Association between ranitidine use with potential NDMA impurities and risk of cancer in Korea.

N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002-2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81-1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.

Survival, Prognosis, and Clinical Feature of Refractory Myasthenia Gravis: a 15-year Nationwide Cohort Study.

BACKGROUND: Myasthenia gravis (MG) is a rare classic autoimmune disease where immunosuppressant therapies have been successful to reduce MG attributable mortality fairly well. However, patients with refractory MG (rMG) among the actively treated MG (aMG) are nonresponsive to conventional therapy and display high disease severity, which calls for further research. We aimed to determine survival, prognosis, and clinical feature of patients with rMG compared to non-rMG. METHODS: Retrospective nationwide cohort study using Korea's healthcare database between 2002 and 2017 was conducted. Patients with rMG (n = 47) and non-rMG (n = 4,251) who were aged > 18 years, followed-up for ≥ 1 year, and prescribed immunosuppressants within 2 years after incident MG diagnosis were included. Patients with rMG were defined as administered plasma exchange or intravenous immunoglobulin at least 3 times per year after receiving ≥ 2 immunosuppressants. All-cause mortality, myasthenic crisis, hospitalization, pneumonia/sepsis, and emergency department (ED) visits were measured using Cox proportional hazard models and pharmacotherapy patterns for rMG were assessed. RESULTS: The rMG cohort included a preponderance of younger patients and women. The adjusted hazard ratio was 2.49 (95% confidence interval, 1.26-4.94) for mortality, 3.14 (2.25-4.38) for myasthenic crisis, 1.54 (1.15-2.06) for hospitalization, 2.69 (1.74-4.15) for pneumonia/sepsis, and 1.81 (1.28-2.56) for ED visits for rMG versus non-rMG. The immunosuppressant prescriptions were more prevalent in patients with rMG, while the difference was more remarkable before rMG onset rather than after rMG onset. CONCLUSION: Despite the severe prognosis of rMG, the strategies for pharmacotherapeutic regimens were similar in those two groups, suggesting that intensive monitoring and introduction of timely treatment options in the early phase of MG are required.

Pre-validation of a Calu-3 epithelium cytotoxicity assay for predicting acute inhalation toxicity of chemicals.

Although in vivo inhalation toxicity tests have been widely conducted, the testing of many chemicals is limited for economic and ethical reasons. Therefore, we previously developed an in vitro acute inhalation toxicity test method. The goal of the present pre-validation study was to evaluate the transferability, reproducibility, and predictive capacity of this method. After confirming the transferability of the Calu-3 epithelium cytotoxicity assay, reproducibility was evaluated using 20 test substances at three independent institutions. Cytotoxicity data were analyzed using statistical methods, including the intra-class correlation coefficient and Bland-Altman plots for within- and between-laboratory reproducibility. The assay for the 20 test substances showed excellent agreement within and between laboratories. To evaluate the predictive capacity, 77 test substances were analyzed for acute inhalation toxicity. Accuracy was measured using a cutoff of 40%, and the relevance was analyzed as a receiver-operating characteristic (ROC) curve. An accuracy of 72.73% was obtained, and the area under the ROC curve was 0.77, indicating moderate performance. In this study, we found that the in vitro acute inhalation toxicity test method demonstrated good reliability and relevance for predicting the acute toxicity of inhalable chemicals. Hence, this assay has potential as an alternative test for screening acutely toxic inhalants.

The risk factors and incidence of major infectious diseases in patients with ankylosing spondylitis receiving tumor necrosis factor inhibitors.

OBJECTIVES: This study aimed to evaluate the risk factor and incidence of infections in patients receiving tumor necrosis factor inhibitor (TNFi) therapy for ankylosing spondylitis using data from the national health insurance service. METHODS: This was a retrospective cohort study. Data regarding patients with ankylosing spondylitis prescribed TNFis were obtained from an insurance claims database of the Health Insurance Review & Assessment Service in Korea. Outcomes used were incidence rates of serious infection, pneumonia, tuberculosis, and herpes zoster during the follow-up period as well as the relationship between each TNFi and sex, hazard ratio (HR) of infection-related risk factors, and incidence of infections. RESULTS: A total of 2515 patients were included. There were no significant differences among the hazard ratios of TNFis for serious infection, pneumonia, and herpes zoster. However, the hazard ratio of tuberculosis was significantly higher for infliximab than for etanercept (adjusted HR 8.40 [95% confidence interval: 1.06-66.91]). In the subgroup analysis by sex, women treated with golimumab had a significantly higher hazard of herpes zoster than those treated with etanercept (adjusted HR 12.40 [95% confidence interval: 1.40-109.58]). CONCLUSION: We recommend that risk factors for these infectious diseases be identified prior to prescribing TNFis in these patients.

Dose Reduction of Tumor Necrosis Factor Inhibitor and its Effect on Medical Costs for Patients with Ankylosing Spondylitis.

INTRODUCTION: Tumor necrosis factor inhibitors (TNFis) may be administered at a reduced dose to patients with ankylosing spondylitis (AS) for various reasons. However, in practice, there is insufficient evidence of how the dose reduction of TNFi is implemented and the amount of medical costs it reduces. In this study, we investigated treatment patterns among patients with AS who were administered various TNFis. The effect on medical costs related to AS was also investigated using Korea's insurance claims database. METHODS: From the insurance claims database of the Health Insurance Review & Assessment Service in South Korea, patients with AS newly treated with TNFis (etanercept, adalimumab, golimumab, and infliximab) between July 1, 2013, and June 30, 2016, were enrolled. Patients treated with the TNFis were followed up for 2 years. Treatment patterns (continuation and discontinuation of TNFi) and dose reduction (< 50% of recommended dose) in patients who continued treatment were analyzed and compared among the TNFi groups using the Chi-square test. Healthcare costs between the dose reduction and maintenance groups were compared using general linear modeling. RESULTS: Of 1352 patients, 764 (56.51%) continued using TNFis for 2 years, and 17.8% of these were administered reduced doses. TNFi dose reduction was the most frequent in 36 (24.83%) patients using etanercept, followed by those using adalimumab (21.97%), golimumab (11.70%), and infliximab (11.98%) (p = 0.0028). For each TNFi group, the total healthcare cost significantly decreased, that is, by 24.85% for adalimumab, 31.80% for etanercept, 26.34% for golimumab, and 35.52% for infliximab (p < 0.0001). CONCLUSIONS: TNFi dose reduction was identified in 17.8% of the patients with AS, and the patterns were different for each TNFi. Additionally, the dose reductions significantly reduced the medical costs associated with AS, that is, from 24.85 to 35.52% of the total medical expenditure.

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.

Benzodiazepine Use and Risk of Acute Angle-Closure Glaucoma: A Population-Based Case-Crossover Study.

INTRODUCTION: Theoretically, benzodiazepines (BZDs) can narrow the iridocorneal angle and induce acute angle-closure glaucoma (AACG). However, little evidence exists regarding this association. OBJECTIVE: The objective of this study was to assess whether the use of BZDs is associated with the risk of AACG. METHODS: We conducted a population-based case-crossover study using the nationwide claims database of the National Health Insurance Service in Korea. Patients with newly diagnosed AACG-between 1 January 2013 and 31 December 2016-who had received at least one BZD prescription prior to AACG diagnosis were enrolled. The date of AACG diagnosis was set as the index date. We assessed BZD use by each patient during a 30-day case period prior to the index date and three consecutive control periods that preceded this date. We used conditional logistic regression that adjusted for concomitant medications to determine the odds ratio for the use of BZDs in the case period compared with that in the control period in patients with incident AACG. RESULTS: Of the 11,093 patients with incident AACG, 6709 received a prescription for BZD prior to diagnosis. BZD use was associated with an increased risk of AACG [adjusted odds ratio (aOR) = 1.40; 95% confidence interval (CI) 1.27-1.54]. AACG risk was similar for short-acting (aOR = 1.40, 95% CI 1.24-1.57) and long-acting BZDs (aOR = 1.33, 95% CI 1.18-1.50). CONCLUSION: We found that BZD use was associated with AACG risk in the Korean population. Clinicians should carefully monitor the occurrence of visual disturbance in BZD-treated patients.

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.

Twelve-year trend in the use of zolpidem and physicians' non-compliance with recommended duration: a Korean national health insurance database study.

OBJECTIVES: Abuse of zolpidem has sporadically been reported and little is known regarding nationwide patterns of zolpidem use in Korea. This study investigates the extent of zolpidem usage exceeding the recommended duration and the predictors. METHODS: We conducted a drug utilization study using the national sample cohort database of the Korea National Health Insurance Corporation between 2002 and 2013. The study subjects were patients treated with zolpidem in the outpatient setting. An episode was defined as a period of continuous zolpidem therapy. The provider-based episode allowed for a gap of up to 3 days between two consecutive prescriptions from the same institution. The person-based episode allowed for a gap of up to 3 days, regardless of institution. We calculated the proportion of zolpidem use for periods over 30 days and conducted logistic regression analyses to investigate the relevant predictors. An adjusted odds ratio (aOR) with a 95% confidence interval (CI) was estimated for each predictor. RESULTS: The usage of zolpidem is dramatically increased by approximately 18 times since zolpidem was authorized in the market (1181 in 2002 vs. 21,399 in 2013). The treatment duration in 8.3% of episodes exceeded 30 days out of 75,087 zolpidem users. The odds of zolpidem prescription exceeding 30 days were highest in patients aged 65 years and older (aOR = 2.13, 95% CI 1.78-2.53) and at tertiary hospitals (aOR = 2.14, 95% CI 1.68-2.72). Women were more likely than men to be treated with zolpidem for over 30 days. CONCLUSION: We found dramatic increase of zolpidem use from 2002 to 2013. In 8.3% of the prescribed episodes of zolpidem, the recommended duration was exceeded. Efforts are required to reduce prescriptions that are inconsistent with the recommended guidelines for older patients, women, and in tertiary hospitals.

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.

Healthcare utilization and medical expenditure of Korean psoriasis patients: A descriptive result using a health insurance database.

BACKGROUND: Epidemiological evidence regarding healthcare utilization and medical expenditure of patients with psoriasis in Korea is needed. To analyze the differences in healthcare utilization and financial burdens between patients with and without psoriasis and compare these patterns according to the disease severity. METHODS: We conducted a descriptive cross-sectional study using a sample of the National Health Insurance database between January 1, 2012 and December 31, 2013. We included patients diagnosed with psoriasis and those with nonpsoriasis skin diseases, matched for age, sex, income, and geographical region. The patients with psoriasis were further divided into mild and moderate-to-severe psoriasis groups. Each patient was followed up for 1 year to estimate their healthcare utilization and medical expenditure since their initial diagnosis. Healthcare utilization was defined as the sum of outpatient visits and inpatient stays per person. We conducted McNemar test or Bowker test of symmetry to compare the baseline characteristics and used the Wilcoxon matched-pair signed-rank test to compare the healthcare utilization and direct costs with a 5% significance level. RESULTS: Our study subjects were 4016 patients with psoriasis and equally matched 4016 patients with nonpsoriasis skin diseases. Compared with patients without psoriasis, those with psoriasis had more days of healthcare service use (5.26 vs 4.19, P < .001) and higher medical expenditures within 1 year per person (209,320 vs 117,968 won, P < .001). Patients with moderate-to-severe psoriasis had more days of healthcare service use (12.71 vs 3.25, P < .001) and higher medical expenditures within 1 year per person (611,688 vs 107,445 won, P < .001) than those with mild psoriasis. CONCLUSION: Patients with psoriasis had higher burdens of healthcare utilization than those without psoriasis, and patients with moderate-to-severe psoriasis had the greatest burdens.