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Lung Chan,1 Chen-Huan Chen,2 Juey-Jen Hwang,3 San-Jou Yeh,4 Kou-Gi Shyu,5 Ruey-Tay Lin,6 Yi-Heng Li,7 Larry Z Liu,8 Jim Z Li,9 Wen-Yi Shau,10 Te-Chang Weng,10 1Department of Neurology, Shuang-Ho Hospital, School of Medicine, College of Medicine, Taipei Medical University, New Taipei, 2Department of Internal Medicine, Faculty of Medicine, National Yang-Ming University, 3Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 4Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, 5Division of Cardiology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 6Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, 7Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 8Pfizer Inc, New York, NY, USA; 9Pfizer Inc, San Diego, CA ,USA; 10Pfizer Ltd., New Taipei City, Taiwan Abstract: Hypertension is a major risk factor for strokes and myocardial infarction (MI). Given its effectiveness and safety profile, the calcium channel blocker amlodipine is among the most frequently prescribed antihypertensive drugs. This analysis was conducted to determine the costs and quality-adjusted life years (QALYs) associated with the use of amlodipine and valsartan, an angiotensin II receptor blocker, in preventing stroke and MI in Taiwanese hypertensive patients. A state transition (Markov) model was developed to compare the 5-year costs and QALYs for amlodipine and valsartan. Effectiveness data were based on the NAGOYA HEART Study, local studies, and a published meta-analysis. Utility data and costs of MI and stroke were retrieved from the published literature. Medical costs were based on the literature and inflated to 2011 prices; drug costs were based on National Health Insurance prices in 2014. A 3% discount rate was used for costs and QALYs and a third-party payer perspective adopted. One-way sensitivity and scenario analyses were conducted. Compared with valsartan, amlodipine was associated with cost savings of New Taiwan Dollars (NTD) 2,251 per patient per year: costs were NTD 4,296 and NTD 6,547 per patient per year for amlodipine and valsartan users, respectively. Fewer cardiovascular events were reported in patients receiving amlodipine versus valsartan (342 vs 413 per 10,000 patients over 5 years, respectively). Amlodipine had a net gain of 58 QALYs versus valsartan per 10,000 patients over 5 years. Sensitivity analyses showed that the discount rate and cohort age had a larger effect on total cost and cost difference than on QALYs. However, amlodipine results were more favorable than valsartan irrespective of discount rate or cohort age. When administered to Taiwanese patients for hypertension control, amlodipine was associated with lower cost and more QALYs compared with valsartan due to a lower risk of stroke and MI events. Keywords: cost-effectiveness, pharmacoeconomic, Markov model, CCB, ARB

The economic trend and the health care landscape are rapidly evolving across Asia. Effective real-world data (RWD) for regulatory and clinical decision-making is a crucial milestone associated with this evolution. This necessitates a critical evaluation of RWD generation within distinct nations for the use of various RWD warehouses in the generation of real-world evidence (RWE). In this article, we outline the RWD generation trends for 2 contrasting nation archetypes: "Solo Scholars"-nations with relatively self-sufficient RWD research systems-and "Global Collaborators"-countries largely reliant on international infrastructures for RWD generation. The key trends and patterns in RWD generation, country-specific insights into the predominant databases used in each country to produce RWE, and insights into the broader landscape of RWD database use across these countries are discussed. Conclusively, the data point out the heterogeneous nature of RWD generation practices across 10 different Asian nations and advocate for strategic enhancements in data harmonization. The evidence highlights the imperative for improved database integration and the establishment of standardized protocols and infrastructure for leveraging electronic medical records (EMR) in streamlining RWD acquisition. The clinical data analysis and reporting system of Hong Kong is an excellent example of a successful EMR system that showcases the capacity of integrated robust EMR platforms to consolidate and produce diverse RWE. This, in turn, can potentially reduce the necessity for reliance on numerous condition-specific local and global registries or limited and largely unavailable medical insurance or claims databases in most Asian nations. Linking health technology assessment processes with open data initiatives such as the Observational Medical Outcomes Partnership Common Data Model and the Observational Health Data Sciences and Informatics could enable the leveraging of global data resources to inform local decision-making. Advancing such initiatives is crucial for reinforcing health care frameworks in resource-limited settings and advancing toward cohesive, evidence-driven health care policy and improved patient outcomes in the region., (©Guilherme Silva Julian, Wen-Yi Shau, Hsu-Wen Chou, Sajita Setia. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 15.08.2024.)

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., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

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., (©Wen-Yi Shau, Handoko Santoso, Vincent Jip, Sajita Setia. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.06.2024.)

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., (©Wen-Yi Shau, Sajita Setia, Ying-Jan Chen, Tsu-yun Ho, Salil Prakash Shinde, Handoko Santoso, Daniel Furtner. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.09.2023.)

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., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Perspectives in Clinical Research.)

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., (© 2023. The Author(s).)

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., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Real-world data (RWD) related to patient health status or health care delivery can be broadly defined as data collected outside of conventional clinical trials, including those from databases, treatment and disease registries, electronic medical records, insurance claims, and information directly contributed by health care professionals or patients. RWD are used to generate real-world evidence (RWE), which is increasingly relevant to policy makers in Asia, who use RWE to support decision-making in several areas, including public health policy, regulatory health technology assessment, and reimbursement; set priorities; or inform clinical practice., Objective: To support the achievement of the benefits of RWE in Asian health care strategies and policies, we sought to identify the linked contemporary databases used in real-world studies from three representative countries-India, Thailand, and Taiwan-and explore variations in results based on these countries' economies and health care reimbursement systems by performing a systematic scoping review. Herein, we describe the protocol and preliminary findings of our scoping review., Methods: The PubMed search strategy covered 3 concepts. Concept 1 was designed to identify potential RWE and RWD studies by applying various Medical Subject Headings (MeSH) terms ("Treatment Outcome," "Evidence-Based Medicine," "Retrospective Studies," and "Time Factors") and related keywords (eg, "real-world," "actual life," and "actual practice"). Concept 2 introduced the three countries-India, Taiwan, and Thailand. Concept 3 focused on data types, using a combination of MeSH terms ("Electronic Health Records," "Insurance, Health," "Registries," "Databases, Pharmaceutical," and "Pharmaceutical Services") and related keywords (eg, "electronic medical record," "electronic healthcare record," "EMR," "EHR," "administrative database," and "registry"). These searches were conducted with filters for language (English) and publication date (publications in the last 5 years before the search). The retrieved articles will undergo 2 screening phases (phase 1: review of titles and abstracts; phase 2: review of full texts) to identify relevant and eligible articles for data extraction. The data to be extracted from eligible studies will include the characteristics of databases, the regions covered, and the patient populations., Results: The literature search was conducted on September 27, 2022. We retrieved 3,172,434, 1,094,125, and 672,794 articles for concepts 1, 2, and 3, respectively. After applying all 3 concepts and the language and publication date filters, 2277 articles were identified. These will be further screened to identify eligible studies. Based on phase 1 screening and our progress to date, approximately 44% (1003/2277) of articles have undergone phase 2 screening to judge their eligibility. Around 800 studies will be used for data extraction., Conclusions: Our research will be crucial for nurturing advancement in RWD generation within Asia by identifying linked clinical RWD databases and new avenues for public-private partnerships and multiple collaborations for expanding the scope and spectrum of high-quality, robust RWE generation in Asia., International Registered Report Identifier (irrid): DERR1-10.2196/43741., (©Wen-Yi Shau, Sajita Setia, Salil Prakash Shinde, Handoko Santoso, Daniel Furtner. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.12.2022.)

Objective: Our understanding of therapeutic inertia in diabetes care is incomplete in terms of an assessment across a nationwide population. The key objectives of this investigation were to measure therapeutic inertia and link this phenomenon to the important surrogate outcome of hemoglobin A1c (HbA1c) control in a nationwide cohort., Patients and Methods: We performed a retrospective cohort study over 18 months. Laboratory and prescription data were collected for 41,948 patients (women: 53.1%) with diabetes who had at least two HbA1c results. The association between treatment intensity and glycemic control, using the change in HbA1c during the observation period, and whether the HbA1c outcome was greater than 9% were examined., Results: Among the patients who exhibited a secondary HbA1c result exceeding 9%, 8,630 (78.26%) had undergone intensified therapy at the time of the index HbA1c measurement, and among these patients, the incidence ratio of the last HbA1c outcome exceeding 9% after 6 to 18 months was 0.779-fold (95% Cl 0.728 to 0.834) greater than those who had not received intensified therapy (p < .001)., Conclusions: After tracking patient data for a particular period, we found that patients with diabetes who received intensified therapy achieved surrogate outcomes of HbA1c control that were more favorable.

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., (Copyright © 2020. Published by Elsevier B.V.)

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)., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Evidence and treatment guidelines support the use of statins in patients with established atherosclerotic cardiovascular disease (ASCVD) for secondary prevention of subsequent cardiovascular (CV) event. However, treatment adherence and persistence are still a concern., Methods: We constructed a retrospective population-based cohort of patients, who initiated statin treatment within 90 days after discharge from hospital for ASCVD using the claims database of Taiwan National Health Insurance. Proportion of days covered (PDC) was used to measure statin adherence, and PDC ≥80% was defined as good adherence. The study outcomes were subsequent rehospitalisation or in-hospital death due to composite ASCVD, myocardial infarction or ischaemic stroke. Their associations with statin prescription adherence or persistence were analysed using time-dependent Cox proportional hazards model., Results: The study cohort included 185 252 postdischarge statin initiators. There were 50 015 subsequent ASCVD rehospitalisations including 2858 in-hospital death during 7 years of study period. Good adherence was significantly associated with lower risk of ASCVD rehospitalisation (adjusted HR (aHR) 0.90; 95% CI 0.87 to 0.92) and significantly lower risk of in-hospital death (aHR 0.59; 95% CI 0.53 to 0.65). Compared with constant use of statin, patients in the three less persistent states (recent stop, non-persistence and intermittent use) were associated with higher risk of subsequent ASCVD rehospitalisation, aHRs were 1.16, 1.13 and 1.26, respectively (all p<0.05). The increased risks were consistent with specific outcome of acute myocardial infarction and ischaemic stroke. Also, patients in the recent stop period had significantly higher risk for fatal CV event., Conclusions: Good adherence and persistence to statin therapy are significantly associated with lower risk of secondary ASCVD rehospitalisation and in-hospital death., Competing Interests: Competing interests: Among the authors of this study, WYS, JZL and SF are employees of Pfizer. STH, STC and MSL received research grant from Pfizer. VCT, who is an employee of APCER, received funding from Pfizer. CLL received consultancy fee from Pfizer., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Objective To measure therapeutic inertia by characterizing prescription patterns using secondary data obtained from the nationwide diabetes mellitus pay-for-performance (DM-P4P) programme in Taiwan. Methods Using reimbursement claims from Taiwan's National Health Insurance Research Database, a nationwide retrospective cohort study was undertaken of patients with diabetes mellitus who participated in the DM-P4P programme from 2006-2008. Glycosylated haemoglobin results were used to evaluate modifications in therapy in response to poor diabetes control. Prescription patterns were used to assign patients to either a therapeutic inertia group or an intensified treatment group. Therapeutic inertia was defined as the failure to act on a known problem. Results The research sample comprised of 168 876 patients with diabetes mellitus who had undergone 899 135 tests. Of these, 37.4% (336 615 visits) of prescriptions were for a combination of two types of drug and 27.7% (248 788 visits) were for a combination of three types of drug. The proportion of patients in the intensified therapy group who were prescribed more than two types of drug was considerably higher than that in the therapeutic inertia group. Conclusion In many cases in the therapeutic inertia group only a single type of hypoglycaemic drug was prescribed or the dosage remained unchanged.

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., (©AlphaMed Press.)

Background: Platinum-based chemotherapy is the standard first-line therapy for patients with advanced lung squamous cell carcinoma (SCC). We compared the effectiveness of first-line chemotherapy regimens., Methods: We searched the database of the Taiwan Cancer Registry for patients with newly diagnosed advanced lung SCC from 2004 to 2007. Medication prescription data were retrieved from the database of National Health Insurance, Taiwan. We identified patients who received standard first-line platinum-based chemotherapy, which was defined as chemotherapy with a platinum (P) compound (cisplatin or carboplatin) in addition to 1 of the 4 chemotherapy agents, including gemcitabine (G), docetaxel (D), paclitaxel (T), and vinorelbine (V). Deaths were identified by searching the National Death Registry. Overall survival (OS) was compared between patients who underwent different therapies., Results: In total, 2790 patients were identified; 983 patients (35.2%) received standard first-line chemotherapy with P and G (58.1%), D (14.5%), T (11.6%), or V (15.8%). Older patients (age ≥ 70 years) were less likely to receive P + D than P + G, P + T, or P + V (P = .018). Patients who received P + G, P + D, P + T, or P + V had similar OS (median, 8.9, 7.9, 9.5, and 8.2 months; P = .816). In multivariate analyses adjusting for age, sex, and stage, the first-line chemotherapy regimen was not a predictor for OS. With P + G as the reference group, the adjusted hazard ratios of P + D, P + T, and P + V were 1.03, 0.90, and 1.02, respectively (P = .710)., Conclusions: In patients with advanced lung SCC, various regimens did not have a significant effect on survival outcomes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To evaluate whether aspirin can reduce the risk of colorectal cancer in people with diabetes., Methods: We studied ≥ 30-year-old people with diabetes, included in the Longitudinal Health Insurance Database 2005 in Taiwan, who were treated with hypoglycaemic drugs. We used a time-varying Cox regression model to adjust for immortal time bias and to estimate the adjusted hazard ratio and 95% CI for the association between aspirin use and colorectal cancer occurrence., Results: We studied a total of 60 828 people with diabetes (31 176 men and 29 652 women). Their mean (sd) age was 58.72 (13.33) years. A total of 26 494 people were taking aspirin. Aspirin use 3-5 times/week (moderate frequency) for > 5 years (long duration) was found to reduce the risk of colorectal cancer by 46% (hazard ratio 0.54, 95% CI 0.34-0.86). Aspirin use > 5 times/week (high frequency) for 4-5 years (moderate duration) and > 5 years reduced the risk of colorectal cancer by 56 and 68%, respectively (hazard ratio 0.44, 95% CI 0.24-0.80; hazard ratio 0.32, 95% CI 0.20-0.50). Low frequency (≤ 2 times/week) and/or short duration (≤ 3 years) of aspirin use did not reduce the risk of colorectal cancer., Conclusions: Aspirin use with high frequency and long duration reduced the risk of colorectal cancer in people with diabetes in a frequency- and duration-dependent manner, whereas low frequency and/or short duration of aspirin use did not. The dosage, frequency and duration of aspirin use that are sufficient to prevent the incidence of colorectal cancer in people with diabetes require further study., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

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., (© 2015 S. Karger AG, Basel.)

This article presents an analysis conducted on the patterns related to therapeutic inertia with the aim of uncovering how variables at the patient level and the healthcare provider level influence the intensification of therapy when it is clinically indicated. A cohort study was conducted on 899,135 HbA1c results from 168,876 adult diabetes patients with poorly controlled HbA1c levels. HbA1c results were used to identify variations in the prescription of hypoglycemic drugs. Logistic regression and hierarchical linear models (HLMs) were used to determine how differences among healthcare providers and patient characteristics influence therapeutic inertia. We estimated that 38.5% of the patients in this study were subject to therapeutic inertia. The odds ratio of cardiologists choosing to intensify therapy was 0.708 times that of endocrinologists. Furthermore, patients in medical centers were shown to be 1.077 times more likely to be prescribed intensified treatment than patients in primary clinics. The HLMs presented results similar to those of the logistic model. Overall, we determined that 88.92% of the variation in the application of intensified treatment was at the within-physician level. Reducing therapeutic inertia will likely require educational initiatives aimed at ensuring adherence to clinical practice guidelines in the care of diabetes patients., (© 2014, The American College of Clinical Pharmacology.)

Purpose: Long-acting insulin analogues were developed to facilitate consistent glycemic control without excessive hypoglycemia. However, structural modifications of the insulin molecule can alter biological responses and binding characteristics with specific receptors. The aim of this study was to estimate the risk of sight-threatening diabetic retinopathy (STDR) associated with treatment using long-acting insulin analogues compared with intermediate-acting insulin in patients with type 2 diabetes mellitus (T2DM)., Methods: A retrospective cohort consisting of patients with T2DM aged 20 years of age and older with newly initiated treatment with long-acting insulin analogues (glargine and detemir) and intermediate-acting human insulin was identified from the National Health Insurance database between January 2004 and December 2006 and was subdivided into different cohorts. The risk of the development of STDR was determined by Cox regression models and compared between different cohorts., Findings: Of the 46,739 eligible patients, initiators of insulin glargine, insulin detemir, and neutral protamine Hagedorn (NPH) insulin were identified for comparison using propensity-score matching methods. Long-acting insulin analogues were not associated with changed risk for STDR by intention-to-treat and time-varying use approaches between either matched or unmatched cohorts., Implications: The strategies that aim at preventing diabetic retinopathy by treating T2DM patients with long-acting insulin analogues remain further prospective studies with longer follow-up period to validate our observations within an appropriate dosage range and to further evaluate the safety of long-acting insulin analogues on reducing the progression of diabetic retinopathy., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

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., (©AlphaMed Press.)

Importance: The prevalence of diabetic retinopathy (DR) is high in individuals with diabetes mellitus. Published estimates for sight-threatening DR (STDR) prevalence range widely. There is a need for precise contemporary estimates of the prevalence and incidence of STDR for providing optimal strategies of clinical management in Taiwan., Objective: To determine the precise contemporary estimates of the prevalence and incidence of STDR in patients with type 2 diabetes mellitus in Taiwan., Design, Setting, and Participants: Data were collected from a representative database, the Longitudinal Health Insurance Database 2005, from 2005 to 2011, on a total of 2926 incident cases of patients with STDR among 63,582 patients with type 2 diabetes. Sight-threatening DR was defined as clinically significant macular edema, severe nonproliferative DR, or proliferative DR according to the classification of the Early Treatment Diabetic Retinopathy Study research group. Sex-specific and age-adjusted incidence and prevalence rates of STDR were analyzed for patients with type 2 diabetes and STDR identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and procedure codes., Main Outcomes and Measures: Procedure codes were used to determine the diagnosis of STDR., Results: The number of incident cases of STDR increased in line with the increasing diabetic population during 2005-2011. Sex differences in the age-adjusted incidence rates were observed, showing a declining trend from 10.84 (95% CI, 10.69%-10.99%) to 6.00 (95% CI, 5.86%-6.14%) per 1000 person-years for women (P < .001) contrasting with an increasing trend in men, from 14.86 (95% CI, 14.71%-15.01%) to 21.89 (95% CI, 21.76%-22.02%) per 1000 person-years (P < .001). The age-adjusted prevalence rates of STDR were in decreasing trends for both sexes, with a mean of 2.75% for women and 2.87% for men. Apart from apparent sex differences in prevalence rates of STDR, increasing trends were observed among younger patients (aged <60 years)., Conclusions and Relevance: We found considerable variation in the incidence trends between sexes. Our findings provide evidence that the incident cases of STDR have increased among patients with type 2 diabetes, but the overall prevalence of STDR is in a declining trend in Taiwan, suggesting that decreased mortality rate, better diabetes management, and early detection of treatable DR might contribute to the prevalence patterns.

Background: Limited information about tumor status and the time at which antiviral therapy was initiated may have influenced effect estimation in previous research. The aim of this study was to investigate the effect of antiviral therapies on HBV-related HCC progression and deaths in patients receiving curative treatment based on clear clinical-pathological cancer status and the association of start time of adjuvant antiviral therapy initiation and outcomes., Methodology: A nationwide inception cohort study of newly diagnosed HCC patients who suffered from viral hepatitis B and received curative HCC therapy as the first course of treatment were identified from the Taiwan Cancer Registry between January 1, 2004, and December 31, 2009. Matched Cox proportional hazards models based on propensity score matching and incorporated time-varying exposure were used to estimate adjusted hazard ratios and 95% confidence intervals (CIs)., Findings: Among 3,855 HCC patients with HBV, antiviral therapy was administered to 490 (12.7%) following curative treatment. Antiviral-treated patients had a higher percentage of young age, early stage, and smaller tumor size of HCC compared with untreated patients. After propensity score matching, treated patients demonstrated a higher risk of HCC progression (hazard ratio, 1.42; 95%CI, 1.20-1.69) and death from all causes (1.45; 1.15-1.82) than untreated patients. Similar results were also obtained in sub-cohort of patients who were alive with cancer-free status at least one year after receiving curative treatment and the sub-cohort of patients with liver resection. The interval length between initiation of antiviral therapy and first-line curative treatment did not show a significant association with all-cause mortality., Conclusions: This study found that adjuvant antiviral therapy did not reduce the risk of HCC progression or mortality in HBV-related HCC patients after cancer status adjusting.

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.

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., (© 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Published by International Society for Pharmacoeconomics and Outcomes Research (ISPOR) All rights reserved.)

Background: Randomized trials suggest that radiofrequency ablation (RFA) may be more effective than percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC). However, the survival advantage of RFA needs confirmation in daily practice., Methods: We conducted a population-based cohort study using the Taiwan Cancer Registry, National Health Insurance claim database and National Death Registry data from 2004 through 2009. Patients receiving PEI or RFA as first-line treatment for newly-diagnosed stage I-II HCC were enrolled., Results: A total of 658 patients receiving RFA and 378 patients receiving PEI treatment were included for final analysis. The overall survival (OS) rates of patients in the RFA and PEI groups at 5-year were 55% and 42%, respectively (p < 0.01). Compared to patients that received PEI, those that received RFA had lower risks of overall mortality and first-line treatment failure (FTF), with adjusted hazard ratios (HRs) [95% confidence interval (CI)] of 0.60 (0.50-0.73) for OS and 0.54 (0.46-0.64) for FTF. The favorable outcomes for the RFA group were consistently significant for patients with tumors > 2 cm as well as for those with tumors < 2 cm. Consistent results were also observed in other subgroup analyses defined by gender, age, tumor stage, and co-morbidity status., Conclusion: RFA provides better survival benefits than PEI for patients with unresectable stage I-II HCC, irrespective of tumors > 2 cm or ≤ 2 cm, in contemporary clinical practice.

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.

Background: Since a report of lenticular opacities in dogs treated with high dosages of statins, the debate on the relationship between statin therapy and cataracts has not reached a conclusion., Objective: The aim of this study was to evaluate the association between statin therapy and the risk of cataract surgery in an elderly ethnic Chinese population using time-dependent analysis to minimize immortal time bias., Methods: A retrospective cohort study using the Longitudinal Health Insurance Database 2005 randomly sampled from the National Health Insurance Research Database, Taiwan, was conducted. A total of 50,165 adults aged between 65 and 90 years in 1998 without records of statin therapy or diagnosis of cataracts between July 1997 and December 1997 were included in the analysis. The first record of lens extraction within the follow-up period (1998-2009) was set as the study endpoint. A propensity score was derived using a logistic regression model to model the receipt of statin therapy as a function of the baseline characteristics for every subject. We used the time-dependent Cox regression model to test the relative hazard of undergoing cataract surgery between statin users and non-users, while use of statins was treated as a time-dependent variable, controlling for baseline age and individual propensity score., Results: Of the 50,165 enrolled subjects, 17,670 individuals with an incident lens extraction were identified during a median follow-up of 10.7 years. The incidence of cataract surgery was 49.7/1,000 person-years in the statin-using period compared with 38.5/1,000 person-years in the statin-non-using period. The adjusted hazard ratio of cataract surgery was 1.20 (95 % CI 1.14-1.27; P < 0.001) in statin users compared with statin non-users., Conclusion: Statin therapy was associated with a modestly increased risk of cataract surgery. We suggest regular checks for lens opacity in statin users.

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.

Object: We sought to explore factors associated with persistence of antidepressant treatment in Taiwan and to compare persistence rates across various antidepressants., Method: This was a retrospective cohort study using medical claims in Taiwan. We collected data of all new antidepressant users with depressive disorder, aged 18 years or older, during the study period from January 1, 1998, to July 4, 2009. Overall antidepressant treatment persistence was defined as undergoing treatment for 180 days without exceeding a 30-day gap. We also assess the cause of treatment change of initial monotherapy, including discontinuation, switching or combination. The competing risks method was used to estimate cause-specific cumulative incidence and to determine associated factors., Results: Only 17.4% of patients continued overall antidepressant treatment and 7.6% continued initial antidepressant monotherapy for 180 days or more. Most patients change initial monotherapy through discontinuation, followed by switching and combination. Male gender, older age, comorbidity with anxiety or sleep disorders, and more concomitant use of drugs were associated with lower discontinuation rate. In terms of antidepressant comparisons, we found that patients treated with selective serotonin reuptake inhibitors are less likely to change initial monotherapy., Conclusion: The overall persistence of antidepressant treatment in Taiwan was lower than in other countries., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This study assessed the association between second-generation antipsychotic medications and risk of pneumonia requiring hospitalization in patients with schizophrenia because the evidence is limited in the population. We enrolled a nationwide cohort of 33,024 inpatients with schizophrenia ranged in age from 18 to 65 years, who were derived from the National Health Insurance Research Database in Taiwan from 2000 to 2008. Cases (n = 1741) were defined as patients who developed pneumonia after their first psychiatric admissions. Risk set sampling was used to match each case with 4 controls by age, sex, and the year of the first admission based on nested case-control study. Antipsychotic exposure was categorized by type, duration, and daily dose, and the association between exposure and pneumonia was assessed using conditional logistic regression. We found that current use of clozapine (adjusted risk ratio = 3.18, 95% CI: 2.62-3.86, P < .001) was associated with a dose-dependent increase in the risk. Although quetiapine, olanzapine, zotepine, and risperidone were associated with increased risk, there was no clear dose-dependent relationship. Amisulpride was associated with a low risk of pneumonia. The use of clozapine combined with another drug (olanzapine, quetiapine, zotepine, risperidone, or amisulpride), as assessed separately, was associated with increased risk for pneumonia. In addition, with the exception of amisulpride, each drug was associated with increased risk for pneumonia at the beginning of treatment. Clinicians who prescribe clozapine to patients with schizophrenia should closely monitor them for pneumonia, particularly at the start of therapy and when clozapine is combined with other antipsychotics.

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., (Copyright © 2012 American Cancer Society.)

Study Objective: To develop the Pharmacy-Based Disease Indicator (PBDI), and to evaluate its performance versus the diagnosis-based Deyo version of the Charlson Index in predicting subsequent-year hospitalization in adults., Design: Retrospective cohort analysis., Data Source: Longitudinal health insurance database derived from the national health insurance system in Taiwan., Patients: Two adult populations were identified: 697,823 individuals who were at least 18 years of age on January 1, 2005 (dataset 2005), and 714,072 who were at least 18 years of age on January 1, 2006 (dataset 2006)., Measurements and Main Results: Based on the Chronic Disease Score framework and the Anatomical Therapeutic Chemical classification system, we developed the PBDI, a comorbidity measure that is a function of 37 drug categories that correspond to major diseases in Taiwan. The relationship between individuals' PBDI score and subsequent-year hospitalization was evaluated by use of logistic regression models. Covariates in the models included age group, sex, PBDI score, and Deyo score. Using the two overlapping adult populations, we calculated both the PBDI score and the Deyo score for each individual in each year. Using subsequent-year hospitalization as the outcome and each comorbidity measure as the predictor, we demonstrated that the c statistic of the PBDI versus the Deyo version of the Charlson Index was 0.72 versus 0.69 for both the 2005 and 2006 populations. The Akaike information criterion, Bayesian information criterion, model calibration, and reclassification measures also confirmed the utility of the PBDI., Conclusion: The PBDI demonstrated acceptable predictive performance for subsequent-year hospitalization. It can be used as a general comorbidity measure to describe the health status of populations based on data derived from population-based automated health care databases., (© 2013 Pharmacotherapy Publications, Inc.)

Background: In the last few years there have been changed in the pattern of consumption of antihypertensive drugs in other countries. Factors causing this variability include differences in the effectiveness of detection, guidelines for the management of hypertension, and differences in national health insurance systems among countries., Aim: The aim of this study was to reveal patterns in the use of antihypertensive drugs in Taiwan over a six year period (2001 to 2006) and compare these results with data from other countries., Materials and Methods: This study performed descriptive analysis of data from the National Health Insurance Research Database (NHIRD) of Taiwan, and compared these findings with similar findings from around the world. Quantities were standardized using the defined daily dose (DDD) per 1000 inhabitants per day (DID) in accordance with WHO anatomical therapeutic classification and DDD measurement methodology., Results: The total number of DDDs prescribed in Taiwan increased from 0.66 billion in 2001 to 1.08 billion in 2006, representing 80.6 and 129.2 DID in 2001 and 2006, respectively. This indicates a significant increase in the prescription of antihypertensive drugs in Taiwan over this period. The average annual increase ranged from 10.7% for calcium channel blockers (CCBs) to 22.1% for angiotensin II receptor blockers (ARBs). All of these patterns were statistically significant (p < 0.05). The rapid increase in the use of ARBs resulted in its surpassing ACEIs with the second highest DID (21.9) in 2006. Though the proportional use of CCBs and ARBs has increased significantly, the use of thiazide diuretics remains low., Conclusions: The consumption of antihypertension drugs in Taiwan increased during the period studied and the highest average annual increases were for ARBs and CCBs. Overall consumption of antihypertension drugs also increased in other countries, but differences in the relative increase for each class of drug suggest that further study may be required to clarify the origins and causes.

Purpose: The epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population., Patients and Methods: The Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox's proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses., Results: A total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p=0.524) and TTF (median, 5.5 versus 3.4 months, p=0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR]=1.04, p=0.629) and treatment failure (adjusted HR=0.94, p=0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS., Conclusions: Gefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Isolated increase in serum alkaline phosphatase (IISAlp) is frequently observed in liver transplant recipients visiting outpatient clinics. However, whether the increase is associated with risk factors or poor survival is unknown., Methods: We retrospectively reviewed the medical records of liver transplant recipients who were followed up during 1999-2009 and had IISAlp 1 month after liver transplantation, which was sustained for at least 6 months. Clinical parameters, survival, and risk factors were analyzed and compared between recipients who survived longer than 6 months after transplantation., Results: Among 307 liver transplant recipients, 44 had IISAlp. Compared with the control group, the patients with IISAlp were more frequently of the pediatric population, recipients of female donor or living-related partial liver grafts, and found to have biliary-related pretransplant disorders, lower body weight, and shorter warm ischemic time (P < 0.01). One patient with IISAlp died of acute myeloid leukemia during the follow-up period. The mean time to observation of IISAlp after liver transplantation was 6.3 ± 0.8 months. The mean follow-up duration was 5.5 ± 0.2 years. Stepwise multivariate analysis showed that being a pediatric or living-related liver transplant recipient was an independent risk factor for IISAlp, with adjusted hazard ratios (95% confidence interval) of 5.41 (2.59-11.28) and 3.0 (0.98-9.27), respectively., Conclusions: Therefore, being a pediatric or living-related liver transplant recipient was an independent risk factor for IISAlp. However, IISAlp was not associated with poor survival after liver transplantation. Hence, patients who have undergone liver transplantation do not require frequent routine examination of serum alkaline phosphatase levels., (Copyright © 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

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 β2 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.

Background: The abundance of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs), which serve as surrogate markers for angiogenesis, may be affected by chemotherapy. We studied their dynamic change during consecutive cycles of chemotherapy., Methods: We collected blood samples from 15 breast cancer patients, who received a total of 56 courses of systemic chemotherapy, and measured the CECs, viable CECs (V-CECs), and CEPs by six-color flow cytometry within the seven days prior to chemotherapy, twice a week during the first and second cycles of chemotherapy, and then once a week during the subsequent cycles., Results: The CEC, V-CEC, and CEP levels all significantly decreased from day 1 of treatment to the first week of chemotherapy. After one week of chemotherapy, the CEC and V-CEC levels returned to a level similar to day 1. The CEP level remained significantly reduced after the first week of chemotherapy, but gradually rebounded until the next course of chemotherapy. After six cycles of chemotherapy, the total number of CEC and V-CEC cells trended toward a decrease and the CEP cells toward an increase. Clinical factors, including the existence of a tumor, chemotherapy regimens, and the use of granulocyte colony stimulating factor, did not significantly affect these results., Conclusions: The CEC and CEP counts change dynamically during each course of chemotherapy and after the chemotherapy cycles, providing background data for any future study planning to use CECs and CEPs as surrogate markers of angiogenesis in antiangiogenesis treatments combined with chemotherapy.

Objective: This study examined trends in antidepressant utilization in Taiwan between 2000 and 2009., Methods: We collected data from the National Health Insurance Research Database of all incident antidepressant use. We described the incidence, prevalence, and therapeutic indications of antidepressant use. We tested the trends by using logistic regression analyses with adjustment for age and sex., Results: Overall, the prevalence of antidepressant use per 1000 persons increased from 32.1 in 2000 to 46.3 in 2009; however, the incidence per 1000 persons declined from 20.8 in 2000 to 16.5 in 2009. For antidepressant classes, the prescriptions of selective serotonin reuptake inhibitors and other new agents increased during the study periods; however, the use of tricyclic antidepressants, trazodone, and monoamine oxidase inhibitors declined. For therapeutic indications, we found increasing trends of antidepressant use for sleep and adjustment disorders; however, the rates of antidepressant use for mood disorder, anxiety disorders, and non-psychiatric conditions decreased., Conclusions: Regarding the new use of antidepressants in Taiwan between 2000 and 2009, we found that the decreased incidence of antidepressant use might be attributed mainly to the decreased use of tricyclic antidepressants and monoamine oxidase inhibitors. Decreased use among middle-aged and older persons and fewer antidepressant prescriptions for non-psychiatric conditions were also noted., (Copyright © 2012 John Wiley & Sons, Ltd.)

The magnitude of risk between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding (UGIB) is still unknown in patients with psychiatric diseases. The aim of this study was to quantify the risk of UGIB induced by use of antidepressants with different affinities for serotonin transporters in psychiatric patients using Taiwan's nationwide health insurance claims database. We conducted a propensity score- matched retrospective cohort study and identified 304,606 psychiatric patients who initiated antidepressant treatment during the 2005-2006 period. Antidepressants were classified as high- (HA group), intermediate- (IA group), or low-affinity (LA group) serotonin reuptake inhibitors. Patients in the LA group were matched 1:1 to those in the HA and IA groups according to their propensity scores. Subjects who were successfully matched were followed up from the date of antidepressant initiation to first hospitalization for UGIB, drug discontinuation, transition to or addition of antidepressants in another group, or the study's end (whichever occurred first). A total of 153,486 psychiatric patients were successfully matched, and 498 first UGIB events were identified. Compared with the LA group, patients in the HA group had a higher risk for UGIB (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.11-1.71). The HR (95% CI) of the IA group was 1.11 (95% CI, 0.88-1.41). The trend for elevated UGIB risk with increasing affinity of serotonin transporters was statistically significant (P < 0.01). Elderly patients and those with prior UGIB history were more susceptible to the harmful effects. Our findings suggest that the use of high-affinity serotonin reuptake inhibitors may increase the risk for UGIB in psychiatric patients.

Background: Insufficient data are available on the survival of recurrent hepatocellular carcinoma after primary hepatectomy in patients receiving different treatments. We evaluated retrospectively the effects of treatment modalities on long-term survival., Methods: Between 2001 and 2007, 435 posthepatectomy hepatocellular carcinoma patients who developed recurrence were grouped by treatment modality into re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups. Treatment strategies for both primary hepatocellular carcinoma and its recurrence were selected using the same criteria. Postrecurrence survival was estimated using the Kaplan-Meier method and compared using the Cox proportional hazard model with adjusted independent prognostic factors. Survival rates after primary resection without recurrence were also compared., Results: In re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups, the 2-year postrecurrence survival rates were 90%, 96%, 75%, and 20%, respectively, and the 5-year survival rates were 72%, 83%, 56%, and 0%, respectively. The adjusted hazard of death was less for the re-resection and radiofrequency ablation groups than for the transarterial chemoembolization group, and the adjusted hazard ratios for the re-resection and radiofrequency ablation groups were 0.45 (95% confidence interval, 0.20-0.98) and 0.25 (0.08-0.81), respectively. The adjusted hazard ratio (95% confidence interval) of death for the radiofrequency ablation group compared to the re-resection group was 0.64 (0.19-2.19). Survival in the single resection group did not differ from that in the re-resection and radiofrequency ablation groups., Conclusion: Postrecurrence survival in the re-resection and radiofrequency ablation groups was significantly better than that in the transarterial chemoembolization group and similar to that of patients in the primary resection without recurrence group., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Previous studies have documented the increased cardiovascular risk associated with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs). Despite this, many old NSAIDs are still prescribed worldwide. Most of the studies to date have been focused on specific oral drugs or limited by the number of cases examined. We studied the risk of new acute myocardial infarction (AMI) hospitalization with current use of a variety of oral and parenteral NSAIDs in a nationwide population, and compared our results with existing evidence., Methods: We conducted a case-crossover study using the Taiwan's National Health Insurance claim database, identifying patients with new AMI hospitalized in 2006. The 1-30 days and 91-120 days prior to the admission were defined as case and matched control period for each patient, respectively. Uses of NSAIDs during the respective periods were compared using conditional logistic regression and adjusted for use of co-medications., Results: 8354 new AMI hospitalization patients fulfilled the study criteria. 14 oral and 3 parenteral NSAIDs were selected based on drug utilization profile among 13.7 million NSAID users. The adjusted odds ratio, aOR (95% confidence interval), for risk of AMI and use of oral and parenteral non-selective NSAIDs were 1.42 (1.29, 1.56) and 3.35 (2.50, 4.47), respectively, and significantly greater for parenteral than oral drugs (p for interaction<0.01). Ketorolac was associated with the highest AMI risk among both of oral and parenteral NSAIDs studied, the aORs were 2.02 (1.00, 4.09) and 4.27 (2.90, 6.29) respectively. Use of oral flurbiprofen, ibuprofen, sulindac, diclofenac, and parenteral ketoprofen were also significantly associated with increased AMI risk. The results of the present study were consistent with the majority of evidence from previous studies., Conclusions: The collective evidence revealed the tendency of increased AMI risk with current use of some NSAIDs. A higher AMI risk associated with use of parenteral NSAIDs was observed in the present study. Ketorolac had the highest associated risk in both oral and parenteral NSAIDs studied. Though further investigation to confirm the association is warranted, prescribing physicians and the general public should be cautious about the potential risk of AMI when using NSAIDs.