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Allopurinol‐related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA‐B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real‐world remain unelucidated. This study aimed to evaluate population differences in allopurinol‐related SCAR incidence related to genetic and/or other risk factors among East Asians in the real‐world. A population‐based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54–0.72 and 1.01–1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29–0.40 and 0.77–0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02–0.08 and 0.09–0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA‐B*58:01 against alleles responsible for phenytoin‐ or carbamazepine‐related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol‐related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol‐related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol‐related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA‐B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real‐world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol‐related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real‐world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real‐world evidence of population differences in allopurinol‐related SCAR development risk among East Asians, which was consistent with differences in reported HLA‐B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol‐related SCARs in the real‐world considering risk factors based on the patients’ ethnicity. Our approach is useful for evaluating population differences in the real‐world.

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.

Background The association between cardioprotective aspirin and risk of age-related macular degeneration (AMD) is still controversial up to date. We aimed to analyze the risk of AMD between aspirin users and non-aspirin users. Method This was a retrospective cohort study by using claims data from the National Health Insurance Research Database. Patients aged more than 45 years old who initiated aspirin during 2002 to 2012 were followed till 2013. We first selected an age and sex-matched cohort, then identified aspirin users and non-aspirin users as propensity score-matched cohort. Cox proportional hazard regression model was applied to compare their hazards and 95% confidence intervals. Incidence of newly developed AMD, neovascular AMD, and other-AMD was calculated. Results We identified 204 085 regular aspirin users and 478 048 non-aspirin users from our datasets. The univariate HR was 2.85 (95% CI, 2.75-2.96), and the multivariate HR was 2.54 (95% CI, 2.44-2.65). In the PS-matched cohort, the HR was 2.38 (95% CI, 2.25-2.52). The incidence of aspirin users for AMD risk was 11.95 per 1000 person-year, while the incidence of non-aspirin users was only 3.92 per 1000 person-year. Conclusion Patients with regular use of aspirin had higher risk in developing AMD compared to non-aspirin users and suggest to have regular visual acuity and funduscopic examination.

Purpose Home-time has been found to correlate well with modified Rankin Scale (mRS) scores in patients with stroke. This study aimed to determine its correlations in patients with different types of stroke at various time points after stroke in a non-Western population. Methods This study used linked data from multi-center stroke registry databases and a nationwide claims database of health insurance. Functional outcomes as measured with the modified Rankin Scale were obtained from the registry databases and home-time was derived from the claims database. Spearman correlation coefficients were used to assess the correlation between home-time and mRS scores. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of home-time in predicting good functional outcome. Results This study included 7959 patients hospitalized for stroke or transient ischemic attack (TIA), for whom mRS scores were available in 6809, 6694, and 4330 patients at 90, 180, and 365 days, respectively. Home-time was highly correlated with mRS scores at the three time-points in patients with ischemic (Spearman's rho -0.69 to -0.83) or hemorrhagic (Spearman's rho -0.86 to -0.88) stroke, but the correlation was only weak to moderate in those with TIA (Spearman's rho -0.32 to -0.58). Home-time predicted good functional outcome with excellent discrimination in patients with ischemic (AUCs >0.8) or hemorrhagic (AUCs >0.9) stroke but less so in those with TIA (AUCs >0.7). Conclusion Home-time was highly correlated with mRS scores and showed excellent discrimination in predicting good functional outcome in patients with ischemic or hemorrhagic stroke. Home-time could serve as a valid surrogate measure for functional outcome after stroke.

Understanding different cardiometabolic safety profiles of antipsychotics helps avoid unintended outcomes among young patients. We conducted a population-based study to compare cardiometabolic risk among different antipsychotics in children, adolescents and young adults. From Taiwan’s National Health Insurance Database, 2001–2013, we identified two patient cohorts aged 5–18 (children and adolescents) and 19–30 (young adults), diagnosed with psychiatric disorders and newly receiving antipsychotics, including haloperidol and sulpiride, and second generation antipsychotics (SGA, including olanzapine, quetiapine, risperidone, amisulpride, aripiprazole, paliperidone, and ziprasidone). Risperidone users were considered the reference group. We analyzed electronic medical records from seven hospitals in Taiwan and confirmed findings with validation analyses of identical design. Primary outcomes were composite cardiometabolic events, including type 2 diabetes mellitus, hypertension, dyslipidemia, and major adverse cardiovascular events. Multivariable Cox proportional hazards regression models compared cardiometabolic risk among antipsychotics. Among 29,030 patients aged 5–18 and 50,359 patients aged 19–30 years, we found 1200 cardiometabolic event cases during the total follow-up time of 37,420 person-years with an incidence of 32.1 per 1000 person-years. Compared to risperidone, olanzapine was associated with a significantly higher risk of cardiometabolic events in young adults (adjusted hazard ratio, 1.57; 95% CIs 1.13–2.18) but not in children and adolescents (1.85; 0.79–4.32). Specifically, we found young adult patients receiving haloperidol (1.52; 1.06–2.20) or olanzapine (1.75; 1.18–2.61) had higher risk of hypertension compared with risperidone users. Results from validation analyses concurred with main analyses. Antipsychotics’ various risk profiles for cardiometabolic events merit consideration when selecting appropriate regimes. Due to cardiometabolic risk, we suggest clinicians may consider to select alternative antipsychotics to olanzapine in children, adolescents and young adults.

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 Refereed/Peer-reviewed

Aims The risk of antipsychotic-associated cardiovascular and metabolic events may differ among countries, and limited real-world evidence has been available comparing the corresponding risks among children and young adults. We, therefore, evaluated the risks of cardiovascular and metabolic events in children and young adults receiving antipsychotics. Methods We conducted a multinational self-controlled case series (SCCS) study and included patients aged 6–30 years old who had both exposure to antipsychotics and study outcomes from four nationwide databases of Taiwan (2004–2012), Korea (2010–2016), Hong Kong (2001–2014) and the UK (1997–2016) that covers a total of approximately 100 million individuals. We investigated three antipsychotics exposure windows (i.e., 90 days pre-exposure, 1–30 days, 30–90 days and 90 + days of exposure). The outcomes were cardiovascular events (stroke, ischaemic heart disease and acute myocardial infarction), or metabolic events (hypertension, type 2 diabetes mellitus and dyslipidaemia). Results We included a total of 48 515 individuals in the SCCS analysis. We found an increased risk of metabolic events only in the risk window with more than 90-day exposure, with a pooled IRR of 1.29 (95% CI 1.20–1.38). The pooled IRR was 0.98 (0.90–1.06) for 1–30 days and 0.88 (0.76–1.02) for 31–90 days. We found no association in any exposure window for cardiovascular events. The pooled IRR was 1.86 (0.74–4.64) for 1–30 days, 1.35 (0.74–2.47) for 31–90 days and 1.29 (0.98–1.70) for 90 + days. Conclusions Long-term exposure to antipsychotics was associated with an increased risk of metabolic events but did not trigger cardiovascular events in children and young adults.

Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was -5.0 U/L (95% confidence interval [CI] -6.4, -3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI -0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was -26.5 U/L (95% CI -28.6, -24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.

BackgroundTo compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin.MethodsWe conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications.ResultsWe identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95).ConclusionThe risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

Taiwan's National Health Insurance Research Database (NHIRD) exemplifies a population-level data source for generating real-world evidence to support clinical decisions and health care policy-making. Like with all claims databases, there have been some validity concerns of studies using the NHIRD, such as the accuracy of diagnosis codes and issues around unmeasured confounders. Endeavors to validate diagnosed codes or to develop methodologic approaches to address unmeasured confounders have largely increased the reliability of NHIRD studies. Recently, Taiwan's Ministry of Health and Welfare (MOHW) established a Health and Welfare Data Center (HWDC), a data repository site that centralizes the NHIRD and about 70 other health-related databases for data management and analyses. To strengthen the protection of data privacy, investigators are required to conduct on-site analysis at an HWDC through remote connection to MOHW servers. Although the tight regulation of this on-site analysis has led to inconvenience for analysts and has increased time and costs required for research, the HWDC has created opportunities for enriched dimensions of study by linking across the NHIRD and other databases. In the near future, researchers will have greater opportunity to distill knowledge from the NHIRD linked to hospital-based electronic medical records databases containing unstructured patient-level information by using artificial intelligence techniques, including machine learning and natural language processes. We believe that NHIRD with multiple data sources could represent a powerful research engine with enriched dimensions and could serve as a guiding light for real-world evidence-based medicine in Taiwan.

Purpose The Chang Gung Research Database (CGRD), the largest multi-institutional electronic medical records (EMR) collection in Taiwan, provides good access for researchers to efficiently use the standardized patient-level data. This study evaluates the capacity and representativeness of the CGRD to promote secondary use of EMR data for clinical research with more accurate estimates. Methods The National Health Insurance Research Database (NHIRD) which covers over 99.9% of the Taiwanese population served as the comparator in this study. We compare the data components of the CGRD with the NHIRD, including records for health care facilities, patients, diagnoses, drugs, and procedures. Using the chi-square test, we compared the distributions of age categories and sex of patients, and the rates of their health conditions between NHIRD and CGRD based on the year 2015. Results The CGRD contains more clinical information such as pathological and laboratory results than the NHIRD. The CGRD includes 6.1% of outpatients and 10.2% of hospitalized patients from the NHIRD. We found the CGRD includes more elderly outpatients (23.5% vs 12.5%) and pediatric inpatients (19.7% vs 14.4%) compared with the NHIRD. We found patients' sex distributions were similar between CGRD and NHIRD, but coverage rates of severe conditions, such as cancer, were higher than other health conditions in CGRD. Conclusions The CGRD could serve as the basis for accurate estimates in medical studies. However, researchers should pay special attention to selection biases since patients' characteristics from CGRD differ from those of the national database.

INTRODUCTION Taiwan's National Health Insurance Program approved reimbursement of prophylactic coagulation factor replacement therapy (CFRT) for patients with haemophilia (PWH) in 2014. AIM To examine 15-year trends and the impact of reimbursement for prophylactic CFRT on its utilization and related medical costs for PWH. METHODS We analysed Taiwan's National Health Insurance Database from 2003 to 2017. We included patients with haemophilia A (PWHA) or B (PWHB) receiving coagulating factor. Female patients were excluded because of small sample size. We analysed annual consumption of CFRT units and medical costs. High proportion of days covered (PDC) with CFRT served as an indicator for prophylactic treatment since it reflects routine use of CFRT. We applied interrupted time series analysis (ITSA) to evaluate the impact of reimbursement for prophylactic CFRT on usage patterns and medical costs. RESULTS We included 896 male PWHA and 181 male PWHB, with 38.1% and 37.0% aged under 18 years, respectively. By ITSA, we found the trends in coagulation factor consumption and PDC significantly increased after reimbursement for prophylactic CFRT in both PWHA and PWHB (p values for trend change

Background Antipsychotics remain the first choice of treatment for post-stroke psychosis, despite an increased risk of mortality reported in elderly patients. We aimed to compare the mortality risk among antipsychotics in elderly patients with stroke using the stroke registry for external adjustment. Methods We conducted a retrospective cohort study to identify patients aged above 65 years who were admitted for stroke in the National Health Insurance Database (NHID) from 2002 to 2014. The first date of antipsychotic use after the stroke hospitalization was defined as the index date. Covariates including diseases, medications and external information on smoking, BMI, stroke severity and disability, that were unavailable in the NHID were obtained from the linked Multicenter Stroke Registry (MSR) and used for propensity score calibration (PSC). The main outcome was one-year all-cause mortality. Results Stroke patients in the NHID prescribed with haloperidol, quetiapine and risperidone numbered 22,235, 28,702 and 8 663, respectively. In the PSC-adjusted analyses, haloperidol [adjusted hazard ratio (aHR) = 1.22; 95% CI 1.18–1.27] and risperidone (aHR = 1.31; 95% CI 1.24–1.38) users had a higher mortality risk than quetiapine users. When the dosage was higher than 0.5 defined daily dose (DDD), haloperidol and risperidone users had a significant mortality risk as compared with those taking a lower dose. Conclusions In post-stroke elderly patients, quetiapine would pose less mortality risk than risperidone and haloperidol at doses higher than 0.5 DDD. When haloperidol or risperidone is indicated, starting with a lower dose is suggested to avoid excess risk.

Antihypertensive medications have represented a tremendous financial burden to the health care plan globally. The utilization pattern of the antihypertensive agents was examined in this study to analyze the underlying reasons responsible for the pharmaceutical expenditure in Taiwan during 1997 to 2002. The claims data were obtained from National Health Insurance Research Database (NHIRD), which include ambulatory service record and prescription data of the entire population. Drug expenditure was decomposed into 5 components: relative drug price, number of patients treated, average physician visit per patient, defined daily dose (DDD) per physician visit and a residual. Total antihypertensive drug spending increased 102% during this period, mainly due to the compounding effect from the increment of patients treated (34%) and DDD per physician visit (33%). The aggregate residual for antihypertensive agents only exerts a 7% effect. Detailed residual analysis revealed that the brand-name product did have 11% increment, while the generic product had a 12% decrement. It also showed that hospital sector had a positive 11% residual, while primary care clinics had an 11% decrement. The most important factors that contribute to the expenditure surge of antihypertensive agents are the number of treated patients and DDD per physician visit. While physicians at the hospital sector adopted more new and innovative medications, their counterparts at the primary care clinics tended to switch some off-patent products to the generics.

This study aimed to evaluate the long term impact of a new pharmacological class antihypertensive medicine-angiotensin Ⅱ antagonist (AIIA) on the clinical utilization of existing antihypertensive medications in Taiwan. Claims data of medical service and prescriptions of antihypertensive agents during 1997 to 2002 were obtained from National Health Insurance Research Database (NHIRD). Gross growth of defined daily dose (DDD) and prescription numbers, clinical market share and prescription market share analysis, market penetration time and DDDs/prescription were used to assess AIIA's impact on the angiotensin converting enzyme inhibitors (ACEI), s-Blockers, calcium channel blockers (CCB) and other miscellaneous antihypertensive agents. CCB had the highest gross growth of DDDs and prescription at 117.1 and 3.4 million increments, respectively. Analysis of clinical market share revealed that the introduction of AIIA had the most significant impact to the clinical utilization of miscellaneous antihypertensive agents (-5.5%) and a moderate impact on both s-blockers (-4.5%) and ACEI (-4.1%). Whereas the greatest impact of prescription market share was observed with miscellaneous antihypertensive agents (-6.5%), a moderate impact with ACEI (-2.3%) and a very minor impact with s-blockers (-0.9%). CCB, however, had a positive clinical market share (+3.9%) and prescription market share (+2.4%) correlated with AIIA. AIIA utilization implicated by relative growth strength for the clinical market share and prescription market share at medical center, regional hospital, district hospital and primary care clinic were 4.95:3.77:2.77:1 and 5.28:4.17:2.94:1, respectively. The introduction of AIIA did not affect the decreasing trend of clinical utilization of miscellaneous antihypertensive agents and s-blockers since this downtrend started before AIIA introduction. On the other hand, there was increasing usage of CCB and AIIA to control hypertension in Taiwan. Medical centers were the early adaptors for AIIA and played an important role in the utilization diffusion of AIIA.

PURPOSE Magnesium stearate (MgSt) is a widely used excipient in pharmaceutical formulations but should be avoided in aspirin preparations as it hydrolyzes aspirin. We hypothesized that preparations of aspirin-containing MgSt (MgSt-ASA) are less effective in preventing thrombosis in clinical settings. The risk of composite cardiovascular events in patients treated with MgSt-ASA preparations for preventing secondary stroke was evaluated. METHODS This retrospective cohort study used Taiwan's claims data from 1997 to 2013. Patients who were discharged after ischemic stroke (IS) and administered with only MgSt-ASA or non-MgSt-ASA preparations were enrolled. Composite events including all-cause mortality, IS hospitalization, and myocardial infarction-related hospitalization in the follow-up period under therapy with MgSt-ASA or non-MgSt-ASA preparations were considered primary outcomes. Hazard ratios (HRs) were adjusted with the baseline comorbidities and medications using the Cox model. RESULTS A total of 19 500 patients with IS (60% males, average age 67 years) were identified, which included 2064 patients receiving MgSt-ASA treatment initially and 17 436 patients receiving non-MgSt-ASA preparation initially. The crude incidence of composite events was 11.65 per 100 person-years, whereas it was 11.45 and 13.90 per 100 person-years for patients receiving non-MgSt-ASA and MgSt-ASA treatments, respectively. The risk of composite events was higher in patients receiving MgSt-ASA preparations than in those receiving non-MgSt-ASA formulations, with the adjusted HR being 1.23 at 95% confidence interval of 1.02 to 1.47. CONCLUSIONS MgSt-ASA preparation use was associated with a higher risk of composite events than non-MgSt-ASA preparations. Review of aspirin formulations under regulatory intervention is warranted.

Tamoxifen or aromatase inhibitor (AI) therapy may prevent breast cancer recurrence, however, adverse effects may lead to treatment discontinuation. Evidence regarding the occurrence of AI-associated musculoskeletal problems among Asians is scarce. We identified women with breast cancer-initiating tamoxifen or AIs from the Taiwan National Health Insurance Research Database (2007&ndash, 2012). Using multivariable cause-specific hazard models, we examined the association between endocrine therapy and the risk of any arthritis and carpal tunnel syndrome, adjusting for age, prior cancer treatment, and other health status factors. Among 32,055 eligible women with breast cancer (mean age = 52.6 &plusmn, 11.5 years), 87.4% initiated tamoxifen, 3.9% initiated anastrozole, 8.0% initiated letrozole, and 0.7% initiated exemestane. AI users had a higher 1-year cumulative incidence for any arthritis (13.0% vs. 8.2%, p &lt, 0.0001) and carpal tunnel syndrome (1.4% vs. 0.8%, p = 0.008). Compared to tamoxifen users, AI users had a higher risk of any arthritis [adjusted hazard ratio (aHR) = 1.21, 95%CI = 1.09&ndash, 1.34] and carpal tunnel syndrome (aHR = 1.68, 95%CI = 1.22&ndash, 2.32). No significant difference was observed in the risks of any arthritis and carpal tunnel syndrome across different AIs. Taxane use was not associated with any arthritis (aHR = 0.92, 95%CI = 0.81&ndash, 1.05) or carpal tunnel syndrome (aHR = 0.97, 95%CI = 0.67&ndash, 1.40) compared to other chemotherapies. Taiwanese women with breast cancer-initiating AIs had an increased risk of arthritis and carpal tunnel syndrome compared to those who initiated tamoxifen.

Purpose Home-time has been found to correlate well with modified Rankin Scale (mRS) scores in patients with stroke. This study aimed to determine its correlations in patients with different types of stroke at various time points after stroke in a non-Western population. Methods This study used linked data from multi-center stroke registry databases and a nationwide claims database of health insurance. Functional outcomes as measured with the modified Rankin Scale were obtained from the registry databases and home-time was derived from the claims database. Spearman correlation coefficients were used to assess the correlation between home-time and mRS scores. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of home-time in predicting good functional outcome. Results This study included 7959 patients hospitalized for stroke or transient ischemic attack (TIA), for whom mRS scores were available in 6809, 6694, and 4330 patients at 90, 180, and 365 days, respectively. Home-time was highly correlated with mRS scores at the three time-points in patients with ischemic (Spearman’s rho −0.69 to −0.83) or hemorrhagic (Spearman’s rho −0.86 to −0.88) stroke, but the correlation was only weak to moderate in those with TIA (Spearman’s rho −0.32 to −0.58). Home-time predicted good functional outcome with excellent discrimination in patients with ischemic (AUCs >0.8) or hemorrhagic (AUCs >0.9) stroke but less so in those with TIA (AUCs >0.7). Conclusion Home-time was highly correlated with mRS scores and showed excellent discrimination in predicting good functional outcome in patients with ischemic or hemorrhagic stroke. Home-time could serve as a valid surrogate measure for functional outcome after stroke.

Background: Antipsychotics remain the first choice of treatment for post-stroke psychosis, despite an increased risk of mortality reported in elderly patients. We aimed to compare the mortality risk among antipsychotics in elderly patients with stroke using the stroke registry for external adjustment. Methods: We conducted a retrospective cohort study to identify patients aged above 65 years who were admitted for stroke in the National Health Insurance Database (NHID) from 2002 to 2014. The first date of antipsychotic use after the stroke hospitalization was defined as the index date. Covariates including diseases, medications and external information on smoking, BMI, stroke severity and disability, that were unavailable in the NHID were obtained from the linked Multicenter Stroke Registry (MSR) and used for propensity score calibration (PSC). The main outcome was one-year all-cause mortality Findings: Stroke patients in the NHID prescribed with haloperidol, quetiapine and risperidone numbered 22 235, 28 702 and 8 663, respectively. In the PSC-adjusted analyses, haloperidol [adjusted hazard ratio (aHR) = 1.22; 95% CI 1.18–1.27] and risperidone (aHR = 1.31; 95% CI 1.24–1.38) users had a higher mortality risk than quetiapine users. Haloperidol and risperidone exhibited a dose-response relationship with mortality risk after controlling for confounders. When the dosage was higher than 0.5 defined daily dose (DDD), haloperidol and risperidone users had a significant mortality risk as compared with those taking a lower dose. The sensitivity analyses showed similar patterns. Interpretation: In post-stroke elderly patients, quetiapine would be favored over risperidone and haloperidol at doses higher than 0.5 DDD. When haloperidol or risperidone is indicated, starting with a lower dose is suggested to avoid excess risk. Funding Statement: This research was supported in part by the Ministry of Science and Technology, Taiwan [grant number MOST 107-2320-B-006-035]. Declaration of Interests: The authors declare they have no conflict of interest with respect to this research study and paper. Ethics Approval Statement: The research protocol was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB No. A-EX-106-016).

ObjectiveTo evaluate the influence of pharmacists' dispensing workload (PDW) on pharmacy services as measured by prescription suggestion rate (PSR) and dispensing error rate (DER).MethodThis was an observational study in northern and southern Taiwan's two largest medical centers, from 2012 to 2018. We calculated monthly PDW as number of prescriptions divided by number of pharmacist working days. We used monthly PSR and DER as outcome indicators for pharmacists' review and dispensing services, respectively. We used Poisson regression model with generalized estimation equation methods to evaluate the influence of PDW on PSR and DER.ResultsThe monthly mean of 463,587 (SD 32,898) prescriptions yielded mean PDW, PSR and DER of 52 (SD 3) prescriptions per pharmacist working days, 30 (SD 7) and 8 (SD 2) per 10,000 prescriptions monthly, respectively. There was significant negative impact of PDW on PSR (adjusted rate ratio, aRR: 0.9786; 95%CI: 0.9744-0.9829) and DER (aRR: 0.9567; 95%CI: 0.9477-0.9658). Stratified analyses by time periods (2012-2015 and 2016-2018) revealed the impact of PDW on PSR to be similar in both periods; but with positive association between PDW and DER in the more recent one (aRR: 1.0086, 95%CI: 1.0003-1.0169).ConclusionsReduced pharmacist workload was associated with re-allocation of pharmacy time to provide prescription suggestions and, more recently, decrease dispensing errors. Continuous efforts to maintain appropriate workload for pharmacists are recommended to ensure prescription quality.

Additional file 1: Figure S1. Overview of Study design. Table S1. ICD codes for co-morbidity. Table S2. List for co-medication. Table S3. As-treated analyses of the changes in clinical parameters from the baseline to 1 year post treatment. Table S4. Subgroup analyses of the changes in clinical parameters from the baseline to 1 year post treatment.

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

Background There are few data on ticagrelor in Asian patients. This study evaluated clinical outcomes with ticagrelor and clopidogrel in Taiwanese patients with acute myocardial infarction (AMI).Methods and Results:We used the Taiwan National Health Insurance Research Database to identify 27,339 AMI patients aged ≥18 years between January 2012 and December 2014, and only patients who survived greater than or equal to 30 days after AMI and took dual antiplatelet therapy were included. Cohorts of ticagrelor and clopidogrel were matched 1:8, based on propensity score matching, to balance baseline covariates. The primary efficacy endpoints were death from any cause, AMI, or stroke. The safety endpoints consisted of major gastrointestinal bleeding or intracerebral hemorrhage. Following propensity matching, the primary efficacy endpoint rate was 22% lower in the ticagrelor group than in the clopidogrel group (10.6% and 16.2%, respectively; adjusted HR, 0.779; 95% CI: 0.684-0.887). The safety endpoint rate was similar between the ticagrelor and clopidogrel groups (3.2% and 4.1% respectively; adjusted HR, 0.731; 95% CI: 0.522-1.026). Conclusions In real-world AMI Taiwanese patients, ticagrelor seemed to offer better anti-ischemic protection than clopidogrel, without an increase in the rate of major bleeding. A large-scale randomized trial is needed to assess the efficacy and safety of ticagrelor in East Asian AMI patients.

Background Stroke severity is an important outcome predictor for intracerebral hemorrhage (ICH) but is typically unavailable in administrative claims data. We validated a claims-based stroke severity index (SSI) in patients with ICH in Taiwan. Methods Consecutive ICH patients from hospital-based stroke registries were linked with a nationwide claims database. Stroke severity, assessed using the National Institutes of Health Stroke Scale (NIHSS), and functional outcomes, assessed using the modified Rankin Scale (mRS), were obtained from the registries. The SSI was calculated based on billing codes in each patient's claims. We assessed two types of criterion-related validity (concurrent validity and predictive validity) by correlating the SSI with the NIHSS and the mRS. Logistic regression models with or without stroke severity as a continuous covariate were fitted to predict mortality at 3, 6, and 12 months. Results The concurrent validity of the SSI was established by its significant correlation with the admission NIHSS (r = 0.731; 95% confidence interval [CI], 0.705–0.755), and the predictive validity was verified by its significant correlations with the 3-month (r = 0.696; 95% CI, 0.665–0.724), 6-month (r = 0.685; 95% CI, 0.653–0.715) and 1-year (r = 0.664; 95% CI, 0.622–0.702) mRS. Mortality models with NIHSS had the highest area under the receiver operating characteristic curve, followed by models with SSI and models without any marker of stroke severity. Conclusions The SSI appears to be a valid proxy for the NIHSS and an effective adjustment for stroke severity in studies of ICH outcome with administrative claims data.

Compared with other countries, Taiwan has had relatively few cases during the COVID-19 pandemic. One of the many measures the government implemented was a system for rationing and distributing surgical masks to the public while prioritizing allocation of masks to health care workers. This essay describes the role of community pharmacists in implementing the system and distributing masks to the public.

Background Sodium glucose cotransporter 2 (SGLT2) inhibitors have shown greater reductions of cardiovascular event risks than dipeptidyl peptidase-4 (DPP4) inhibitors, whereby possible mechanisms may involve the better pleiotropic effects of SGLT2 inhibitors. However, no published data are currently available to directly compare glycemic and pleiotropic effects in real-world type 2 diabetes patients initiating SGLT2 inhibitors or DPP4 inhibitors. Method We conducted a retrospective cohort study by analyzing the Chang Gung Research Database, the largest multi-institutional electronic medical records database in Taiwan. We included patients newly receiving SGLT2 inhibitor or DPP4 inhibitor intensification therapy for type 2 diabetes from 2016 to 2017. We matched SGLT2 inhibitor users to DPP4 inhibitor users (1:4) by propensity scores to ensure comparable characteristics between the groups. We primarily evaluated 1-year post-treatment changes of hemoglobin A1c (HbA1c) after SGLT2 inhibitor or DPP4 inhibitor initiation, using two-tailed independent t-test. We also evaluated post-treatment changes in body weight, systolic blood pressure (SBP), alanine aminotransferase (ALT) and estimated glomerular filtration rate (eGFR) values, associated with SGLT2 inhibitors and DPP4 inhibitors. Results We identified a cohort of 2028 SGLT2 inhibitors and 8112 matched DPP4 inhibitors new users. SGLT2 inhibitors and DPP4 inhibitors showed similar HbA1c reductions (− 1.0 vs. − 1.1%; P = 0.076), but patients receiving SGLT2 inhibitors had greater improvements in body weight (− 1.5 vs. − 1.0 kg; P = 0.008), SBP (− 2.5 vs. − 0.7 mmHg; P 2; P Conclusion SGLT2 inhibitors had glucose-lowering effects comparable to those of DPP4 inhibitors but more favorable pleiotropic effects on body weight, ALT and eGFR changes, potentially improving type 2 diabetes patients’ cardio-metabolic disease risks.

Understanding different cardiometabolic safety profiles of antipsychotics helps avoid unintended outcomes among young patients. We conducted a population-based study to compare cardiometabolic risk among different antipsychotics in children, adolescents and young adults. From Taiwan's National Health Insurance Database, 2001-2013, we identified two patient cohorts aged 5-18 (children and adolescents) and 19-30 (young adults), diagnosed with psychiatric disorders and newly receiving antipsychotics, including haloperidol and sulpiride, and second generation antipsychotics (SGA, including olanzapine, quetiapine, risperidone, amisulpride, aripiprazole, paliperidone, and ziprasidone). Risperidone users were considered the reference group. We analyzed electronic medical records from seven hospitals in Taiwan and confirmed findings with validation analyses of identical design. Primary outcomes were composite cardiometabolic events, including type 2 diabetes mellitus, hypertension, dyslipidemia, and major adverse cardiovascular events. Multivariable Cox proportional hazards regression models compared cardiometabolic risk among antipsychotics. Among 29,030 patients aged 5-18 and 50,359 patients aged 19-30 years, we found 1200 cardiometabolic event cases during the total follow-up time of 37,420 person-years with an incidence of 32.1 per 1000 person-years. Compared to risperidone, olanzapine was associated with a significantly higher risk of cardiometabolic events in young adults (adjusted hazard ratio, 1.57; 95% CIs 1.13-2.18) but not in children and adolescents (1.85; 0.79-4.32). Specifically, we found young adult patients receiving haloperidol (1.52; 1.06-2.20) or olanzapine (1.75; 1.18-2.61) had higher risk of hypertension compared with risperidone users. Results from validation analyses concurred with main analyses. Antipsychotics' various risk profiles for cardiometabolic events merit consideration when selecting appropriate regimes. Due to cardiometabolic risk, we suggest clinicians may consider to select alternative antipsychotics to olanzapine in children, adolescents and young adults.

Background Hemodialysis patients have a high risk of mortality. The most common causes of death are cardiovascular disease and infection. The potential hazard or benefit associated with vitamin D use and cardiovascular or infection outcome is poorly characterized. Methods We conducted a retrospective observational cohort study by recruiting 52,757 patients older than 20 years from Taiwan National Health Insurance Research Database (NHIRD) who initiated maintenance hemodialysis between 2001 and 2009. Patients who were prescribed activated vitamin D before the 360th day from hemodialysis initiation were defined as vitamin D users. The primary outcome of interest includes occurrence of acute myocardial infarction (AMI), ischemic stroke, lower limb amputation, and hospitalization for infection, respectively, while death events are treated as competing events. We conducted competing risk analysis using subdistribution hazard regression model to estimate subdistribution hazard ratios (SHRs) in relation to various outcomes. Results During the median follow-up of 1019 days, the vitamin D users had a lower crude mortality rate, lower incidences of AMI, ischemic stroke, amputation, and hospitalization for infection compared with non-users. Taking into consideration competing events of death, vitamin D users were associated with a lower hazard of lower limb amputation (SHR 0.84 [95% CI, 0.74–0.96]) and hospitalization for infection (SHR 0.90 [95% CI, 0.87–0.94]), but not AMI or ischemic stroke, after adjustment for potential confounders. Subgroup analyses and dose response evaluation both showed a consistent association of activated vitamin D treatment with decreased risk of amputation and infection. Conclusion The findings suggest that therapeutic activated vitamin D use in hemodialysis patients may be beneficial for decreasing infection events and amputation, of which the latter is a complication of peripheral vascular disease, rather than reducing major atherosclerotic cardiovascular events such as AMI or ischemic stroke.

To investigate the incidence of new onset type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors (dutasteride or finasteride) for long term treatment of benign prostatic hyperplasia.Population based cohort study.UK Clinical Practice Research Datalink (CPRD; 2003-14) and Taiwanese National Health Insurance Research Database (NHIRD; 2002-12).Men in the CPRD who received dutasteride (n=8231), finasteride (n=30 774), or tamsulosin (n=16 270) were evaluated. Propensity score matching (2:1; dutasteride to finasteride or tamsulosin) produced cohorts of 2090, 3445, and 4018, respectively. In the NHIRD, initial numbers were 1251 (dutasteride), 4194 (finasteride), and 86 263 (tamsulosin), reducing to 1251, 2445, and 2502, respectively, after propensity score matching.Incident type 2 diabetes using a Cox proportional hazard model.In the CPRD, 2081 new onset type 2 diabetes events (368 dutasteride, 1207 finasteride, and 506 tamsulosin) were recorded during a mean follow-up time of 5.2 years (SD 3.1 years). The event rate per 10 000 person years was 76.2 (95% confidence interval 68.4 to 84.0) for dutasteride, 76.6 (72.3 to 80.9) for finasteride, and 60.3 (55.1 to 65.5) for tamsulosin. There was a modest increased risk of type 2 diabetes for dutasteride (adjusted hazard ratio 1.32, 95% confidence interval 1.08 to 1.61) and finasteride (1.26, 1.10 to 1.45) compared with tamsulosin. Results for the NHIRD were consistent with the findings for the CPRD (adjusted hazard ratio 1.34, 95% confidence interval 1.17 to 1.54 for dutasteride, and 1.49, 1.38 to 1.61 for finasteride compared with tamsulosin). Propensity score matched analyses showed similar results.The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5α-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.