Differences in outcomes of hospitalizations for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease.

BACKGROUND: The treatment effects on hospitalization for heart failure (hHF) from sodium-glucose cotransporter 2 (SGLT2) inhibitors may vary among type 2 diabetes (T2D) patients depending on whether or not they have established atherosclerotic cardiovascular diseases (ASCVD). We aimed to examine differences in hHF outcomes after dapagliflozin or empagliflozin use between T2D patients with and without a history of established ASCVD. METHODS: We conducted a retrospective multi-institutional cohort study in Taiwan. We included T2D patients newly receiving dapagliflozin or empagliflozin during 2016-2019, and followed them up until December 31, 2020. We implemented 1:1 propensity score matching to create homogenous groups for comparisons. We generated Cox proportional hazard models to compare the risk of hHF between dapagliflozin and empagliflozin (reference group). We included interaction terms of SGLT2 inhibitor and ASCVD history in the regression models to examine effect modification by ASCVD. RESULTS: We included a total cohort of 9,586 dapagliflozin new users and 9,586 matched empagliflozin new users. The overall hHF risks were similar for dapagliflozin and empagliflozin (HR: 0.90, 95% CI 0.74-1.09). However, differential hHF risks between dapagliflozin and empagliflozin were observed only in the subgroup without ASCVD (HR: 0.67, 95% CI 0.49-0.90), while not in the subgroup with ASCVD (HR: 1.12, 95% 0.87-1.45), and the p-value for examining interaction was 0.0097. CONCLUSION: In this study, history of established ASCVD was associated with different hHF risks among SGLT2 inhibitors. For T2D patients without ASCVD, dapagliflozin may offer a more favorable hHF reduction effect, compared to empagliflozin, in clinical practice. Future prospective studies should be conducted to validate our findings.

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 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.

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.

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.

Medication knowledge to be improved in participants in community universities in Taiwan: Outcome of a nationwide community university program.

BACKGROUND/PURPOSE: To assess knowledge improvement by the participants in a pharmacist-facilitated national community education program over a 4-month semester and to identify the educational needs of adults related to medications. METHODS: This was a single-group, pre- and post-program comparative study. From February 2005 to February 2006, 1983 community residents participating in the education program implemented at 57 community universities nationwide were included. A questionnaire consisting of 50 true/false questions was administered before and after the program to assess the participants' medication knowledge. Paired t test was used to analyze the pre- and post-program differences and generalized linear mixed models were applied to examine the demographic variables that might influence the background knowledge and outcome after adjusting for school effects. RESULTS: A total of 848 participants (42.8%) completed the pre-to-post questionnaire. Baseline medication knowledge was positively correlated with participants' education level and negatively correlated with age. Significant improvement (11.3%, p < 0.001) in medication knowledge was evident at the end of the program. The age and education level were significant determinants in the improvement of the pre-to-post program test score. The specific areas that required improvement most in the knowledge of the participants were: instructions on refill prescriptions, proper storage of medication, the health insurance system, drug use in special populations, and over-the-counter drugs. CONCLUSION: This national program improved participants' medication knowledge over a 4-month period. Patient counseling focusing more on the knowledge deficiency identified in this study during patient care is recommended.

Validation of acute myocardial infarction cases in the national health insurance research database in taiwan.

BACKGROUND: The aim of this study was to determine the validity of acute myocardial infarction (AMI) diagnosis coding in the National Health Insurance Research Database (NHIRD) by cross-comparisons of discharge diagnoses listed in the NHIRD with those in the medical records obtained from a medical center in Taiwan. METHODS: This was a cross-sectional study comparing records in the NHIRD and discharge notes in one medical center (DNMC) in the year 2008. Positive predictive values (PPVs) for AMI diagnoses were evaluated by reviewing the relevant clinical and laboratory data recorded in the discharge notes of the medical center. Agreement in comorbidities, cardiac procedures, and antiplatelet agent (aspirin or clopidogrel) prescriptions between the two databases was evaluated. RESULTS: We matched 341 cases of AMI hospitalizations from the two databases, and 338 cases underwent complete chart review. Of these 338 AMI cases, 297 were confirmed with clinical and lab data, which yielded a PPV of 0.88. The consistency rate for coronary intervention, stenting, and antiplatelet prescription at admission was high, yielding a PPV over 0.90. The percentage of consistency in comorbidity diagnoses was 95.9% (324/338) among matched AMI cases. CONCLUSIONS: The NHIRD appears to be a valid resource for population research in cardiovascular diseases.

Comparative stroke risk of antiepileptic drugs in patients with epilepsy.

PURPOSE: Patients with epilepsy have higher stroke-related morbidity and mortality, leading to the suspicion that the increased stroke events may be associated with antiepileptic drug (AED) exposure. We evaluated the comparative risk of stroke in adult patients with epilepsy receiving phenytoin (PHT), valproic acid (VPA), or carbamazepine (CBZ) to help determine the stroke risk for Asian patients with specific AED exposure. METHODS: We conducted a population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database (NHIRD). The cohort consists of adult patients with epilepsy who were new to PHT, CBZ, or VPA monotherapy and without prior stroke history. Patients were followed for 5 years. The event of interest was a hospitalization or emergency visit due to stroke. Cox proportional hazard models were used to estimate the comparative risk of AEDs. Subanalyses included an evaluation of different subtypes of stroke, the propensity score matched technique, the intention-to-treat approach, and stratification analyses. KEY FINDINGS: Patients receiving PHT had a significantly higher stroke risk (adjusted hazard ratio [HR] 1.72; 95% confidence interval [CI] 1.20-2.47), followed by VPA (adjusted HR 1.27; 95% CI 0.78-2.07), when compared with CBZ. The results of all subanalyses showed a consistent trend of higher stroke risk with PHT use. In addition, there appeared to be a dose-response relationship between stroke risk and PHT prescriptions. SIGNIFICANCE: The stroke risk was higher in PHT but not significantly different in VPA as compared to CBZ. Physicians should reconsider using PHT for patients with epilepsy who already have a higher risk of stroke.

Use of antiepileptic drugs and risk of hypothyroidism.

PURPOSE: This study aimed to investigate the risk of clinically significant hypothyroidism among all the currently available antiepileptic drugs (AED). METHODS: The Taiwan National Health Insurance Research Database (NHIRD) from 2004 to 2010 was analyzed using a prescription sequence symmetry analysis, and thyroxine treatment was used as a proxy to identify a hypothyroidism event. A cohort of patients who have been treated with both AED and thyroxine was selected, and the chronological order of AED and thyroxine use constituted the basis of the prescription sequence symmetry analysis. A causal relationship was suspected if there was a significantly higher proportion of patients who initiated thyroxine after AED than those who initiated thyroxine before AED. The ratio of the two proportions was described as a sequence ratio. To benchmark the effect size of AEDs on thyroid function, amiodarone was selected as the reference indicator. RESULTS: A total of 1,878,189 AED users was found in the database, with 16,200 of them also used thyroxine. The adjusted sequence ratio of thyroxine use after each AED was 1.75 (99% confidence interval, 1.58-1.94) for phenytoin, 1.34 (1.20-1.49) for valproate, 1.25 (1.15-1.36) for phenobarbital, 1.21 (1.08-1.34) for carbamazepine, and 1.22 (1.03-1.46) for oxcarbazepine. The risk of hypothyroidism from phenytoin use within a shorter time frame was similar that associated with amiodarone use. No association was shown in most of the new generation AEDs. CONCLUSION: The results indicated an increased risk of hypothyroidism among patients using AEDs, especially phenytoin, valproate, phenobarbital, carbamazepine, and oxcarbazepine. The findings also provided strong grounds for further investigations on acute thyroid adverse effect induced by phenytoin.

Association between recently raised anticholinergic burden and risk of acute cardiovascular events: nationwide case-case-time-control study.

OBJECTIVE: To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults. DESIGN: Case-case-time-control study (ie, incorporating a case crossover design and a control crossover design consisting of future cases). SETTING: Taiwan's National Health Insurance Research Database. PARTICIPANTS: 317 446 adults aged ≥65 who were admitted to hospital because of an incident acute cardiovascular event between 2011 and 2018. Acute cardiovascular events included myocardial infarction, strokes, arrhythmias, conduction disorders, and cardiovascular death. MAIN OUTCOME MEASURES: The anticholinergic burden was measured for each participant by adding up the anticholinergic scores for individual drugs using the Anticholinergic Cognitive Burden Scale. Scores were classified into three levels (0 points, 1-2 points, and ≥3 points). For each participant, anticholinergic burden levels during hazard periods (day -1 to -30 before the cardiovascular event) were compared with randomly selected 30 day reference periods (ie, periods between days -61 and -180). Conditional logistic regression determined odds ratios with 95% confidence intervals to evaluate the association between acute cardiovascular events and recently raised anticholinergic burden. RESULTS: The crossover analyses included 248 579 current cases. Participants' average age on the index date was 78.4 years (standard deviation 0.01), and 53.4% were men. The most frequently prescribed drugs with anticholinergic activity were antihistamines (68.9%), gastrointestinal antispasmodics (40.9%), and diuretics (33.8%). Among patients with varying levels of anticholinergic burden in different periods, more patients carried higher levels of anticholinergic burden during hazard periods than during reference periods. For example, 17 603 current cases had 1-2 points of anticholinergic burden in the hazard period with 0 points in the reference period, while 8507 current cases had 0 points in the hazard period and 1-2 points in the reference period. In the comparison of 1-2 points versus 0 points of anticholinergic burden, the odds ratio was 1.86 (95% confidence interval 1.83 to 1.90) in the case crossover analysis and 1.35 (1.33 to 1.38) in the control crossover analysis, which yielded a case-case-time-control odds ratio of 1.38 (1.34 to 1.42). Similar results were found in the comparison of ≥3 versus 0 points (2.03, 1.98 to 2.09) and ≥3 versus 1-2 points (1.48, 1.44 to 1.52). The findings remained consistent throughout a series of sensitivity analyses (eg, cut-off points for anticholinergic burden categories were redefined and different scales were used to measure anticholinergic burden). CONCLUSIONS: An association was found between recently raised anticholinergic burden and increased risk of acute cardiovascular events. Furthermore, a greater increase in anticholinergic burden was associated with a higher risk of acute cardiovascular events.

Post-discharge use of antipsychotics in patients with hospital-acquired delirium and associated risk of mortality - A population-based nested case-control study.

OBJECTIVE: To evaluate post-discharge use of antipsychotics in patients with incident hospital-acquired delirium and the associated risk of mortality. METHODS: We conducted a nested case-control study for patients newly diagnosed with hospital-acquired delirium and subsequently discharged from hospital using Taiwan's National Health Insurance Database (NHID) from 2011 to 2018. RESULTS: The use of antipsychotics after discharge did not increase the risk of mortality (adjusted OR: 1·03; 95% CI: 0·98-1·09). CONCLUSIONS: The findings suggested that using antipsychotics after discharge in patients with hospital-acquired delirium may not increase the risk of mortality.

Risk of Thrombosis Following the First Dose of ChAdOx1 nCoV-19 Vaccine in Patients Undergoing Maintenance Hemodialysis: A Self-Controlled Case Series Study.

Background: The ChAdOx1 nCoV-19 vaccine is associated with vaccine-induced thrombosis and thrombocytopenia (VITT). Patients with end-stage renal disease (ESRD) under hemodialysis are at elevated risk of heparin-induced thrombocytopenia, which shares similar mechanisms with VITT. We aimed to examine the risk of VITT after the first dose of ChAdOx1 nCoV-19 vaccine using a self-controlled case series analysis (SCCS) in the hemodialyzed ESRD population. Methods: Drawing from the largest multi-center electronic medical records database in Taiwan, we identified adult patients, with or without hemodialysis, between 1st December, 2020, and 31st December, 2021, who received a first dose of ChAdOx1 nCoV-19 vaccine and had an outcome of thrombocytopenia, venous thrombosis, or arterial thrombosis. We calculated the incident rate ratios (IRRs) of outcomes in different periods at risk, compared to periods not at risk. Results:  We identified 59 hemodialysis patients and 41 non-dialysis patients with an outcome. The SCCS analyses showed, for the hemodialysis group, a significantly increased risk of outcomes during the period 31 to 60 days post-exposure to ChAdOx1 nCoV-19 vaccine (IRR: 2.823; 95% CI: 1.423-5.600). However, in non-dialysis patients there was no increase in risks during any of the post-exposure risk periods. Conclusion: For ESRD patients under hemodialysis, the first dose of ChAdOx1 nCoV-19 vaccine was associated with a 2.8-fold increase in risk of thrombosis.

A New Drug Safety Signal Detection and Triage System Integrating Sequence Symmetry Analysis and Tree-Based Scan Statistics with Longitudinal Data.

Purpose: Development and evaluation of a drug-safety signal detection system integrating data-mining tools in longitudinal data is essential. This study aimed to construct a new triage system using longitudinal data for drug-safety signal detection, integrating data-mining tools, and evaluate adaptability of such system. Patients and Methods: Based on relevant guidelines and structural frameworks in Taiwan's pharmacovigilance system, we constructed a triage system integrating sequence symmetry analysis (SSA) and tree-based scan statistics (TreeScan) as data-mining tools for detecting safety signals. We conducted an exploratory analysis utilizing Taiwan's National Health Insurance Database and selecting two drug classes (sodium-glucose co-transporter-2 inhibitors (SGLT2i) and non-fluorinated quinolones (NFQ)) as chronic and episodic treatment respectively, as examples to test feasibility of the system. Results: Under the proposed system, either cohort-based or self-controlled mining with SSA and TreeScan was selected, based on whether the screened drug had an appropriate comparator. All detected alerts were further classified as known adverse drug reactions (ADRs), events related to other causes or potential signals from the triage algorithm, building on existing drug labels and clinical judgement. Exploratory analysis revealed greater numbers of signals for NFQ with a relatively low proportion of known ADRs; most were related to indication, patient characteristics or bias. No safety signals were found. By contrast, most SGLT2i signals were known ADRs or events related to patient characteristics. Four were potential signals warranting further investigation. Conclusion: The proposed system facilitated active and systematic screening to detect and classify potential safety signals. Countries with real-world longitudinal data could adopt it to streamline drug-safety surveillance.

Comparative clinical effectiveness of various 5-HT3 RA antiemetic regimens on chemotherapy-induced nausea and vomiting associated with hospital and emergency department visits in real world practice.

PURPOSE: The aim of this study was to compare the risk of chemotherapy-induced nausea and vomiting (CINV) events for various 5-HT(3) RAs in patients who received moderately (MEC) or highly emetogenic chemotherapy (HEC) by evaluating hospital or emergency department (ED) admissions. METHODS: PharMetrics claims database was used to identify patients diagnosed with breast cancer (BC) who were initiated on cyclophosphamide-based adjuvant chemotherapy or with lung cancer (LC) initiated on carboplatin-based or cisplatin-based chemotherapy between 2005 and 2008. Patients were stratified in two groups: those initiated and maintained on palonosetron versus those treated with any other 5-HT(3) RA regimens in the 6-month post first chemotherapy. Risk for CINV events, identified by ICD-9-CM for nausea, vomiting, and/or dehydration, were estimated using logistic regressions, controlling for age, gender, comorbidity, and total chemotherapy doses or days. RESULTS: Of the 4,868 cyclophosphamide-treated BC, 5,414 carboplatin-treated LC, and 1,692 cisplatin-treated LC identified, there were 1,864 BC (38.5%), 1,806 carboplatin-treated LC (33.4%), and 390 cisplatin-treated LC (23.0%) in the palonosetron-only group. Palonosetron-only group had significantly lower probability of CINV events associated with ED/hospital admissions in all three cohorts (3.5% vs. 6.3% in BC, 9.5% vs. 13.8% in carboplatin-treated LC, and 16.4% vs. 22.6% in cisplatin-treated LC, all at p < 0.05). Logistic regressions found palonosetron-only group had significantly lower risk of CINV events (odds ratios = 0.550, 0.653, and 0.689 in BC, carboplatin-treated LC and cisplatin-treated LC, respectively, p < 0.05). CONCLUSION: Patients with lung or breast cancer receiving MEC or HEC had significantly lower risk of CINV events associated with hospital/ED admissions if initiated and maintained on palonosetron relative to patients receiving 5-HT(3) RA regimens.

Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.

BACKGROUND: 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. METHODS: Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. RESULTS: Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05). CONCLUSIONS: Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.

Validation of Risk Scores for Predicting Atrial Fibrillation Detected After Stroke Based on an Electronic Medical Record Algorithm: A Registry-Claims-Electronic Medical Record Linked Data Study.

Background: Poststroke atrial fibrillation (AF) screening aids decisions regarding the optimal secondary prevention strategies in patients with acute ischemic stroke (AIS). We used an electronic medical record (EMR) algorithm to identify AF in a cohort of AIS patients, which were used to validate eight risk scores for predicting AF detected after stroke (AFDAS). Methods: We used linked data between a hospital stroke registry and a deidentified database including EMRs and administrative claims data. EMR algorithms were constructed to identify AF using diagnostic and medication codes as well as free clinical text. Based on the optimal EMR algorithm, the incidence rate of AFDAS was estimated. The predictive performance of 8 risk scores including AS5F, C2HEST, CHADS2, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, and Re-CHARGE-AF scores, were compared using the C-index, net reclassification improvement, integrated discrimination improvement, calibration curve, and decision curve analysis. Results: The algorithm that defines AF as any positive mention of AF-related keywords in electrocardiography or echocardiography reports, or presence of diagnostic codes of AF was used to identify AF. Among the 5,412 AIS patients without known AF at stroke admission, the incidence rate of AFDAS was 84.5 per 1,000 person-year. The CHASE-LESS and AS5F scores were well calibrated and showed comparable C-indices (0.741 versus 0.730, p = 0.223), which were significantly higher than the other risk scores. Conclusion: The CHASE-LESS and AS5F scores demonstrated adequate discrimination and calibration for predicting AFDAS. Both simple risk scores may help select patients for intensive AF monitoring.

Positive Predictive Value of ICD-10 Codes for Cerebral Venous Sinus Thrombosis in Taiwan's National Health Insurance Claims Database.

OBJECTIVE: This study aims to determine the positive predictive value (PPV) of case definitions for cerebral venous sinus thrombosis (CVST) in Taiwan's National Health Insurance claims database based on the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnostic codes. STUDY DESIGN AND SETTING: Inpatient records with ICD-10-CM codes of G08, I629, I636, or I676 were retrieved from the claims data of all hospital branches of Chang Gung Medical Foundation. Manual review of the medical records and images was performed in order to ascertain the diagnosis. The PPV of various case definitions for CVST was estimated. RESULTS: Of the 380 hospitalizations, 166 and 214 were determined to be true-positive and false-positive episodes of acute CVST, respectively. The PPV of the ICD-10-CM codes of G08, I629, I636, and I676 was 88.2%, 2.0%, 100.0%, and 91.3%, respectively. The PPV generally increased when acute CVST was defined as a primary diagnosis or as ICD-10-CM codes plus anticoagulant use. Miscoding in other conditions, tentative diagnosis, and remote episode of CVST were determined as the main reasons for false-positive diagnosis of acute CVST. CONCLUSION: This study determined the PPV of ICD-10-CM codes for identifying CVST, which may offer a reference for future claims-based research.