A Real-World Safety Profile in Neurological, Skin, and Sexual Disorders of Anti-Seizure Medications Using the Pharmacovigilance Database of the Korea Adverse Event Reporting System (KAERS).

(1) Background: The utilization of high-quality evidence regarding the safety of anti-seizure medications (ASMs) is constrained by the absence of standardized reporting. This study aims to examine the safety profile of ASMs using real-world data. (2) Methods: The data were collected from the Korea Adverse Event Reporting System Database (KAERS-DB) between 2012 and 2021. In total, 46,963 adverse drug reaction (ADR)-drug pairs were analyzed. (3) Results: At the system organ class level, the most frequently reported classes for sodium channel blockers (SCBs) were skin (37.9%), neurological (16.7%), and psychiatric disorders (9.7%). For non-SCBs, these were neurological (31.2%), gastrointestinal (22.0%), and psychiatric disorders (18.2%). The most common ADRs induced by SCBs were rash (17.8%), pruritus (8.2%), and dizziness (6.7%). Non-SCBs were associated with dizziness (23.7%), somnolence (13.0%), and nausea (6.3%). Rash, pruritus, and urticaria occurred, on average, two days later with SCBs compared to non-SCBs. Sexual/reproductive disorders were reported at a frequency of 0.23%. SCBs were reported as the cause more frequently than non-SCBs (59.8% vs. 40.2%, Fisher's exact test, p < 0.0001). (4) Conclusions: Based on real-world data, the safety profiles of ASMs were identified. The ADRs induced by SCBs exhibited different patterns when compared to those induced by non-SCBs.

Clinical and economic burden of immune tolerance induction in entire patients with hemophilia A: Insights from a real-world Korean setting.

INTRODUCTION: The most notable challenge facing hemophilia A treatment is the development of inhibitors against factor VIII, resulting in increased clinical and socioeconomic burdens due to the need for expensive bypassing agents (BPAs). Although immune tolerance induction (ITI) is currently the primary approach for inhibiting and reducing the inhibitors, the lengthy duration of ITI necessitates the continued use of BPA to manage bleeding episodes. In this study, we aimed to obtain real-world evidence on the clinical and economic aspects and associated burdens experienced by patients with hemophilia A with inhibitors undergoing ITI in Korea. METHODS: Claims data from January 1, 2007, to December 31, 2020, were used in this study. The study cohort comprised patients with hemophilia A undergoing ITI, who were categorized into three groups: successful, failed, or continuation of ITI. We evaluated clinical and economic burdens, including monthly healthcare visits, medication costs, and total medical expenses. RESULTS: The study involved 33 cases of ITI across 32 patients. Excluding seven continuation cases where success could not be determined at the observation point, the estimated success rate of ITI was 80.8 %. The median duration of ITI for all patients was 25.7 months. While no significant disparities were noted in the ITI duration between successful and unsuccessful cases (24.51 vs. 25.66 months), substantial discrepancies were observed in the duration of BPA usage (11.10 vs. 25.66 months) and the number of prescribed BPAs (1.79 vs. 2.97). CONCLUSION: Successful ITI reduced both clinical and economic burdens, resulting in decreased monthly medication expenses and overall medical costs.

Recent updates on treatment patterns in patients with treated attention-deficit/hyperactivity disorders from a nationwide real-world database in South Korea.

The prevalence of attention-deficit/hyperactivity disorder (ADHD) is steadily increasing across Korea. We analyzed ADHD patients with ADHD medications (Rx) characteristics and treatment patterns compared to patients without Rx and identified the differences between pediatric-/adult- and active-/transient-patients with Rx. Using a nationwide claims dataset from 2020 to 2021, we conducted a prevalence-based cross-sectional study and analyzed the recent patients' characteristics and patterns among ADHD patients. Among 132 017 ADHD patients with Rx, differences from 20 312 without Rx across all characteristics except sex. We found significant differences in characteristics and treatment patterns between pediatric-/adult- and active-/transient-patients with Rx. Age-specific sex ratios notably diverged in pediatric patients (61.2%), but remained similar in adults, revealing significant psychiatric comorbidities differences. Active-patients peaked at 6-11 years (41.4%), while transient-patients at 18-30 years (36.1%). Predominantly, methylphenidate (89.7%), atomoxetine (27.8%), and clonidine (2.8%) were prescribed, with 85% experiencing treatment changes within methylphenidate formulations. In pediatric patients, extended-release methylphenidate was preferred (56.1%), adults favored oral delivery system methylphenidate (71.5%), and active-patients had higher treatment rates than transient-patients across all patterns, with low monotherapy rates. This study provides epidemiologic insights into recent characteristics and treatment patterns of ADHD patients with Rx in Korea, providing valuable evidence for identifying those actively receiving ADHD treatment in future healthcare policy decisions.

Low-Intensity Statin Plus Ezetimibe Versus Moderate-Intensity Statin for Primary Prevention: A Population-Based Retrospective Cohort Study in Asian Population.

BACKGROUND: While moderate-intensity statin therapy is recommended for primary prevention, statins may not be utilized at a recommended intensity due to dose-dependent adverse events, especially in an Asian population. However, evidence supporting the use of low-intensity statins in primary prevention is limited. OBJECTIVE: We sought to compare clinical outcomes between a low-intensity statin plus ezetimibe and a moderate-intensity statin for primary prevention. METHODS: This population-based retrospective cohort study used the Korean nationwide claims database (2002-2019). We included adults without atherosclerotic cardiovascular diseases who received moderate-intensity statins or low-intensity statins plus ezetimibe. The primary outcome was a composite of all-cause mortality, myocardial infarction, and ischemic stroke. The safety outcomes were liver and muscle injuries and new-onset diabetes mellitus (DM). We used standardized inverse probability of treatment weighting (sIPTW) and propensity score matching (PSM). RESULTS: In the sIPTW model, 1717 and 36 683 patients used a low-intensity statin plus ezetimibe and a moderate-intensity statin, respectively. In the PSM model, each group included 1687 patients. Compared with moderate-intensity statin use, low-intensity statin plus ezetimibe use showed similar risks of the primary outcome (hazard ratio [HR] = 0.92, 95% CI = 0.81-1.12 in sIPTW and HR = 1.16, 95% CI = 0.87-1.56 in PSM model). Low-intensity statin plus ezetimibe use was associated with decreased risks of liver and muscle injuries (subHR [sHR] = 0.84, 95% CI = 0.74-0.96 and sHR = 0.87, 95% CI = 0.77-0.97 in sIPTW; sHR = 0.84, 95% CI = 0.72, 0.96 and sHR = 0.82, 95% CI = 0.72-0.94 in PSM model, respectively). For new-onset DM and hospitalization of liver and muscle injuries, no difference was observed. CONCLUSION AND RELEVANCE: Low-intensity statin plus ezetimibe may be an alternative to moderate-intensity statin for primary prevention. Our findings provide evidence on safety and efficacy of statin therapy in Asian population.

The experiences of students with intellectual and developmental disabilities, parents, and teachers regarding health self-advocacy program with school-home connection: a qualitative study.

Background: Despite the importance of health as a significant indicator of quality of life, individuals with intellectual and developmental disabilities (IDD) often face low expectations, stigma, and insufficient opportunities in health care and education. In response, we developed a health self-advocacy program with a school-home connection for students with IDD to promote self-directed health care and verified its effectiveness by implementing the program for students with IDD. Objective: This study aimed to explore participants' program experiences and support needs to reduce the stigma surrounding individuals with IDD and provide implications for enhancing health self-advocacy skills. Methods: Individual and focus group interviews were conducted with 14 students, six parents, and four teachers who participated in the program. The collected data were analyzed using the constant comparative method. Results: The following five main themes emerged: (a) the gap between perception and practice in health care; (b) advantages and influencing factors of the program; (c) challenges in program implementation; (d) outcomes of program implementation; and (e) support needs for promoting health self-advocacy. Conclusion: Based on these findings, implications are provided and discussed to reduce the stigma surrounding individuals with IDD and enhance health self-advocacy.

Clinical pharmacokinetic study of tacrolimus in continuous intravenous administration for lung transplantation.

Tacrolimus is a cornerstone of immunosuppression after lung transplantation. However, there are no clear guidelines on how to administer the drug and the duration to achieve the required therapeutic range in the early phase of lung transplantation. This is a single-center cohort study of adult patients who had lung transplantation. Tacrolimus was administered beginning with a low dose of 0.01 mg/kg/day immediately after transplantation. In addition, the designated clinical pharmacist conducted a daily intervention with trough concentrations to achieve the target of 10-15 ng/mL. Time in the therapeutic range (TTRin, %), time to the therapeutic range (TTRto, days), and coefficient of variation (CoV) of tacrolimus were evaluated for the 2-week post-transplant period. A total of 67 adult patients who had received first-time lung transplantation were included in the analysis. The median percentage of tacrolimus TTRin was 35.7% (21.4-42.9%) for the 2-week postoperative period. The median day of TTRto was 7 days (5-9 days), and the median tacrolimus trough concentration was 10.02 ng/mL (7.87-12.26 ng/mL) for the 2-week postoperative period. The median CoV of tacrolimus was 49.7% (40.8-61.6%). Acute kidney injury following tacrolimus infusion occurred in 23 (34.3%) patients, but there was no neurotoxicity or acute cellular rejection within 1 month of the postoperative period. In conclusion, continuous intravenous administration with the daily measure and dose titration of tacrolimus trough concentrations allowed the therapeutic range of tacrolimus to be reached within 1 week without significant adverse events, although the pharmacokinetic parameters were highly variable over time.

A comparison of methods for the measurement of adherence to antihypertensive multidrug therapy and the clinical consequences: a retrospective cohort study using the Korean nationwide claims database.

OBJECTIVES: In observational studies, the methods used to measure medication adherence may affect assessments of the clinical outcomes of drug therapy. This study estimated medication adherence to multidrug therapy in patients with hypertension using different measurement methods and compared their impacts on clinical outcomes. METHODS: This was a retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort database (2006-2015). Adults diagnosed with hypertension who initiated multidrug antihypertensive therapy in the index year 2007 were included. Adherence was defined as over 80% compliance. Adherence to multidrug antihypertensive therapy was measured in 3 ways using the proportion of days covered (PDC) with 2 approaches to the end-date of the study observations: PDC with at least one drug (PDCwith≥1), PDC with a duration weighted mean (PDCwm), and the daily polypharmacy possession ratio (DPPR). The primary clinical outcome was a composite of cardiovascular and cerebrovascular disease-specific hospitalizations or all-cause mortality. RESULTS: In total, 4,226 patients who initiated multidrug therapy for hypertension were identified. The mean adherence according to the predefined measurements varied from 72.7% to 79.8%. Non-adherence was associated with an increased risk of a primary outcome. The hazard ratios (95% confidence intervals, CIs) primary outcomes varied from 1.38 (95% CI, 1.19 to 1.59) to 1.44 (95% CI, 1.25 to 1.67). CONCLUSIONS: Non-adherence to multidrug antihypertensive therapy was significantly associated with an increased risk of a primary clinical outcome. Across the varying estimates based on different methods, medication adherence levels were similar. These findings may provide evidence to support decision-making when assessing medication adherence.

Clinical outcomes and predictors of a gap in direct-acting oral anticoagulant therapy in the elderly: A time-varying analysis of a nationwide cohort study.

INTRODUCTION: As direct-acting oral anticoagulants (DOACs) have short half-lives of around 12 h, even a short gap in DOAC therapy may diminish anticoagulation effects, increasing risks of adverse clinical outcomes. We aimed to evaluate clinical consequences of a gap in DOAC therapy with atrial fibrillation (AF) and to identify its potential predictors. MATERIALS AND METHODS: In this retrospective cohort study, we included DOAC users aged over 65 years with AF from the 2018 Korean nationwide claims database. We defined a gap in DOAC therapy as no claim for a DOAC one or more days after the due date of a refill prescription. We used a time-varying-analysis method. The primary outcome was a composite of death and thrombotic events including ischemic stroke/transient ischemic attack or systemic embolism. Potential predictors of a gap included sociodemographic and clinical factors. RESULTS AND CONCLUSIONS: Among 11,042 DOAC users, 4857 (44.0 %) patients had at least one gap. Standard national health insurance, non-metropolitan locations of medical institutions, history of liver disease, chronic obstructive pulmonary disease, cancer, or dementia, and use of diuretics or non-oral agents were associated with increased risks of a gap. In contrast, history of hypertension, ischemic heart disease, or dyslipidemia were associated with a decreased risk of a gap. A short gap in DOAC therapy was significantly associated with a higher risk of the primary outcome compared to no gap (hazard ratio 4.04, 95 % confidence interval 2.95-5.52). The predictors could be utilized to identify at-risk patients to provide additional support to prevent a gap.

Effect of nationwide concurrent drug utilization review program on drug-drug interactions and related health outcome.

BACKGROUND: A computerized drug utilization review (DUR) program has provided physicians and pharmacists with alerts on drug-drug interactions (DDIs), drug-age precautions and therapeutic duplication in Korea since 2010. OBJECTIVE: The purpose of this study was to evaluate the impact of the DUR program on health outcomes associated with DDIs. METHODS: An uncontrolled before-after study was performed to investigate the impact of the nationwide DUR program on DDIs and related health outcomes. The study population consisted of people who used two types of DDI pairs before DUR implementation (from January 2009 to December 2010) and post-DUR implementation (from January 2012 to December 2013); (i) benzodiazepines with concurrent use of metabolic enzyme inhibitors and (ii) QTc (heart-rate corrected QT interval) prolongation agents. The main outcome measures were all-cause and cause-specific hospitalization admissions or emergency department (ED) visits. RESULTS: This study included 107 874 people who used benzodiazepines with enzyme inhibitors and 8489 who received co-medication of QTc prolongation agents. For patients receiving a combination of benzodiazepines and enzyme inhibitors, both all-cause hospitalization and cause-specific hospitalization decreased after DUR implementation, from 43.2% to 41.7% and from 4.6% to 4.5% (adjusted odds ratio [OR] = 0.96; 95% confidence interval (CI), 0.93-0.98; OR = 0.89, 95% CI = 0.84-0.99, respectively). For patients receiving co-medication of QTc prolongation agents, all-cause hospitalization (54.2%) was lower than before (54.9%) (OR = 0.87, 95% CI = 0.79-0.96), but no significant change was found for cause-specific hospitalization and ED visits. CONCLUSION: Implementation of a DUR program may reduce the adverse health outcomes posed by DDIs in patients on combination of benzodiazepines and enzyme inhibitors potentially QTc-prolongation agents.

Comparing the Sensitivities of Measures of Adherence to Antihypertensive Drugs Using Korean National Health Insurance Claims Data.

PURPOSE: Numerous studies have utilized various forms of adherence measures. However, methods for measuring adherence are inconsistent. Moreover, few studies are available that have compared sensitivities of the effects of several criteria on medication adherence. This study aims to compare measures of adherence using varied analytical decisions. MATERIALS AND METHODS: We included three measures for adherence: proportion of days covered with one or more medications (PDCwith≥1), duration weighted mean PDC (PDCwm), and daily polypharmacy possession ratio (DPPR). We compared the sensitivities of the measures by changing parameters in the Korean nationwide claims database. First, we used PDCwith≥1 as our base model. Then, we divided an adherence measure algorithm into three categories: (1) definition of data cleaning, (2) inclusion criteria and observation period, and (3) calculation methods of medication adherence. The categories included eight decision nodes that incorporated 25 alternative options. Finally, we assessed the medication adherence for the base-case with commonly used values and then varied to measure with each alternative option. RESULTS: The base-case included 14,288 beneficiaries with antihypertensives. Among eight decisions, both handling an end-date-of-study and overlaps had the strongest impacts on measuring PDCwith≥1, PDCwm, and DPPR, with small differences in sample size. Instead of the estimates of adherence from PDCwm, those of PDCwith≥1 and DPPR were similar. Furthermore, a tendency toward a higher medication adherence was observed with a smaller study population. CONCLUSION: The decisions regarding identifying an end-date-of-study and overlaps showed meaningful impacts of all three measures including PDCwith≥1, PDCwm, and DPPR on measuring medication adherence.

Comprehensive Trends and Patterns of Antihypertensive Prescriptions Using a Nationwide Claims Database in Korea.

PURPOSE: The number of people receiving antihypertensive prescriptions in Korea has increased more than threefold from 2002 to 2016. However, previous studies regarding the current use of these medications have been fairly limited. We aimed to examine the current trends and changes in the patterns of antihypertensive prescriptions based on a nationwide claims database. PATIENTS AND METHODS: Patients receiving antihypertensive medications over 30 days, without any limited therapeutic indication, were identified using the Health Insurance Review and Assessment Service (HIRA) database between 2015 and 2017. For each patient, the use of antihypertensive medication was specified as the class of drug used for the longest duration in each year. RESULTS: A total of 8,625,821 patients in 2015, 8,997,829 patients in 2016, and 9,357,751 patients in 2017 taking antihypertensives were included in this study. Angiotensin II receptor blockers (ARB) (35.9% in 2015 and 38.9% in 2017) and calcium channel blockers (CCB) (37.1% in 2015 and 35.2% in 2017) for monotherapy, ARB+CCB combinations (49.3% in 2015 and 56.3% in 2017) for dual therapy, and ARB+CCB+diuretics combinations (48.8% in 2015 and 48.9% in 2017) for more than triple therapy were the most frequently prescribed. Subjects aged ≥70 showed the highest prescription rate of antihypertensives compared with those <70; however, a decreasing trend presented from 62.3% in 2015 to 54.2% in 2017. Additionally, in subjects aged >70 years, the rate in women was higher than that in men, but this was reversed in younger patients. While changes arose in the patterns of the use of antihypertensives, these were similar each year. CONCLUSION: The trends and changes in the patterns of the use of antihypertensive medications were affected by age, sex, and type of therapy. Our findings may contribute to a better understanding of the actual status regarding the use of antihypertensive medications in Korea.

Study of hospitalization and mortality in Korean diabetic patients using the diabetes complications severity index.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase from 7.7% in 2017 to 8.4% in 2045 worldwide. Diabetes complications contribute to morbidity and mortality. To evaluate whether the diabetes complications severity index (DCSI) was associated with increased risks of mortality and hospitalization. METHODS: A retrospective cohort study was conducted using the National Health Insurance Database (NHID) sample cohort of 1,102,047 patients (2002-2015) in Korea. Diabetes complications were evaluated at 2 years after the initial diagnosis and during the subsequent follow-up period (mean duration 6.56 ± 2.81 years). The type and severity of complications were evaluated on the basis of the International Classification of Disease Ninth (ICD-9) codes used in DCSI with 7 categories and 55 subcategories of complications. The Cox proportional hazard and Poisson regression models were used to evaluate the mortality and hospitalization rates. The incidence and relative risk of diabetes complications as well as the risk of mortality and hospitalization were the main outcome measures. RESULTS: A total of 27,871 patients were finally included and grouped by the number of complications present at 2 years. Four hundred ninety patients (5.37%) died without complications, 659 (7.31%) died with one complication and 1153 (11.85%) died with two or more complications. As DCSI at index date increased, the risk of additional new diabetes complications increased by 26% [relative risk (RR) 1.26, 95% CI 1.25-1.27]. The risks of mortality and hospitalization were linearly related to DCSI [hazard ratio 1.13 (95% CI 1.11-1.16), relative risk 1.04 (95% CI 1.03-1.06)]. CONCLUSIONS: Patients with higher incidence and severity of diabetes complications have increased risks of mortality and hospitalization.

Impact of Statin Use on Dementia Incidence in Elderly Men and Women with Ischemic Heart Disease.

This study aimed to determine the association between statins and the prevention of dementia according to sex differences in elderly patients with ischemic heart disease (IHD). We performed a nationwide retrospective cohort study using the Korean Health Insurance Review and Assessment Service database (2007-2015). Among the 264,036 eligible patients aged ≥65 years with IHD, statin users were compared with non-users by propensity score matching at a 1:1 ratio (71,587 in each group). The primary outcome was dementia risk by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Differential risks of dementia were assessed by sex in the subgroups of statin types, exposure duration, and patient age, implying that sex is an influential factor for the link between statin use and dementia incidence. Among seven commonly prescribed statins, rosuvastatin was associated with the greatest preventive effect on dementia incidence, with an adjusted HR of 0.82 (95% CI = 0.78-0.87). In a subgroup analysis organized by sex, the differential risk of dementia incidence was assessed in each statin group, implying that sex is an influential factor for the link between statin and dementia. This study suggests that appropriate statin use considering sex differences may have beneficial effects on the development of dementia.

Efficacy of Aspirin in the Primary Prevention of Cardiovascular Diseases and Cancer in the Elderly: A Population-Based Cohort Study in Korea.

INTRODUCTION: Aspirin is widely used to prevent cardiovascular diseases (CVDs). However, the balance of its benefits and risks in the primary prevention of CVDs and cancer is unclear, especially in elderly Asians. The present study aimed to evaluate the efficacy of aspirin in the primary prevention of major adverse cardiac and cerebrovascular events (MACCE), bleeding risk, and cancer in elderly Koreans with cardiovascular (CV) risk factors. METHODS: This retrospective cohort study used data from the Korean National Health Insurance Service-Senior cohort database (2002-2015). Patients aged 60-90 years with hypertension, type 2 diabetes mellitus (T2DM), or dyslipidemia were identified. Aspirin users were compared with non-users using propensity score matching at a 1:3 ratio. The primary outcome was MACCE, a composite of CV mortality, myocardial infarction, and ischemic stroke. The secondary outcomes were the components of MACCE, all-cause mortality, angina pectoris, heart failure, the incidence and mortality of cancer, and the risks of hemorrhagic stroke and gastrointestinal bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a Cox proportional hazard model. RESULTS: A total of 3366 aspirin users and 10,089 non-users were finally included in the study. During a mean follow-up of 7.8 years, the incidence of MACCE was 15.2% in aspirin users and 22.4% in non-users. The risk of MACCE was significantly lower in aspirin users than in non-users (HR 0.76; 95% CI 0.69-0.85), and this risk was significantly reduced in patients using aspirin over 5 years (HR 0.52; 95% CI 0.46-0.60). Aspirin use was associated with a 21% reduction in the risk of primary cancer (HR 0.79; 95% CI 0.70-0.88) and cancer-related mortality (HR 0.72; 95% CI 0.61-0.84). No significant differences in bleeding risks were observed between the two groups. CONCLUSION: Aspirin reduced the risks of MACCE and cancer without increasing the bleeding risk in elderly Koreans with hypertension, T2DM, or dyslipidemia. Moreover, the benefits of the long-term use of aspirin in reducing the risks of MACCE were demonstrated. However, the decision of using aspirin for primary prevention must be carefully made on an individual basis, while estimating the benefit-risk balance of aspirin.

Effects of sarpogrelate on microvascular complications with type 2 diabetes.

Background Diabetes is a major cause of microvascular complications. Renin-angiotensin-aldosterone blockers have been known to have the benefits of delaying onset and progression of diabetic complications including nephropathy. Objective To evaluate the effect of sarpogrelate, an antiplatelet agent, on the new onset diabetic complications in patients with type 2 diabetes mellitus. Setting A 1108-bed tertiary university hospital in Korea. Methods A retrospective cohort study was conducted using electronic medical records between 2010 and 2015 in Korea. The study cohort of the propensity score matched patients with or without sarpogrelate was evaluated for the diabetic complications identified with the diagnosis codes in T2DM patients on the metformin based antidiabetic therapy. Nephropathy was further evaluated for progression of kidney function. Main outcome measure The incidence of composite microvascular complications included nephropathy, neuropathy, and retinopathy. Results The 1:2 propensity score matched 478 out of 14,440 patients were included in the final analysis with or without sarpogrelate (162 vs. 316 patients). The incidence of nephropathy, neuropathy, and retinopathy was 1.23% versus 5.38% (HR 0.21, 95% CI 0.05-0.92), 1.23% versus 4.43% (HR 0.26, 95% CI 0.06-1.14), and 6.17% versus 6.33% (HR 0.93, 95% CI 0.43-1.97) with sarpogrelate and without sarpogrelate, respectively. Changes in the estimated glomerular filtration rate and urine albumin creatinine ratio were not significantly different between the groups. Conclusion In Korean patients, sarpogrelate, an antiplatelet agent, was associated with reducing the incidence and progression of nephropathyin type 2 diabetes, but not associated with the composite endpoints including neuropathy and retinopathy.

Effects of Statin Therapy on the Risk of Intracerebral Hemorrhage in Korean Patients with Hyperlipidemia.

STUDY OBJECTIVE: Statins are widely used for primary and secondary prevention of cardiovascular and cerebrovascular disease. Several large randomized trials have suggested that statins might increase the risk of intracerebral hemorrhage (ICH); studies have also shown interethnic variability in responses to statins. This study aimed to determine the association between statin use and the risk of ICH in patients with hyperlipidemia among a Korean population. DESIGN: Population-based, retrospective cohort study. DATA SOURCE: Korean National Health Insurance Service-National Sample Cohort database (2002-2015). PATIENTS: A total of 313,368 patients, aged 40-85 years, without a history of hemorrhagic stroke were included after being diagnosed with hyperlipidemia between January 2003 and December 2013 (for follow-up through December 2015). Of those, statin users were compared with nonusers by using propensity score matching in a 1:1 ratio (21,797 in each group). The study groups were matched for age, sex, Charlson Comorbidity Index score, follow-up duration, comorbidities, and concurrent medications. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was occurrence of an ICH event. Secondary endpoints were mortality (all-cause, major adverse cardiovascular and cerebrovascular event related, and stroke related) and outcomes after ICH (e.g., recurrent ICH and mortality after primary ICH event). The Cox proportional hazard model was used to evaluate the ICH risk of statins. Subgroup analyses were performed based on ICH-related risk factors. During a mean follow-up period of 6.4 years, ICH occurred in 456 of the 43,594 patients (1.05%). Statin use was significantly associated with a decreased ICH risk (adjusted hazard ratio [aHR] 0.78, 95% confidence interval [CI] 0.65-0.94). Compared with nonusers, statin users showed significantly lower all-cause mortality (aHR 0.61, 95% CI 0.57-0.64), cardiovascular and cerebrovascular disease-related mortality (aHR 0.75, 95% CI 0.65-0.85), and stroke-related mortality (aHR 0.69, 95% CI 0.54-0.88). No significant differences in recurrence and mortality after an ICH event were noted between study groups. CONCLUSION: Statin therapy was associated with a decreased ICH risk and improvements in ischemic cardiovascular and cerebrovascular outcomes in Korean patients with hyperlipidemia. Further large-scale clinical studies are needed to clarify the impact of statins on the risk of developing ICH.

Durability of initial antidiabetic monotherapy and subsequent treatment adjustment patterns among newly treated type 2 diabetes patients.

BACKGROUND: As newly available antidiabetic drugs (ADs) are used more commonly as initial hypoglycemic choice for early stage diabetes patients, there is an urgent need to investigate how these agents may differ in treatment durability relative to metformin. This study aimed to investigate the incidence and risk of treatment adjustment among newly treated type 2 diabetes mellitus (T2DM) patients receiving an oral AD as initial monotherapy. METHODS: T2DM patients registered in the National Health Insurance Program who were newly prescribed an oral AD were identified. Time to treatment addition or switch to alternative antidiabetic therapy was determined using the Kaplan-Meier survival analysis. Cox proportional hazards regression was performed to estimate the hazard ratio (HR) after adjusting for potential confounding factors. RESULTS: The median time to treatment adjustment was shorter for sulfonylureas (SUs), dipeptidyl peptidase-4 (DPP-4) inhibitors, alphaglucosidase (AG) inhibitors, and thiazolidinediones (TZDs) compared to that for metformin. Initiation of therapy with SUs or DPP-4 inhibitors was associated with a significantly higher risk of both treatment addition and switching than with metformin (HR 1.49 versus 1.47 for overall treatment adjustment, respectively). In contrast, among incident users of AG inhibitors or TZDs, only the hazard of switch was substantially increased compared to metformin starters (6.19, 95% confidence interval [CI] 5.77-6.64 and 7.31, 95% CI 6.35-8.42, respectively). When addition and switch events were collectively assessed, the risk of treatment adjustment was significantly elevated in all non-metformin cohorts. CONCLUSION: Our results demonstrated that the durability of metformin as an initial monotherapy was superior to that of other ADs, including newer classes of antidiabetics, and appeared to be more effective in delaying treatment adjustment in real-world clinical practice.

Comparative Effectiveness of Combination Therapy with Statins and Angiotensin-Converting Enzyme Inhibitors versus Angiotensin II Receptor Blockers in Patients with Coronary Heart Disease: A Nationwide Population-Based Cohort Study in Korea.

STUDY OBJECTIVE: Patients with coronary heart disease (CHD) frequently use the combination of a statin and renin-angiotensin-aldosterone system (RAAS) blocker, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), to control lipid levels and blood pressure, respectively, and the use of ARBs is increasing in Korean patients. Few studies are available, however, that have compared combination therapy with statin-ACEIs versus statin-ARBs. The objective of this study was to evaluate whether ARBs are associated with a reduced risk of major adverse cardiovascular and cerebrovascular events (MACCEs) compared with ACEIs when used in combination with statins in patients with established CHD. DESIGN: Population-based retrospective cohort study. DATA SOURCE: Korean National Health Insurance Service-National Sample Cohort database. PATIENTS: A total of 6577 adults who started statin-RAAS blocker combination therapy (1870 in the statin-ACEI cohort and 4707 in the statin-ARB cohort) after being diagnosed with CHD between January 2003 and December 2013 were included. Of these, 3676 propensity score-matched patients (1838 in the statin-ACEI cohort and 1838 in the statin-ARB cohort) were included in the final analyses. MEASUREMENTS AND MAIN RESULTS: The primary outcome was MACCE (major adverse cardiovascular and cerebrovascular events), a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), ischemic stroke, and revascularization. Incidences and incidence rates of MACCE were calculated to estimate the differences between the two cohorts. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using a Cox proportional hazard model. The incidence of MACCE was 19.9% and 14.7%, and incidence rates were 11.7 and 8.1 per 100 person-years in the statin-ACEI and statin-ARB cohorts, respectively. The risk of MACCE was significantly lower in the statin-ARB cohort (adjusted HR 0.69, 95% CI 0.59-0.81). CONCLUSION: A MACCE was less likely to occur in patients who received a statin-ARB than in those who received a statin-ACEI. Similar trends were seen in cardiovascular mortality and the occurrence of recurrent MI but not stroke. The availability of statin-ARB fixed-dose combinations may have contributed to the improved outcomes in the statin-ARB cohort by reducing pill burden and improving medication adherence. Further research is warranted to validate our findings and to address whether a particular statin-ARB combination is more effective than other combinations.

Correction: Awareness and attitude of the public toward personalized medicine in Korea.

[This corrects the article DOI: 10.1371/journal.pone.0192856.].