Enhancing Taiwan's healthcare sustainability: A Delphi study on national medicines policy reforms.

BACKGROUND/PURPOSE: The National Medicines Policy (NMP) is crucial as it sets the framework for ensuring access to affordable, high-quality medicines and promoting their rational use, which is essential for public health and the efficiency of the healthcare system. This study aims to evaluate the current state of Taiwan's NMP, identify pressing issues for improvement, and establish actionable suggestions through expert consensus to ensure the sustainable provision and use of medications. METHODS: A modified two-round Delphi technique was employed. The first-round survey identified key issues and suggestions for policy improvement, while the second-round survey evaluated the feasibility and effectiveness of these suggestions. The expert panel, consisting of 50 specialists from pharmacy, medicine, public health, and the pharmaceutical industry, evaluated key issues related to the NMP's efficacy using a 4-point Likert scale. RESULTS: The first-round survey identified 13 key issues in Taiwan's NMP, primarily focusing on the rational use and accessibility of medications. The second-round survey proposed 54 policy improvement suggestions for these issues, of which 20 were considered strong suggestions and 23 were moderate suggestions. The policy recommendations cover medication reimbursement, pharmacy professional services, administration, legislation, and education. CONCLUSION: The study highlights the urgent need for reforms in Taiwan's NMP, providing specific policy improvement suggestions to ensure high-quality medications and pharmaceutical services while supporting the sustainable operation of Taiwan's NHI system. The study underscores the significance of proactive measures to fortify healthcare sustainability in the face of evolving healthcare landscapes.

Changing Reimbursement Criteria on Anti-VEGF Treatment Patterns Among Wet Age-Related Macular Degeneration and Diabetic Macular Edema Patients: An Interrupted Time Series Analysis.

BACKGROUND: To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan. METHODS: An interrupted time series analysis (ITSA) was performed using Taiwan's National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection. RESULTS: The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes. CONCLUSION: This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.

Sex-specific associations between prolonged serum uric acid levels and risk of major adverse cardiovascular events.

Background: While hyperuricemia has been correlated with cardiovascular (CV) diseases, further evidence is required to evaluate the implications of stable serum uric acid (sUA) levels, especially concerning low sUA. This study aimed to investigate prolonged stable sUA levels and CV events/mortality. Methods: We conducted a retrospective cohort study at a medical center using electronic medical records linked with the national claims database. Patients with at least two sUA measurements, with intervals ranging from 6 months to 4 years, were included. The mean of the first two eligible sUA measurements were analyzed, stratified by sex. Outcomes of interest comprised major adverse cardiovascular events (MACE), heart failure hospitalization, CV and all-cause mortality. Results: This study included 33,096 patients (follow-up: men 6.6 years, women 6.4 years). After multivariable adjustment, cubic spline models showed that long-term high sUA levels were consistently associated with a higher risk of MACE, heart failure hospitalization, CV and all-cause mortality. A U-shaped association was observed between sUA levels and all-cause mortality in both sexes and between sUA levels and CV mortality in women. The impact of sUA, especially lower levels, on CV events and mortality was more pronounced in women than in men. Conclusion: Long-term high sUA levels are consistently associated with increased risk of CV events and mortality. A U-shaped association between sUA levels and all-cause mortality was observed in both men and women and was pronounced in women. The findings underscore the importance of considering sUA levels, especially in women, when assessing CV risk.

Impact of an integrated medication management model on the collaborative working relationship among healthcare professionals in a hospital: an explanatory mixed methods study.

An integrated medication management (IMM) model was implemented in a medical center ward to improve the delivery of clinical pharmaceutical services (CPSs). This model incorporated a ward-based clinical pharmacist who performed medication reconciliation and medication reviews. It was perceived to promote interprofessional collaboration between pharmacists and non-pharmacist healthcare professionals (NPHPs, including attending physicians, nurse practitioners, and registered nurses). This study aimed to evaluate the effects of the IMM on NPHPs' intentions to collaborate with pharmacists and understand the mechanism of the impact of the IMM on interprofessional collaboration. A sequential explanatory mixed methods design was employed in the study. Initially, a questionnaire was administered to assess the effects of the IMM on NPHPs' intentions to collaborate with pharmacists. The NPHPs' experiences with the IMM were then documented using semi-structured interviews with inductive thematic analysis. Fifty-eight NPHPs completed the questionnaire, and NPHPs from the intervention ward reported a higher intention to discuss patient-related medication issues with pharmacists, indicating collaboration. Eleven NPHPs were interviewed, and they stated having better working relationships with pharmacists, experiencing more effective CPSs, and noting improved communication with pharmacists. The integration of quantitative and qualitative findings demonstrates that the critical mechanism of the IMM in promoting collaborative relationships is to integrate pharmacists into medical practice, which familiarizes NPHPs with pharmacists' roles, improves communication, and enables pharmacists to identify NPHPs' needs. To summarize, allowing ward-based pharmacists to engage in medical teams on a regular basis appears vital for improving interprofessional teamwork. Furthermore, stakeholders aiming to promote CPS in their institutions should consider the needs and communication channels among NPHPs.

Impact of integrated medication management program on medication errors in a medical center: an interrupted time series study.

BACKGROUND: Medication errors (MEs) are harmful to patients during hospitalization, especially elderly patients. To reduce MEs, an integrated medication management (IMM) model was developed in a 2500-bed medical center, allowing a clinical pharmacist to participate in the daily ward round and perform medication reconciliation and medication reviews. This study aimed to evaluate the impact of the IMM model on MEs and medication utilization using a quasi-experimental design. METHODS: We conducted an interrupted time-series study using the aggregated data of monthly admissions from two wards of a medical center, where one ward served as the intervention and the other served as the external control. The pre- and post-intervention phases comprised of 40 and 12 monthly observational units, respectively. The primary outcome was the mean number of ME reports, which were further investigated for different ME types. The mean number of daily inpatient prescriptions, mean number of daily self-prepared medications, and median daily medication costs were measured. All outcomes were measured per admission episode. Segmented regression was used to evaluate the level and slope changes in the outcomes after IMM model implementation, and subgroup analyses were performed to examine the effects on different groups. RESULTS: After IMM model implementation, the mean number of ME reports increased (level change: 1.02, 95% confidence interval [CI]: 0.68 to 1.35, P < 0.001). The number of reports has shown a dramatic increase in omissions or medication discrepancies, inappropriate drug choices, and inappropriate routes or formulations. Furthermore, the mean number of daily inpatient prescriptions was reduced for patients aged ≥75 years (level change: -1.78, 95% CI: -3.06 to -0.50, P = 0.009). No significant level or slope change was observed in the control ward during the post-intervention phase. CONCLUSIONS: The IMM model improved patient safety and optimized medication utilization by increasing the reporting of MEs and decreasing the number of medications used.

Impact of the Requirement of Bone Mineral Density Evidence on Utilization of Anti-osteoporosis Medications, Clinical Outcome and Medical Expenditures of Patient With Hip Fracture in Taiwan.

BACKGROUND: Since 2011, Taiwan's National Health Insurance Administration (NHIA) issued a regulation on the reimbursement to anti-osteoporosis medications (AOMs). This study aimed to evaluate the impact of this regulation in reimbursement on the utilization of AOMs, clinical outcomes and associated medical expenditures of patients with incident hip fractures. METHODS: By using the National Health Insurance Research Database (NHIRD), patients with incident hip fracture from 2006 to 2015 were identified as our study cohort. Patients younger than 50 years old or prescribed with AOMs within one year prior to incident fracture were excluded. Outcomes of interest were quarterly estimates of the proportion of patients who received bone mineral density (BMD) examination, who were prescribed AOMs, as well as who encountered subsequent osteoporotic fracture-related visits and associated medical expenditures. Particularly, age- and gender specific estimates were reported. An interrupted time series study design with segmented regression model was used to quantitatively explore the impact of the changes of the reimbursement criteria on the level (immediate) and trend (long-term) changes of these outcomes. RESULTS: Our study enrolled 118 493 patients with incident hip fracture with those patients aged older than 80 years old accounting for the largest proportion. A significantly decreased trend of AOMs prescription rates was observed immediately post regulation except for female aged between 65 and 80, while the long-term pattern showed no significant difference. However, the percentage of patients encountered subsequent osteoporotic fracture-related visit was not statistically different between pre- and post-regulation periods. Noteworthy, the policy regulation was associated with an increasing trend of osteoporotic fracture associated medical expenditures, especially for patients older than 80 years old. CONCLUSION: The regulation on the reimbursement for AOMs decreased the prescribing rate of AOMs immediately although the effect did not sustain thereafter. However, higher subsequent osteoporotic fracture-related medical expenditures were introduced, especially among those very old population.

Formulation and stability of an extemporaneously compounded propafenone hydrochloride oral suspension for children with arrhythmia.

OBJECTIVES: In children, supraventricular tachycardia is the most common form of arrhythmia, and propafenone is an effective class Ic antiarrhythmic agent used in this population. No suitable paediatric-specific, dosing-flexible preparation is available in Taiwan. The objective of this study was to develop a formulation of propafenone oral suspension prepared from commercially available propafenone tablets and commercially available oral syrup vehicles for related patients. METHODS: An oral suspension of propafenone hydrochloride at a concentration of 10 mg/mL was prepared by mixing finely grounded propafenone hydrochloride tablets and a 1:1 mixture of Ora-Plus and Ora-Sweet. The beyond-use date was determined by analysing the samples stored at room temperature or 2-8℃ at time 0 and on days 7, 14, 21, 28, 35, 42, 56, and 90. Parameters to be inspected included appearance, pH measurement, high-performance liquid chromatography analysis, and microbial limit tests. RESULTS: On the basis of the physicochemical and microbial stability results, the 10 mg/mL oral suspension of propafenone hydrochloride was stable at 2-8℃ and room temperature for at least 90 days. The suspension did not exhibit significant changes in drug concentration or pH level at any time point. Moreover, no apparent changes or microbial contaminations were observed for at least 90 days. CONCLUSIONS: Propafenone hydrochloride in a 10 mg/mL oral suspension prepared by diluting fine powder with a 1:1 mixture of Ora-Plus and Ora-Sweet and stored in high-density polyethylene bottles and has a beyond-use date of 90 days when stored at 2-8℃ or room temperature. This finding enables us to improve the accuracy of dosage administration and reduce the risk of medication errors affecting the paediatric population.

Effects of a pharmacist-managed anticoagulation outpatient clinic in Taiwan: evaluation of patient knowledge, satisfaction, and clinical outcomes.

Objective: The study aimed to evaluate the improvement of patient knowledge of warfarin use, satisfaction with pharmacists, and the quality of international normalized ratio (INR) control after the implementation of an anticoagulant clinic (ACC) service.Methods: This was a prospective single-group pre- and post-comparison study. Patients who were at least 20 years of age and participated in a pharmacist-managed ACC service were enrolled from February 2012 to September 2015. Each participant completed a self-administered questionnaire before and after the ACC service to evaluate changes in warfarin knowledge. Another questionnaire was distributed after the ACC to evaluate participants' satisfaction with the pharmacist service in the ACC. The INR levels before and after the ACC intervention were obtained to calculate the proportion of time spent in the therapeutic INR range (time in therapeutic range, TTR). Paired t-tests were used to compare changes in participants' knowledge related to warfarin use. Multiple linear regressions were performed to explore the predictors associated with the participants' knowledge scores and TTR after the ACC intervention.Results: One hundred and forty-eight participants were enrolled in this study. A significant improvement (31.5%,p<0.001) in the knowledge of warfarin use was observed at the end of the ACC intervention. The interaction between warfarin and food was the most confusing factor for participants in warfarin use. More than 95% of the participants perceived a positive value of the pharmacist-managed ACC service. However, the consultation fee was the least satisfactory of the ACC service. The average TTR increased from 51.0±34.3% to 78.6±24.5% (p<0.001) after the ACC service was implemented. Participants' education levels and baseline knowledge scores were significant determinants associated with the knowledge improvement in the appropriate warfarin use (p<0.001).Conclusions: A pharmacist-managed ACC improved patient knowledge of warfarin use and INR control, and led to high satisfaction with the pharmacist service in the ACC in Taiwan. Pharmacists should focus on patients with lower education levels to facilitate their understanding of the appropriate warfarin use for better health outcomes.

Pharmacokinetics and dosing of vancomycin in patients undergoing sustained low efficiency daily diafiltration (SLEDD-f): A prospective study.

BACKGROUND/PURPOSE: The pharmacokinetics of vancomycin in patients who undergo sustained low efficiency daily diafiltration (SLEDD-f) is not clear. This study aimed to determine the appropriate vancomycin dosage regimen for patients receiving SLEDD-f. METHODS: This prospectively observational study enrolled critically ill patients older than 18 years old that used SLEDD-f as renal replacement therapy and received vancomycin treatment. An 8-h SLEDD-f was performed with FX-60 (high-flux helixone membrane, 1.4 m2). Serial blood samples were collected before, during, and after SLEDD-f to analyse vancomycin serum concentrations. Effluent fluid samples (a mixture of dialysate and ultrafiltrate) were also collected to determine the amount of vancomycin removal. RESULTS: Seventeen patients were enrolled, and 10 completed the study. The amount of vancomycin removal was 447.4 ± 88.8 mg (about 78.4 ± 18.4% of the dose administered before SLEDD-f). The vancomycin concentration was reduced by 57.5 ± 14.9% during SLEDD-f, and this reduction was followed by a rebound with duration of one to three hours. The elimination half-life of vancomycin decreased from 64.1 ± 35.7 h before SLEDD-f to 7.0 ± 3.0 h during SLEDD-f. CONCLUSION: Significant amount of vancomycin removed during SLEDD-f. Despite the existence of post-dialysis rebound, a sufficient supplemental dose is necessary to maintain therapeutic range.

Timing of anti-osteoporosis medications initiation after a hip fracture affects the risk of subsequent fracture: A nationwide cohort study.

OBJECTIVE: The optimal time after hip fracture to start prophylactic anti-osteoporosis medications (AOMs) remains uncertain, especially in real-world practice. Therefore, we investigated how timing of AOMs initiation affects the risk of subsequent osteoporotic fractures, and what factors influence timing of AOMs prescription. METHOD: Patients ≥50 years old with diagnostic codes indicating hospitalization for hip fracture (n = 77,930) were identified from the Taiwan National Health Insurance Research Database; 9986 who were prescribed AOMs ≤1 year after a newly-diagnosed hip fracture were grouped into those who started AOMs from: ≤14 days (very early); 15-84 days (early); 85-252 days (late); and 253-365 days (very late). Associations with fracture-related hospitalizations after an index fracture were analyzed using a multivariate, time-dependent Cox proportional hazards model, and between-group differences compared by log-rank testing. Factors influencing timing of AOMs initiation were elucidated using multivariate logistic regression analyses. RESULTS: Compared to AOMs initiation from 15 to 84 days, initiation after 252 days was associated with significantly increased risk of fracture-related hospitalization (HR = 1.93, 95% CI 1.29-2.89). Both sensitivity and pre-specified subgroup analyses yield similar results. Among patients with high adherence to AOMs, the increased risk of subsequent fracture-related hospitalization among very late users was profound (HR = 2.56, 95% CI 1.41-4.64). CONCLUSION: Timing of AOMs initiation was significantly associated with age, index year, index hospital length of stay as well as the accreditation level and geographic region of index hospital. After adjusting factors associated with timing of AOMs initiation and patients' adherence, the anti-fracture benefit of AOMs still depends crucially on the timely initiation of AOMs.

Development of a Neuroprotective Erythropoietin Modified with a Novel Carrier for the Blood-Brain Barrier.

Extremely high doses of erythropoietin (EPO) has been used for neuroprotection in ischemia-reperfusion brain injury to deliver sufficient amounts of EPO across the blood-brain barrier (BBB); however, harmful outcomes were observed afterward. We aimed to test the ability of HBHAc (heparin-binding haemagglutinin adhesion c), an intracellular delivery peptide for macromolecules, as an EPO carrier across the BBB. The cellular internalization and transcytosis ability of HBHAc-modified EPO (EPO-HBHAc) were evaluated in bEnd.3 cells and in the bEnd.3/CTX TNA2 co-culture BBB model, respectively. Subsequently, the NMDA-induced-toxicity model and ischemia-reperfusion rat model were used to understand the neuronal protective activity of EPO-HBHAc. The biodistribution of EPO-HBHAc was demonstrated in rats by the quantification of EPO-HBHAc in the brain, plasma, and organs by ELISA. Our results demonstrate that EPO-HBHAc exhibited significantly higher cellular internalization in dose- and time-dependent manners and better transcytosis ability than EPO. In addition, the transported EPO-HBHAc in the co-culture transwell system maintained the neuronal protective activity when primary rat cortical neurons underwent NMDA-induced toxicity. The calculated cerebral infarction area of rats treated with EPO-HBHAc was significantly reduced compared to that of rats treated with EPO (29.9 ± 7.0% vs 48.9 ± 7.9%) 24 h after occlusion in 3VO rat experiments. Moreover, the EPO amount in both CSF and damaged cortex from the EPO-HBHAc group was 4.0-fold and 3.0-fold higher than the EPO group, respectively. These results suggest that HBHAc would be a favorable tool for EPO brain delivery and would further extend the clinical applications of EPO in neuroprotection.

Study of the intracellular delivery mechanism of a pH-sensitive peptide modified with enhanced green fluorescent protein.

The targeted delivery of therapeutic agents is a promising approach to enhance the efficacy and reduce the toxicity of cancer treatments. Understanding the intracellular endocytic mechanisms of a cell penetrating peptide (CPP) in an acidic environment is important for targeted delivery of macromolecules to tumours. In this study, we constructed a pH-sensitive CPP-based delivery system for the intracellular delivery of macromolecules. A pH-sensitive CPP, HBHAc, was fused with a model protein, enhanced green fluorescent protein (EGFP), through recombinant DNA technology. We found that is essential that negatively charged proteoglycans on the cell surface interact with HBHAc-EGFP prior to the cellular uptake of HBHAc-EGFP. The uptake was significantly restricted at 4 °C under pH conditions of both 6.5 and 7.5. The increased positive charge of HBHAc-EGFP under the acidic condition leads to a pH-dependent cellular uptake, and we observed that the internalisation of HBHAc-EGFP was significantly higher at pH 6.5 than at pH 7.5 (p < .05). Thus, with pH-sensitive activity, HBHAc is expected to improve tumour-targeted intracellular protein delivery. Moreover, our findings provide a new insight that the endocytic pathway may change under different pH conditions and suggest that this unique phenomenon benefits pH-sensitive drug delivery for tumour therapy.

Treatment patterns of lipid-lowering therapies and possible statin intolerance among statin users with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan.

OBJECTIVES: To assess treatment patterns of statin and/or ezetimibe and possible statin intolerance among patients initiating statin or statin plus ezetimibe and with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan. METHODS: A retrospective cohort study using Taiwan's 2005 to 2013 National Health Insurance Research Database (NHIRD) was conducted. Patients with history of clinical ASCVD or DM (without previous clinical ASCVD) and initiating statin or statin plus ezetimibe therapy during 2006 to 2012 were identified. The treatment initiation date was defined as index date. Treatment patterns (including discontinuation, reinitiation, subtraction, switching, and augmentation), adherence (medication possession ratio [MPR]), persistence (gap no greater than 60 d) of statin and/or ezetimibe, and possible statin intolerance during 12-month follow-up from the index date were examined. RESULTS: Among patients initiating statin or statin plus ezetimibe, 11 092 patients with history of clinical ASCVD and 31 100 patients with DM but without clinical ASCVD were analysed. The discontinuation, reinitiation, and switching rates among patients with clinical ASCVD were 54.0%, 11.3%, and 25.7% during 12-month follow-up period, respectively. Among patients with DM, the rates were 57.5%, 14.2%, and 28.5%. The MPRs of statin among clinical ASCVD and DM cohorts were 0.62 and 0.60, respectively. As for ezetimibe, the MPRs were 0.56 and 0.59. Persistence to statin treatment was 46.1% among ASCVD patients and 42.6% among DM patients. Among the ASCVD and DM cohorts, possible statin intolerance was observed among 19.9% and 21.4% of patients, respectively. CONCLUSIONS: Large number of patients with either ASCVD or DM discontinued lipid-lowering therapies with suboptimal adherence and persistence among Taiwanese population. There is a large unmet medical need to provide safe and more effective therapies, which can be used in combination with statins or alone, to reduce the risk of CV events and improve outcomes in high-risk patients.

A Web-Based Clinical System for Cohort Surveillance of Specific Clinical Effectiveness and Safety Outcomes: A Cohort Study of Non-Vitamin K Antagonist Oral Anticoagulants and Warfarin.

BACKGROUND: Conventional systems of drug surveillance lack a seamless workflow, which makes it crucial to have an active drug surveillance system that proactively assesses adverse drug events. OBJECTIVE: The aim of this study was to develop a seamless, Web-based workflow for comparing the safety and effectiveness of drugs in a database of electronic medical records. METHODS: We proposed a comprehensive integration process for cohort surveillance using the National Taiwan University Hospital Clinical Surveillance System (NCSS). We studied a practical application of the NCSS that evaluates the drug safety and effectiveness of novel oral anticoagulants (NOACs) and warfarin by cohort tree analysis in an efficient and interoperable platform. RESULTS: We demonstrated a practical example of investigating the differences in effectiveness and safety between NOACs and warfarin in patients with nonvalvular atrial fibrillation (AF) using the NCSS. We efficiently identified 2357 patients with nonvalvular AF with newly prescribed oral anticoagulants between 2010 and 2015 and further developed 1 main cohort and 2 subcohorts for separately measuring ischemic stroke as the clinical effectiveness outcome and intracranial hemorrhage (ICH) as the safety outcome. In the subcohort of ischemic stroke, NOAC users exhibited a significantly lower risk of ischemic stroke than warfarin users after adjusting for age, sex, comorbidity, and comedication in an intention-to-treat (ITT) analysis (P=.01) but did not exhibit a significantly distinct risk in an as-treated (AT) analysis (P=.12) after the 2-year follow-up. In the subcohort of ICH, NOAC users did not exhibit a different risk of ICH both in ITT (P=.68) and AT analyses (P=.15). CONCLUSIONS: With a seamless and Web-based workflow, the NCSS can serve the critical role of forming associations between evidence and the real world at a medical center in Taiwan.

Comparing Cardiovascular Safety of Febuxostat and Allopurinol in the Real World: A Population-Based Cohort Study.

OBJECTIVE: To determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. PATIENTS AND METHODS: We conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. RESULTS: A total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. CONCLUSION: The use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.

Risk of cardiovascular events associated with dipeptidyl peptidase-4 inhibitors in patients with diabetes with and without chronic kidney disease: A nationwide cohort study.

BACKGROUND: Cardiovascular events associated with oral hypoglycemic agents (OHAs) have raised significant safety concerns. This study assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4i) and the risk of cardiovascular events in patients with type 2 diabetes mellitus with or without chronic kidney disease (CKD). STUDY DESIGN: A retrospective cohort study using Taiwan's National Health Insurance Research Database. SETTINGS AND PARTICIPANTS: Our study included patients with type 2 diabetes who received OHAs between March 1, 2009, and December 31, 2012. All eligible subjects were classified into CKD and non-CKD cohorts and further categorized as the DPP-4i and non-DPP-4i users in each cohort. METHODS: The DPP-4i and non-DPP-4i groups were matched 1:1 by propensity score to attenuate potential selection bias. Propensity score was estimated by logistic regression, using demographics, co-medications, comorbidities. and adapted diabetic complication severity index at baseline. OUTCOMES: Outcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction, cardiovascular death (major adverse cardiac events [MACE]), and hospitalization for heart failure (hHF). COX proportional hazard models were applied to examine the association between DPP-4i and outcomes of interest. RESULTS: We identified 37,641 and 87,604 patients with type 2 diabetes with and without CKD, respectively. After propensity score matching, 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients were included for analysis. In the CKD cohort, DPP-4i were associated with a 25% increased risk of hHF (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 15.0 vs. 9.9, HR = 1.25; 95% CI 1.01-1.54, p = 0.037) but not with the risk of MACE (HR = 0.89, p = 0.144). In the non-CKD cohort, DPP-4i were associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 9.8 vs. 12.6 HR = 0.73; 95% CI 0.61-0.87, p = 0.0007), but not the risk of hHF (HR = 1.09, p = 0.631). CONCLUSIONS: DPP-4i were found to be associated with decreased risk of MACE in the non-CKD cohort in our study. However, DPP-4i were associated with increased risk of hHF in the CKD cohort. DPP-4i in the CKD cohort should be used cautiously.

Factors affecting serum concentration of dabigatran in Asian patients with non-valvular atrial fibrillation.

BACKGROUND/PURPOSE: Dabigatran is effective in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation. Although the therapeutic window for dabigatran is wide, its pharmacokinetic properties can differ between specific populations. This study aimed to establish a real-life plasma dabigatran concentration database and investigate potential factors affecting this concentration in Asians. METHODS: Patients under dabigatran therapy were recruited. Plasma dabigatran concentration was determined in trough and peak blood samples by using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Factors affecting the dabigatran concentration were investigated. RESULTS: A total of 46 patients (33 male, 71.7%) were prospectively enrolled. Most of them were receiving a low dose regimen (110 mg twice daily, n = 38, 82.6%). The trough and peak concentrations were significantly correlated (p < 0.001), and the trough concentration was higher in patients aged ≥75 years, body weight ≤60 kg, creatinine clearance (CrCl) ≤50 mL/min, CHA2DS2-VASc score >3 points, and HAS-BLED score ≥3 points. Multiple linear regression analysis identified body weight and serum creatinine as key factors predicting trough concentration (p = 0.003 and 0.005, respectively). Importantly, drug adherence was the only independent factor associated with low trough concentration, defined as the lowest 20th percentile in our study cohort (n = 10, hazard ratio = 9.07; 95% CI, 1.12 to 73.22; p = 0.004). CONCLUSION: Dabigatran monitoring may be considered for patients at risk of overexposure, especially those with low body weight and renal insufficiency, and also for detecting those with extremely low drug concentration.

Effect of statin use on the risk of medically attended acute respiratory illness among influenza vaccinated elderly.

OBJECTIVES: The immunomodulatory effects of statins may reduce the immune response induced by influenza vaccines. However, evidence regarding the effect of statin use on the effectiveness of seasonal influenza vaccines against medically attended acute respiratory illness (MAARI) in the elderly remains scarce. METHODS: We conducted a retrospective cohort study using data from Taiwan's National Health Insurance Research Database. Elderly adults aged ≧ 66 years who were vaccinated with seasonal influenza vaccines during the 2007-2008 to 2012-2013 influenza seasons were enrolled for this analysis. We compared the risk of MAARI between statin and non-statin users. Propensity score matching and conditional logistic regression models were used to analyze the data. RESULTS: A total of 440,180 elderly were included in this study. In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02-1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02-1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (ORsimvastatin: 1.14, 95% CI: 1.10-1.18; ORlovastatin: 1.18, 95% CI: 1.12-1.25). CONCLUSIONS: Statin exposure, especially simvastatin and lovastatin, was associated with a higher risk of MAARI in the seasonal influenza vaccinated elderly. Future studies exploring the differences between individual statins and mechanisms of their immunomodulatory effects are necessary.

Identifying Unmet Treatment Needs for Patients With Osteoporotic Fracture: Feasibility Study for an Electronic Clinical Surveillance System.

BACKGROUND: Traditional clinical surveillance relied on the results from clinical trials and observational studies of administrative databases. However, these studies not only required many valuable resources but also faced a very long time lag. OBJECTIVE: This study aimed to illustrate a practical application of the National Taiwan University Hospital Clinical Surveillance System (NCSS) in the identification of patients with an osteoporotic fracture and to provide a high reusability infrastructure for longitudinal clinical data. METHODS: The NCSS integrates electronic medical records in the National Taiwan University Hospital (NTUH) with a data warehouse and is equipped with a user-friendly interface. The NCSS was developed using professional insight from multidisciplinary experts, including clinical practitioners, epidemiologists, and biomedical engineers. The practical example identifying the unmet treatment needs for patients encountering major osteoporotic fractures described herein was mainly achieved by adopting the computerized workflow in the NCSS. RESULTS: We developed the infrastructure of the NCSS, including an integrated data warehouse and an automatic surveillance workflow. By applying the NCSS, we efficiently identified 2193 patients who were newly diagnosed with a hip or vertebral fracture between 2010 and 2014 at NTUH. By adopting the filter function, we identified 1808 (1808/2193, 82.44%) patients who continued their follow-up at NTUH, and 464 (464/2193, 21.16%) patients who were prescribed anti-osteoporosis medications, within 3 and 12 months post the index date of their fracture, respectively. CONCLUSIONS: The NCSS systems can integrate the workflow of cohort identification to accelerate the survey process of clinically relevant problems and provide decision support in the daily practice of clinical physicians, thereby making the benefit of evidence-based medicine a reality.

Risk of stroke associated with use of nonsteroidal anti-inflammatory drugs during acute respiratory infection episode.

BACKGROUND: Previous studies suggested that acute respiratory infection (ARI) could trigger stroke and that use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with increased risk of stroke. In many countries, NSAIDs have been widely used among patients with ARI or common cold for pain and fever relief. However, studies evaluating whether NSAIDs use during ARI episodes may further increase the risk of stroke were very limited. METHODS AND RESULTS: During 2007 to 2011, 29 518 patients with an incident hospitalization of stroke were identified. The date of admission was defined as the index date. Using case-crossover design, we compared the following exposure status between the case period (1- to 7-d period before the index date) and matched control period (366- to 372-d period before the index date): NSAIDs use during ARI episodes, ARI episodes without NSAIDs use, NSAIDs use only, or no exposure. Multivariable conditional regression models were used to estimate odds ratios adjusting potential confounders. The results suggested that NSAIDs use during ARI episodes was associated with a 2.3-fold increased risk of stroke (ischemic: adjusted odds ratio, aOR 2.27, 95% confidence interval, 95% CI, 2.00-2.58; hemorrhagic: aOR 2.28, 95% CI, 1.71-3.02). We also determined that parenteral NSAIDs were associated with much higher risk of stroke in patients with ARI. CONCLUSIONS: Nonsteroidal anti-inflammatory drugs use during ARI episodes, especially parenteral NSAIDs use, was associated with a further increased risk of stroke.