Background: Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy. Methods: We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model. Results: Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65–1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60–4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60–4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy. Conclusion This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.

Background: Cancer patients have an increased risk of cardiovascular outcomes and are susceptible to coronavirus disease 2019 (COVID-19) infection. We aimed to assess the cardiovascular safety of COVID-19 vaccination for cancer patients in South Korea. Methods: We conducted a self-controlled case series study using the K-COV-N cohort (2018– 2021). Patients with cancer aged 12 years or older who experienced cardiovascular outcomes were identified. Cardiovascular outcomes were defined as myocardial infarction, stroke, venous thromboembolism (VTE), myocarditis, or pericarditis, and the risk period was 0–28 days after receiving each dose of COVID-19 vaccines. A conditional Poisson regression model was used to calculate the incidence rate ratio (IRR) with 95% confidence interval (CI). Results: Among 318,105 patients with cancer, 4,754 patients with cardiovascular outcomes were included. The overall cardiovascular risk was not increased (adjusted IRR, 0.99 [95% CI, 0.90–1.08]) during the whole risk period. The adjusted IRRs of total cardiovascular outcomes during the whole risk period according to the vaccine type were 1.07 (95% CI, 0.95–1.21) in the mRNA vaccine subgroup, 0.99 (95% CI, 0.83–1.19) in the ChAdOx1 nCoV-19 vaccine subgroup, and 0.86 (95% CI, 0.68–1.10) in the mix-matched vaccination subgroup. However, in the analysis of individual outcome, the adjusted IRR of myocarditis was increased to 11.71 (95% CI, 5.88–23.35) during the whole risk period. In contrast, no increased risk was observed for other outcomes, such as myocardial infarction, stroke, VTE, and pericarditis. Conclusion For cancer patients, COVID-19 vaccination demonstrated an overall safe profile in terms of cardiovascular outcomes. However, caution is required as an increased risk of myocarditis following COVID-19 vaccination was observed in this study.

Purpose: Nivolumab and regorafenib are second-line therapies for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the effectiveness of nivolumab and regorafenib. Materials and Methods: We retrospectively reviewed patients with HCC treated with nivolumab or regorafenib after sorafenib failure. Progression-free survival (PFS) and overall survival (OS) were analyzed. An inverse probability of treatment weighting using the propensity score (PS) was performed to reduce treatment selection bias. Results: Among the 189 patients recruited, 137 and 52 patients received regorafenib and nivolumab after sorafenib failure, respectively. Nivolumab users showed higher Child-Pugh B patients (42.3% vs. 24.1%) and shorter median sorafenib maintenance (2.2 months vs. 3.5 months) compared to regorafenib users. Nivolumab users showed shorter median OS (4.2 months vs. 7.4 months, p=0.045) than regorafenib users and similar median PFS (1.8 months vs. 2.7 months, p=0.070). However, the median overall and PFS did not differ between the two treatment groups after the 1:1 PS matching (log-rank p=0.810 and 0.810, respectively) and after the stabilized inverse probability of treatment weighting (log-rank p=0.445 and 0.878, respectively). In addition, covariate-adjusted Cox regression analyses showed that overall and PFS did not significantly differ between nivolumab and regorafenib users after 1:1 PS matching and stabilized inverse probability of treatment weighting (all p>0.05). Conclusion Clinical outcomes of patients treated with nivolumab and regorafenib after sorafenib treatment failure did not differ significantly.

Background: and Purpose We investigated the trends in the prescribing of antiseizure medication (ASM) over a 9-year period, and provide real-world data regarding ASM prescriptions of patients with epilepsy in South Korea. Methods: This study used data in the Korean National Health Information Database for the period from 2009 to 2017. We included 18 oral ASMs, which were classified into older and newer ASMs based on them first becoming available on the market before or after 1991, respectively. The annual trends in ASM prescriptions were plotted over the 9-year study period, and changes in these trends were evaluated as average annual percentage changes (AAPCs) using Poisson regression. Age- and sex-stratified analyses were also conducted. Results: Overall, the proportion of prescriptions involving polytherapy with three or more ASMs increased from 10.08% in 2009 to 10.99% in 2017 (AAPC=0.9%, p<0.001) over the 9-year study period. Among monotherapies, although valproate (VPA) was the most frequently prescribed ASM, the prescription rate of levetiracetam (LEV) steadily increased regardless of age and sex over the study period. The monotherapy prescription trends differed depending on age and sex. In the five most frequently used ASM combination regimens, the prescription rates of VPA/LEV, LEV/oxcarbazepine, and LEV/lamotrigine regimens showed increasing tendencies. In contrast, prescription rates for all combined regimens of older ASMs declined over time in all age groups. Conclusions This is the first epidemiological study of the changes in prescription trends for ASM in South Korea based on nationwide data from 2009 to 2017. We found progressive increases in the use of newer ASMs for both monotherapy and duotherapy, and for polytherapy with three or more ASMs over the 9-year study period.

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

Background: and Purpose There have been few reports on recent trends in the occurrence of epilepsy. The aim of this study was to estimate the incidence and prevalence of epilepsy and analyze their annual trends in Korea over the period 2009–2017. Methods: This nationwide population-based study was carried out using the National Health Insurance Service of Korea database. A prevalent case was defined as one of a patient receiving a prescription of anticonvulsants under the diagnostic codes for epilepsy or seizure. An incident case was ascertained by confirming the absence of any epilepsy-related diagnostic codes and anticonvulsant prescription for 2 years or more before the operational definition for a prevalent case was met. Alternative operational definitions for epilepsy were tested. The temporal trends of the incidence and prevalence of epilepsy were analyzed using a Poisson regression model, and are expressed as average annual percentage changes (AAPCs). Results: The incidence of epilepsy increased from 28.7/100,000 persons in 2009 to 35.4/100,000 persons in 2017. The prevalence increased gradually from 3.4/1,000 persons in 2009 to 4.8/1,000 persons in 2017. These increasing trends were more evident among elderly subjects aged ≥75 years and in those who had codes for epilepsy or seizure as an additional diagnosis. Age standardization revealed a less prominent but still increasing trend in both incidence (AAPC=0.48%) and prevalence (AAPC=3.11%). Conclusions There have been increasing trends in both the prevalence and incidence of epilepsy in Korea between 2009 and 2017. This finding appears to be related to societal aging and the high incidence of symptomatic epilepsy in the elderly population.

Objective: To explore the perception of drug utilization review (DUR) system and DUR modernization pilot project among healthcare professionals and patients. Methods: We conducted 8 times of focus group interviews (FGI) between August 1, 2019 to December 31, 2019. The healthcare professionals and patients who participated in the DUR modernization pilot project were included in the present study. Based on the type of project participation or medical institution, the participants were divided into the following four groups: group 1, hospital; group 2, clinic; group 3, pharmacy; and group 4, patient. Within each group, interviews were conducted under a pre-defined agenda to identify the implicit perceptions of the participants; the contents of the interviews were, then, categorized. Results: Healthcare professionals established a consensus on the positive aspects of the DUR system and DUR modernization pilot project. However, substantial concerns remain, such as additional workload associated with monitoring adverse events or acquiring consents from patients. Furthermore, a difference of opinion over the DUR convenience system was observed. Among 3 DUR convenience system, the personal medication history review service was highly utilized, but pop-up hold function and communication system was rarely used. Conclusion We observed that systematic intervention using the DUR system is effective for both healthcare providers and consumers. Adverse events caused by inappropriate drug use can be prevented by continuous patient monitoring. Therefore, the role of DUR system needs to be expanded to establish a safe drug management system.

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

Background: and Purpose There have been few reports on recent trends in the occurrence of epilepsy. The aim of this study was to estimate the incidence and prevalence of epilepsy and analyze their annual trends in Korea over the period 2009–2017. Methods: This nationwide population-based study was carried out using the National Health Insurance Service of Korea database. A prevalent case was defined as one of a patient receiving a prescription of anticonvulsants under the diagnostic codes for epilepsy or seizure. An incident case was ascertained by confirming the absence of any epilepsy-related diagnostic codes and anticonvulsant prescription for 2 years or more before the operational definition for a prevalent case was met. Alternative operational definitions for epilepsy were tested. The temporal trends of the incidence and prevalence of epilepsy were analyzed using a Poisson regression model, and are expressed as average annual percentage changes (AAPCs). Results: The incidence of epilepsy increased from 28.7/100,000 persons in 2009 to 35.4/100,000 persons in 2017. The prevalence increased gradually from 3.4/1,000 persons in 2009 to 4.8/1,000 persons in 2017. These increasing trends were more evident among elderly subjects aged ≥75 years and in those who had codes for epilepsy or seizure as an additional diagnosis. Age standardization revealed a less prominent but still increasing trend in both incidence (AAPC=0.48%) and prevalence (AAPC=3.11%). Conclusions There have been increasing trends in both the prevalence and incidence of epilepsy in Korea between 2009 and 2017. This finding appears to be related to societal aging and the high incidence of symptomatic epilepsy in the elderly population.

Objective: To explore the perception of drug utilization review (DUR) system and DUR modernization pilot project among healthcare professionals and patients. Methods: We conducted 8 times of focus group interviews (FGI) between August 1, 2019 to December 31, 2019. The healthcare professionals and patients who participated in the DUR modernization pilot project were included in the present study. Based on the type of project participation or medical institution, the participants were divided into the following four groups: group 1, hospital; group 2, clinic; group 3, pharmacy; and group 4, patient. Within each group, interviews were conducted under a pre-defined agenda to identify the implicit perceptions of the participants; the contents of the interviews were, then, categorized. Results: Healthcare professionals established a consensus on the positive aspects of the DUR system and DUR modernization pilot project. However, substantial concerns remain, such as additional workload associated with monitoring adverse events or acquiring consents from patients. Furthermore, a difference of opinion over the DUR convenience system was observed. Among 3 DUR convenience system, the personal medication history review service was highly utilized, but pop-up hold function and communication system was rarely used. Conclusion We observed that systematic intervention using the DUR system is effective for both healthcare providers and consumers. Adverse events caused by inappropriate drug use can be prevented by continuous patient monitoring. Therefore, the role of DUR system needs to be expanded to establish a safe drug management system.