Integrated Real-World Data Warehouses Across 7 Evolving Asian Health Care Systems: Scoping Review.

BACKGROUND: Asia consists of diverse nations with extremely variable health care systems. Integrated real-world data (RWD) research warehouses provide vast interconnected data sets that uphold statistical rigor. Yet, their intricate details remain underexplored, restricting their broader applications. OBJECTIVE: Building on our previous research that analyzed integrated RWD warehouses in India, Thailand, and Taiwan, this study extends the research to 7 distinct health care systems: Hong Kong, Indonesia, Malaysia, Pakistan, the Philippines, Singapore, and Vietnam. We aimed to map the evolving landscape of RWD, preferences for methodologies, and database use and archetype the health systems based on existing intrinsic capability for RWD generation. METHODS: A systematic scoping review methodology was used, centering on contemporary English literature on PubMed (search date: May 9, 2023). Rigorous screening as defined by eligibility criteria identified RWD studies from multiple health care facilities in at least 1 of the 7 target Asian nations. Point estimates and their associated errors were determined for the data collected from eligible studies. RESULTS: Of the 1483 real-world evidence citations identified on May 9, 2023, a total of 369 (24.9%) fulfilled the requirements for data extraction and subsequent analysis. Singapore, Hong Kong, and Malaysia contributed to ≥100 publications, with each country marked by a higher proportion of single-country studies at 51% (80/157), 66.2% (86/130), and 50% (50/100), respectively, and were classified as solo scholars. Indonesia, Pakistan, Vietnam, and the Philippines had fewer publications and a higher proportion of cross-country collaboration studies (CCCSs) at 79% (26/33), 58% (18/31), 74% (20/27), and 86% (19/22), respectively, and were classified as global collaborators. Collaboration with countries outside the 7 target nations appeared in 84.2% to 97.7% of the CCCSs of each nation. Among target nations, Singapore and Malaysia emerged as preferred research partners for other nations. From 2018 to 2023, most nations showed an increasing trend in study numbers, with Vietnam (24.5%) and Pakistan (21.2%) leading the growth; the only exception was the Philippines, which declined by -14.5%. Clinical registry databases were predominant across all CCCSs from every target nation. For single-country studies, Indonesia, Malaysia, and the Philippines favored clinical registries; Singapore had a balanced use of clinical registries and electronic medical or health records, whereas Hong Kong, Pakistan, and Vietnam leaned toward electronic medical or health records. Overall, 89.9% (310/345) of the studies took >2 years from completion to publication. CONCLUSIONS: The observed variations in contemporary RWD publications across the 7 nations in Asia exemplify distinct research landscapes across nations that are partially explained by their diverse economic, clinical, and research settings. Nevertheless, recognizing these variations is pivotal for fostering tailored, synergistic strategies that amplify RWD's potential in guiding future health care research and policy decisions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/43741.

Real-world evidence of lorlatinib therapy in Taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). METHODS: This multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. RESULTS: Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5-78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3-21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. CONCLUSION: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Treatment benefit of upfront autologous stem cell transplantation for newly diagnosed multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: Upfront high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains a profitable strategy for newly diagnosed multiple myeloma (MM) patients in the context of novel agents. However, current knowledge demonstrates a discrepancy between progression-free survival (PFS) and overall survival (OS) benefit with HDT/ASCT. METHODS: We conducted a systematic review and meta-analysis that included both randomized controlled trials (RCTs) and observational studies evaluating the benefit of upfront HDT/ASCT published during 2012 to 2023. Further sensitivity analysis and meta-regression were also performed. RESULTS: Among the 22 enrolled studies, 7 RCTs and 9 observational studies had a low or moderate risk of bias, while the remaining 6 observational studies had a serious risk of bias. HDT/ASCT revealed advantages in complete response (CR) with an odds ratio (OR) of 1.24 and 95% confidence interval (CI) 1.02 ~ 1.51, PFS with a hazard ratio (HR) of 0.53 (95% CI 0.46 ~ 0.62), and OS with an HR of 0.58 (95% CI 0.50 ~ 0.69). Sensitivity analysis excluding the studies with serious risk of bias and trim-and-fill imputation fundamentally confirmed these findings. Older age, increased percentage of patients with International Staging System (ISS) stage III or high-risk genetic features, decreased proteasome inhibitor (PI) or combined PI/ immunomodulatory drugs (IMiD) utilization, and decreased follow-up duration or percentage of males were significantly related to a greater survival advantage with HDT/ASCT. CONCLUSIONS: Upfront ASCT remains a beneficial treatment for newly diagnosed MM patients in the period of novel agents. Its advantage is especially acute in high-risk MM populations, such as elderly individuals, males, those with ISS stage III or high-risk genetic features, but is attenuated with PI or combined PI/IMiD utilization, contributing to divergent survival outcomes.

Integrated Real-World Study Databases in 3 Diverse Asian Health Care Systems in Taiwan, India, and Thailand: Scoping Review.

BACKGROUND: The use of real-world data (RWD) warehouses for research in Asia is on the rise, but current trends remain largely unexplored. Given the varied economic and health care landscapes in different Asian countries, understanding these trends can offer valuable insights. OBJECTIVE: We sought to discern the contemporary landscape of linked RWD warehouses and explore their trends and patterns in 3 Asian countries with contrasting economies and health care systems: Taiwan, India, and Thailand. METHODS: Using a systematic scoping review methodology, we conducted an exhaustive literature search on PubMed with filters for the English language and the past 5 years. The search combined Medical Subject Heading terms and specific keywords. Studies were screened against strict eligibility criteria to identify eligible studies using RWD databases from more than one health care facility in at least 1 of the 3 target countries. RESULTS: Our search yielded 2277 studies, of which 833 (36.6%) met our criteria. Overall, single-country studies (SCS) dominated at 89.4% (n=745), with cross-country collaboration studies (CCCS) being at 10.6% (n=88). However, the country-wise breakdown showed that of all the SCS, 623 (83.6%) were from Taiwan, 81 (10.9%) from India, and 41 (5.5%) from Thailand. Among the total studies conducted in each country, India at 39.1% (n=133) and Thailand at 43.1% (n=72) had a significantly higher percentage of CCCS compared to Taiwan at 7.6% (n=51). Over a 5-year span from 2017 to 2022, India and Thailand experienced an annual increase in RWD studies by approximately 18.2% and 13.8%, respectively, while Taiwan's contributions remained consistent. Comparative effectiveness research (CER) was predominant in Taiwan (n=410, or 65.8% of SCS) but less common in India (n=12, or 14.8% of SCS) and Thailand (n=11, or 26.8% of SCS). CER percentages in CCCS were similar across the 3 countries, ranging from 19.2% (n=10) to 29% (n=9). The type of RWD source also varied significantly across countries, with India demonstrating a high reliance on electronic medical records or electronic health records at 55.6% (n=45) of SCS and Taiwan showing an increasing trend in their use over the period. Registries were used in 26 (83.9%) CCCS and 31 (75.6%) SCS from Thailand but in <50% of SCS from Taiwan and India. Health insurance/administrative claims data were used in most of the SCS from Taiwan (n=458, 73.5%). There was a consistent predominant focus on cardiology/metabolic disorders in all studies, with a noticeable increase in oncology and infectious disease research from 2017 to 2022. CONCLUSIONS: This review provides a comprehensive understanding of the evolving landscape of RWD research in Taiwan, India, and Thailand. The observed differences and trends emphasize the unique economic, clinical, and research settings in each country, advocating for tailored strategies for leveraging RWD for future health care research and decision-making. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/43741.

Cost-effectiveness of statin therapy for secondary prevention among patients with coronary artery disease and baseline LDL-C 70-100 mg/dL in Taiwan.

BACKGROUND: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70-100 mg/dL in Taiwan could be cost-effective. METHODS: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. RESULTS: Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER. CONCLUSION: Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.

Long-term statin adherence in patients after hospital discharge for new onset of atherosclerotic cardiovascular disease: a population-based study of real world prescriptions in Taiwan.

BACKGROUND: Despite the recommendations of statins treatment for secondary prevention of atherosclerotic cardiovascular disease (ASCVD), treatment adherence and persistence are still a concern. This study examined the real world practice of long-term adherence and persistence to statins treatment initiated after hospital discharge for ASCVD, and their associated factors in a nationwide cohort. METHODS: Post discharge statin prescriptions between 2006 and 2012 were extracted from the Taiwan National Health Insurance claims database. Good adherence, defined as proportion of days covered (PDC) ≥0.8 and mean medication possession ratio (MPR), was measured every 180-day period. Non-persistence was defined on the date patients failed to refill statin for 90 days after the end of the last prescription. Their associations with influential factors were analyzed using a generalized estimating equation and Cox's proportional hazard model. RESULTS: There was a total of 185,252 post-discharge statin initiations (from 169,624 patients) and followed for 467,398 patient-years in the study cohort. Percentage of good adherence (mean MPR) was 71% (0.87) at 6-months; declined to 54% (0.68), 47% (0.59), and 42% (0.50) at end of year 1, 2, and 7, respectively. Persistence in statin treatment was 86, 67, 50, and 25% at 6-month, 1-, 2-, and 7-year, respectively. Comparing the statin-cohort initiated from year 2006 to 2012, 1-year persistence increased from 58 to 73%, and 1-year good adherence improved from 45 to 61%. Factors associated with sub-optimal adherence and non-persistence included: prescription by primary care clinics or non-cardiology specialties; patients' age > 75 years; no history of previous statin use; ASCVD events with ischemic stroke diagnosis; comorbidities of renal disease, liver disease, depression, and chronic obstructive pulmonary disease. CONCLUSIONS: Despite the improving trends, long-term adherence and persistence of statin treatment were suboptimal in Taiwan. Strategies to maintain statin treatment adherence and persistence need to be implemented to further enhance the positive trend.

The net clinical benefits of febuxostat versus allopurinol in patients with gout or asymptomatic hyperuricemia - A systematic review and meta-analysis.

BACKGROUND AND AIMS: Systemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia. METHODS AND RESULTS: PubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24-2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30-085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55-0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76-0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00-1.67, P = 0.05) after the CARES study was included. CONCLUSION: Febuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia. REGISTRATION NUMBER: PROSPERO(CRD42018091657).

The Prognostic Impact of Type 2 Diabetes Mellitus on Early Cervical Cancer in Asia.

BACKGROUND: Many studies have shown that type 2 diabetes mellitus (DM) increases the risk for several types of cancer but not cervical cancer (CC). Although DM and insulin-like growth factor 1 have preclinical and clinical implications for CC, less is known about the prognostic impact of DM on patients with early stage CC. PATIENTS AND METHODS: We used the nationwide Taiwan Cancer Registry database to collect the characteristics of stage I-IIA cervical cancer patients diagnosed between 2004 and 2008. DM and other comorbidities were retrieved from the National Health Insurance database. Cervical cancer-specific survival (CSS) and overall survival (OS) times of patients according to DM status were estimated using the Kaplan-Meier method. We used a Cox proportional hazards model to calculate adjusted hazard ratios (HRs) for the effects of DM and other risk factors on mortality. RESULTS: A total of 2,946 patients had primary stage I-IIA CC and received curative treatments, and 284 (9.6%) had DM. The 5-year CSS and OS rates for patients with DM were significantly lower than those without DM (CSS: 85.4% vs. 91.5%; OS: 73.9% vs. 87.9%). After adjusting for clinicopathologic variables and comorbidities, DM remained an independent unfavorable prognostic factor for CSS (adjusted HR: 1.46) and OS (adjusted HR: 1.55). CONCLUSION: In Asian patients with early cervical cancer, DM is an independent unfavorable prognostic factor influencing both OS and CSS, even after curative treatments. IMPLICATIONS FOR PRACTICE: Type 2 diabetes mellitus (DM) increases the incidence of several types of cancer but not cervical cancer (CC); however, less is known about the impact of DM on patients who already have CC. This study suggests that DM may increase the risk of cancer recurrence and death for early stage CC patients, even after curative treatments. Incorporating DM control should be considered part of the continuum of care for early stage CC patients, and close surveillance during routine follow-up in this population is recommended.

Treatment efficacy differences of sorafenib for advanced hepatocellular carcinoma: a meta-analysis of randomized clinical trials.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a heterogeneous disease. We explored whether any specific subgroups of patients may gain more survival benefits from sorafenib as the first-line therapy for advanced HCC. METHODS: PubMed and the Cochrane library were searched for phase III clinical trials that compared sorafenib with other treatments as first-line therapy for advanced HCC. We retrieved data from the published articles and then calculated synthesized hazard ratios (HRs) of overall mortality for patients of different subgroups, using patients who received other treatments as the reference. RESULTS: Four phase III clinical trials comparing sorafenib with other treatments were included in this study. The HRs were not significantly different between patients from various geographic regions (p = 0.183), patients with different Eastern Cooperative Oncology Group performance statuses (p = 0.699), or patients with different tumor involvement (p = 0.221). By contrast, the synthesized HR for hepatitis C virus (HCV)+ patients was 0.65 [95% confidence interval (CI) 0.53-0.80], which was significantly lower than that for HCV- patients (0.87, 95% CI 0.79-0.96, p = 0.013). CONCLUSIONS: As the first-line therapy for advanced HCC, sorafenib might provide more survival benefits to HCV+ patients than to HCV- patients.

Treatment of patients with dual hepatitis C and B by peginterferon α and ribavirin reduced risk of hepatocellular carcinoma and mortality.

OBJECTIVE: Whether peginterferon α and ribavirin combination therapy reduces risk of hepatocellular carcinoma (HCC) or improves survival in patients dual-infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) is unknown. Since it is ethically impossible to conduct a randomised trial to learn the long-term efficacy, we rely upon the large database to explore the effectiveness of combination therapy among dual-infected patients. DESIGN: Data for this population-based retrospective cohort study were obtained from the treatment programme, Cancer Registry, National Health Insurance and death certification. We examined the risk of HCC, mortality and adverse events in 1096 treated and 18 988 untreated HCV-HBV dually-infected patients. Outcomes were analysed using the bias corrected inverse probability weighting (IPW) by propensity scores. Outcomes of HCV-HBV dually-infected and HCV mono-infected patients receiving the same treatment were compared using new user design with IPW estimators to adjust for confounding. RESULTS: After adjustment, combination therapy significantly reduced the risk of HCC (HR 0.76, 95% CI 0.59 to 0.97), liver-related mortality (HR 0.47, 95% CI 0.37 to 0.6) and all-cause mortality (HR 0.42, 95% CI 0.34 to 0.52). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Treatment was associated with an increase in the incidence of thyroid dysfunction (HR 1.9, p<0.001) and mood disorders (HR 1.81, p=0.005). CONCLUSIONS: This is the first evidence showing that combination therapy decreased the risk of HCC and improved survival in HCV-HBV dually-infected patients despite a slight increase in the incidence of thyroid and mood disorders.

Type 2 diabetes mellitus is associated with increased mortality in Chinese patients receiving curative surgery for colon cancer.

BACKGROUND: We investigated the association between diabetes mellitus (DM) and the prognosis of patients with early colon cancer who had undergone curative surgery. METHODS: From three national databases of patients in Taiwan, we selected a cohort of colon cancer patients who had been newly diagnosed with stage I or stage II colon cancer between January 1, 2004 and December 31, 2008 and had undergone curative surgery. We collected information regarding DM (type 2 DM only), the use of antidiabetic medications, other comorbidities, and survival outcomes. The colon cancer-specific survival (CSS) and the overall survival (OS) were compared between patients with and without DM. RESULTS: We selected 6,937 colon cancer patients, among whom 1,371 (19.8%) had DM. The colon cancer patients with DM were older and less likely to receive adjuvant chemotherapy but had a similar tumor stage and grade, compared with colon cancer patients without DM. Compared with colon cancer patients without DM, patients with DM had significantly shorter OS (5-year OS: 71.0% vs. 81.7%) and CSS (5-year CSS: 86.7% vs. 89.2%). After adjusting for age, sex, stage, adjuvant chemotherapy, and comorbidities in our multivariate analysis, DM remained an independent prognostic factor for overall mortality (adjusted hazards ratio: 1.32, 95% confidence interval: 1.18-1.49), but not for cancer-specific mortality. Among the colon cancer patients who had received antidiabetic drug therapy, patients who had used insulin had significantly shorter CSS and OS than patients who had not. CONCLUSION: Among patients who receive curative surgery for early colon cancer, DM is a predictor of increased overall mortality.

Budget impact analysis-principles of good practice: report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force.

BACKGROUND: Budget impact analyses (BIAs) are an essential part of a comprehensive economic assessment of a health care intervention and are increasingly required by reimbursement authorities as part of a listing or reimbursement submission. OBJECTIVES: The objective of this report was to present updated guidance on methods for those undertaking such analyses or for those reviewing the results of such analyses. This update was needed, in part, because of developments in BIA methods as well as a growing interest, particularly in emerging markets, in matters related to affordability and population health impacts of health care interventions. METHODS: The Task Force was approved by the International Society for Pharmacoeconomics and Outcomes Research Health Sciences Policy Council and appointed by its Board of Directors. Members were experienced developers or users of BIAs; worked in academia and industry and as advisors to governments; and came from several countries in North America and South America, Oceania, Asia, and Europe. The Task Force solicited comments on the drafts from a core group of external reviewers and, more broadly, from the membership of the International Society for Pharmacoeconomics and Outcomes Research. RESULTS: The Task Force recommends that the design of a BIA for a new health care intervention should take into account relevant features of the health care system, possible access restrictions, the anticipated uptake of the new intervention, and the use and effects of the current and new interventions. The key elements of a BIA include estimating the size of the eligible population, the current mix of treatments and the expected mix after the introduction of the new intervention, the cost of the treatment mixes, and any changes expected in condition-related costs. Where possible, the BIA calculations should be performed by using a simple cost calculator approach because of its ease of use for budget holders. In instances, however, in which the changes in eligible population size, disease severity mix, or treatment patterns cannot be credibly captured by using the cost calculator approach, a cohort or patient-level condition-specific model may be used to estimate the budget impact of the new intervention, accounting appropriately for those entering and leaving the eligible population over time. In either case, the BIA should use data that reflect values specific to a particular decision maker's population. Sensitivity analysis should be of alternative scenarios chosen from the perspective of the decision maker. The validation of the model should include at least face validity with decision makers and verification of the calculations. Data sources for the BIA should include published clinical trial estimates and comparator studies for the efficacy and safety of the current and new interventions as well as the decision maker's own population for the other parameter estimates, where possible. Other data sources include the use of published data, well-recognized local or national statistical information, and, in special circumstances, expert opinion. Reporting of the BIA should provide detailed information about the input parameter values and calculations at a level of detail that would allow another modeler to replicate the analysis. The outcomes of the BIA should be presented in the format of interest to health care decision makers. In a computer program, options should be provided for different categories of costs to be included or excluded from the analysis. CONCLUSIONS: We recommend a framework for the BIA, provide guidance on the acquisition and use of data, and offer a common reporting format that will promote standardization and transparency. Adherence to these good research practice principles would not necessarily supersede jurisdiction-specific BIA guidelines but may support and enhance local recommendations or serve as a starting point for payers wishing to promulgate methodology guidelines.

Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan.

BACKGROUND: Observational studies and fatal case reports raise concern about the safety of severe dysglycemia associated with fluoroquinolone use. The objective of this study was to assess the risk of severe dysglycemia among diabetic patients who received different fluoroquinolones. METHODS: In a population-based inception cohort study of diabetic patients covering the period from January 2006 to November 2007, outpatient new users of levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins, and macrolides orally were identified. Study events were defined as emergency department visits or hospitalization for dysglycemia within 30 days following the initiation of antibiotic therapy. Results were analyzed with adjusted multinomial propensity score. RESULTS: A total of 78 433 diabetic patients receiving the antibiotics of interest were included in the study. The absolute risk of hyperglycemia per 1000 persons was 6.9 for moxifloxacin and 1.6 for macrolides. In contrast, the risk of hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of levofloxacin, ciprofloxacin, and moxifloxacin compared with macrolides were 1.75 (1.12-2.73), 1.87 (1.20-2.93), and 2.48 (1.50-4.12), respectively, for hyperglycemia and 1.79 (1.33-2.42), 1.46 (1.07-2.00), and 2.13 (1.44-3.14), respectively, for hypoglycemia. Patients taking moxifloxacin faced a significantly higher risk of hypoglycemia than those receiving ciprofloxacin. A significant increase in the risk of hypoglycemia was also observed among patients receiving moxifloxacin concomitantly with insulin (AOR, 2.28; 95% CI, 1.22-4.24). CONCLUSIONS: Diabetics using oral fluoroquinolones faced greater risk of severe dysglycemia. The risk of hypoglycemia varied according to the type of fluoroquinolone administered, and was most commonly associated with moxifloxacin.

Hospital volume of percutaneous radiofrequency ablation is closely associated with treatment outcomes for patients with hepatocellular carcinoma.

BACKGROUND: Hospital volume for several major operations is associated with treatment outcomes. In this study, the authors explored the influence of hospital radiofrequency ablation (RFA) volume on the prognosis of patients who received RFA for hepatocellular carcinoma (HCC). METHODS: The authors searched for all patients who were diagnosed with stage I or stage II HCC from 2004 to 2006 and who received RFA as first-line therapy in a population-based cohort. Overall survival (OS) and liver cancer-specific survival (CSS) were compared according to hospital volume. A Cox proportional hazards model was used for multivariate analysis. RESULTS: In total, 661 patients received first-line RFA for stage I and II HCC in 28 hospitals. Among these, there were 480 patients (72.6%) in the high-volume group (those who received RFA at hospitals that treated >10 first-line patients per year), and there were 181 patients (27.4%) in the low-volume group (those who received RFA at hospitals that treated ≤ 10 first-line patients per year). The sex, age, stage, tumor size, and year of diagnosis for patients in the 2 groups did not differ significantly. Patients in the high-volume group demonstrated significantly longer OS and CSS than those in the low-volume group (5-year OS rate, 58.7% vs 47.2%; P = .001; 5-year CSS rate, 67.1% vs 57.1%; P = .009). After adjusting for covariates, high-volume hospitals remained an independent predictor of longer OS (hazard ratio, 0.57; P < .001) and CSS (hazard ratio, 0.57; P = .003). CONCLUSIONS: Patients who received first-line RFA for HCC in high-volume hospitals demonstrated better survival outcomes.

Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials.

BACKGROUND: The active-treatment comparative safety information for all inhaled medications in patients with chronic obstructive pulmonary disease (COPD) is limited. We aimed to compare the risk of overall and cardiovascular death for inhaled medications in patients with COPD. METHODS: Through systematic database searching, we identified randomised controlled trials of tiotropium Soft Mist Inhaler, tiotropium HandiHaler, long-acting ß2 agonists (LABAs), inhaled corticosteroids (ICS), and LABA-ICS combination with at least a 6-month treatment duration. Direct comparison and mixed treatment comparison (MTC) meta-analyses were conducted to estimate the pooled ORs of death for each comparison. RESULTS: 42 trials with 52 516 subjects were included. The MTC meta-analysis with the fixed effect model indicated tiotropium Soft Mist Inhaler was associated with an universally increased risk of overall death compared with placebo (OR 1.51; 95% CI 1.06 to 2.19), tiotropium HandiHaler (OR 1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to 2.44) and LABA-ICS (OR 1.90; 95% CI 1.28 to 2.86). The risk was more evident for cardiovascular death, in patients with severe COPD, and at a higher daily dose. LABA-ICS was associated with the lowest risk of death among all treatments. No excess risk was noted for tiotropium HandiHaler or LABA. The results were similar for MTC and direct comparison meta-analyses, with less precision in the random effects model. CONCLUSION: Our study provided a comparative safety spectrum for each category of inhaled medications. Tiotropium Soft Mist Inhaler had a higher risk of mortality and should be used with caution.

Pneumonia risk and use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.

BACKGROUND: Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. METHODS: We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 1997-2007 were analyzed. The case period was defined as the 30 days before admission; the periods 90 to 120 days and 180 to 210 days before admission were used as control periods. Prescribing status of ACE inhibitors and ARBs during the 3 periods was assessed for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) for pneumonia associated with use of ACE inhibitors and ARBs. RESULTS: We identified 10 990 cases of hospitalization for new pneumonia. After adjustment for time-variant confounding factors, pneumonia was not associated with use of ACEI or ARBS: the ORs were 0.99 (95% CI, 0.81-1.21) and 0.96 (0.72-1.28), respectively. No association was seen for cumulative defined daily doses (DDDs), as compared with nonusers, for 0 to 30, 31 to 60, or more than 60 DDDs. The results were found to be robust in sensitivity analysis. CONCLUSIONS: Neither the use nor cumulative dose of ACE inhibitors or ARBs was associated with pneumonia among the Taiwanese general population.

Generating fit-for-purpose real-world evidence in Asia: How far are we from closing the gaps?

Evidence generated by randomized controlled trials (RCTs) does not often represent the patient journey and clinical outcomes in the real world due to limited external validity or generalizability. Studies based on real-world data are intended to generalize results to the broader population; however, if the influence of external factors or confounders is not effectively managed, the cause-and-effect relationship and internal validity may be challenged, resulting in flawed results. The collection of quality real-world evidence (RWE) is crucial in Asia as there is often an underrepresentation of Asian populations in RCTs. In addition, few countries in Asia are catching up with the Western world in issuing practical foundational principles and guidance for conducting and adopting evidence for regulatory and reimbursement decisions. However, privacy and data protection laws are generally lagging behind technological developments in electronic medical records. While leveraging RWE in clinical and regulatory decision-making holds excellent potential, collective efforts across industry, governments, and research institutions are required for generating standardized practices and building capabilities for developing fit-for-purpose RWE in Asia.

Risk of cognitive impairment in men with advanced prostate cancer treated with NHAs: A systematic review and network meta-analysis.

Novel hormonal agents (NHAs) have significantly improved outcomes in men with advanced prostate cancer. However, it remains unclear whether NHAs are associated with subsequent cognitive impairment. Thus, we sought to perform a network meta-analysis to compare the risk of cognitive impairment across NHA types. Databases (PubMed, Embase, Scopus, and Web of Science), trial registries (Clinicaltrial.gov), the European Medicines Agency, and the US Food and Drug Administration drug safety reports were searched from inception through July 30, 2021. Eligible studies were clinical trials evaluating the risk of cognitive impairment between NHAs and placebo/standard care. Two independent investigators extracted the data and performed quality assessments using the Cochrane Risk of Bias Tool and ROBINS-I. We estimated the risk ratios by the frequentist approach and calculated the ranking probabilities of all treatments with the surface under the cumulative ranking probabilities. The primary outcome and secondary outcome were odds ratio (OR) and incidence rate ratio of cognitive impairment, respectively. We identified 15 trials with 14,723 participants comparing HNAs with placebo/standard care. Treatments associated with cognitive impairment, from the most to the least, were enzalutamide (OR, 3.66; 95% confidence interval [CI], 2.84-4.73), apalutamide (OR, 1.76; 95% CI, 1.08-2.87), abiraterone acetate (OR, 1.64; 95% CI, 1.01-2.45), and darolutamide (OR, 1.11 95% CI, 0.51-2.39). After adjustment of treatment time duration, enzalutamide still had the highest risk of cognitive impairment with an incidence rate ratio of 2.17 (95% CI, 1.65-2.78). These findings suggest that NHAs, especially enzalutamide, may increase the risk of cognitive impairment compared with placebo/standard care.

Survival following surgery with or without adjuvant chemotherapy for stage I-IIIA non-small cell lung cancer: an east asian population-based study.

BACKGROUND: Asian ethnicity is associated with a distinct molecular etiology, treatment response, and survival outcome among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I-IIIA NSCLC. METHODS: This study recruited patients aged ≥18 years with histologically proven stage IA-IIIA NSCLC registered in the Taiwan Cancer Registry database in January 2004 to December 2007. Platinum-containing adjuvant chemotherapy had to be started within 90 days of the primary surgery. Kaplan-Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time. RESULTS: This study included 2,231 patients with stage IA-IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group for both stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival outcome of stage II (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.39-0.94; p = .024) and IIIA (HR, 0.71; 95% CI, 0.52-0.96; p = .029) patients. Among these patients, those who received adjuvant chemotherapy had a superior overall survival outcome for both genders, for the subgroup of patients aged ≥70 years, and for those with adenocarcinoma. CONCLUSION: Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC.

Diabetes mellitus is associated with increased mortality in patients receiving curative therapy for hepatocellular carcinoma.

BACKGROUND: Diabetes mellitus (DM) is closely associated with hepatocarcinogenesis. This study explores the prognostic impact of DM in patients who received curative therapy for localized hepatocellular carcinoma (HCC). METHODS: Patients who had been diagnosed with stage I or II HCC in 2003 and 2004 and received surgical resection or local ablation therapy were identified from the population-based Taiwan National Cancer Registry. Data pertaining to DM and other comorbidities were retrieved from the Taiwan National Health Insurance database. Liver cancer-specific survival (LCS), liver disease-related survival (LDS) and overall survival (OS) rates were compared between patients with and without DM. The presence of other comorbidities and tumor status were adjusted using multivariate analysis. RESULTS: A total of 931 patients who fulfilled the study criteria were analyzed; 185 (20%) of them had DM (type 1 or type 2). The LCS, LDS, and OS rates were significantly worse for patients with DM than patients without DM (all p < .001). After adjusting for age, sex, tumor stage, treatment, and the presence of other comorbidities, DM remained an independent predictor of poorer LCS (hazard ratio [HR] = 1.57; p < .001), LDS (HR = 1.70; p < .001), and OS (HR = 1.69; p < .001). The associations between DM and mortality were consistent among subgroups, irrespective of tumor size, stage, treatment modality, and liver cirrhosis. CONCLUSIONS: DM is an independent factor for poorer prognosis in patients who received curative therapy for localized HCC.