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.

Trends in coagulation factor replacement therapy and medical costs in patients with haemophilia in Taiwan: A population-based, 15-year analysis.

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 <0.05). The overall medical costs per patient increased with increasing consumption of coagulation factor; however, ITSA revealed non-CFRT cost decreased after reimbursement of prophylactic CFRT for both PWHA and PWHB (p values <.05). CONCLUSION: Reimbursement for prophylactic CFRT facilitated growth in rates of prophylactic CFRT and increased related costs, but curbed rising non-CFRT costs. These findings provide strong grounds for future cost-effectiveness studies to leverage prophylactic CFRT for its therapeutic benefits.

Comparative cardiometabolic risk of antipsychotics in children, adolescents and young adults.

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.

Favorable pleiotropic effects of sodium glucose cotransporter 2 inhibitors: head-to-head comparisons with dipeptidyl peptidase-4 inhibitors in type 2 diabetes patients.

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 < 0.001) and ALT values (- 4.1 vs. - 0.0 U/l; P < 0.001) and smaller declines in eGFR values (- 2.0 vs. - 3.5 ml/min/1.73 m2; P < 0.001) when compared to DPP4 inhibitors. 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.

Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study.

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.

The use of activated vitamin D and risks of hospitalization for infection and amputation in incident hemodialysis patients in Taiwan: a nationwide population-based cohort study.

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.

Increased risk of coronary heart disease among patients with idiopathic inflammatory myositis: a nationwide population study in Taiwan.

OBJECTIVE: To evaluate the risk of incident coronary heart disease (CHD) among patients with DM and PM in a general population context. METHODS: We conducted a retrospective cohort study using the Taiwan National Health Insurance Research Database containing records covering the years from 2000 to 2010. DM and PM were confined for the purposes of this study to those aged ⩾18 years who were eligible for the Taiwan catastrophic illness certificate. The diagnoses, CHD outcomes and cardiovascular risk factors were identified from electronic claims data. We conducted two cohort analyses: CHD and DM, and CHD and PM, excluding for each analysis individuals with CHD already identified at baseline. Data for the comparison group was obtained from the Longitudinal Health Insurance database, comprising 1 million persons randomly sampled from the total beneficiaries during 2000. We estimated hazard ratios comparing myositis with comparison cohorts, adjusting for potential cardiovascular risk factors. RESULTS: A total of 1145 patients with idiopathic myositis were identified, along with 732 723 control patients aged ⩾18 years. The incidence rates of CHD were 15.1 in DM and 30.1 in PM per 1000 person-years, vs 8.4 and 10.5 per 1000 person-years in the comparison cohort. The adjusted hazard ratios for CHD in patients with idiopathic myositis were 2.21 (95% CI 1.64, 2.99) for DM and 3.73 (95% CI 2.83, 4.90) for PM. CONCLUSION: Results of this general population-based cohort study suggest that DM and PM are associated with an increased risk of CHD.

Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study.

BACKGROUND: To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. METHODS: We 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. RESULTS: We 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). CONCLUSION: The 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.

The Chang Gung Research Database-A multi-institutional electronic medical records database for real-world epidemiological studies 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.

Detecting Potential Adverse Drug Reactions Using a Deep Neural Network Model.

BACKGROUND: Adverse drug reactions (ADRs) are common and are the underlying cause of over a million serious injuries and deaths each year. The most familiar method to detect ADRs is relying on spontaneous reports. Unfortunately, the low reporting rate of spontaneous reports is a serious limitation of pharmacovigilance. OBJECTIVE: The objective of this study was to identify a method to detect potential ADRs of drugs automatically using a deep neural network (DNN). METHODS: We designed a DNN model that utilizes the chemical, biological, and biomedical information of drugs to detect ADRs. This model aimed to fulfill two main purposes: identifying the potential ADRs of drugs and predicting the possible ADRs of a new drug. For improving the detection performance, we distributed representations of the target drugs in a vector space to capture the drug relationships using the word-embedding approach to process substantial biomedical literature. Moreover, we built a mapping function to address new drugs that do not appear in the dataset. RESULTS: Using the drug information and the ADRs reported up to 2009, we predicted the ADRs of drugs recorded up to 2012. There were 746 drugs and 232 new drugs, which were only recorded in 2012 with 1325 ADRs. The experimental results showed that the overall performance of our model with mean average precision at top-10 achieved is 0.523 and the rea under the receiver operating characteristic curve (AUC) score achieved is 0.844 for ADR prediction on the dataset. CONCLUSIONS: Our model is effective in identifying the potential ADRs of a drug and the possible ADRs of a new drug. Most importantly, it can detect potential ADRs irrespective of whether they have been reported in the past.

Cardiovascular and Bleeding Risks in Acute Myocardial Infarction Newly Treated With Ticagrelor vs. Clopidogrel in Taiwan.

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.

Comparative safety of NSAIDs for gastrointestinal events in Asia-Pacific populations: A multi-database, international cohort study.

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.

Assessing the effect of oral activated vitamin D on overall survival in hemodialysis patients: a landmark analysis.

BACKGROUND: Patients with end stage renal disease have a high all-cause and cardiovascular mortality. Secondary hyperparathyroidism and vitamin D deficiency are considered part of the mechanism for the excess mortality observed. We aimed to evaluate the relationship between vitamin D use and all-cause mortality. METHODS: In this retrospective cohort study, we included all incident patients who started hemodialysis in Taiwan between 2001 and 2009. Patients were followed from landmark time, i.e., the 360th day from hemodialysis initiation, through the end of 2010 or death. We evaluated the association between activated vitamin D use or not before landmark time and all-cause mortality using conditional landmark analysis with Cox regression. We used group-based trajectory model to categorize high-dose versus average-dose users to evaluate dose-response relationships. RESULTS: During the median follow-up of 1019 days from landmark time, vitamin D users had a lower crude mortality rate than non-users (8.98 versus 12.93 per 100 person-years). Compared with non-users, vitamin D users was associated with a lower risk of death in multivariate Cox model (HR 0.91 [95% CI, 0.87-0.95]) and after propensity score matching (HR 0.94 [95% CI, 0.90-0.98]). High-dose vitamin D users had a lower risk of death than conventional-dose users, HR 0.75 [95% CI, 0.63-0.89]. The association of vitamin D treatment with reduced mortality did not alter when we re-defined landmark time as the 180th day or repeated analyses in patients who underwent hemodialysis in the hospital setting. CONCLUSIONS: Our findings supported the survival benefits of activated vitamin D among incident hemodialysis patients.

Pay for performance program reduces treatment needed diabetic retinopathy - a nationwide matched cohort study in Taiwan.

BACKGROUND: Pay-for-Performance programs have shown improvement in indicators monitoring adequacy and target achievement in diabetic care. However, less is known regarding the impact of this program on the occurrence and long-term effects of diabetic retinopathy. The objective of this study was to determine the effect of pay-for-performance program on the development of treatment needed for diabetic retinopathy in type 2 diabetes patients. METHODS: We conducted a nationwide retrospective cohort study with a matching design using the Taiwan National Health Insurance Research Database from 2000 to 2012. The outcome was defined as the treatment needed diabetic retinopathy. We matched Pay-for-Performance and non-Pay-for-Performance groups for age, gender, year diabetes was diagnosed and study enrollment, and duration of follow-up. RESULTS: A total of 9311 patients entered the study cohort, of whom 2157 were registered in the Pay-for-Performance group and 7154 matched in the non-Pay-for-Performance group. The incidence of treatment needed diabetic retinopathy was not significantly different in two groups. However, the incidence of treatment needed diabetic retinopathy was significantly different if restricted the non-Pay-for-Performance group who had at least 1 eye examination or optical coherence tomography within 1 year (adjusted hazard ratio, 0.78; 95% confidence interval, 0.64-0.94). CONCLUSIONS: Pay-for-Performance is valuable in preventing the development of treatment needed diabetic retinopathy, which could be attributed to the routine eye examination required in the Pay-for-Performance program. We could improve our diabetic care by promoting eye health education and patient awareness on the importance of regular examinations.

Sequence symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies.

Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice. SSA is based on analyzing the sequences of medications; if one medication (drug B) is more often initiated after another medication (drug A) than before, it may be an indication of an adverse effect of drug A. The main advantage of the method is that it requires a minimal dataset and is computationally efficient. By design, SSA controls time-constant confounders. However, the validity of SSA may be affected by time-varying confounders, as well as by time trends in the occurrence of exposure or outcome events. Trend effects may be adjusted by modeling the expected sequence ratio in the absence of a true association. There is a potential for false positive or negative results and careful consideration should be given to potential sources of bias when interpreting the results of SSA studies.

Risks of newly onset hemorrhagic stroke in patients with neovascular age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) is an eye disease causing blindness in the elderly. It shares many common possible pathogenic mechanisms with cardiovascular diseases. Many studies have discussed the association between AMD and stroke, but the results were inconsistent. Our aim was to determine the associations between neovascular AMD and the risk of stroke in the Taiwanese population. METHODS: This is a retrospective cohort study. We used claims data from National Health Insurance Research Database. Patients aged more than 45 years without stroke, myocardial infarction, or any AMD were selected from 2001 to 2008 and followed until 2010. The index date was defined as the date of nAMD diagnosis (ICD-9 code, 362.52). The comparison group was patients without an nAMD diagnosis with age- and sex-matched to nAMD subjects at a ratio of up to 10 to 1. Kaplan-Meier survival analysis and Cox regression analysis were used. The incidence of stroke events (ICD-9 codes, 430-434) and their subtypes (hemorrhagic and ischemic) were primary outcomes. Secondary outcomes included acute myocardial infarction (AMI), composite AMI/stroke, and all-cause mortality. RESULTS: Patients with nAMD had a higher risk of developing stroke, with an adjusted HR of 1.30 (95% CI, 1.01-1.68). A higher risk for hemorrhagic stroke (HR, 1.70, 95% CI, 1.03-2.83) was also found. No significant differences were observed in ischemic stroke, the composite of AMI/stroke, and all-cause mortality. CONCLUSIONS: Patients with nAMD had a significantly higher risk of developing stroke, which was driven mainly by the increased risk of developing the hemorrhagic subtype.

Statin Adherence After Ischemic Stroke or Transient Ischemic Attack Is Associated With Clinical Outcome.

BACKGROUND: Statin therapy is beneficial for ischemic stroke patients, but little is known about whether statin adherence affects clinical outcome. We therefore evaluated the effect of statin adherence in patients with ischemic stroke or transient ischemic attack (TIA). METHODS AND RESULTS: From Taiwan Bureau of National Health Insurance database, we enrolled patients with no prior statin therapy admitted for ischemic stroke or TIA between January 2002 and December 2005. Patients were grouped based on statin adherence according to medication possession ratio (MPR): good adherence (MPR >80%; n=2,274), intermittent adherence (MPR=40-80%; n=3,710), and poor adherence (MPR <40%; n=9,424). The study endpoint was the composite outcome of recurrent ischemic stroke, hemorrhagic stroke, and acute coronary event 1 year after statin initiation. Follow-up data were obtained through December 2010. During follow-up, composite endpoints occurred in 5,354 patients (34.7%): good adherence, 798 patients (35.1%); intermittent adherence, 1,338 patients (36.1%); and poor adherence, 3,218 patients (34.1%). Compared with the good adherence group, patients in the poor adherence group and intermittent adherence group had higher risk of worse clinical outcome (adjusted HR, 1.26 and 1.16, respectively; 95% CI: 1.17-1.37 and 1.07-1.27, respectively). CONCLUSIONS: Good statin adherence was associated with better clinical outcome in patients with acute ischemic stroke or TIA. (Circ J 2016; 80: 731-737).

Comparative risk of oral ulcerations among antipsychotics users - population-based retrospective cohort study.

PURPOSE: The study aimed to evaluate the comparative risk of oral ulcerations among antipsychotic medications. METHODS: We analyzed the National Health Insurance Research Database of Taiwan and included patients newly initiated with a single antipsychotic agent including haloperidol, sulpiride, olanzapine, quetiapine, risperidone, or amisulpride during 2002 to 2010. The outcome of interest was oral ulceration, defined by the presence diagnoses of stomatitis and mucositis, aphthous-like ulceration and oral burns, or dispensing of stomatological corticosteroids included triamcinolone, dexamethasone, hydrocortisone, and prednisolone. We conducted Cox proportional hazards regression to compare the risks of oral ulceration among antipsychotics. RESULTS: The rate of oral ulcerations was highest in the amisulpride group (217.7 per 1000 person-year), followed by quetiapine (193.9 per 1000 person-year), olanzapine (161.9 per 1000 person-year), sulpiride (147.1 per 1000 person-year), risperidone (115.6 per 1000 person-year), haloperidol (107.5 per 1000 person-year) and aripiprazole (49.8 per 1000 person-year). Compared with haloperidol users, the adjusted hazard ratio (AHR) was 1.40 (95% CI, 1.12-1.73) in olanzapine, 1.48 (95% CI, 1.30-1.69) in quetiapine, 1.27 (95% CI, 1.19-1.44) in sulpiride, 1.68 (95% CI, 0.97-2.59) in amisulpride, 1.02 (95% CI, 0.83-1.45) in risperidone, and 0.41 (95% CI, 0.24-0.72) in aripiprazole users by Cox regression model. CONCLUSION: Olanzapine, quetiapine, and sulpiride posed a higher risk, while aripiprazole posed a lower risk of oral ulcerations compared with haloperidol in subjects with newly initiated antipsychotic therapy. Risperidone and amisulpride tended to have higher risk of oral ulcerations, but this was not statistically significant.

Validity of a stroke severity index for administrative claims data research: a retrospective cohort study.

BACKGROUND: Ascertaining stroke severity in claims data-based studies is difficult because clinical information is unavailable. We assessed the predictive validity of a claims-based stroke severity index (SSI) and determined whether it improves case-mix adjustment. METHODS: We analyzed patients with acute ischemic stroke (AIS) from hospital-based stroke registries linked with a nationwide claims database. We estimated the SSI according to patient claims data. Actual stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) and functional outcomes measured with the modified Rankin Scale (mRS) were retrieved from stroke registries. Predictive validity was tested by correlating SSI with mRS. Logistic regression models were used to predict mortality. RESULTS: The SSI correlated with mRS at 3 months (Spearman rho = 0.578; 95 % confidence interval [CI], 0.556-0.600), 6 months (rho = 0.551; 95 % CI, 0.528-0.574), and 1 year (rho = 0.532; 95 % CI 0.504-0.560). Mortality models with the SSI demonstrated superior discrimination to those without. The AUCs of models including the SSI and models with the NIHSS did not differ significantly. CONCLUSIONS: The SSI correlated with functional outcomes after AIS and improved the case-mix adjustment of mortality models. It can act as a valid proxy for stroke severity in claims data-based studies.

Hormone therapy and risk of venous thromboembolism among postmenopausal women in Taiwan - a 10-year nationwide population-based study.

BACKGROUND: The incidence of venous thromboembolism (VTE) in Asians is lower than in Caucasians, but the risk of VTE associated with hormone therapy (HT) in Taiwanese postmenopausal women has not been determined. METHODS AND RESULTS: From Taiwan's National Health Insurance Research Database, we established matched cohorts (HT users and nonusers) of postmenopausal women aged ≥50 years between 1 January 1998 and 31 December 2008. We calculated the 2-year incidence of VTE in HT users and nonusers. HT users and nonusers were matched 1:1 based on propensity-score matching. Cox regression hazard model was used to identify risk factors of VTE. We initially identified 499,594 HT users and 424,963 nonusers. There were higher percentages of cancer and cardiovascular events among the HT nonusers. After matching, the VTE incidence was 4.4 vs. 2.6 per 10,000 patient-years (adjusted hazard ratio 1.796, 95% confidence interval 1.272-2.537) in HT users and nonusers, respectively. The Cox regression hazard model showed that HT use, older age, malignancy, heart failure, and recent major surgery were independent risk factors for VTE. CONCLUSIONS: Although the incidence of VTE was very low among this cohort of Taiwanese postmenopausal women, oral HT was still associated with an increased risk of VTE. Therefore, physicians should be aware of other potential VTE risk factors when prescribing oral HT to postmenopausal women.