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.

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.

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 clinical evidence communications and drug regulation changes concerning rosiglitazone on prescribing patterns of antidiabetic therapies.

PURPOSE: Cardiovascular safety alerts about rosiglitazone resulted in regulatory actions in several countries in 2010, but the Food and Drug Administration eliminated access restrictions in 2013, reflecting new evidence concerning the drug safety. We investigated the effects of safety signals and regulation shifts concerning rosiglitazone on prescribing of antidiabetic drugs (ADs). METHODS: Patient data were extracted from the Korean health insurance claims database for 2007 to 2015. Linear regression and interrupted time series analyses were performed to examine drug utilization trends and the impact of 5 milestone events regarding rosiglitazone safety on AD utilization. RESULTS: A steady growth was observed in the AD consumption, with metformin preserving its dominant market share throughout the period. Pioglitazone use has increased since 2008 in response to safety issues surrounding rosiglitazone. A significant decline in rosiglitazone use was observed after Nissen's meta-analysis and safety warnings (2007) and after restriction/suspension of access to rosiglitazone (2010), associated with a drop in prevalence by 29.5%/year and 99.5%/year, respectively. The most common AD newly started among users who discontinued rosiglitazone in 2010 was pioglitazone, followed by dipeptidyl peptidase-4 (DPP-4) inhibitors. Our concomitancy analysis showed that DPP-4 inhibitors have overtaken sulfonylureas since 2014 as the most common add-on to metformin. CONCLUSIONS: The most frequently added AD in diabetes patients who had switched off rosiglitazone in 2010 was pioglitazone, followed by DPP-4 inhibitors. Despite new evidence from a long-term clinical trial and the Food and Drug Administration's subsequent decision to eliminate access restrictions on rosiglitazone in 2013, domestic regulations were left intact; hence, its use remained negligible in Korea.

Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers.

1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.

Potentially inappropriate medication use at ambulatory care visits by elderly patients covered by National Health Insurance in Korea.

OBJECTIVES: Potentially inappropriate medication (PIM) use is an important and preventable safety concern in the care of elderly patients and has been associated with adverse drug reactions, hospitalization, and mortality. Although PIM use for the elderly is a common and serious public health issue worldwide, there are few studies examining PIM use in the ambulatory care setting in Korea. METHODS: To examine the prevalence and risk factors of PIM use from ambulatory care visits by elderly patients covered by National Health Insurance (NHI) in Korea, the nationwide prescription claims data of elderly patients' ambulatory care visits in 2006 were analyzed. RESULTS: Potentially inappropriate prescriptions were identified using extensive criteria that included Beers', Zhan's, and Canadian criteria. In 2006, 3,770,978 elderly patients received 40,995,267 prescriptions. 36.7% of the total prescriptions for elderly patients who visited ambulatory care clinics were identified as PIM use. Findings in this study indicated that the strongest risk factors for PIM prescriptions were the number of drugs prescribed and visit characteristics. CONCLUSION: Therefore, it is necessary to develop the explicit criteria of PIM prescription in Korea that can be included in the Drug Utilization Review (DUR) system, which is expected to lead to more appropriate and judicious prescribing.

Physicians' and pharmacists' acceptance of online, real-time "drug combinations to avoid" messages.

UNLABELLED: Drug-induced prolongation of the electrocardiogram QT interval, a risk factor for ventricular arrhythmia and death, has been observed for some small drugs with masses < 1 kDa. Over the last two decades, patient exposure to large molecule monoclonal antibody drugs with masses > 40 kDa has increased dramatically; hence, the aim of this study was to systematically review the scientific literature for evidence of QT prolongation induced by these drugs. METHODS: The PubMed and Embase databases were searched for cases indicative of drug-induced QT prolongation for 28 pre-identified monoclonal antibody drugs authorized in Europe. Cases were identified by applying a standardized search string and a subsequent text search and manual review. In parallel, the public European Medicines Agency (EMA) database was searched for reported frequencies of adverse events indicative of QT prolongation. RESULTS: A valid case of drug-induced QT prolongation, caused indirectly by hypocalcaemia, could be identified for only 1 out of 28 monoclonal antibody drugs (denosumab) from the PubMed and Embase search. The EMA database showed no hits for denosumab. Considering that hypocalcaemia-mediated QT prolongation is an already-identified and labelled risk for denosumab, the current study did not identify any additional evidence of QT prolongation caused by monoclonal antibody drugs.

Effect of DA-8031, a novel oral compound for premature ejaculation, on male rat sexual behavior.

OBJECTIVES: DA-8031 is a potent and selective serotonin transporter inhibitor developed for the treatment of premature ejaculation. The aim of the present study was to investigate the effects of DA-8031 on male sexual behavior in a rat model. METHODS: Sexual behavior was examined after an acute oral administration of 10, 30 or 100 mg/kg of DA-8031 in copulation studies with female rats. Pharmacokinetic parameters were calculated after oral administration of DA-8031 at a dose level of 30 mg/kg. RESULTS: DA-8031 treatment produced a dose-dependent increase in ejaculation latency time and showed statistical significance at 30 and 100 mg/kg dosage levels compared with the vehicle (P < 0.05). In addition, DA-8031 treatment reduced the mean number of ejaculations in a dose-dependent manner. No changes in post-ejaculatory interval, numbers of mounts, intromissions or ejaculations were observed at any dose. In pharmacokinetic study, the blood concentration of DA-8031 peaked at 0.38 ± 0.14 h after oral administration, and then rapidly declined with a half-life of 1.79 ± 0.32 h. CONCLUSIONS: Treatment with DA-8031 delays the ejaculation latency time without affecting the initiation of mounting behavior or post-ejaculatory interval in rats. Furthermore, DA-8031 is rapidly absorbed and eliminated after oral administration in rats. These preclinical findings provide a clue for the clinical testing of DA-8031 as an "on-demand" agent for premature ejaculation.

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.

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.

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.

Increased risk of cardiovascular disease among kidney cancer survivors: a nationwide population-based cohort study.

Background: Cardiovascular disease (CVD) is a major concern of morbidity and mortality among cancer survivors. However, few evidence exists on the short- and long-term risk of CVD in kidney cancer (KCa) survivors. Methods: In this nationwide, large population-based retrospective cohort study, we used the Korean national health insurance and medical checkup survey linkage database (2007-2021), drawn from the entire Korean population. We included adults diagnosed with KCa as the first primary cancer and matched them to an individual without KCa at a 1:5 ratio. The primary outcome was CVD incidence, including myocardial infarction, stroke, atrial fibrillation, heart failure, peripheral arterial occlusion, and venous thromboembolism (VTE). We evaluated CVD risk at 6 months, 1 year, and 5 years following cancer diagnosis, using Fine-Gray competing risk models that accounted for death as a competing factor. Results: A total of 149,232 participants were included (KCa survivors: N=20,093 and matched non-KCa individuals: N=129,139). After 6-month follow-up, KCa survivors showed an increased risk of CVD compared to the general population (subdistribution hazard ratio (HR) 2.70, 95% confidence interval (CI) 2.31-3.15). After 1 year, KCa survivors had a higher risk of CVD (HR=1.77, 95% CI: 1.56-2.00). After 5 years, this elevated CVD risk remained (HR=1.10, 95% CI: 1.03-1.18), with VTE identified as the primary contributing disease (HR=3.05, 95% CI:2.59-3.59). Conclusion: KCa survivors had an increased risk of CVD up to 5 years after cancer diagnosis compared to the general population. Our findings emphasize the importance of comprehensive healthcare management for both CVD and KCa throughout cancer survivorship.

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.

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 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.

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.

Spontaneously reported hepatic adverse drug events in Korea: multicenter study.

Hepatic adverse drug reactions (ADRs) to certain drugs may differ within each country, reflecting different patterns of prescription, socioeconomic status, and culture. The purpose of this study was to assess the suspected cause of hepatic ADRs using the spontaneously reported pharmacovigilance data from Korea. A total of 9,360 spontaneously reported adverse drug events (ADEs) from nine Pharmacovigilance Centers were analyzed. Risk of hepatic ADEs was assessed by calculating the reporting odds ratio (ROR). Of the 9,360 cases, 567 hepatic ADEs were reported. The most frequently prescribed drug classes inducing hepatic ADEs were anti-tuberculotics, cephalosporins, valproic acids, penicillins, quinolones, non-steroidal anti-inflammatory drugs (NSAIDs), anti-viral agents, and statins. ROR values were especially high in anti-tuberculosis drugs, systemic antifungal drugs for systemic use, anti-epileptics, propylthiouracil, and herbal medicines. Underlying diseases such as tuberculosis (6.9% vs 0.9%), pneumonia (4.9% vs 1.7%), intracranial injury including skull fracture (4.5% vs 0.9%), HIV (3.4% vs 0.4%), subarachnoid hemorrhage (2.8% vs 0.5%), and osteoporosis (2.4% vs 1.4%) were significantly more common in hepatic ADE group. In conclusion, anti-infective drugs, anti-epileptics, NSAIDs and statins are the most common suspects of the spontaneously reported hepatic ADEs, in Korea. Careful monitoring for such reactions is needed for the prescription of these drugs.

A novel algorithm for detection of adverse drug reaction signals using a hospital electronic medical record database.

PURPOSE: Quantitative analytic methods are being increasingly used in postmarketing surveillance. However, currently existing methods are limited to spontaneous reporting data and are inapplicable to hospital electronic medical record (EMR) data. The principal objectives of this study were to propose a novel algorithm for detecting the signals of adverse drug reactions using EMR data focused on laboratory abnormalities after treatment with medication, and to evaluate the potential use of this method as a signal detection tool. METHODS: We developed an algorithm referred to as the Comparison on Extreme Laboratory Test results, which takes an extreme representative value pair according to the types of laboratory abnormalities on the basis of each patient's medication point. We used 10 years' EMR data from a tertiary teaching hospital, containing 32,033,710 prescriptions and 115,241,147 laboratory tests for 530,829 individual patients. Ten drugs were selected randomly for analysis, and 51 laboratory values were matched. The sensitivity, specificity, positive predictive value, and negative predictive value of the algorithm were calculated. RESULTS: The mean number of detected laboratory abnormality signals for each drug was 27 (±7.5). The sensitivity, specificity, positive predictive value, and negative predictive value of the algorithm were 64-100%, 22-76%, 22-75%, and 54-100%, respectively. CONCLUSION: The results of this study demonstrated that the Comparison on Extreme Laboratory Test results algorithm described herein was extremely effective in detecting the signals characteristic of adverse drug reactions. This algorithm can be regarded as a useful signal detection tool, which can be routinely applied to EMR data.

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.

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.