Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer.

Importance: The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases. Objective: To investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator. Design, Setting, and Participants: This national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023. Exposure: Oral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator. Main Outcomes and Measures: Hazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes. Results: Among 127 710 patients with cancer eligible for the study (80 386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37 308 patients received VEGFR-TKIs and 90 402 patients received capecitabine. Among 27 535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged ≥65 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24). Conclusions and Relevance: In this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.

Impact of Propofol-based Total Intravenous Anesthesia Versus Inhalation Anesthesia on Long-term Survival After Cancer Surgery in a Nationwide Cohort.

OBJECTIVE: To compare the impact of propofol-based total intravenous anesthesia (TIVA) versus inhalational anesthesia (IA) on the overall survival following cancer surgery. BACKGROUND: The association between intraoperative anesthetics and patients' long-term outcomes following cancer surgery remains controversial. METHODS: This retrospective cohort study used nationwide data from the Korean National Health Insurance Service. Adult patients who underwent cancer resection surgery (breast, gastric, lung, liver, kidney, colorectal, pancreatic, esophageal, and bladder cancer) under general anesthesia between January 2007 and December 2016 were included. Patients were divided into propofol-based TIVA or IA groups according to the type of anesthesia received. A total of 312,985 patients (37,063 in the propofol-based TIVA group and 275,922 patients in the IA group) were eligible for analysis. The primary outcome was the comparison of overall survival following surgery between the groups in each cancer type. We compared the all-cause mortality between the 2 groups, stratified by cancer type using time-dependent Cox regression after propensity score-based inverse probability of treatment weighting. We further examined the comparison of overall survival in a meta-analysis using data from our study and previously published data comparing propofol-based TIVA with IA after cancer surgery. RESULTS: The number of deaths in the propofol-based TIVA and IA groups was 5037 (13.6%) and 45,904 (16.6%), respectively; the median (interquartile range) follow-up duration was 1192 (637-2011) days. Multivariable Cox proportional hazards regression analysis revealed no significant association between the type of general anesthesia and overall survival after cancer surgery in the weighted cohort for each cancer type (all P >0.05) and for total population [adjusted hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.93-1.04]. In a meta-analysis, single-center studies showed higher overall survival in the TIVA group than in the IA group (pooled adjusted HR: 0.65, 95% CI: 0.47-0.91, P =0.01), while multicenter studies showed insignificant pooled adjusted HRs (pooled adjusted HR: 1.05, 95% CI: 0.82-1.33, P =0.71). CONCLUSIONS: There is no association between the type of general anesthesia used during cancer surgery and postoperative overall, 1-, and 5-year survival.

Risk of Fractures in Older Adults with Chronic Non-cancer Pain Receiving Concurrent Benzodiazepines and Opioids: A Nested Case-Control Study.

OBJECTIVE: The aim of this study was to investigate the relationship between the concurrent use of benzodiazepines and opioids and the risk of fractures in older patients with chronic non-cancer pain. METHODS: Patients with osteoarthritis or low back pain (≥ 65 years of age) included in the Korean National Health Insurance Service-National Sample Cohort database of Korea and with an incident diagnosis of hip, humeral, or forearm fracture between 2011 and 2015 were identified as cases. For each case, four controls were matched for age (within 5 years), sex, and year of cohort entry. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for fractures associated with concurrent use of benzodiazepines and opioids using a conditional logistic regression analysis, adjusting for comorbidities and comedications. RESULTS: The aOR (95% CI) for the concurrent use of benzodiazepines and opioids was 1.45 (1.22-1.71), compared with those of non-use within 30 days before the index date. The aOR was 1.65 (1.22-2.23) in patients who were continuously receiving benzodiazepines and were newly initiated with concurrent opioids. The aORs for concurrent use were 1.95 (1.39-2.74) and 1.27 (1.03-1.56) in the case of hip fracture and forearm fracture, respectively. CONCLUSION: The concurrent use of benzodiazepines and opioids was associated with an increased risk of fractures in older patients with chronic non-cancer pain. Therefore, patients continuously receiving benzodiazepines in whom opioids are newly initiated need careful monitoring, and such combined therapy should be limited to the shortest duration possible.

Change Point Analysis for Detecting Vaccine Safety Signals.

It is important to detect signals of abrupt changes in adverse event reporting in order to notice public safety concerns and take prompt action, especially for vaccines under national immunization programs. In this study, we assessed the applicability of change point analysis (CPA) for signal detection in vaccine safety surveillance. The performances of three CPA methods, namely Bayesian change point analysis, Taylor's change point analysis (Taylor-CPA), and environmental time series change point detection (EnvCpt), were assessed via simulated data with assumptions for the baseline number of events and degrees of change. The analysis was validated using the Korea Adverse Event Reporting System (KAERS) database. In the simulation study, the Taylor-CPA method exhibited better results for the detection of a change point (accuracy of 96% to 100%, sensitivity of 7% to 100%, specificity of 98% to 100%, positive predictive value of 25% to 85%, negative predictive value of 96% to 100%, and balanced accuracy of 53% to 100%) than the other two CPA methods. When the CPA methods were applied to reports of syncope or dizziness following human papillomavirus (HPV) immunization in the KAERS database, Taylor-CPA and EnvCpt detected a change point (Q2/2013), which was consistent with actual public safety concerns. CPA can be applied as an efficient tool for the early detection of vaccine safety signals.

Characterizing tramadol users with potentially inappropriate co-medications: A latent class analysis among older adults.

BACKGROUND: Although tramadol is an effective weak opioid analgesic, careful monitoring of potential central nervous system adverse reactions in older adults is needed, especially when used with concomitant medications which may trigger the adverse effects. We aimed to characterize tramadol users with potentially inappropriate co-medications in older adults using a latent class analysis (LCA). METHOD: Patients aged 65 years or older using tramadol and receiving potentially inappropriate co-medications were included from a nationwide healthcare claims database. We defined antidepressants, first-generation antihistamines, and anxiolytics as potentially inappropriate co-medications. We applied an LCA for grouping tramadol users based on the common characteristics of medication use and healthcare utilization, and each patient was probabilistically assigned to a class. Patients' characteristics in different latent classes were compared. Potential adverse drug reactions (ADRs) was defined as the any visits for emergency department after the occurrence of potentially inappropriate co-medications. Logistic regression analysis was used to examine the association between latent classes and potential ADRs. RESULTS: We identified four distinct latent classes of tramadol users representing different patterns of co-medications: multiple potential drug-drug interaction (pDDI) combination users, antihistamines-tramadol users, antidepressants-tramadol users, and anxiolytics-tramadol users. Multiple pDDI combination users showed high proportion of regular tramadol use, tended to visit more medical institutions, and had a high Charlson comorbidity score. The duration of use of potentially inappropriate co-medications with tramadol was the longest in multiple pDDI combination users and the shortest in antihistamines-tramadol users. When compared with antihistamines-tramadol users, increased potential ADR risk was observed in multiple pDDI combination users (adjusted odds ratio (OR), 1.81; 95% confidence interval (CI), 1.75-1.88), antidepressants-tramadol users (1.24; 1.19-1.29), and anxiolytics-tramadol users (1.04; 1.00-1.08). CONCLUSIONS: Four distinct classes were identified among older adults using tramadol and potentially inappropriate co-medications. Differences in potential ADR risk were observed between these classes. These findings may help to identify patients at a high risk for ADRs owing to potentially inappropriate co-medications with tramadol.

Trends in Extracorporeal Membrane Oxygenation Application and Outcomes in Korea.

The use of extracorporeal membrane oxygenation (ECMO) is increasing despite the limited evidence in survival benefit. This study aimed to analyze the changes of in-hospital mortality, medical costs, and other outcomes in ECMO therapy. We used 2004-2017 data from a nationwide healthcare administrative claims database in Korea. Overall, 14,775 ECMO procedures were performed in 14,689 patients at 112 hospitals. We found a 170-fold and a 334-fold increase in the number of ECMO procedures and related costs, respectively. For indications, the performance of ECMO for heart or lung transplantation and respiratory failure increased, whereas that for cardiovascular surgery decreased. The duration of ECMO increased from a median of 3 days (IQR, 2-5 days) in 2004 to 4 days (IQR, 2-9 days) in 2017. The overall in-hospital mortality rate was 68.6%, and this improved over time, especially for lung transplantation and respiratory failure patients. Bleeding-related complications and the transfusion amount also decreased. Hospitals with higher case volume showed better survival outcomes. The median cost per procedure and per day was 26,538 USD (IQR, 14,646-47,862 USD) and 1,560 USD (IQR, 903-2,929 USD), respectively, and increased with time. A trend toward greater resource use and better outcomes requires additional cost-effective analysis based on indications.

Effect of hydroxychloroquine pre-exposure on infection with SARS-CoV-2 in rheumatic disease patients: a population-based cohort study.

OBJECTIVES: Early in vitro studies have suggested that hydroxychloroquine (HCQ) is a potentially useful drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. This study was conducted to determine whether HCQ had a preventive effect on coronavirus disease 2019 (COVID-19) in rheumatic disease patients who were taking HCQ. METHODS: We conducted a population-based retrospective cohort study using the records of the Korean Health Insurance Review and Assessment (HIRA) claim records. The clinical data of patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) who were tested for SARS-CoV-2 were investigated. We compared the attack rate of COVID-19 between those who underwent HCQ therapy within 14 days before the test for SARS-CoV-2 (HCQ users) and HCQ non-users. Data were analysed using logistic regression models, χ2, and Student's t-tests. RESULTS: As of 15th May 2020, 2066 patients with RA or SLE were tested for COVID-19. Among them, 31.4% (649/2066) were treated with HCQ. Most HCQ users (93.7%, 608/649) were taking 200-400 mg/day recommended for the treatment of rheumatic diseases. The attack rate of COVID-19 in the HCQ users (2.3%, 15/649) did not differ from that in the HCQ non-users (2.2%, 31/1417) (p 0.86). CONCLUSIONS: HCQ prophylactic use at a usual dose did not prevent COVID-19 in patients with rheumatic disease.

Inhaled Corticosteroids and COVID-19 Risk and Mortality: A Nationwide Cohort Study.

Inhaled corticosteroids (ICS) could increase both the risk of coronavirus disease 2019 (COVID-19) and experiencing poor outcomes. To compare the clinical outcomes between ICS users and nonusers, COVID-19-related claims in the Korean Health Insurance Review and Assessment database were evaluated. To evaluate susceptibility to COVID-19 among patients with COPD or asthma, a nested case-control study was performed using the same database. In total, 7341 patients were confirmed to have COVID-19, including 114 ICS users and 7227 nonusers. Among 5910 patients who were hospitalized, death was observed for 9% of ICS users and 4% of nonusers. However, this association was not significant when adjusted for age, sex, region, comorbidities, and hospital type (aOR, 0.94; 95% CI, 0.43-2.07). The case-control analysis of COPD compared 640 cases with COVID-19 to 2560 matched controls without COVID-19, and the analysis of asthma compared 90 cases with COVID-19 to 360 matched controls without COVID-19. Use of ICS was not significantly associated with COVID-19 among patients with COPD (aOR, 1.02; 95% CI, 0.46-2.25) or asthma (aOR, 0.38; 95% CI, 0.13-1.17). Prior ICS use was not significantly associated with COVID-19 in patients with COPD or asthma, nor with clinical outcomes among patients with COVID-19.

Concomitant Use of NSAIDs or SSRIs with NOACs Requires Monitoring for Bleeding.

PURPOSE: Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used in patients with atrial fibrillation (AF) because of their effectiveness in preventing stroke and their better safety, compared with warfarin. However, there are concerns for an increased risk of bleeding associated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors (SSRIs) with NOACs. In this study, we aimed to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or SSRIs with NOACs after being diagnosed with AF. MATERIALS AND METHODS: A nested case-control analysis to assess the safety of NSAIDs and SSRIs among NOAC users with AF was performed using data from Korean National Health Insurance Service from January 2012 to December 2017. Among patients who were newly prescribed NOACs, 1233 cases hospitalized for bleeding events were selected, and 24660 controls were determined. RESULTS: The risk of bleeding events was higher in patients receiving concomitant NSAIDs [adjusted odds ratio (aOR) 1.41; 95% confidence interval (CI) 1.24-1.61] or SSRIs (aOR 1.92; 95% CI 1.52-2.42) with NOACs, compared to no use of either drug, respectively. The risk of upper gastrointestinal bleeding was higher in patients receiving concomitant NSAIDs or SSRIs without proton pump inhibitors (PPIs) (NSAIDs: aOR 2.47; 95% CI 1.26-4.83, SSRI: aOR 10.8; 95% CI 2.41-2.48) compared to no use. CONCLUSION: When NSAIDs or SSRIs are required for NOAC users with AF, physicians need to monitor bleeding events and consider the use of PPIs, especially for combined use of both drugs or when initiating NOACs treatment.

Conducting and Reporting a Clinical Research Using Korean Healthcare Claims Database.

An increasing number of studies are using healthcare claims databases to assess healthcare intervention utilization patterns or outcomes in real-world clinical settings. However, methodological issues affecting study design or data analysis can make conducting and reporting these types of studies difficult. This review presents an overview of the types of information contained in claims data, describes some advantages and limitations of using claims data for research purposes, and outlines steps for utilizing the Korea Health Insurance Review and Assessment and National Health Insurance Service databases. The study also reviews epidemiological approaches utilizing healthcare claims databases (including cross-sectional, case-control, case-crossover, and cohort designs) with respect to protocol development, analysis, and reporting of results, and introduces relevant guidelines and checklists, including the Guidelines for Good Pharmacoepidemiology Practices, the Strengthening the Reporting of Observational Studies in Epidemiology checklist, and the Risk of Bias in Nonrandomized Studies of Interventions tool.