Antibiotic use and risk of autism spectrum disorder and attention-deficit/hyperactivity disorder: a population-based cohort study.

BACKGROUND: The gut microbiota is believed to influence neurodevelopment through the gut-brain axis, but prior studies have shown inconsistent results regarding early childhood antibiotic exposure and subsequent risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The purpose of this study was to evaluate the hypothesis that exposure to antibacterial agents in the first 2 years of life increases the risk of ASD and/or ADHD. METHODS: This was a retrospective cohort study using 2003-2019 data from the National Health Insurance Research Database in Taiwan. Livebirths born between 2004 and 2016 were identified and separated into singleton, full sibling, and exposure-discordant sibling pair cohorts. The exposure group included children who filled at least one prescription for antibacterial agents between 0 and 2 years old in outpatient settings. The outcome, ASD and/or ADHD, was defined by at least one inpatient or outpatient diagnosis. The maximum follow-up age was 15 years in this study. Potential neonatal, maternal and paternal confounders were adjusted for. Cox proportional hazards models were used to estimate the relative event risk. RESULTS: The final sample contained 946,581 children in the singleton cohort, 1,142,693 children in the full sibling cohort, and 352,612 children in the exposure-discordant sibling pair cohort. Antibiotic exposure marginally increased the risk of ASD and/or ADHD in the singleton cohort (adjusted hazard ratio [aHR]: 1.06, 95% confidence interval [CI]: 1.04-1.07) and in the full sibling cohort (aHR: 1.03, 95% CI: 1.01-1.04). A slight decrease in the risk of ASD and/or ADHD was observed in the exposure-discordant sibling pair cohort (aHR: 0.92, 95% CI: 0.90-0.94). CONCLUSIONS: The results suggest that early life antibiotic exposure has minimal impact on the risk of ASD and/or ADHD. Given that the estimated effects are marginal and close to null, concerns about ASD and/or ADHD risk increase should not postpone or deter timely and reasonable antibiotic use.

Kidney outcomes with SGLT2is for type 2 diabetes patients: does background treatment with metformin or RASis matter?

Introduction: There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes. Methods: SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases. Results: After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions. Conclusion: Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes.

Correction: Valuation of the EQ-5D-5L in Taiwan.

[This corrects the article DOI: 10.1371/journal.pone.0209344.].

Comparison of different direct oral anticoagulant regimens in atrial fibrillation patients with high bleeding risk.

BACKGROUND: The optimal dose of direct oral anticoagulants (DOACs) to prevent ischemic stroke (IS) and systemic thromboembolism (STE) in atrial fibrillation (AF) patients with a predisposing bleeding risk remains unclear. OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of different DOAC dosage regimens in AF patients with high bleeding risk but low thrombosis risk. METHODS: This retrospective observational study was conducted with the National Health Insurance claims database in Taiwan to include AF patients aged 20 up to 75 years, under DOAC therapy, with CHA2DS2-VASc score of 1 for males and 2 for females and HAS-BLED score ≥3. Standard-dose regimen was defined as dabigatran 300 mg, rivaroxaban 20 mg, apixaban 10 mg, or edoxaban 60 mg per day. Any other lower-dose regimen were defined as the low-dose regimen. The primary outcomes were IS and major bleeding (MB). The secondary outcomes were STE, gastrointestinal bleeding, intracranial hemorrhage, and cardiovascular death. RESULTS: A total of 964 patients were included (52.1% standard-dose regimen). Median HAS-BLED score was 3 [interquartile range 3-3]. Compared with standard-dose group, patients in the low-dose group had a significantly increased risk of IS (adjusted hazard ratio [aHR] 5.13; 95% confidence interval 1.37-19.22) and STE (aHR 3.14 [1.05-9.37]) but similar risk of MB (aHR 0.45 [0.12-1.67]). The risks of other hemorrhage and cardiovascular death were similar between the 2 dose groups. CONCLUSION: Among patients with a predominant bleeding risk but relatively low thrombosis risk, the low-dose DOAC regimen is not a more appropriate selection than standard-dose regimen.

The Report of Community-Based and Government-Endorsed Screening Program of Atrial Fibrillation in Taiwan.

BACKGROUND: Although international guidelines recommended opportunistic screening for atrial fibrillation (AF), the community-based AF screening program incorporated into the government-endorsed health care system is rarely reported in Asian countries. OBJECTIVES: We aimed to test the feasibility of adding AF screening into the preexistent adult health check program and report the AF detection rate and percentages of OAC prescriptions before and after AF screening with the involvement of public health care systems. METHODS: We performed this program in three counties (Chiayi county, Keelung City, and Yilan county) in Taiwan which have their own official preexistent adult health check programs conducted by public health bureaus for years. However, electrocardiography (ECG) was not included in these programs before. We cooperated with the public health bureaus of the three counties and performed single-lead 30-second ECG recording for every participant. RESULTS: From January to December 2020, AF screening was performed in 199 sessions with 23,572 participants. AF was detected in 278 subjects with a detection rate of 1.19% (age ≥65 years: 2.39%; ≥75 years: 3.73%). The mean CHA2DS2-VASc score of these 278 subjects was 2.36, with 91% of them had a score ≥1 (males) or ≥2 (females). The number needed to screen was 42 and 27 for subjects aged ≥65 and ≥75 years, respectively. The prescription rate of OACs significantly increased from 11.4 to 60.6% in Chiayi county and from 15.8 to 50.0% in Keelung City after screening (both p-values <0.001). CONCLUSION: This community-based and government-endorsed AF screening project in Taiwan demonstrated that incorporation of AF screening into the preexistent adult health check programs through co-operations with the government was feasible. Actions to detect AF, good education, and well-organized transferring plan after AF being detected with the involvement of public health care systems could result in a substantial increase in the prescription rate of OACs.

Beyond 10-year lead-times in EQ-5D-5L: leveraging alternative lead-times in willingness-to-accept questions to capture preferences for worse-than-dead states and their implication.

BACKGROUND: A fixed 10-year lead-time in composite time-trade-off (C-TTO) tasks might compromise the precision of utility values below - 1. This study explored how alternative lead-times (ALTs) influence EQ-5D-5L value sets and their implications in economic evaluations. METHODS: Leveraging data from Taiwan's EQ-5D-5L valuation and capitalizing on its exploratory willingness-to-accept question, we explored participants' quantification of "worse-than-dead (WTD)" health states with ALTs up to 50 years. We then derived alternative value sets incorporating these ALTs through interval regression and compared them against those from conventional models. To evaluate their impact on health change valuation, we simulated utility differences for all possible EQ-5D-5L health-state-pairs using each value set. RESULTS: With a salient floor effect observed in the C-TTO values, the model with ALT led to a wider range of predicted utilities ( - 2.3897 ~ 1), compared with those of conventional models (generalized least squares (GLS): - 0.7773 ~ 1; Tobit-GLS: - 0.9583 ~ 1). Compared to the Tobit-GLS model, the model with ALT increased the numerical distance in 80% of health-state-pairs, with 11% decreasing and 9% altering direction (e.g., positive to negative) in utility differences. CONCLUSIONS: While ALTs offer insights into patient preferences, their integration into economic evaluations might require rescaling. Future research should prioritize advanced rescaling methods or enhanced elicitation strategies for populations with substantial censoring. This is pivotal for improving the elicitation of extreme WTD states and accurately discerning the relative distances between health states. Countries developing EQ-5D-5L value sets should consider pilot studies and incorporating region-specific questions on social determinants, especially where pronounced floor effects are suspected.

Ticagrelor vs Clopidogrel in Acute Myocardial Infarction Patients With a History of Ischemic Stroke.

OBJECTIVE: To investigate whether use of ticagrelor compared to clopidogrel is associated with different risks for thrombotic events or major bleeding among acute myocardial infarction (AMI) patients with a prior history of acute ischemic stroke. PATIENTS AND METHODS: This retrospective cohort study used the Health and Welfare Database in Taiwan. Stroke patients prescribed ticagrelor plus aspirin or clopidogrel plus aspirin after a primary hospitalization for AMI between July 1, 2013, and December 31, 2018, were included. Inverse probability of treatment weighting was applied to balance covariates between treatment groups. The primary effectiveness outcome included a composite measure of AMI, acute ischemic stroke, or all-cause mortality. The primary safety outcome included a composite measure of intracranial hemorrhage (ICH) and major gastrointestinal bleeding. The secondary effectiveness and safety outcomes comprised each of the individual components that make up the primary effectiveness and safety outcomes, respectively. RESULTS: A total of 1691 eligible patients were included in the study, of whom 734 (43.4%) received ticagrelor plus aspirin and 957 received clopidogrel plus aspirin. There were no significant differences observed in the primary and secondary effectiveness outcomes between the two study groups. However, the use of ticagrelor was associated with a higher risk of ICH (ticagrelor: 8.68 per 1000 person-year; clopidogrel: 2.17 per 1,000 person-year; HR, 3.34; 95% CI, 1.27 to 8.81, P = .01) compared with clopidogrel. CONCLUSION: In AMI patients with a history of acute ischemic stroke, the risks of cardiovascular events were comparable between ticagrelor plus aspirin and clopidogrel plus aspirin. However, ticagrelor was associated with a higher risk of ICH. Ticagrelor should be used cautiously in AMI patients with a history of acute ischemic stroke.

Machine Learning Models for ASCVD Risk Prediction in an Asian Population - How to Validate the Model is Important.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is prevalent worldwide including Taiwan, however widely accepted tools to assess the risk of ASCVD are lacking in Taiwan. Machine learning models are potentially useful for risk evaluation. In this study we used two cohorts to test the feasibility of machine learning with transfer learning for developing an ASCVD risk prediction model in Taiwan. Methods: Two multi-center observational registry cohorts, T-SPARCLE and T-PPARCLE were used in this study. The variables selected were based on European, U.S. and Asian guidelines. Both registries recorded the ASCVD outcomes of the patients. Ten-fold validation and temporal validation methods were used to evaluate the performance of the binary classification analysis [prediction of major adverse cardiovascular (CV) events in one year]. Time-to-event analyses were also performed. Results: In the binary classification analysis, eXtreme Gradient Boosting (XGBoost) and random forest had the best performance, with areas under the receiver operating characteristic curve (AUC-ROC) of 0.72 (0.68-0.76) and 0.73 (0.69-0.77), respectively, although it was not significantly better than other models. Temporal validation was also performed, and the data showed significant differences in the distribution of various features and event rate. The AUC-ROC of XGBoost dropped to 0.66 (0.59-0.73), while that of random forest dropped to 0.69 (0.62-0.76) in the temporal validation method, and the performance also became numerically worse than that of the logistic regression model. In the time-to-event analysis, most models had a concordance index of around 0.70. Conclusions: Machine learning models with appropriate transfer learning may be a useful tool for the development of CV risk prediction models and may help improve patient care in the future.

A risk stratification model modified from the U.S. guideline could be applied in an Asian population with or without ASCVD.

AIM: This study aimed to evaluate the performance of a modified US (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models. MATERIAL AND METHODS: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan. RESULTS: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68-0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high-vs. high-risk group (HR=1.91, 95% CI 1.53-2.39), high-vs. moderate-risk group (HR=2.08, 95% CI 1.60-2.69), and moderate-vs. low-risk group (HR=3.14, 95% CI 1.63-6.03). After adjusting for the MUS model, a history of ASCVD was not a significant predictor of adverse cardiovascular outcomes within each risk group. CONCLUSION: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention.

Real-world epidemiology, treatment patterns and disease burden of patients diagnosed with chronic hepatitis B in Taiwan.

BACKGROUND AND AIMS: This study aimed to update the epidemiology, clinical, and economic outcomes of patients diagnosed with chronic hepatitis B (CHB) infection in Taiwan. METHODS: This is a retrospective observational study using claims data from the National Health Insurance Research Database. Cases were identified between 2010 and 2019 using CHB diagnosis codes and claims for alanine aminotransferase laboratory tests or CHB treatment within one year of the first CHB diagnosis. Patient characteristics, epidemiology, clinical, and economic outcomes were described. RESULTS: A total of 730 154 CHB-diagnosed cases were identified. The prevalence of diagnosed CHB increased from 1.13% in 2010 to 2.43% in 2019, with the highest occurring among those aged 55-64 years (4.76%) and 45-54 years (4.37%) and being higher in men (2.98%) than in women (2.21%). The majority of newly diagnosed CHB patients were 35 years of age or older (86.6%), with a median age of 49 years. After a median follow-up period of 6.42 years, 12.5%, 7.9%, 2.8%, and 0.35% were diagnosed with cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation respectively. Among 456 706 incident CHB-diagnosed patients, 17.4% had received at least one CHB medication, with the majority taking entecavir (67.9%). Patients with increasing disease severity had higher healthcare resource utilization, and inpatient costs accounted for 48.9%-65.5% of the overall medical cost in different health states. CONCLUSION: Despite the decreasing incidence of newly diagnosed CHB, the prevalence of diagnosed CHB remains high and poses a significant healthcare challenge owing to the high economic burden associated with the complications of CHB.

Cardiovascular Event Recurrence and Costs after First Myocardial Infarction, Ischemic Stroke, or Intracerebral Hemorrhage in Taiwan.

Background/Objectives: We aimed to assess the incidence of recurrent cardiovascular (CV) events after the first myocardial infarction (MI), ischemic stroke (IS), or intracerebral hemorrhage (ICH) and to estimate acute and follow-up medical costs. Methods: Using Taiwan's National Health Insurance Research Database, we identified patients with their first MI, IS, or ICH between 2011 and 2017. The cumulative incidence rates of second CV events (including events of the same type [recurrent] or of the other two types) were estimated. The costs for hospitalization and all-cause follow-up were calculated for the first and recurrent CV events and are presented as median (Q1~Q3) in 2017 US dollars. Results: We identified 70,428 patients with a first MI, 123,857 with a first IS, and 41,347 with a first ICH. The cumulative incidence rates of recurrence during the first year and after six years were 3.9% and 10.1% for MI, 5.3% and 13.8% for IS, and 3.9% and 8.9% for ICH, respectively. For first and recurrent nonfatal events, acute hospitalization costs were $4,729 (3,737~5,985) and $4,459 (2,887~6,026) for MI; $1,136 (756~2,183) and $1,224 (774~2,412) for IS; and $2,985 (1,264~8,831) and $2,170 (1,183~4,675) for ICH, respectively. Total annual costs for nonfatal first events in the first year and second year of follow-up were $2413 (1,393~6,120) and $1,293 (654~2,868) for MI, $2,174 (1,040~5,472) and $1,394 (602~3,265) for IS, and $2,963 (995~8,352) and $1,185 (405~3,937) for ICH, respectively. Conclusions: In patients with a first MI, IS, and ICH, recurrent CV events continue to substantially impact public health and escalate the economic burden.

Factors Affecting the Effectiveness of Discharge Planning Implementation: A Case-Control Cohort Study.

BACKGROUND: In many hospitals, a discharge planning team works with the medical team to provide case management to ensure high-quality patient care and improve continuity of care from the hospital to the community. However, a large-scale database analysis of the effectiveness of overall discharge planning efforts is lacking. PURPOSE: This study was designed to investigate the clinical factors that impact the efficacy of discharge planning in terms of hospital length of stay, readmission rate, and survival status. METHODS: A retrospective study was conducted based on patient medical records and the discharge plans applied to patients hospitalized in a regional medical center between 2017 and 2018. The medical information system database and the care service management information system maintained by the Ministry of Health and Welfare were used to collect data and explore patients' medical care and follow-up status. RESULTS: Clinical factors such as activities of daily living ≤ 60, having indwelling catheters, having poor control of chronic diseases, and insufficient caregiver capacity were found to be associated with longer hospitalization stays. In addition, men and those with indwelling catheters were found to have a higher risk of readmission within 30 days of discharge. Moreover, significantly higher mortality was found after discharge in men, those ≥ 75 years old, those with activities of daily living ≤ 60, those with indwelling catheters, those with pressure ulcers or unclean wounds, those with financial problems, those with caregivers with insufficient capacity, and those readmitted 14-30 days after discharge. CONCLUSIONS: The findings of this study indicate that implementing case management for discharge planning does not substantially reduce the length of hospital stay nor does it affect patients' readmission status or prognosis after discharge. However, age, underlying comorbidities, and specific disease factors decrease the efficacy of discharge planning. Therefore, active discharge planning interventions should be provided to ensure transitional care for high-risk patients.

Prescribing patterns for attention deficit hyperactivity disorder among children and adolescents in Taiwan from 2004 to 2017.

This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0-212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004-2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.

Association of Major Adverse Cardiac Events and Beta-Blockers in Patients with and without Atherosclerotic Cardiovascular Disease: Long-Term Follow-Up Results of the T-SPARCLE and T-PPARCLE Registry in Taiwan.

Beta-blockers are widely used, but the benefit is now challenged in patients at risk of atherosclerotic cardiovascular disease (ASCVD) in the present coronary reperfusion era. We aimed to identify the risk factors of a major adverse cardiac event (MACE) and the long-term effect of beta-blockers in two large cohorts in Taiwan. Two prospective observational cohorts, including patients with known atherosclerosis cardiovascular disease (T-SPARCLE) and patients with at least one risk factor of ASCVD but without clinically evident ASCVD (T-PPARCLE), were conducted in Taiwan. The primary endpoint is the time of first occurrence of a MACE (cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, and cardiac arrest with resuscitation). Between December 2009 and November 2014, with a median 2.4 years follow-up, 11,747 eligible patients (6921 and 4826 in T-SPARCLE and T-PPARCLE, respectively) were enrolled. Among them, 273 patients (2.3%) met the primary endpoint. With multivariate Cox PH model analysis, usage of beta-blocker was lower in patients with MACE (42.9% vs. 52.4%, p < 0.01). In patients with ASCVD, beta-blocker usage was associated with lower MACEs (hazard ratio 0.72; p < 0.001), but not in patients without ASCVD. The event-free survival of beta-blocker users remained higher during the follow-up period (p < 0.005) of ASCVD patients. In conclusion, in ASCVD patients, reduced MACE was associated with beta-blocker usage, and the effect was maintained during a six-year follow-up. Prescribing beta-blockers as secondary prevention is reasonable in the Taiwanese population.

The effects of mineralocorticoid receptor antagonists on cardiovascular outcomes in patients with end-stage renal disease and heart failure.

AIMS: Mineralocorticoid receptor antagonists (MRAs) have been shown to provide survival benefits in patients with heart failure; however, MRA use in patients with chronic kidney disease has been limited by safety concerns. The effects of MRAs on outcomes in patients with end-stage renal disease (ESRD) and heart failure remain unknown. The aim of this study was to evaluate the effects of MRAs on cardiovascular outcomes in patients with heart failure under maintenance dialysis in a real-world setting. METHODS AND RESULTS: A retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database (NHIRD). Patients diagnosed with heart failure and ESRD and who started maintenance dialysis between 1 January 2001 and 31 December 2013 were identified. Patients were grouped according to MRA prescription. The outcomes of interest included cardiovascular (CV) death, hospitalization for heart failure (HHF), all-cause mortality, acute myocardial infarction (AMI), ischaemic stroke, any coronary revascularization procedures, and new-onset hyperkalaemia. Propensity score matching was performed at a 1:3 ratio between MRA users and non-users to minimize selection bias. A total of 50 872 patients who satisfied our inclusion and exclusion criteria were identified. After 1:3 matching, 2176 patients were included in the MRA group, and 6528 patients were included in the non-MRA group. The risk of CV death was significantly lower among patients who received MRAs than those who did not (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80-0.95), as was the risk of all-cause mortality (HR 0.88, 95% CI 0.83-0.94). Reductions in the risks of CV death and all-cause mortality were more prominent among patients undergoing haemodialysis and those with coronary artery disease. CONCLUSIONS: In patients undergoing regular dialysis who are diagnosed with heart failure, the use of MRAs is associated with lower risks of all-cause mortality and CV death. The benefits of MRA treatment in heart failure may persist in patients with ESRD. Further investigations through randomized controlled trials are needed to assess the efficacy and safety of MRAs in this high-risk population.

Effectiveness of statins for the primary prevention of cardiovascular disease in the Asian elderly population.

BACKGROUND: Population aging is a global trend, and the elderly have a higher risk of atherosclerotic cardiovascular disease (ASCVD) and related mortality. Statins have been observed to reduce cardiovascular events in patients with ASCVD. However, compared with secondary prevention, the benefits of statins for primary prevention are undetermined among the elderly. AIMS: This study aimed to evaluate the effectiveness of statins in an elderly population without a history of cardiovascular disease (CVD). METHODS: The study was carried out using the National Taiwan University Hospital Integrated Medical Database and the National Health Insurance Research Database in Taiwan. Patients aged 65 years and older without a history of CVD were identified between 1 February 2008 and 31 December 2015. New statin users were 1:4 matched to nonusers based on certain variables. The risks of major adverse cardiovascular events (MACEs) and all-cause mortality were estimated using Cox proportional hazards models. Further, we applied marginal structural models to account for time-varying low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: A total of 2761 new statin users and 9503 nonusers were selected after matching; the mean age was 71.8 years, and 63% were women. At a median follow-up of 4.8 years, statin use was associated with reduced risk of MACEs (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.52-0.98) and mortality (HR: 0.72, 95% CI: 0.55-0.93) when accounting for time-varying LDL-C. No significant differences in effect were detected between subgroups. CONCLUSION: Statin use could be beneficial for the primary prevention of CVD in elderly Asians.

Comparison of Clinical Outcomes Among Different Fixed-Dose Combinations of Long-Acting Muscarinic Antagonists and Long-Acting ß2-Agonists in Patients With COPD.

BACKGROUND: Researchers have yet to obtain conclusive evidence differentiating among fixed-dose combinations (FDCs) of long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) for COPD in terms of real-world clinical outcomes. RESEARCH QUESTION: What are the differences between available LAMA/LABA FDCs in the risk of acute exacerbation (AE) and cardiovascular events? STUDY DESIGN AND METHODS: This retrospective cohort study based on a national insurance claims database included patients with COPD ≥ 40 years of age who were newly prescribed glycopyrronium (GLY)/indacaterol (IND), umeclidinium (UMEC)/vilanterol (VI), or tiotropium (TIO)/olodaterol (OLO) FDC between January 1, 2015, and June 30, 2019. Propensity score matching and Cox regression models were used to compare outcomes of AE and cardiovascular events associated with LAMA/LABA FDC treatment. RESULTS: Among the 44,498 patients identified and included, 15,586 received GLY/IND, 20,460 received UMEC/VI, and 8,452 received TIO/OLO. Baseline characteristics were well balanced after 1:1 matching of UMEC/VI and GLY/IND, 2:1 matching of UMEC/VI and TIO/OLO, and 2:1 matching of GLY/IND and TIO/OLO. Risk of severe AE was lower among patients treated with UMEC/VI or GLY/IND than among those who received TIO/OLO (UMEC/VI vs TIO/OLO: 17.85 vs 29.32 per 100 person-years; hazard ratio, 0.76; 95% CI, 0.68-0.84; GLY/IND vs TIO/OLO: 15.54 vs 25.53 per 100 person-years; hazard ratio, 0.77; 95% CI, 0.67-0.88). In addition, GLY/IND users tended to have a lower risk of cardiovascular events than TIO/OLO users, but the difference dissipated when restricting follow up to a shorter duration. INTERPRETATION: Our results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings.

Application of the U.S. Food and Drug Administration's Sentinel Routine Querying Tools to the Taiwan Sentinel Data Model-formatted National Health Insurance Research Database.

The U.S. Food and Drug Administration's Sentinel System is a leading distributed data network for drug safety surveillance in the world. The National Health Insurance Research Database (NHIRD) in Taiwan was converted into the Taiwan Sentinel Data Model (TSDM) based on the Sentinel Common Data Model (SCDM) version 6.0.2. The goal of this study was to investigate the feasibility of applying the same study designs, analytic choices, and analytic tools as used by the U.S. Sentinel System to examine the same drug-outcome associations in the TSDM-formatted NHIRD. Four known drug-outcome associations previously examined by the U.S. Sentinel System were selected as the use cases: (1) use of angiotensin-converting enzyme inhibitors (ACEIs) and risk of angioedema, (2) use of warfarin and risk of gastrointestinal bleeding, (3) use of oral clindamycin and risk of Clostridioides difficile infection (CDI), and (4) use of glyburide and risk of serious hypoglycemia. We followed the same study designs and analytic choices used by the U.S. Sentinel System and applied the Sentinel Routine Querying Tools to answer the same study questions within the TSDM-formatted NHIRD. The results showed that ACEIs were associated with a non-significant increase in risk of angioedema compared to beta-blockers (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.89-1.64); warfarin was associated with a higher risk of gastrointestinal bleeding compared to statins (HR: 1.72; 1.50-1.98); glyburide was associated with an increased risk of hypoglycemia compared to glipizide (HR: 1.61, 1.30-2.00). We were unable to evaluate the association between oral clindamycin and risk of CDI due to the low event number. Our study demonstrated that it was feasible to directly apply the publicly available Sentinel Routine Querying Tools within the TSDM-formatted NHIRD. However, sources of heterogeneity other than design and analytic differences should be carefully considered when comparing the results between the two systems.

Antipsychotic Use in Early Pregnancy and the Risk of Maternal and Neonatal Complications.

OBJECTIVE: To assess the association between antipsychotic use in early pregnancy and the risk of maternal and neonatal metabolic complications. METHODS: We conducted a population-based retrospective cohort study (January 1, 2010, to December 31, 2016) using the Health and Welfare Database in Taiwan. Pregnant women (18 to 49 years of age) were grouped as antipsychotic users (ie, received oral antipsychotic monotherapy during the first 20 weeks of pregnancy) and nonusers. Antipsychotic users were further categorized into first-generation antipsychotic and second-generation antipsychotic users. Propensity score methods, including matching and inverse probability of treatment weighting, were used to balance covariates. Conditional logistic regression and Cox proportional hazards models were used to compare risks of maternal (gestational diabetes mellitus, preterm birth) and neonatal (low birth weight [LBW], macrosomia) outcomes. RESULTS: Antipsychotic users had a notably higher risk of preterm birth compared with nonusers (adjusted HR, 1.29; 95% CI, 1.04 to 1.60), but the risk of gestational diabetes mellitus (HR, 1.21; 95% CI, 0.94 to 1.56), LBW (odds ratio [OR], 1.07; 95% CI, 0.84 to 1.37), and macrosomia (OR, 1.36; 95% CI, 0.63 to 2.92) did not differ between the two groups. Among women who received antipsychotics, the odds of LBW were significantly higher in second-generation antipsychotic users compared with first-generation antipsychotic users (adjusted OR, 1.32; 95% CI, 1.04 to 1.68). CONCLUSION: This study found that using antipsychotics in early pregnancy did not result in a greater risk of metabolic complications both for mothers and newborns. For women requiring treatment with antipsychotics during pregnancy, they should be monitored for the risk of preterm birth and low infant birth weight.

Prognostic Factors for Clinical Outcomes in Patients with Newly Diagnosed Advanced-stage Hodgkin Lymphoma: A Nationwide Retrospective Study.

INTRODUCTION: While Hodgkin lymphoma (HL) is mostly curable, outcomes for advanced-stage HL remain unsatisfactory. The International Prognostic Score and its modifications were developed to predict HL prognosis; however, more straightforward prognostic factors are needed. This study aimed to identify simpler prognostic factors for advanced-stage newly diagnosed HL (NDHL). METHODS: This retrospective study used the Taiwan National Health Insurance Research Database and the Taiwan Cancer Registry. Patients with advanced-stage NDHL receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD-like regimens between 2009 and 2016 were enrolled. Cox proportional hazards models were used to identify prognostic factors for the time to next treatment (TTNT) and overall survival (OS). We used the time-dependent area under the receiver operating characteristic curve (AUROC) to evaluate model performance. RESULTS: The study included 459 patients with advanced-stage NDHL. A bimodal age distribution (peaks 20-44 and >65 years) was observed. Over a median follow-up of 4.7 years, the complete remission and OS rates were 52% and 76%, respectively. Age ≥60 years (adjusted hazard ratio [aHR]: 1.73, 95% confidence interval [CI]: 1.23-2.43), extranodal involvement (1.40, 1.05-1.87), B symptoms (1.53, 1.13-2.06), and Charlson Comorbidity Index (CCI) ≥1 (1.49, 1.08-2.06) were significantly associated with a shorter TTNT. The time-dependent AUROC was .65. With a time-dependent AUROC of .81, age ≥60 years (4.55, 2.90-7.15) and CCI ≥1 (1.86, 1.18-2.91) were risk factors for worse OS. CONCLUSION: Older age and more comorbidities were risk factors for an inferior OS in advanced-stage NDHL, while older age, extranodal involvement, B-symptoms, and higher CCI were significantly associated with disease relapse.