Trends of polypharmacy among older people in Asia, Australia and the United Kingdom: a multinational population-based study.

BACKGROUND: Polypharmacy among older people represents a global challenge due to its association with adverse drug events. The reported prevalence of polypharmacy varies widely across countries, and is particularly high in Asian countries. However, there is no multinational study using standardised measurements exploring variations in prescribing trends. OBJECTIVE: To compare polypharmacy trends in older people in Asia, Australia and the United Kingdom. DESIGN: Multinational, retrospective, time-trend, observational study using a common study protocol. SETTING: Outpatient and community settings. SUBJECTS: All individuals aged ≥ 65 years between 2013 and 2016. METHODS: We defined polypharmacy as the concomitant use of ≥5 medications for ≥45 days per year. We estimated the annual prevalence of polypharmacy and calculated average annual percentage change (AAPC) to assess the time trends. RESULTS: A total of 1.62 million individuals were included in this study. The highest prevalence of polypharmacy was observed in Hong Kong (46.4%), followed by Taiwan (38.8%), South Korea (32.0%), the United Kingdom (23.5%) and Australia (20.1%) in 2016. For the time trend, the Asian region showed a steady increase, particularly in Hong Kong and South Korea (AAPC: Hong Kong, 2.7%; South Korea, 1.8%; Taiwan, 1.0%). However, Australia and the United Kingdom showed a decreasing trend (Australia, -4.9%; the United Kingdom, -1.1%). CONCLUSIONS: Polypharmacy prevalence in older people was higher in Hong Kong, Taiwan and South Korea, with an increasing trend over time, compared with Australia and the United Kingdom. Our findings underline the necessity to monitor polypharmacy among older people in Asia by conducting government-level interventions and introducing medicine-optimisation strategies.

Analytical Approaches to Reduce Selection Bias in As-Treated Analyses with Missing In-Hospital Drug Information.

INTRODUCTION: While much attention has focused on immeasurable time bias as a potential exposure misclassification bias, it may also result in potential selection bias in cohort studies using an as-treated (or per protocol) exposure definition in which patients are censored upon treatment discontinuation. METHODS: We examined analytical approaches to minimise informative censoring due to the absence of in-hospital drug data using a case study of ß-blocker use and mortality in heart failure. We conducted a cohort study using Korea's healthcare database, including inpatient and outpatient drug data. Using an as-treated exposure definition, patients were followed up until death, ß-blocker discontinuation (in the exposed), ß-blocker initiation (in the unexposed), or end of study period. In 'complete prescription' analysis using inpatient and outpatient drug data, we estimated hazard ratios (HR) and 95% confidence intervals (CI) using a Cox proportional hazard model. In outpatient drug-based analyses, we attempted to reduce the bias using stabilised inverse probability weighting (IPW) for treatment crossovers, hospitalisation, and all artificial censorings. RESULTS: An HR of 0.89 (95% CI 0.74-1.07) for ß-blocker use versus non-use for all-cause mortality was found in 'complete prescription' analysis. Benefits were exaggerated when follow-up was assessed using outpatient drug data only (HR 0.71; 95% CI 0.57-0.89). Weighting by stabilised IPW for treatment crossovers and hospitalisation reduced the bias. CONCLUSIONS: When using an as-treated exposure definition, missing in-hospital drug data induced selection bias in our case study. Using IPW for censoring mitigated bias from the hospitalisation-induced censorings.

Comparative Treatment Persistence with Bone-Targeting Agents Among Asian Patients with Bone Metastases from Solid Tumors: A Multinational Retrospective Cohort Study.

BACKGROUND: The efficacy of bone-targeting agents has been confirmed, but the generalizability of results to Asia is in question. OBJECTIVE: We aimed to evaluate and compare treatment persistence and re-initiation with different bone-targeting agents among patients with bone metastases from solid tumors. METHODS: This population-based cohort study included patients with bone metastasis with breast, lung, or prostate cancer who initiated bone-targeting agents, including denosumab, zoledronic acid, and pamidronate in Taiwan (2013-17), Hong Kong (2013-17), and Korea (2012-16). We described the patients' persistence with bone-targeting agents, by evaluating the interruption probability, and compared risks of treatment interruption. The rates of re-initiation with index bone-targeting agents were evaluated. RESULTS: We included 5127 patients (denosumab: 3440, zoledronic acid: 1210, pamidronate: 477) from Taiwan, 883 patients (denosumab: 458, zoledronic acid: 357, pamidronate: 68) from Hong Kong, and 4800 patients (zoledronic acid: 4068, pamidronate: 732) from Korea. Compared with zoledronic acid, denosumab had a lower risk of interruption in Taiwan (adjusted hazard ratio: 0.44; 95% confidence interval 0.40-0.48) and Hong Kong (0.36; 0.28-0.45). However, pamidronate was more likely to be interrupted than zoledronic acid in Taiwan (1.31; 1.11-1.54) and Korea (2.06; 1.83-2.32), but not in Hong Kong (1.13; 0.71-1.78). After discontinuation, original treatments with denosumab in Taiwan and zoledronic acid in Hong Kong were more likely to be resumed, while in Korea, the rates were similar among the bisphosphonates. CONCLUSIONS: Denosumab was associated with a lower risk of interruption than bisphosphonates in patients with bone metastases in Taiwan and Hong Kong. Further investigations may be required to verify patients' actual reasons for discontinuation.

Bone-targeting agents in major solid tumour metastases: a multinational cohort study.

OBJECTIVE: To describe the epidemiology, clinical characteristics and utilisation patterns of bone-targeting agents (BTAs) in patients with bone metastases from breast, prostate and lung cancer. METHODS: This is a multinational retrospective cohort study including patients with three major solid tumours (breast, prostate and lung cancer) and newly initiated on BTAs (ie, denosumab, zoledronic acid and pamidronate). Records were retrieved from nationwide health databases from Hong Kong and Taiwan (HK and TW: 2013-2017) and Korea (KR: 2012-2016). Descriptive analyses included the annual incidence rates of bone metastases and the cumulative incidence curves of BTA initiation. We used Sankey diagrams to visualise the dynamic BTA utilisation patterns. RESULTS: The annual incidence rate of bone metastases ranged from 3.5% to 4.5% in TW, from 9.6% to 10.3% in HK and from 2.9% to 3.8% in KR. We identified 14.1% (5127), 9.3% (883) and 9.4% (4800) of patients with bone metastases newly initiated on BTAs in TW, HK and KR, respectively. The most frequently used BTA in TW (67.1%) and HK (51.9%) was denosumab, while in KR (84.8%) it was zoledronic acid. Sankey diagrams indicated the proportion of patients remaining on denosumab was highest in TW and HK, while it was zoledronic acid in KR. Specifically, in TW, patients who were on bisphosphonates or had discontinued treatment frequently switched to or reinitiated denosumab. CONCLUSIONS: We found the rate of BTA utilisation remained low across all sites and tumour types in recent years. The dynamic utilisation patterns of BTAs provide better understanding of the treatment landscape for future evaluation of associated outcomes of patients.

Treatment pattern in postmenopausal women with osteoporosis: a population-based cohort study in South Korea.

INTRODUCTION: The treatment landscape of postmenopausal osteoporosis (OP) in an Asian population is yet to be explored. MATERIALS AND METHODS: We conducted a retrospective cohort study to explore treatment patterns and characteristics associated with treatment interruption in postmenopausal women diagnosed with OP between 2008 and 2014. Treatment pattern assessment included the initial distribution of OP medications and treatment interruption rate according to the treatment groups during a 3-year follow-up period. We used multivariate logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) to identify factors associated with treatment interruption. RESULTS: Of 21,813 patients, 87.9% initiated oral bisphosphonates (BP), followed by ibandronate intravenous (IV; 5.4%), selective estrogen receptor modulators (SERMs; 5.2%), pamidronate IV (1.4%) and zoledronic acid (0.06%). Treatment interruption was most notable in the first year of treatment, with cumulative treatment interruption rates highest for oral BP (76.3%) and lowest for pamidronate IV (50.5%). Compared to oral BP users, users of ibandronate IV (OR 0.34, 95% CI 0.30-0.39), pamidronate IV (0.49, 0.39-0.63), zoledronic acid (0.26, 0.09-0.77), and SERMs (0.50, 0.44-0.57) were less likely to interrupt treatment. Of characteristics assessed, presence of rheumatoid arthritis increased the odds of treatment interruption in ibandronate IV group (3.94, 2.12-7.33), and concomitant use of glucocorticoids for oral BP (1.11, 1.03-1.19) and pamidronate IV (2.04, 1.06-3.93) groups, respectively. CONCLUSION: Given the frequent treatment interruptions across all OP medications, our findings on the factors associated with treatment interruption will serve to implement targeted interventions in reinforcing persistence to OP treatment.

Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors.

Recent evidence suggests that gut microbiota dysbiosis adversely affects the efficacy of immune checkpoint inhibitors (ICIs). Our objective was to investigate the association between concomitant use of proton pump inhibitors (PPIs) and ICIs, and poor prognosis in patients with nonsmall cell lung cancer (NSCLC). We conducted a cohort study using a completely enumerated lung cancer cohort from a nationwide healthcare database in South Korea. We identified 2963 patients treated with ICIs as second-line or later therapy for stage ≥IIIB NSCLC. PPI use was ascertained within 30-days before and on the date of ICI initiation, and nonuse was defined as no prescription of PPIs during this period. Using national vital statistics in South Korea, we assessed the risk of all-cause mortality associated with concomitant PPI use through a propensity score-matched Cox proportional hazard model. Among 1646 patients included after 1:1 propensity score-matching, concomitant PPI use was associated with a 28% increased risk of all-cause mortality, compared to nonuse (adjusted hazard ratio [HR] 1.28; 95% confidence intervals [CIs], 1.13-1.46). We observed an increased risk when we restricted the analysis to new users of PPI (adjusted HR = 1.64; 95% CI = 1.25-2.17). Subgroup analysis showed that PPI use was associated with high mortality risk among patients with viral hepatitis (adjusted HR = 2.72; 95% CI = 1.54-4.78; Pinteraction = .048). Our study indicates that PPI use is associated with poor prognosis in NSCLC patients treated with ICIs. Further prospective studies are required to determine the risk-benefit balance of concomitant use of PPIs and ICIs.

10-Year Fracture Risk in Postmenopausal Women with Osteopenia and Osteoporosis in South Korea.

BACKGROUND: In South Korea, women aged 66 years are eligible for complimentary bone mineral density (BMD) screening via the National Screening Program for Transitional Ages. We aimed to evaluate the 10-year fracture risk in women receiving BMD screening between January 2008 and December 2015. METHODS: BMD was classified as normal (T-score ≥-1.0 standard deviation [SD]), osteopenia (T-score <-1.0 SD and >-2.5 SD), and osteoporosis (T score ≤-2.5 SD) from dual-energy X-ray absorptiometry. Follow-up continued from the screening date until a diagnosis for clinical fragility fracture (including sites of the vertebrae, hip, pelvis, clavicle, humerus, forearm, wrist, lower leg, and ankle), censored at the earliest date of trauma, death, or December 2017; fracture was ascertained using diagnostic codes from the National Health Insurance Service database. A multivariable Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of fracture in women with osteopenia or osteoporosis relative to women with normal BMD. RESULTS: Among the 271,197 women screened, 44.0% had osteopenia and 35.2% had osteoporosis. The 10 year cumulative incidence of fragility fractures was 31.1%, 37.5%, and 44.3% in women with normal BMD, osteopenia, and osteoporosis, respectively. Fracture risk was higher in women with osteopenia (HR, 1.31; 95% CI, 1.28 to 1.34) and osteoporosis (HR, 1.68; 95% CI, 1.64 to 1.72) than in women with normal BMD. CONCLUSION: Women with osteopenia and women with osteoporosis, identified by the national BMD screening program, demonstrated a substantially elevated risk of fracture.

Clinical outcomes of COVID-19 following the use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers among patients with hypertension in Korea: a nationwide study.

OBJECTIVES: Recent evidence has shown no harm associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). We sought to further clarify the possible association between ACEI/ARB use and the risk of poor clinical outcomes of COVID-19. METHODS: From the completely enumerated COVID-19 cohort in Korea, we identified 1,290 patients with hypertension, of whom 682 had and 603 did not have records of ACEI/ARB use during the 30-day period before their COVID-19 diagnosis. Our primary endpoint comprised clinical outcomes, including all-cause mortality, use of mechanical ventilation, intensive care unit admission, and sepsis. We used inverse probability of treatment weighting (IPTW) to mitigate selection bias, and a Poisson regression model to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for comparing outcomes between ACEI/ARB users and non-users. RESULTS: Compared to non-use, ACEI/ARB use was associated with lower clinical outcomes (IPTW-adjusted RR, 0.60; 95% CI, 0.42 to 0.85; p=0.005). For individual outcomes, ACEI/ARB use was not associated with all-cause mortality (IPTW-adjusted RR, 0.62; 95% CI, 0.35 to 1.09; p=0.097) or respiratory events (IPTW-adjusted RR, 0.99; 95% CI, 0.84 to 1.17; p=0.904). Subgroup analysis showed a trend toward a protective role of ACEIs and ARBs against overall outcomes in men (IPTW-adjusted RR, 0.84; 95% CI, 0.69 to 1.03; pinteraction=0.008) and patients with pre-existing respiratory disease (IPTW-adjusted RR, 0.74; 95% CI, 0.60 to 0.92; pinteraction=0.002). CONCLUSIONS: We present clinical evidence to support continuing ACE/ARB use in COVID-19 patients with hypertension based on the completely enumerated Korean cohort.

Analytical approaches to minimizing immeasurable time bias in cohort studies.

BACKGROUND: Immeasurable time bias exaggerates drug benefits in pharmacoepidemiological studies due to exposure misclassification arising from the inability to measure in-hospital medications in many health care databases. METHODS: To compare the ability of different methodological approaches to minimize immeasurable time bias, we conducted a cohort study of ß-blocker use and all-cause mortality among patients with heart failure (HF), using a nationwide health care database which contains both in- and outpatient prescriptions. In our gold-standard analysis, we assessed exposure using a time-varying approach involving both in- and outpatient prescriptions. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, with exposure to ß-blockers defined as a time-varying variable. To estimate the magnitude of the immeasurable time bias, we repeated the analyses using outpatient prescriptions only and compared 10 approaches to minimize the bias, which are categorized as restriction, adjustment, assumption and weighting. RESULTS: The HR for ß-blocker use versus non-use was 0.76 (95% CI: 0.71 to 0.80) in our gold-standard analysis. When exposure assessment was restricted to outpatient prescriptions only, ß-blocker use was substantially more protective (HR 0.43, 95% CI: 0.40 to 0.46). Of the 10 approaches examined, adjusting for hospitalization as a time-varying variable successfully minimized the bias (HR 0.75, 95% CI: 0.68 to 0.82). CONCLUSIONS: The immeasurable time bias can result in substantial bias in pharmacoepidemiological studies. Time-varying adjustment for hospitalization appears to reduce the immeasurable time bias in the absence of inpatient medication data.

Prevalence and Its Correlation with Sustained Opioid Use in Korea: A Group-Based Trajectory Analysis.

Long-term use of opioid analgesics can lead to addiction and opioid-related death. We aimed to present the pattern of long-term opioid utilization and identify factors associated with it by using group-based trajectory modeling. We used the nationwide health insurance claims database from 2009 to 2013. Multinomial logistic regression was conducted to estimate the adjusted odds ratio (aOR) and its 95% confidence intervals (CI) for the risk of sustained opioid use associated with various clinical factors. Among 15,327 patients prescribed with opioids, three trajectories were identified: high-sustained users (4.6%, n = 713), early discontinuation (84.2%, n = 12,916), and slow discontinuation (11.2%, n = 1,698). A higher proportion of women (72.8% vs. 58.4%) and elderly patients (55.9% vs. 22.1%) were found in the high-sustained users than the early discontinuation group. Depression (aOR 3.55, 95% CI 1.99-6.35) and epilepsy (aOR 10.12, CI 4.72-21.67) were the two highest comorbidities associated with sustained opioid use in the high-sustained users when compared to the early discontinuation group. Among chronic non-cancer patients, 4.6% were prescribed opioids consistently. Both healthcare providers and patients should be aware of the factors associated with sustained opioid use when prescribing it to patients with mental-related conditions, and its consequent adverse events should be carefully monitored.

Benzodiazepine-Related Cognitive Impairment or Dementia: A Signal Detection Study Using a Case/Non-Case Approach.

OBJECTIVE: The association between benzodiazepine use and the risk of cognitive impairment or dementia has been controversial. Our study aims to detect this association through a case/non-case method using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD) between 2007 and 2016. METHODS: Cases were adverse event (AE)-pairs with suspected cognitive impairment or dementia. 10 non-cases were matched to each case on age and sex. Exposure was defined as use of benzodiazepines, including long-, intermediate-, and short-acting benzodiazepine. We conducted multivariable logistic regression analyses to estimate reporting odds ratios (ROR) and 95% confidence intervals (CI). RESULTS: Of the 1,086,584 AE-pairs, 887 cases were suspected AE-pairs of cognitive impairment or dementia, and 775,444 non-cases were selected. Benzodiazepine use was associated with increased AE-pairs of cognitive impairment or dementia when assessed using those with certain, probable, and/or possible in causality assessments (ROR=2.69, 95% CI=1.66-4.38). Higher ROR estimates were shown in female (2.33, 1.48-3.67) and in those with polypharmacy (2.20, 1.35-3.57). Dementia safety profiles were inconsistent across individual benzodiazepine components. CONCLUSION: These results suggest the potentially increased association between benzodiazepine use and cognitive impairment or dementia in female and those with polypharmacy. Inconsistent safety profiles of benzodiazepine components should be further investigated.

Machine Learning for Detection of Safety Signals From Spontaneous Reporting System Data: Example of Nivolumab and Docetaxel.

Introduction: Various methods have been implemented to detect adverse drug reaction (ADR) signals. However, the applicability of machine learning methods has not yet been fully evaluated. Objective: To evaluate the feasibility of machine learning algorithms in detecting ADR signals of nivolumab and docetaxel, new and old anticancer agents. Methods: We conducted a safety surveillance study of nivolumab and docetaxel using the Korea national spontaneous reporting database from 2009 to 2018. We constructed a novel input dataset for each study drug comprised of known ADRs that were listed in the drug labels and unknown ADRs. Given the known ADRs, we trained machine learning algorithms and evaluated predictive performance in generating safety signals of machine learning algorithms (gradient boosting machine [GBM] and random forest [RF]) compared with traditional disproportionality analysis methods (reporting odds ratio [ROR] and information component [IC]) by using the area under the curve (AUC). Each method then was implemented to detect new safety signals from the unknown ADR datasets. Results: Of all methods implemented, GBM achieved the best average predictive performance (AUC: 0.97 and 0.93 for nivolumab and docetaxel). The AUC achieved by each method was 0.95 and 0.92 (RF), 0.55 and 0.51 (ROR), and 0.49 and 0.48 (IC) for respective drug. GBM detected additional 24 and nine signals for nivolumab and 82 and 76 for docetaxel compared to ROR and IC, respectively, from the unknown ADR datasets. Conclusion: Machine learning algorithm based on GBM performed better and detected more new ADR signals than traditional disproportionality analysis methods.

Uncertain Association Between Benzodiazepine Use and the Risk of Dementia: A Cohort Study.

OBJECTIVE: To examine the association between benzodiazepine use and the risk of dementia. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study, using a nationwide healthcare database of South Korea (2002-2016). The participants included new users of benzodiazepines aged ≥50 years, with no prior prescription record of benzodiazepines or a history of dementia within the previous 5 years (2002-2006). METHODS: Outcome was defined as an incident dementia with specified algorithms using diagnosis and prescription records, with the application of a 5-year lag-time following the index date during which outcomes were censored. We used a multivariable Cox proportional hazard model to estimate hazard ratio (HR) and the 95% confidence interval (CI). Comorbidities and comedications were treated as time-varying covariates in 90-day windows, and an active comparator was used to reduce potential bias from confounding by indication. Active comparators were defined as new-users of antidepressants. RESULTS: Our final participants included 616,256 patients, after propensity score estimation and matching on a 1:1 ratio. We observed a 23% increase in the risk of dementia in benzodiazepine users, compared with that in nonusers, over a mean follow-up period of 5.5 years (HR 1.23, 95% CI 1.14-1.32). A consistent finding was observed when the lag-time duration was extended to 7 years, revealing a close to null association (HR 1.17, 95% CI 1.04-1.30). When new-users of antidepressants were used as the active comparator, no increase in the risk of dementia with benzodiazepines was observed over 7 years (HR 1.01, 95% CI 0.81-1.27). CONCLUSIONS AND IMPLICATIONS: A significant association was observed between benzodiazepine use and the risk of dementia, compared with nonusers. However, a null or negative association was observed with the use of the active comparator, suggesting the absence of a causal association between dementia and benzodiazepine use.

Zoledronic acid and skeletal-related events in patients with bone metastatic cancer or multiple myeloma.

INTRODUCTION: Investigations of ZA effectiveness using large, real-world databases are rare. We examined whether zoledronic acid (ZA) decreased the risk of skeletal-related events (SREs) among patients with bone metastases (BMs) from breast cancer (BC) or prostate cancer (PC), or multiple myeloma (MM) in routine clinical practice. MATERIALS AND METHODS: We conducted a propensity score-matched cohort study using the Korean National Health Insurance database. Our cohort included patients diagnosed with BM after BC or PC, or MM between 2004 and 2015. SRE was defined as having a record of pathologic fracture, spinal cord compression, radiation, or surgery to bone. The incidence of multiple SREs was calculated according to SRE history. We calculated the incidence rate ratio (IRR) to examine the relative difference in the risk of SREs of ZA users compared to those of ZA non-user. RESULTS: Among 111,679 patients, diagnosed with BM and one of the three cancer types, 5608 were included in the analysis after propensity score matching. A decreased risk of SREs was observed for the ZA use in patients with history of SRE in BC [IRR = 0.74, 95% confidence interval (CI) = 0.66-0.83], PC (IRR = 0.86, 95% CI = 0.73-1.02), and MM (IRR = 0.74, 95% CI = 0.59-0.93). For patients without SRE history, ZA use was not associated with decreased risks of SREs, but rather increased the risks (BC: IRR = 1.96, 95% CI 1.87-2.05; PC: IRR = 1.66, 95% CI 1.54-1.80; MM: IRR = 1.92, 95% CI 1.57-2.34). CONCLUSIONS: Our study suggests that the ZA use was associated with a decreased risk of SRE for patients with SRE history. However, no preventive effects of ZA were observed for patients without history.

Prescribing trend of pioglitazone after safety warning release in Korea.

OBJECTIVES: This study was conducted to determine the number of pioglitazone users before and after the issue of the pioglitazone safety warning (intervention) by South Korea's Ministry of Food and Drug Safety on June 10, 2011. STUDY DESIGN: A quasi-experimental interrupted time series study was conducted to examine the number of pioglitazone and other antidiabetic drug users between 2009 and 2015. METHODS: We used the National Health Insurance Service-National Sample Cohort database to estimate the number of pioglitazone and other antidiabetic drug users between 2009 and 2015. Relative and absolute changes in the number of drug users were calculated with 95% CIs. Monthly numbers of drug users were presented according to the maximum likelihood estimation method, and a segmented regression analysis was performed to evaluate the effect of the intervention. A Durbin-Watson statistic and Dickey-Fuller test were used to assess autocorrelation and seasonality, respectively. RESULTS: A total of 80,724 patients with diabetes, including 12,249 pioglitazone users, were investigated. The relative change in pioglitazone users was -8.13% (95% CI, -8.41% to -7.86%). The intervention was associated with an immediate decrease of 177 pioglitazone users per 1000 patients with diabetes (P <.05). Without this intervention, the predicted proportion of pioglitazone users would be 90 per 1000 patients with diabetes, which is 1.5-fold higher than the actually observed rate of 60 per 1000 patients with diabetes. CONCLUSIONS: This intervention led to a moderate decrease in pioglitazone users. Until further evidence is available, caution should be exercised when prescribing pioglitazone to patients with high potential risk of bladder cancer and alternative treatments should be considered.

Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: A 12-year longitudinal nationwide healthcare database study.

BACKGROUND: This study examined the incidence of skeletal-related events (SRE) among patients with breast cancer (BC)- or prostate cancer (PC)-induced bone metastasis or multiple myeloma (MM) based on a population-based, 12-year healthcare database. METHODS: Patients aged ≥18 years with bone metastasis from BC or PC or with MM between 2004 and 2015 were included. SRE was defined as pathologic fracture, spinal cord compression, radiation, or surgery to bone. Patients were followed-up from the initial diagnosis of bone metastasis (for those with BC or PC) or MM until SRE occurrence. To estimate multiple SREs, we applied a 21-day time window to ensure that subsequent SREs occurred independently from the previous event. We calculated the incidence and 95% confidence intervals (CIs), stratified according to the previous SRE history. RESULTS: Our cohort included 53,231 patients, including 23,811 with BC, 19,170 with PC, and 10,250 with MM. The incidence of multiple SREs in the 21-day time window was 1.03 (95% CI = 1.01-1.05) in patients with previous SRE history and 0.19 (95% CI = 0.19-0.20) in those without. The cumulative SRE incidences were 47%, 31.4%, and 38.0% in BC, PC, and MM patients. CONCLUSION: The incidences of multiple SREs in BC- or PC-induced bone metastasis or MM in this 12-year South Korean cohort were slightly higher than those in European countries. Our study provided real-world evidence that patients with BC- or PC-induced bone metastasis or MM are at high risk of SRE.

Characteristics and trends of spontaneous reporting of therapeutic ineffectiveness in South Korea from 2000 to 2016.

Therapeutic ineffectiveness involves drug-related therapeutic failure, inefficacy or resistance and has not been sufficiently studied. Objective of our study was to evaluate reporting trends in therapeutic ineffectiveness by year and describe factors affecting therapeutic ineffectiveness using the Korea Adverse Event Reporting System. Proportion of therapeutic ineffectiveness reports was based on total submitted reports between 2000 and 2016. Utilizing 2016 alone, we compared the characteristics of therapeutic ineffectiveness with age group and gender matching by random extraction. We conducted a logistic regression analysis to estimate reporting odds ratios (ROR) and its 95% confidence intervals (CI) for reports by type of reporters, e.g., doctors, pharmacists, or consumers. We presented most frequent reports by the anatomical main groups and therapeutic subgroups according to the Anatomical Therapeutic Chemical (ATC) classification system. For the 17-years, the proportion of therapeutic ineffectiveness adverse drug reactions reporting ranged from 0.0% to 3.7% between 2000 and 2016. Of 228,939 reports, 2,797 (1.2%) were submitted in 2016. Consumers accounted for 6.92% of reports and doctors accounted for 45.49%, in which, consumers were more likely to report therapeutic ineffectiveness than doctors (adjusted ROR 3.98; 95% CI, 2.92 to 5.41). According to the ATC classification system, "nervous system" was the most frequently reported anatomical group (18.7%) and "parathyroid hormones and analogues" was reported most frequently in the pharmacological subgroup (23.7%). Teriparatide, a drug used to treat osteoporosis, had the most reports (11.0%). Therapeutic ineffectiveness reports may be used as a scientific tool for the reevaluation of respective drugs in order to confirm of its therapeutic effects.

Differential completeness of spontaneous adverse event reports among hospitals/clinics, pharmacies, consumers, and pharmaceutical companies in South Korea.

The differential pattern and characteristics of completeness in adverse event (AE) reports generated by hospitals/clinics, pharmacies, consumer and pharmaceutical companies remain unknown. Thus, we identified the characteristics of complete AE reports, compared with those of incomplete AE reports, using a completeness score. We used Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System Database (KIDS-KD) between January 1, 2016 and December 31, 2016. The completeness score was determined out of a total of 100 points, based on the presence of information on temporal relationships, age and sex of patients, AE progress, name of reported medication, reporting group by profession, causality assessment, and informational text. AE reports were organized into four groups based on affiliation: hospitals/clinics, pharmacies, consumers, and pharmaceutical companies. Affiliations that had median completeness scores greater than 80 points were classified as 'well-documented' and these reports were further analyzed by logistic regression to estimate the adjusted odds ratios and 95% confidence intervals. We examined 228,848 individual reports and 735,745 drug-AE combinations. The median values of the completeness scores were the highest for hospitals/clinics (95 points), followed by those for consumers (85), pharmacies (75), and manufacturers (72). Reports with causality assessment of 'certain', 'probable', or 'possible' were more likely to be 'well-documented' than reports that had causality assessments of 'unlikely'. Serious reports of AEs were positively associated with 'well-documented' reports and negatively associated with hospitals/clinics.

Signal Detection Between Fluoroquinolone Use and the Risk of Rhegmatogenous Retinal Detachment: Sequence Symmetry Analysis Using Nationwide South Korean Healthcare Database Between 2004 and 2015.

BACKGROUND AND OBJECTIVES: The association between fluoroquinolone and rhegmatogenous retinal detachment (RRD) has been controversial as a result of inconsistent findings. We set out to detect a possible association of fluoroquinolone use and risk of RRD, using sequence symmetry analysis (SSA). METHODS: We conducted an SSA, case-only design, using a Korean nationwide healthcare database between 2004 and 2015. Exposure was defined as new fluoroquinolone use and outcome as an incident RRD, defined by a diagnosis of RRD (ICD-10: "H33.0") or surgery for RRD. Pairs of exposure and RRD within a 1-year time-window were included. The sequence ratio (SR) was calculated by the ratio of the number of patients prescribed with exposure first and diagnosed with RRD second divided by the number of patients diagnosed with RRD first and prescribed with exposure second. SR was adjusted (aSR) for underlying trends and 95% confidence intervals (CIs) were calculated. In order to observe whether the estimated ratio stabilized over time, we did repeated time-sequential analyses with the cumulative data starting from the 3-year period 2004-2006 to 2015. RESULTS: Fluoroquinolone use had a greater association with RRD as compared with other antibiotics [fluoroquinolone: 5234 pairs; aSR = 1.70 (95% CI 1.61-1.80), first-generation cephalosporin: 4139 pairs; aSR = 1.39 (95% CI 1.31-1.80), second-generation cephalosporin: 5914 pairs; aSR = 1.31 (95% CI 1.24-1.38), third-generation cephalosporin: 3650 pairs; aSR = 0.88 (95% CI 0.83-0.95), extended-spectrum penicillin: 4823 pairs; aSR = 1.29 (95% CI 1.31-1.47), macrolides: 4115 pairs; aSR = 1.31 (95% CI 1.24-1.39)]. Time-sequential analyses supported the association between fluoroquinolone and RRD. CONCLUSIONS: Our detection suggests a possible association between fluoroquinolone use and RRD. However, possible overestimation and reverse causality bias may have influenced our findings due to the limitation of an SSA design.

Signal detection of benzodiazepine use and risk of dementia: sequence symmetry analysis using South Korean national healthcare database.

Background Benzodiazepine use can potentially cause confusion and delays in mental processes. These well-known side effects appear to be linked to an increased risk of being diagnosed with dementia. Objective To evaluate the possibility of an association between benzodiazepine and dementia. Setting Korean healthcare database from 2002 to 2013. Methods Sequence symmetry analysis was conducted to investigate whether benzodiazepine use increases the risk of dementia or not. We defined exposure as new benzodiazepine users and outcome as new diagnosis of dementia (ICD-10: F00-03, G30, and G318). Benzodiazepines were categorized into two groups (long-acting and short-acting) based on the duration of action. Antidepressants, opioid analgesic, and statin were used as active comparators to rule out any possible non-causal interpretations of our results. The time-trend adjusted sequence ratio (ASR) with 95% confidence intervals (CI) was measured to identify possible associations. Main outcome measure Adjusted sequence ratio. Results Benzodiazepine users were shown to be associated with dementia [benzodiazepine: 4212 pairs, ASR = 2.27 (95% CI 2.11-2.44)]. In addition, long-acting benzodiazepines had a higher ASR than that of short-acting benzodiazepines [long-acting: 3972 pairs, ASR = 2.22 (95% CI 2.06-2.39] and [short-acting: 5213 pairs, ASR = 1.88 (95% CI 1.77-2.00)]. However, our SSA found no duration-response relationship. Conclusion Our signal detection suggests that there is a possible association between benzodiazepines and dementia. Additionally, it proposes that persons receiving long-acting benzodiazepines are at a higher risk of developing dementia than those receiving short-acting benzodiazepines. Further studies are recommended to confirm whether this epidemiological association is a causal effect or not.