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PURPOSE Epidemiologic studies suggest that chronic hepatitis B (CHB) is a risk factor for various primary extrahepatic malignancies. Our aim was to evaluate the associations of CHB and nucleos(t)ide analog (NA) treatment with the risk of the development of extrahepatic malignancies. PATIENTS AND METHODS We conducted an 18-month landmark analysis using nationwide claims data from the National Health Insurance Service of South Korea. Patients newly diagnosed with CHB in 2012-2014 (n = 90,944) and matched-controls (n = 685,436) were included. Patients with CHB were further classified as the NA-treated (CHB+/NA+, n = 6,539) or the NA-untreated (CHB+/NA–, n = 84,405) group. Inverse probability of treatment weighting analysis was applied to balance the treatment groups. Time-varying Cox analysis was performed to evaluate time-varying effect of NA treatment. The primary outcome was the development of any primary extrahepatic malignancy. Development of intrahepatic malignancy and death were considered as competing events. RESULTS During the study period (median = 47.4 months), 30,413 patients (3.9%) developed any extrahepatic malignancy. The CHB+/NA– group had a higher overall risk of extrahepatic malignancy than the CHB+/NA+ group (adjusted subdistribution hazard ratio [aSHR] = 1.28; 95% CI, 1.12 to 1.45; P < .001) or controls (aSHR = 1.22; 95% CI, 1.18 to 1.26; P < .001). There was no difference in the risk of extrahepatic malignancy between the CHB+/NA+ group and the controls (CHB+/NA+ v control: aSHR = 0.96; 95% CI, 0.84 to 1.08; P = .48). In time-varying Cox analysis, the CHB+/NA– patients were associated with a higher risk of extrahepatic malignancy than the CHB+/NA+ patients (aSHR = 1.37; 95% CI, 1.23 to 1.52; P < .001). CONCLUSION Patients with CHB have an elevated risk of developing primary extrahepatic malignancy. Long-term NA treatment was associated with a lower risk of extrahepatic malignancy development among patients with CHB.

Few studies have investigated unspecified or idiopathic pain associated with COIVD-19. This study aimed to provide the incidence rates of unspecified pain and idiopathic pain in patients with COVID-19 for 90 days after COVID-19 diagnosis.A propensity score matched cohort was used, including all patients with COVID-19 in South Korea, and analyzed their electronic medical records. The control group consisted of those who had not had tests for COVID-19 at all. Unspecified pain diagnoses consisted of diagnoses related to pain included in the ICD-10 Chapter XVIII. Idiopathic pain disorders included fibromyalgia, temporomandibular joint disorders, headaches, chronic prostatitis, complex regional pain syndrome, atypical facial pain, irritable bowel syndrome, and interstitial cystitis.After matching, the number of participants in each group was 7,911. For most unspecified pain, the incidences were higher in the COVID-19 group (11.7%; 95% confidence interval [CI], 11.0-12.5) than in the control group (6.5%; 95% CI, 6.0-7.1). For idiopathic pain, only the headaches had a significantly higher incidence in the COVID-19 group (6.6%; 95% CI, 6.1-7.2) than in the control group (3.7%; 95% CI, 3.3-4.1). However, using a different control group that included only patients who visited a hospital at least once for any reasons, the incidences of most unspecified and idiopathic pain were higher in the control group than in the COVID-19 group.Patients with COVID-19 might be at a higher risk of experiencing unspecified pain in the acute phase or after recovery compared with individuals who had not had tests for COVID-19.

Methylphenidate (MPH), a first-line treatment for attention-deficit hyperactivity disorder (ADHD) management, has been the focus of debate for decades regarding its effect on growth. The aim of this PRISMA meta-analysis was to determine the effect of MPH on height in children/adolescents with ADHD, along with factors predictive of this effect. Available full-text articles were systematically reviewed to identify clinical studies of pediatric ADHD patients with height Z-score (HZS) data for monotherapy MPH-treated and non-treated groups. We estimated standardized mean differences (SMDs) of HZS or its changes from baseline (ΔHZS) between groups, then identified associated factors through subgroup analyses and meta-regression. For before-after treatment studies, the paired standard errors of ΔHZS were re-estimated to demonstrate in the forest plot. Risk of bias was analyzed using the Newcastle-Ottawa Scale. Among the 29 eligible studies, 26 before-after studies reported ΔHZS with self-control groups, whereas 11 compared ΔHZS or absolute HZS to other external (healthy/non-medicated) controls. A significant reduction was observed in the post-medicated group compared to the pre-medicated group, with high heterogeneity (SMD = -0.40; 95% confidence interval = [-0.54; -0.27]; I2 = 91%). The study region, ADHD subtype, and stimulant-naïve status of patients at baseline may modify the effect on HZS. Because of the high clinical heterogeneity in observational studies, clinicians should consider the negative effect of MPH on height in ADHD patients by determining whether patients fulfill appropriate high-risk criteria. Further investigations are needed to identify the mechanism and the impact of reduction on the height reached in adulthood.

Background Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. Methods This was a retrospective cohort study using the South Korea National Health Insurance database (2014–2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months’ data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). Results Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75–0.78); mean PPPY total healthcare costs were 2093 USD. Conclusions Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

Benign paroxysmal positional vertigo (BPPV) is among the most common inner ear diseases. Although BPPV is one of the most common causes of dizziness, its pathogenesis remains unknown. Air pollutants might reach the middle ear through the eustachian tube and be absorbed into the inner ear through the round window membrane, increasing the risk of BPPV. We investigated the relationship between air pollution and BPPV risk. Data were extracted from the Korean Health Insurance Review and Assessment Service database, which contains health claims information of the entire South Korean population. Variables of interest included the number of patients diagnosed with BPPV in Seoul, South Korea, patients' clinical and demographic characteristics, and osteopenia status. Seoul's daily air pollution indicators, including SO2, CO, O3, NO2, PM10, and PM2.5, were obtained from the Korea Environment Corporation website. Overdispersed Poisson regression analysis was performed. In the multivariable analysis, NO2 air concentration (ppb) was associated with increased incidence of BPPV. In analysis stratified by gender, levels of NO2 were associated with increased incidence of BPPV in both men and women. In the analysis stratified by age, NO2 air concentration was associated with increased incidence of BPPV among all adults over the age of 19 years. In the analysis stratified by osteopenia status, NO2 was associated with increased incidence of BPPV in patients with and without osteopenia. Air levels of NO2 were associated with increased incidence of BPPV in the present study. This finding contributes toward a better understanding of BPPV pathogenesis and improved prevention and management of this condition.

Purpose This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer.Materials and Methods We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer.Results Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)–negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05).Conclusion Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.

Background Patients with bipolar disorder (BD) and depressive episodes are usually diagnosed with major depressive disorder (MDD). It is clinically important to estimate diagnostic conversion rate from MDD to BD and identify factors characterizing MDD patients at highest risk. We investigated conversion rate from depression to BD, stratified by age and sex, and associated psychopharmacological treatment patterns. Methods Data were extracted from the National Health Insurance to include 817,759 patients 18 years or older with new-onset antidepressant-treated depression between 2011 and 2015. We estimated rate of conversion from unipolar depression to BD stratified by age and sex during follow-up (357,343 person-years) and investigated the related medication patterns. Results During follow-up (median, 155 days; range, 2–1,442 days), 19,179 patients had diagnostic conversion to BD. Conversion rate was highest for patients aged 18–29 years; it gradually decreased with age until 60–69 years. Overall conversion rate to BD was 58.48 per 1,000 person-years for males and 50.97 per 1,000 person-years for females. For patients aged 18–39 years, the rate was higher for females. Patients with conversion to BD were prescribed more antidepressants. When the diagnosis changed to BD, 51% of patients were prescribed additional antipsychotics and/or mood stabilizers. Limitations The limited follow-up period may have underestimated conversion rate to BD. Data were restricted to participants with pharmaceutically treated depression. Conclusions The rate of diagnostic conversion from depression to BD differed by sex and age and was highest for females aged 18–29 years. Diagnostic conversion was accompanied by relevant prescription changes.

Background End-stage renal disease yields susceptibility to both ischemia and bleeding. The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is not established in dialysis patients, who are usually excluded from randomized studies. Since recent studies implied the benefits of prolonged DAPT >12 months in chronic kidney disease, we investigated the effectiveness and safety of prolonged DAPT in dialysis patients with higher cardiovascular risks. Methods In this nationwide population-based study, we analyzed dialysis patients who underwent DES implantation from 2008 to 2015. Continued DAPT was compared with discontinued DAPT using landmark analyses, including free-of-event participants at 12 (n = 2246), 15 (n = 1925) and 18 months (n = 1692) after DES implantation. The primary outcome was major adverse cardiovascular events (MACEs): a composite of mortality, nonfatal myocardial infarction, coronary revascularization and stroke. Major bleeding was a safety outcome. Inverse probability of treatment weighting Cox regression was performed. Results Mean follow-up periods were 278.3–292.4 days, depending on landmarks. Overall, incidences of major bleeding were far lower than those of MACE. Continued DAPT groups showed lower incidences of MACE and higher incidences of major bleeding, compared with discontinued DAPT groups. In Cox analyses, continued DAPT reduced the hazards of MACE at the 12- [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.61–0.90; P = 0.003], 15- (HR = 0.78, 95% CI 0.64–0.96; P = 0.019) and 18-month landmarks (HR = 0.79, 95% CI 0.63–0.99; P = 0.041), but without a significant increase in major bleeding at 12 (HR = 1.39, 95% CI 0.90–2.16; P = 0.14), 15 (HR = 1.13, 95% CI 0.75–1.70; P = 0.55) or 18 months (HR = 1.27, 95% CI 0.83–1.95; P = 0.27). Conclusions Prolonged DAPT reduced MACE without significantly increasing major bleeding in patients who were event-free at 12 months after DES implantation. In deciding on DAPT duration, prolonged DAPT should be considered in dialysis patients.

The objective of this case/non-case study was to detect rebamipide-related pulmonary adverse events (AE) compared with other drugs for acid-related disorders based on population-level data.From 2009 to 2018, AE reports on drugs for acid-related disorders, which are anatomical therapeutic chemical code A02B drugs, in the Korea Adverse Events Reporting System (KAERS) database were examined. The reporting odds ratio (ROR) was calculated, and the odds of reporting pulmonary AE for rebamipide and all other A02B drugs were compared. Furthermore, a stratified analysis according to patients' age and sex was conducted.Altogether 13 (0.05%) and 157 (0.11%) cases of pulmonary AE were reported for rebamipide and all other A02B drugs, respectively. The risk of reporting pulmonary AE was significantly lower for rebamipide than for all other A02B drugs (ROR 0.49, 95% confidence interval [CI] 0.28-0.87). The number of reports of pulmonary AE for rebamipide was significantly higher among patients aged ≥65 years than those aged65 years (ROR 19.36, 95% CI 2.50-149.97).Rebamipide was less often reported for pulmonary AE. However, healthcare professionals need to be aware of the risk of pulmonary AE in elderly patients.

Background Pregnancy concurrent with, shortly before, or after breast cancer poses unique challenges because hormonal changes in pregnancy potentially interact with breast cancer outcomes. Materials and Methods We studied a cohort of 3,687 female patients of reproductive age ( Results Forty-five patients with postpartum breast cancer were significantly more likely to have advanced stage, hormone receptor-negative tumor and to be younger than 35 years at diagnosis than those without postpartum breast cancer. This trend was not observed with 18 patients with breast cancer during pregnancy. The unadjusted 5-year survival rates were 77% versus 96% for patients with postpartum breast cancer versus their counterparts, 89% versus 96% for patients with breast cancer during pregnancy versus their counterparts, and 98% versus 96% for patients with pregnancy after breast cancer versus their counterparts, respectively. In the multivariable analyses, postpartum breast cancer exhibited hazard ratios for death of 1.57 (95% confidence interval [CI], 0.82–2.99), whereas those for breast cancer during pregnancy and pregnancy after breast cancer were 1.09 (95% CI, 0.15–7.91) and 0.86 (95% CI, 0.26–2.83), respectively. Conclusion Postpartum breast cancer, but not breast cancer during pregnancy, was associated with advanced stage, younger age at diagnosis ( Implications for Practice Although pregnancy around the time of diagnosis of breast cancer is expected to become increasingly common with maternal age at first childbirth on the rise, data on the prognostic impact of pregnancy have been inconsistent and rare from Asian populations. In this investigation of a Korean patient cohort with breast cancer, pregnancy-associated breast cancer was associated with advanced stage, younger age at diagnosis (

Media has become a major source of information on health and plays a role in the decision-making process on health topics. We aimed to evaluate the association between zolpidem use and media broadcasts that reported the suicide risk. We obtained the data of adult outpatients who have been prescribed zolpidem or other hypnotics from the National Patient Sample database (2015–2017). We evaluated the change in zolpidem or other hypnotic prescription trends based on the prescription rate and average daily prescribed dose before and after July 2016, using interrupted time series analysis. A total of 129,787 adult patients had at least one zolpidem prescription in 3 years. The prescription rate of zolpidem after the broadcast decreased significantly by 0.178% (95% confidence interval (CI): −0.214, −0.142), whereas that of other hypnotic users did not differ from that before the broadcast (−0.020%, 95% CI: −0.088, 0.047). However, the trends in the prescription rate before and after the broadcast did not differ for zolpidem and other hypnotics. Broadcasting medication safety through major public media could have an effect on medication use. After broadcasting about the suicide risk of zolpidem, its overall prescription rate decreased immediately, but the trend was not changed.

BACKGROUND Social media has become a new source for obtaining real-world data on adverse drug reactions. Many studies have investigated the use of social media to detect early signals of adverse drug reactions. However, the trustworthiness of signals derived from social media is questionable. To confirm this, a confirmatory study with a positive control (eg, new black box warnings, labeling changes, or withdrawals) is required. OBJECTIVE This study aimed to evaluate the use of social media in detecting new black box warnings, labeling changes, or withdrawals in advance. METHODS This scoping review adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. A researcher searched PubMed and EMBASE in January 2021. Original studies analyzing black box warnings, labeling changes, or withdrawals from social media were selected, and the results of the studies were summarized. RESULTS A total of 14 studies were included in this scoping review. Most studies (8/14, 57.1%%) collected data from a single source, and 10 (71.4%) used specialized health care social networks and forums. The analytical methods used in these studies varied considerably. Three studies (21.4%) manually annotated posts, while 5 (35.7%) adopted machine learning algorithms. Nine studies (64.2%) concluded that social media could detect signals 3 months to 9 years before action from regulatory authorities. Most of these studies (8/9, 88.9%) were conducted on specialized health care social networks and forums. On the contrary, 5 (35.7%) studies yielded modest or negative results. Of these, 2 (40%) used generic social networking sites, 2 (40%) used specialized health care networks and forums, and 1 (20%) used both generic social networking sites and specialized health care social networks and forums. The most recently published study recommends not using social media for pharmacovigilance. Several challenges remain in using social media for pharmacovigilance regarding coverage, data quality, and analytic processing. CONCLUSIONS Social media, along with conventional pharmacovigilance measures, can be used to detect signals associated with new black box warnings, labeling changes, or withdrawals. Several challenges remain; however, social media will be useful for signal detection of frequently mentioned drugs in specialized health care social networks and forums. Further studies are required to advance natural language processing and mine real-world data on social media.

A recent meta-analysis of individual patient data revealed that preoperative percutaneous transthoracic needle lung biopsy (PTNB) was associated with an increased risk of ipsilateral pleural recurrence in stage I lung cancer. This study aimed to examine whether particular PTNB techniques reduced the risk of pleural recurrence.We retrospectively included 415 consecutive patients with stage I lung cancer who underwent preoperative PTNB and curative resection from 2009 through 2016. Detailed information was collected, including clinical, PTNB technique, radiologic, and pathologic characteristics of lung cancer. Cox regression analyses were performed to identify risk factors for pleural recurrence before and after propensity score matching.The overall follow-up period after PTNB was 62.1 ± 23.0 months, and ipsilateral pleural recurrence occurred in 40 patients. Before propensity score matching, age (p = 0.063), microscopic pleural invasion (p = 0.065), and pathologic tumor size (p = 0.016) tended to be associated with pleural recurrence in univariate analyses and subsequently were matched using a propensity score. After propensity score matching, multivariate analysis revealed that ipsilateral pleural recurrence was associated with a larger target size on computed tomography (hazard ratio [HR] = 1.498; 95% CI, 1.506-2.125; p = 0.023) and microscopic lymphatic invasion (HR = 3.526; 95% CI, 1.491-8.341; p = 0.004). However, no PTNB techniques such as needle gauge, biopsy, or pleural passage numbers were associated with a reduced risk of recurrence.No particular PTNB techniques were associated with reduced pleural seeding after PTNB in stage I lung cancer. Regardless of the technique, PTNB needs to be cautiously applied when early lung cancer is suspected, followed by curative treatment.• Age, microscopic pleural invasion, and pathologic tumor size tended to be associated with pleural recurrence in stage I lung cancer before propensity matching. • After propensity matching, pre-biopsy CT target size and microscopic lymphatic invasion were associated with pleural recurrence. • No particular PTNB techniques were associated with reduced pleural seeding in stage I lung cancer before and after propensity matching.

Objective Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis. Methods A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002–2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1–30, 31–60, and > 60 days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications. Results A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30 days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66–2.12), in the 31–60-day period (1.73, 95% CI 1.48–2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47–1.91). The risks of fracture were greater in men and older patients. Conclusion The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.

BackgroundAs percutaneous transthoracic needle biopsy (PTNB) of the lung is a well-established diagnostic method for the evaluating pulmonary lesions, evidence of safety based on representative data is limited. This study investigated the practice patterns of PTNB of the lung and assessed the incidence and risk factors of PTNB-related severe pneumothorax in Korea.MethodsWe used a national-level health insurance database between January 1, 2007 and December 31, 2015. Patients who underwent PTNB of the lung were identified using procedure codes for organ biopsy, fluoroscopy, computed tomography, chest radiography, and lung-related diagnosis codes. The annual age-/sex-standardized rate of PTNB and the incidence of PTNB-related severe pneumothorax were calculated. We defined severe pneumothorax as the pneumothorax requiring intervention. The odds ratios of risk factors were assessed by a generalized estimating equation model with exchangeable working correlation matrix to address clustering effect within institution.ResultsA total of 66,754 patients were identified between 2007 and 2015. The annual age-/sex-standardized rate of PTNB per 100,000 population was 19.6 in 2007 and 22.4 in 2015, and it showed an increasing trend. The incidence of severe pneumothorax was 2.4% overall: 2.5% in men and 1.2% in women, and 2.6%, 2.7%, 2.1%, 2.1%, 1.9%, 2.4%, and 2.4% from 2009 to 2015. Older age (≥60), male sex, presence of chronic obstructive pulmonary disease, receiving treatment in an urban or rural area versus a metropolitan area, and receiving treatment at a general hospital were significantly associated with the risk of severe pneumothorax.ConclusionsConsidering the increasing trend of PTNB, more attention needs to be paid to patients with risk factors for severe pneumothorax.

Background The incidence and burden of depressive disorders are increasing in South Korea. There are many differences between pharmaceutically treated depression (PTD) and treatment-resistant depression (TRD), including the economic consequences; however, to our knowledge, the economic burden of depression is understudied in South Korea. Therefore, the objective of the present study was to calculate the different economic costs of PTD and TRD in South Korea, specifically by comparing several aspects of medical care. Methods This study comprised patients aged 18 and over who were newly prescribed antidepressants for more than 28 days with a depression code included from January 1, 2012, to December 31, 2012, by the Health Insurance Review and Assessment Service (HIRA). TRD was classified as more than two antidepressant regimen failures in PTD patients. The cost was calculated based on the cost reflected on the receipt registered with HIRA. Results Of the 834,694 patients with PTD, 34,812 patients (4.17%) were converted to TRD. The cost of medical care for TRD (6,610,487 KRW, 5881 USD) was approximately 5 times higher than the cost of non-TRD (1,273,045 KRW, 1133 USD) and was significantly higher for patients with or without depression and suicide codes. Medical expenses incurred by non-psychiatrists were roughly 1.7 times higher than those incurred by psychiatrists. Conclusions TRD patients had significantly higher healthcare costs than PTD patients. Identifying these financial aspects of care for depression can help to establish a more effective policy to reduce the burden on mentally ill patients.

BackgroundReal-world evidence of low-density lipoprotein cholesterol (LDL-C) goal attainment rates for Asian patients is deficient. The objective of this study was to assess the status of dyslipidemia management, especially in high-risk patients with cardiovascular disease (CVD) including stroke and acute coronary syndrome (ACS).MethodsThis was a retrospective cohort study of 514,866 subjects from the National Health Insurance Service-National Health Screening Cohort database in Korea. Participants were followed up from 2002 to 2015. Subjects with a high-risk of CVD prior to LDL-C measurement and subjects who were newly-diagnosed for high-risk of CVD following LDL-C measurement were defined as known high-risk patients (n = 224,837) and newly defined high-risk patients (n = 127,559), respectively. Data were analyzed by disease status: stroke, ACS, coronary heart disease (CHD), peripheral artery disease (PAD), diabetes mellitus (DM) and atherosclerotic artery disease (AAD).ResultsOverall, less than 50% of patients in each disease category achieved LDL-C goals (LDL-C ConclusionsLDL-C goal attainment rates in high-risk patients with CVD and DM in Korea demonstrate unmet medical needs. Proactive management is necessary to bridge the gap between the recommendations of clinical guidelines and actual clinical practice.

Although asthma treatment guidelines recommend regular inhaled medication, real-world treatment patterns and outcomes in South Korea have not been examined. We examined real-world treatment patterns and outcomes among patients treated for asthma in South Korea.This retrospective cohort study utilized data from the South Korean National Health Insurance database (2013-2016). Newly treated patients with asthma aged ≥18 years without history of chronic obstructive pulmonary disease were included. Initial and maintenance medication prescriptions were examined. Treatment discontinuation and switch were described. Asthma exacerbation rates, poor asthma control, and healthcare resource utilization (HRU) were compared between maintenance treatment groups (inhaled versus oral) using adjusted incidence rate ratios (aIRR) and hazard ratios (aHR).Overall, 1,054,707 patients initiated any asthma medication; 37,868 patients initiated inhaled (n = 9,983, 26.4%) or oral (n = 27,885, 73.6%) maintenance medication. More patients initiating inhaled versus oral asthma medication discontinued treatment within 12 months (94.4% vs. 86.3%;Despite current asthma guidelines, more patients in South Korea were prescribed oral than inhaled medications, resulting in suboptimal asthma management and increased HRU. This study highlights the need to reduce oral corticosteroid prescriptions for optimized treatment in asthma management.

PURPOSE A high risk of cardiovascular disease (CVD) is reported for HIV-infected individuals. While a link between abacavir and CVD risk is suggested, an association between abacavir and hypertension remains unclear. This study evaluated hypertension risk with abacavir use in comparison to non-abacavir antiretroviral treatment (ART). MATERIALS AND METHODS From a nationwide cohort of HIV-infected individuals on their initial ART, 6493 who were free of hypertension at baseline were analyzed. The use of ART was treated as a time-varying covariate measured as a daily unit. Incidence rate of hypertension was calculated, and Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) with 95% confidence interval (CI) of incident hypertension overall and among subgroups. RESULTS From the 6493 participants, 24072 person-years (PY) of follow-up were contributed during 2008-2016. The incidence rates of hypertension were 4.6 and 3.6 per 100 PY for abacavir and non-abacavir ART users, respectively. The population attributable fraction of abacavir use on hypertension was 12%. Abacavir exposure did not elevate the risk of hypertension among overall study population [HR, 1.2 (95% CI, 1.0-1.4), p=0.061]. However, those with poor ART adherence, defined as a medication possession ratio

Previous studies suggest an association between atopic dermatitis (AD) and exposure to microorganisms and antibiotics. However, these studies have limitations, and the sole influence on the development of AD was elusive. We performed a nationwide population-based case-control study in a Korean population to investigate the association between AD and early-life infection or antibiotic exposure. A total of 244 805 children with AD from the 2 283 601 children born between January 2010 and December 2014 and an equal number of sex- and age-matched healthy children were enrolled. A conditional logistic regression analysis showed that the episode of infection and antibiotic exposure were associated with an increased risk of AD (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.58-1.63 for infection; and OR, 1.11; 95% CI, 1.09-1.13 for antibiotic exposure). A dose-dependent relationship was observed between risk for AD, the number of infection episodes and antibiotic cycles and the duration of antibiotic exposure. On further analysis using a conditional logistic model, the risk of AD was less when the antibiotics were used during the infection episode than that without the use of antibiotics, especially if the duration of the infection was short. Although our study could not consider the effect of cause or severity of infection, class of antibiotics and genetic or environmental factors of enrolled subjects, our results suggested that infection and antibiotic exposure were associated with an increased risk of AD. In addition, the results also implied that the use of antibiotics during an infection episode can decrease the risk of AD induced by the infection and that appropriate management of infections can minimize the risk of AD induced by infection or antibiotics.

To determine whether percutaneous transthoracic needle biopsy (PTNB) increased the risk of pleural recurrence in stage I non-small-cell lung cancer (NSCLC). In this retrospective study, we reviewed 830 consecutive patients with stage I NSCLC who underwent curative resection between 2004 and 2010. Cox regression analyses with propensity score matching were performed to identify risk factors for pleural recurrence. Of 830 patients, 540 (65.1%) underwent PTNB before surgery, while 290 (34.9%) underwent preoperative bronchoscopic biopsy or intraoperative wedge resection for a pathological diagnosis. Concomitant pleural recurrence occurred in 42 patients (5.1% [95% CI, 3.8–6.8]; 34 [6.3%] PTNB patients and eight [2.8%] non-PTNB patients) and isolated pleural recurrence took place in 26 patients (3.1% [95% CI, 2.1–4.6]; 20 [3.7%] PTNB patients and 6 [2.1%] non-PTNB patients). On multivariate analysis after matching, only visceral pleural invasion was associated with concomitant pleural recurrence (hazard ratio [HR]=3.367; 95% CI, 1.262–8.986; p=0.015) and isolated pleural recurrence (HR=3.216; 95% CI, 1.037–9.978; p=0.043), while PTNB was associated with neither concomitant nor isolated pleural recurrence (p=0.605 and p=0.963, respectively). Among 540 patients undergoing PTNB, the transfissural approach did not have a significant association with pleural recurrence (p=0.539 and p=0.313, respectively); instead, visceral pleural invasion and microscopic lymphatic invasion were significantly associated with concomitant pleural recurrence, and microscopic lymphatic invasion was associated with isolated pleural recurrence (p

Objective We aimed to investigate whether concomitant use of benzodiazepines and opioids is associated with an increased risk of death in a population-based case-crossover setting. Methods We conducted a case-crossover study using the National Sample Cohort database. We introduced a 30-day hazard period before the onset of death and three consecutive previous 30-day control periods with a 30-day washout period. The use of opioids and/or benzodiazepines during the hazard period was compared with that in the three control periods. We performed the conditional logistic regression analysis to estimate the adjusted odds ratios (aORs) and their 95% confidence intervals (CIs). Results A total of 13,161 individuals who previously used benzodiazepines or opioids and died were included in the study. The risk of death was higher in patients with concomitant use of benzodiazepines and opioids (aOR, 1.86; 95% CI, 1.71–2.02) than in those who used either benzodiazepines or opioids only. In the subgroup analysis among concomitant users, the mortality risks were highest in patients aged less than 20 years (aOR, 3.85; 95% CI, 1.65–8.99), male patients (aOR, 2.20; 95% CI, 1.93–2.51), and patients with renal disease (aOR, 2.42; 95% CI, 1.57–3.74). Conclusion In this study, concomitant use of benzodiazepines and opioids was associated with a higher risk of death compared with use of a single drug. The risks and benefits of co-prescribing of benzodiazepines and opioids must be weighed carefully.

Background The Helicobacter pylori eradication rate has decreased with increasing antibiotic resistance. We conducted a prospective, nationwide, multicenter registry study to monitor the real status of H. pylori eradication therapy and to investigate the association between eradication success and antibiotic use density in Korea. Materials and Methods We enrolled 9318 patients undergoing H. pylori eradication therapy from 37 hospitals through “on‐line database registry” from October 2010 to July 2015. Demographic data, detection methods, treatment indications, regimens, durations, compliance, adverse events, and eradication results were collected. The use of all commercially available eradication antibiotics was analyzed through the Korean National Health Insurance data of the Health Insurance Review and Assessment Service. The defined daily dose of antibiotics was used to standardize drug use comparisons. Results Finally, 6738 patients were analyzed. The overall eradication rate of first‐line therapy was 71.8%. The eradication success rates were 71.7%, 86.9%, and 74.0% for standard triple therapy for 7 days, quadruple therapy, and concomitant therapy, respectively. The eradication success rate in naive patients was higher than that in those who previously underwent H. pylori eradication. Eradication success was significantly associated with younger age, female sex, and high compliance. Regional differences in eradication rates were observed. The yearly use density of clarithromycin increased statistically in seven regions across the country from 2010 to 2015. The yearly use density of amoxicillin in the Gyeongsang and Chungcheong areas was significantly increased (P

Background Depression, the leading cause of nonfatal disease burden, has a strong correlation with suicide and affects approximately 7% of the general elderly population. Adverse drug reactions in older patients are particularly important because of reduced drug metabolism, polypharmacy, drug-drug interactions, and drug-disease interactions. Fluoxetine is the first representative selective serotonin reuptake inhibitor but is associated with the possibility of hemorrhage based on its mechanism of action. Serious cases of gastrointestinal bleeding and cerebral hemorrhage have been reported, raising concerns about the safety of this drug. Methods We detected signals of bleeding risk associated with fluoxetine in an elderly population using the Korea Adverse Event Reporting System database. Reporting odds ratios and 95% confidence intervals (CIs) were calculated. Results A total of 16,517 adverse events related to antidepressants were reported. The reporting odds ratios for fluoxetine were 2.34 (95% CI, 1.03-5.34) for total bleeding, 4.41 (95% CI, 1.60-12.15) for major bleeding, 2.06 (95% CI, 0.28-15.03) for gastrointestinal bleeding, and 6.12 (95% CI, 2.14-22.60) for brain hemorrhage compared with those of all other antidepressants. Conclusions We detected safety signals with total bleeding, major bleeding, and brain hemorrhage related to fluoxetine. For patients with a high risk of bleeding, such as the elderly population, prescribing antidepressants other than fluoxetine can be considered. The results of this study provide preliminary evidence of a relationship between fluoxetine and hemorrhage but have wide 95% CIs. Further pharmacoepidemiological studies will be needed to confirm the risk of bleeding associated with fluoxetine.

Background Given the cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs), it is essential to identify the relationship between NSAIDs and cardiovascular outcomes in dialysis patients who have elevated cardiovascular risk. Methods A case-crossover study was conducted to assess the association of NSAIDs with major adverse cardiac and cerebrovascular events (MACCEs) and mortality using the Korean Health Insurance dataset. The case period was defined as 1–30 days prior to the event date and the control periods were defined as 61–90 days and 91–120 days prior to the event date. Results There were 3433 and 8524 incident dialysis patients who experienced MACCEs and mortality, respectively, after exposure to NSAIDs within 120 days before each event. NSAIDs significantly increased the risk of MACCEs {adjusted odds ratio [aOR] 1.37 [95% confidence interval (CI) 1.26–1.50]} and mortality [aOR 1.29 (95% CI 1.22–1.36)]. Nonselective NSAIDs, but not selective cyclooxygenase-2 inhibitors, significantly increased the risk of MACCEs and mortality. However, the MACCE and mortality risk did not increase in a dose-dependent manner in the analysis according to the cumulative defined daily dosage of NSAIDs. The incidence of MACCEs in the case period tended to be more common in patients who had recent exposure to NSAIDs than in patients who did not have recent exposure to NSAIDs. Conclusions Clinicians should be particularly cautious when prescribing NSAIDs to dialysis patients considering the associations of NSAIDs with cardiovascular outcomes and mortality, which might occur independent of the dose and duration of exposure.

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.

We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability., Graphical Abstract

Background/Aims We evaluated the contemporary use of lipid-lowering therapy (LLT) in Korean patients with atherosclerotic cardiovascular disease (ASCVD), and identified factors associated with statin non-prescription. Methods Using the Korean Health Insurance Review and Assessment data, we identified LLT-naïve subjects newly diagnosed with ASCVD between 2011 and 2012, and followed up until 2015. LLT-naïve status was defined as no LLT prescription for 1 year before ASCVD diagnosis. ASCVD was defined as first hospitalization or emergency room visit for coronary artery disease (CAD), acute cerebrovascular disease (CVD), or peripheral artery disease (PAD). Statin intensity was defined per the 2013 American College of Cardiology/American Heart Association guideline for cholesterol treatment. Results The study enrolled 80,884 subjects newly diagnosed with ASCVD, of whom only 48,725 (60.2%) received LLT during the follow-up period. Statin, combination of statin and non-statin, and non-statin LLT were administered in 50.5%, 9.7%, and 0.1% of all subjects, respectively. Statins were prescribed to 80.4% of CAD patients but only to 50.2% and 46.8% of CVD and PAD patients. Statin-based LLT usually had moderate- (77.2%) or high-intensity (18.5%). Subjects not prescribed statins were younger or older (< 40 or ≥ 70 years), more commonly female, and more likely to have comorbidities. Statins were prescribed at the time of ASCVD diagnosis in 45.5% of all subjects, and in 53.0% within 90 days of diagnosis. Conclusions Only 60% of LLT-naïve Korean patients newly diagnosed with ASCVD received statins. Statins were often prescribed in subjects with CAD but less commonly in those with CVD or PAD. Moderate-intensity statins were most frequently used.

Antidepressants are some of the most commonly used psychiatric medications, but little information is available about the effects of antidepressant treatment on the risk of traffic accidents across classes of antidepressants or associated with each substance individually. To investigate the relationship between exposure to antidepressants and risk of fatality in road traffic accidents. We used a Korean national road traffic authority database linked with a national health insurance database between January 1, 2010 and December 31, 2014 and applied a case-crossover design. The study subjects were drivers in South Korea who died from traffic accidents and who had prescriptions for antidepressants within 1 year prior to the date of the accident. We compared the status of prescription for antidepressants with the hazard period and four matched control periods using conditional logistic regression, adjusting for other drug use. The trends of antidepressant utilization were described in terms of the number of prescriptions. A case–case-time-control design was applied to drugs with an increasing trend in use and a significant case-crossover odds ratio (OR). A total of 1250 antidepressant-using drivers were included, and an increased risk was observed during the 30-day hazard period (adjusted OR 1.30; 95% CI 1.03–1.63). Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) showed significant risks, but tricyclic antidepressants did not. However, the associations of all antidepressants, SSRIs, SNRIs, escitalopram, and duloxetine did not remain significant after adjusting for trends in utilization. Paroxetine and milnacipran were associated with increased risks, with no obvious increase in their utilization, but the possibility of confounding by indication could have affected the results for milnacipran. Considering the trends of antidepressant prescription and utilization, the use of paroxetine increased the risk of fatal traffic accidents.

Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.

Background The prevalence of inflammatory bowel disease (IBD) in South Korea is increasing. Although extraintestinal manifestations (EIMs) are an important factor in the clinical outcomes of IBD patients, EIMs have not yet been investigated in Korea. Thus, we conducted a cross-sectional study to assess the prevalence of EIMs in Korean IBD patients. Methods The 2014 claims data from the National Health Insurance System (NHIS) of Korea were used. IBD patients were identified by codes for Crohn disease (CD) and ulcerative colitis (UC) in the NHIS registration system for rare or intractable diseases. International Classification of Diseases, Tenth Edition codes were used to identify EIM cases. To estimate the prevalence of EIMs in the general population of Korea, we used national sample data. Standardized prevalence ratios (SPRs) were calculated to compare the prevalence rates of EIMs among IBD patients to those among the general population of Korea. Results A total of 13,925 CD patients and 29,356 UC patients were identified. CD and UC patients were different in terms of demographics and utilization of medication. Among the 17 EIMs investigated, pyoderma gangrenosum, osteomalacia, Sweet syndrome, and scleritis were observed in very few patients. The SPRs were greater than 1 for all EIMs. Aphthous stomatitis, rheumatoid arthritis, and osteoporosis were highly prevalent in both CD and UC patients, but the SPRs of the EIMs were not high. Conclusion The study confirmed that EIMs are more prevalent among IBD patients than among the general population of Korea. The prevalence of EIMs in IBD patients suggests the need for greater attention and effort in clinical practice.

Background To evaluate oral anticoagulant (OAC) utilization in patients with atrial fibrillation after the changes in the health insurance coverage policy in July 2015. Methods We used the Health Insurance Review and Assessment Service-National Patient Samples (HIRA-NPS) between 2014 and 2016. The HIRA-NPS, including approximately 1.4 million individuals, is a stratified random sample of 3% of the entire Korean population using 16 age groups and 2 sex groups. The HIRA-NPS comprises personal and medical information such as surgical or medical treatment provided, diagnoses, age, sex, region of medical institution, and clinician characteristics. The studied drugs included non-vitamin K antagonist OACs (NOACs) such as apixaban, dabigatran, edoxaban, and rivaroxaban, and were compared with warfarin. We analyzed drug utilization pattern under three aspects: person, time, and place. Results The number of patients with atrial fibrillation who were prescribed OACs was 3,114, 3,954, and 4,828; and the proportions of prescribed NOACs to total OACs were 5.1%, 36.2%, and 60.8% in 2014, 2015, and 2016, respectively. The growth rate of OACs prescription increased from 61.4 patients/quarter before June 2015 to 147.7 patients/quarter thereafter. These changes were predominantly in elderly individuals aged more than 70 years. The proportion of NOACs to OACs showed significant regional difference. Conclusion The change of health insurance coverage policy substantially influenced OACs prescription pattern in whole Korean region. But the impact has been significantly different among regions and age groups, which provides the evidence for developing standard clinical practice guideline on OACs use., Graphical Abstract

Objective There are regional differences in the burden of tuberculosis (TB). Although these differences might be explained by regional differences in the risk factors of TB, whether such risk factors are actually associated with the regional differences in the TB burden remains unclear. This study aimed to investigate the relationship between the risk factors of and regional differences in TB incidence. Methods A cohort study applying nationwide claims database in Republic of Korea included patients newly diagnosed with type 2 diabetes mellitus (DM) in 2009. The main outcome was the incidence of TB defined based on the diagnostic codes combined with anti-tuberculosis treatment repeated within 90 days. Sixteen regions were categorized into 3 groups according to the age- and sex-standardized TB incidence rates. Multivariate logistic regression analysis adjusted for risk factors was performed to identify the determinants of the regional differences in TB incidence. Results Among 331 601 participants newly diagnosed with type 2 DM and with no history of previous TB, 1216 TB cases were observed. The regional TB incidence rates ranged between 2.3 and 5.9/1000 patients. Multivariate analyses did not identify any determinants of regional differences in the TB incidence among the various risk factors, including age, sex, health care utilization, co-morbidities, medication and treatment and complications of DM. Similarly, temperature, humidity and latent TB infection rate also did not affect the results. Conclusions Although substantial regional differences in the TB incidence rate were observed among patients with newly diagnosed DM, no determinants of regional difference were identified among the risk factors.