was estimated using a Bayesian estimation approach based on an individual vancomycin trough concentration. The MIC for vancomycin was determined using a standardised agar dilution method. Additionally, classification was used to identify the vancomycin AUC24/MIC ratio associated with clinical failure. RESULTS: Of the 151 patients identified, 69 were enrolled. All MICs of vancomycin for E. faecium were ≤1.0 µg/mL. The AUC24 and AUC24/MIC ratio were not significantly different between the clinical failure group and the clinical success group (432±123 µg/mL/hour vs 488±92 µg/mL/hour; p=0.075). However, 7 of 12 patients (58.3%) in the clinical failure group and 49 of 57 patients (86.0%) in the clinical success group had a vancomycin AUC24/MIC ratio ≥389 (p=0.041). No significant association between trough concentration or AUC24 ≥600 µg/mL×hour and acute kidney injury was observed (p=0.365 and p=0.487, respectively). CONCLUSION: The AUC24/MIC ratio is associated with the clinical outcome of vancomycin administration in E. faecium bacteraemia. In Japan, where vancomycin-resistant enterococcal infection is rare, empirical therapy with a target AUC24 ≥389 should be recommended.

Safety of mirogabalin and pregabalin in Japanese patients with neuropathic pain: a retrospective cohort study.

BACKGROUND: Few studies have compared the safety risks between the gabapentinoids, pregabalin, and mirogabalin in post-marketing clinical settings. We assessed reported events associated with gabapentinoid use in patients with neuropathic pain. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study between September 2020 and December 2020 using the community pharmacies records in Japan. The pharmacists identified new vs. prevalent users of mirogabalin and pregabalin in September 2020 and reported data regarding baseline and adverse events to the Japan Pharmaceutical Association using web-based questionnaires. The incidence of events and hazard ratio (HR) were consequently compared. RESULTS: New users of mirogabalin and pregabalin were identified (n = 1,650 and 2,244; mean age (SD): 69 (15) and 68 (16) years; women: 59% and 56%, respectively). Although serious events were not reported, a marked difference in HRs of common adverse events, including somnolence (1.6), dizziness (1.3), nausea (2.8), edema (3.1), and acetaminophen (2.0)/antidepressant (2.4) addition, was observed. CONCLUSION: No new serious safety concerns were found for mirogabalin and pregabalin use in patients with neuropathic pain, although the HR of some events indicated increased risk among mirogabalin users. However, further studies are needed as estimates for events occurring in small numbers with wide confidence intervals.

Effects of angiotensin II receptor blockers on serum potassium level and hyperkalemia risk: retrospective single-centre analysis.

OBJECTIVE: To examine the effect of angiotensin II receptor blocker (ARB) treatment on serum potassium level and hyperkalaemia risk in a clinical setting with inpatients and outpatients using calcium channel blockers (CCBs) as a reference standard. METHODS: The increased risk of hyperkalaemia associated with ARB treatment is known, however only a few studies have used an active comparator to examine this risk. In this retrospective study at a 320-bed general hospital in Japan, the hospital information system was used to identify patients with at least one prescription for an ARB (819 patients) or a CCB (1015 patients) who were naive to these drugs before study initiation. Serum potassium levels before and after ARB treatment were compared. Additionally, the unadjusted and adjusted hazard ratios for the risk of hyperkalaemia in the ARB and CCB users were estimated. RESULTS: The serum potassium level was higher in patients receiving ARB treatment (0.05 mEq/L, p=0.02) compared with those on CCB treatment. However, there was no significant association between ARB use and hyperkalaemia (adjusted HR 0.91, 95% CI 0.42 to 1.99, p=0.82). CONCLUSION: The increase in serum potassium level after ARB initiation makes it necessary to monitor serum potassium levels continuously during ARB treatment; however, the risk of hyperkalaemia appeared to be similar for ARB and CCB treatments.

Prevalence of therapeutic drug monitoring and adherence to imatinib in chronic myeloid leukemia in Japan.

OBJECTIVE: The effectiveness of imatinib, a tyrosine kinase inhibitor recommended for the treatment of chronic myeloid leukemia, is associated with high adherence and trough plasma imatinib concentrations of ~ 1,000 ng/mL. However, adherence and therapeutic drug monitoring (TDM) for imatinib have hardly been reported. This study evaluated the prevalence of TDM and adherence to imatinib for chronic myeloid leukemia in Japan. MATERIALS AND METHODS: Monthly insurance claims data for ~ 5.6 million individuals aged 20 - 74 years between June 1, 2005 and December 31, 2017 were studied. Patients with at least one prescription for imatinib were included to calculate adherence and the annual mean prevalence of TDM for imatinib. RESULTS: A total of 498 patients with 9,620 prescriptions of imatinib were included. After 2013, the number of imatinib prescriptions and the number of patients treated with imatinib were over 1,000 and 200, respectively. The mean annual prevalence of TDM for imatinib was 12.2% (95% confidence interval (CI), 8.1 - 16.1%). Antihyperuricemic drugs and steroids increased the likelihood of TDM. The medication possession ratio for assessment of adherence was 93.5% (95% CI: 91.8 - 95.5%). The annual mean prevalence of TDM for imatinib was low, although adherence was high. CONCLUSION: To encourage the measurement of plasma concentrations of imatinib in clinical settings, adding a package insert, a summary of product characteristics, and a patient information leaflet regarding the implementation of TDM is justified and warrants further attention.

Effectiveness and Safety of Reduced and Standard Daily Doses of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: A Cohort Study Using National Database Representing the Japanese Population.

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.

Event Monitoring and Evaluation by Community Pharmacists in Japan: A Pilot Study on Fenofibrate and Pemafibrate.

BACKGROUND: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. AIMS: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. METHODS: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. RESULTS: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. CONCLUSION: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

Metabolic events associated with the use of antipsychotics in children, adolescents and young adults: a multinational sequence symmetry study.

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.

Safety of elobixibat and lubiprostone in Japanese patients with chronic constipation: a retrospective cohort study.

BACKGROUND: We aimed to discuss and compare reported adverse reactions and drug add-ons associated with elobixibat and lubiprostone use in chronic constipation treatment, as the safety of these drugs has not been well examined in post-marketing clinical settings. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, using records of community pharmacies in Japan, we identified new users of elobixibat and lubiprostone. The Japan Pharmaceutical Association sent questionnaires regarding baseline and event data to community pharmacists. The incidence of events and hazard ratio (HR) associated with the study drugs were evaluated. RESULTS: New users of elobixibat (n = 979) and lubiprostone (n = 829) were identified (mean age: 74 and 77 years; females: 59% and 53%, respectively). Although the crude risk ratio of adverse events for elobixibat was 0.79 (95% confidence interval: 0.63-0.99), there was no significant difference in the HR for any of the common events, including drug add-ons (n ≥ 5), compared with those for lubiprostone. CONCLUSION: No new safety concerns have been raised in relation to elobixibat and lubiprostone use for treating chronic constipation, although the HR of different events varied. Further larger-scale study is needed as the estimates for events of small numbers were unstable.

Global epidemiology of hip fractures: a study protocol using a common analytical platform among multiple countries.

INTRODUCTION: Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records. METHODS AND ANALYSIS: This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported. ETHICS AND DISSEMINATION: Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.

Comparison between high and low potency statins in the incidence of open-angle glaucoma: A retrospective cohort study in Japanese working-age population.

Some findings on the association between glaucoma and statins in the Asian population have been reported. We conducted a retrospective cohort study using health insurance claims data maintained by the JMDC Inc., which comprises data on about three million individuals representing 2.4% of the Japanese population. The association between the potency of statins and open-angle glaucoma in Japanese working-age population was examined using a commercially available health insurance claims and enrollment database. We identified 117,036 patients with a prescription of statins between January 1, 2005 and March 31, 2014; 59,535 patients were selected as new statin users. Of these, 49,671 (83%) patients without glaucoma who were prescribed statins for the first time were part of the primary analysis. New users of statin were defined as those with a prescription of statin at the beginning of the study, but without a prescription six months earlier. The cohort comprised 29,435 (59%) and 20,236 (41%) patients with a prescription of high-potency statin (atorvastatin and rosuvastatin) and low-potency statin (pravastatin, fluvastatin, pitavastatin, and simvastatin), respectively. Using Cox proportional hazards regression analysis, hazard ratios (HRs) were estimated for glaucoma adjusted for baseline characteristics. Although some baseline characteristics were not similar between the high-potency and low-potency statin groups, the standardized difference for all covariates was less than 0.1. No associations were found between high-potency statin use and glaucoma (adjusted HR = 1.08; 95% confidence interval, 0.93-1.24) in the primary analyses, using the risk for glaucoma in the low-potency statin group as reference. The risk of glaucoma with individual statin use was not significantly different from that with pravastatin. No significant association was found between high-potency statins and the increased risk of glaucoma in Japanese working-age population. Further studies are needed to examine the association between statins and glaucoma in the elderly population.

Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.

Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.

Drug Prescriptions for Children With ADHD in Japan: A Study Based on Health Insurance Claims Data Between 2005 and 2015.

Objective: The aim of this study is to investigate the trend of prescription drugs for children with ADHD in Japan. Method: Using health insurance claims data of 3,672,951 people between January 2005 and December 2015, we investigated the trend of prescription drugs for 7,856 children with ADHD. Results: After approval in 2007, the proportion of prescriptions for methylphenidate-osmotic-controlled release oral delivery system tablets was 31.4% in 2009 (adjusted odds ratio [AOR] = 2.72; 95% confidence interval [CI] = [2.12, 3.51]) and reached a plateau approximately after 2009 (AOR = 0.96; 95% CI = [0.94, 0.98]). The proportion of prescriptions for atomoxetine increased from 6.1% in 2008 to 21.8% in 2014 (AOR = 1.12; 95% CI = [1.13, 1.18]). The proportion of prescriptions for aripiprazole and ramelteon increased (all trend p < .001). Conclusion: Prescriptions of drugs for children with ADHD have changed. We need to monitor the safety of ADHD medications among children with ADHD.

Positive predictive value of ICD-10 codes for acute myocardial infarction in Japan: a validation study at a single center.

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.

The use of anticoagulants in patients with non-valvular atrial fibrillation between 2005 and 2014: A drug utilization study using claims data in Japan.

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.

Prevalence of Therapeutic Drug Monitoring for Lithium and the Impact of Regulatory Warnings: Analysis Using Japanese Claims Database.

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

Lipid-lowering drugs and risk of new-onset diabetes: a cohort study using Japanese healthcare data linked to clinical data for health screening.

OBJECTIVE: To investigate whether lipid-lowering drugs are associated with new-onset diabetes after adjusting for baseline clinical risk factors for diabetes. DESIGN: A retrospective cohort study. SETTING: Japanese employees of large corporations and their dependents using health insurance claims data linked to clinical and laboratory data for annual health screenings. PARTICIPANTS: All persons aged 20 to 74 years with dyslipidaemia between 1 January 2005 and 31 March 2011. We defined the index date as the first date when the person met the criteria for dyslipidaemia. Persons were excluded if they had lipid-lowering drugs, or had a diagnosis, a treatment or a laboratory test result (haemoglobin A1c ≥6.5% or fasting blood glucose ≥126 mg/dL) indicating diabetes during the 6-month period before the index date. MAIN OUTCOME MEASURES: New-onset diabetes. RESULTS: We identified 68 620 persons with dyslipidaemia. During the mean follow-up period of 1.96 years, 3674 persons started treatment with a lipid-lowering drug: 979 with a low potency statin, 2208 with a high potency statin and 487 with a fibrate. Of 3674 new users of a lipid-lowering drug, 3621 had a period of non-use of any lipid-lowering drugs before starting a lipid-lowering drug. Among statin users, the incidence rate of new-onset diabetes was 124.6 per 1000 person-years compared with 22.6 per 1000 person-years in non-users. After adjusting for confounding factors including clinical data in health screening using Cox proportional hazards models, the HR was 1.91 (95% CI 1.38 to 2.64) for low potency statins and 2.61 (2.11 to 3.23) for high potency statins. CONCLUSION: The use of statins was associated with a 1.9-fold to 2.6-fold increase in the risk of new-onset diabetes in a Japanese population of working age, despite adjusting for clinical risk factors for diabetes.

Proton pump inhibitors and risk of Clostridium difficile infection: a multi-country study using sequence symmetry analysis.

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

Prescription trends in children with pervasive developmental disorders: a claims data-based study in Japan.

BACKGROUND: The only drug approved for pervasive developmental disorders (PDD) in Japan is pimozide. Several psychotropic drugs are also prescribed for offlabel use in Japan, but details regarding their prescription and use are largely unknown. The purpose of this study was to clarify the use of drug treatment in Japanese children with PDD. METHODS: Data were extracted from claims data from the Japan Medical Data Center for children younger than 18 years of age who were newly diagnosed with PDD (International Classification of Diseases version 10 codes: F84) from 2005 to 2010 (total of 3276 patients as of 2010). The prescription rates were presented as the percentage of PDD patients who were prescribed each drug. RESULTS: Prior to 2010, the prescription rates for atypical antipsychotics, other antipsychotics, psychostimulants, all other central nervous system drugs, anticovnvulsants, non-barbiturates, and Parkinson's disease/syndrome drugs significantly increased among the Anatomical Therapeutic Chemical classifications defined as the "nervous system" (trend P≤0.02). The prescription rate for risperidone consistently increased, reaching 6.9% in 2010 (trend P<0.0001), the highest rate of the surveyed drugs among the antipsychotics. The prescription rate for aripiprazole also increased (trend P<0.0001), reaching 1.9% in 2010. The prescription rate for pimozide showed no annual changes, with a low rate of 0.4% in 2010. CONCLUSION: Compared with pimozide, the prescription rates for risperidone, aripiprazole and other psychotropic drugs have increased. Because safety data for these drugs in Japanese children are sparse, there is a need for future safety evaluations of these drugs in Japanese children.

Effect of high-potency statins on HbA1c in patients with or without diabetes mellitus.

BACKGROUND: The increased risk of new-onset diabetes with statin use, including high-potency statins, is well known. However, the effects of high-potency statins on HbA1c are unclear. A retrospective cohort study was conducted to examine the effect of high-potency statins on HbA1c in patients with or without diabetes. The study enrolled new statin users identified via the electronic healthcare database of the general hospital in Japan. METHODS: Following identification of all individuals (n = 4,672) who had been prescribed a lipid lowering drug at least once between January 1, 2010 and July 31, 2014, new statin users were selected (n = 1,136). Patients were excluded if they had been prescribed treatment with a statin within the preceding 6-month period. HbA1c levels before and during high-potency statin treatment were compared using the dependent t-test. In addition, the hazard ratio for the incidence of diabetes with high-potency statin treatment was estimated, using low-potency statins as a reference. RESULTS: In patients with diabetes (n = 153), mean HbA1c (%) levels significantly increased by 0.4 % after high-potency statin use (7.57 ± 1.58; p = 0.0002) compared to baseline (7.18 ± 1.37). Similarly, HbA1c (%) levels significantly increased from 5.78 ± 0.38 to 5.92 ± 0.45 (p < 0.0001) after high-potency statin use in patients without diabetes (n = 165). Furthermore, a trend toward an increase in HbA1c was found for all of the high-potency statins irrespective of a history of diabetes. CONCLUSIONS: The use of high-potency statins may increase HbA1c levels in patients with or without diabetes.