Easy cuts, easy rebound: Drug expenditures with massive price cuts in Korea.

BACKGROUNDS: Since 2012, the Korean government has introduced 46.5% price cut for off-patent medicines in order to reign everescalating drug expenditure. This study sought to appraise the impact of the price cut measure (in the context of Korean National Health Insurance system). METHODS: We employed Korean National Health Insurance database from January 2007 until December 2016 for 120 month period. An interrupted time series analysis with segmented regression analysis was conducted to estimate the impact of price cut on overall drug spending. RESULTS: Drug spending significantly dropped with the price cut by 186.22 billlion Korean Won (KRW) (p < 0.0001) and the trend after the price cut has also significantly decreased by 1.33 billion KRW (p = 0.002). However, it was predicted that total expenditures showed an increasing trend and bounced back to the original level. Quantity prescribed had no significance with the price cut. Unit price had a substantial drop (ß = -41.68, p < 0.0001) with the price-cut, but the trend after the intervention has increased (ß = 0.16, p = 0.656) with no significance. CONCLUSIONS: Although the price cut has successfully countered the everescalating pharmaceutical expenditures in Korea, the impact was temporary. A lack of demand-side measures resulted in an ineffectiveness and unsustainability of policy effect. Thus, more aggressive demand-side measures should be introduced in the Korean context,and both the demand and supply-sides should be balanced.

Signal detection of benzodiazepine use and risk of dementia: sequence symmetry analysis using South Korean national healthcare database.

Background Benzodiazepine use can potentially cause confusion and delays in mental processes. These well-known side effects appear to be linked to an increased risk of being diagnosed with dementia. Objective To evaluate the possibility of an association between benzodiazepine and dementia. Setting Korean healthcare database from 2002 to 2013. Methods Sequence symmetry analysis was conducted to investigate whether benzodiazepine use increases the risk of dementia or not. We defined exposure as new benzodiazepine users and outcome as new diagnosis of dementia (ICD-10: F00-03, G30, and G318). Benzodiazepines were categorized into two groups (long-acting and short-acting) based on the duration of action. Antidepressants, opioid analgesic, and statin were used as active comparators to rule out any possible non-causal interpretations of our results. The time-trend adjusted sequence ratio (ASR) with 95% confidence intervals (CI) was measured to identify possible associations. Main outcome measure Adjusted sequence ratio. Results Benzodiazepine users were shown to be associated with dementia [benzodiazepine: 4212 pairs, ASR = 2.27 (95% CI 2.11-2.44)]. In addition, long-acting benzodiazepines had a higher ASR than that of short-acting benzodiazepines [long-acting: 3972 pairs, ASR = 2.22 (95% CI 2.06-2.39] and [short-acting: 5213 pairs, ASR = 1.88 (95% CI 1.77-2.00)]. However, our SSA found no duration-response relationship. Conclusion Our signal detection suggests that there is a possible association between benzodiazepines and dementia. Additionally, it proposes that persons receiving long-acting benzodiazepines are at a higher risk of developing dementia than those receiving short-acting benzodiazepines. Further studies are recommended to confirm whether this epidemiological association is a causal effect or not.

Projection of future pharmacy service fees using the dispensing claims in hospital and clinic outpatient pharmacies: national health insurance database between 2006 and 2012.

BACKGROUND: Predicting pharmacy service fees is crucial to sustain the health insurance budget and maintain pharmacy management. However, there is no evidence on how to predict pharmacy service fees at the population level. This study compares the status of pharmacy services and constructs regression model to project annual pharmacy service fees in Korea. METHODS: We conducted a time-series analysis by using sample data from the national health insurance database from 2006 and 2012. To reflect the latest trend, we categorized pharmacies into general hospital, special hospital, and clinic outpatient pharmacies based on the major source of service fees, using a 1% sample of the 2012 data. We estimated the daily number of prescriptions, pharmacy service fees, and drugs costs according to these three types of pharmacy services. To forecast pharmacy service fees, a regression model was constructed to estimate annual fees in the following year (2013). The dependent variable was pharmacy service fees and the independent variables were the number of prescriptions and service fees per pharmacy, ratio of patients (≥ 65 years), conversion factor, change of policy, and types of pharmacy services. RESULTS: Among the 21,283 pharmacies identified, 5.0% (1064), 4.6% (974), and 77.5% (16,340) were general hospital, special hospital, and clinic outpatient pharmacies, respectively, in 2012. General hospital pharmacies showed a higher daily number of prescriptions (111.9), higher pharmacy service fees ($25,546,342), and higher annual drugs costs ($215,728,000) per pharmacy than any other pharmacy (p <  0.05). The regression model to project found the ratio of patients aged 65 years and older and the conversion factor to be associated with an increase in pharmacy service fees. It also estimated the future rate of increase in pharmacy service fees to be between 3.1% and 7.8%. CONCLUSIONS: General hospital outpatient pharmacies spent more on annual pharmacy service fees than any other type of pharmacy. The forecast of annual pharmacy service fees in Korea was similar to that of Australia, but not that of the United Kingdom.

Persistence of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: An analysis of the South Korean National Health Insurance Database.

OBJECTIVES: This study examined and compared the persistence of adalimumab, etanercept, infliximab, or abatacept as first- and subsequent-line treatment for rheumatoid arthritis in the South Korean clinical practice. METHODS: We conducted a retrospective cohort study with patients receiving adalimumab, etanercept, infliximab, or abatacept between July 1, 2009 and December 31, 2012, using the nationwide Korean National Health Insurance database. Patients who were receiving a newly initiated biologic treatment and those who switched from other biologic treatment were identified and classified into first- and subsequent-use cohorts, respectively. Treatment patterns during the 1-year after treatment initiation were measured as persistence, and discontinuation including restarting, switching, and stopping. The Cox proportional hazard model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for discontinuation of biologic treatments. RESULTS: We identified 4114 patients for the first-use cohort and 992 patients for the subsequent-use cohort. Treatment persistence with adalimumab, etanercept, and infliximab was observed in 52.5%, 56.1%, and 52.6% of the patients, respectively, in the first-use cohort, without significant differences in duration of persistence among the treatments according to the Cox proportional hazard model. In the subsequent-use cohort, treatment persistence with adalimumab, etanercept, infliximab, and abatacept was observed in 45.7%, 58.5%, 43.0%, and 60.4% of the patients, respectively. The Cox proportional hazard model found that the patients who were receiving etanercept (HR = 0.68, 95% CI: 0.52-0.88) and abatacept (HR = 0.53; 95% CI: 0.37-0.74) were significantly less likely to discontinue the treatment than those who were receiving infliximab. CONCLUSIONS: Adalimumab, etanercept, and infliximab had similar levels of persistence during the 1-year after treatment initiation, when used as first-line treatment. However, when used as a subsequent-line treatment, etanercept and abatacept had higher persistence than infliximab or adalimumab. Persistence could be a consideration when selecting the subsequent-line biologic treatment for patients with rheumatoid arthritis in South Korea.

Prediction of Change in Prescription Ingredient Costs and Co-payment Rates under a Reference Pricing System in South Korea.

BACKGROUND: The reference pricing system (RPS) establishes reference prices within interchangeable reference groupings. For drugs priced higher than the reference point, patients pay the difference between the reference price and the total price. OBJECTIVES: To predict potential changes in prescription ingredient costs and co-payment rates after implementation of an RPS in South Korea. METHODS: Korean National Health Insurance claims data were used as a baseline to develop possible RPS models. Five components of a potential RPS policy were varied: reference groupings, reference pricing methods, co-pay reduction programs, manufacturer price reductions, and increased drug substitutions. The potential changes for prescription ingredient costs and co-payment rates were predicted for the various scenarios. RESULTS: It was predicted that transferring the difference (total price minus reference price) from the insurer to patients would reduce ingredient costs from 1.4% to 22.8% for the third-party payer (government), but patient co-payment rates would increase from a baseline of 20.4% to 22.0% using chemical groupings and to 25.0% using therapeutic groupings. Savings rates in prescription ingredient costs (government and patient combined) were predicted to range from 1.6% to 13.7% depending on various scenarios. Although the co-payment rate would increase, a 15% price reduction by manufacturers coupled with a substitution rate of 30% would result in a decrease in the co-payment amount (change in absolute dollars vs. change in rates). CONCLUSIONS: Our models predicted that the implementation of RPS in South Korea would lead to savings in ingredient costs for the third-party payer and co-payments for patients with potential scenarios.

Comparative safety for cardiovascular outcomes of DPP-4 inhibitors versus glimepiride in patients with type 2 diabetes: A retrospective cohort study.

Concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors persist. This study sought to determine whether there is a differential risk of hospitalization for cardiovascular diseases (CVDs) between DPP-4 inhibitors and glimepiride.We conducted this retrospective cohort study by using the Korean National Health Insurance Service database from December 1, 2008, to December 31, 2013. The study subjects were new users of DPP-4 inhibitors or glimepiride for type 2 diabetes. Outcome was defined as hospitalization for CVDs, including angina pectoris, myocardial infarction, transient cerebral ischemic attack, heart failure, or cerebrovascular disease or any procedure involving coronary artery bypass grafting or percutaneous coronary intervention. We used a Cox proportional hazard model to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs), to assess the risk of CVDs associated with the use of DPP-4 inhibitors compared with glimepiride.The cohort consisted of 1,045,975 patients, with 6504 in the DPP-4 inhibitors group and 13,447 in the glimepiride group. No significant increased risk of total CVDs was found (aHR, 0.87; 95% CI, 0.75-1.01) in the DPP-4 inhibitors versus glimepiride group. A decreased risk of hospitalization for CVDs was found among patients with a history of visit for CVDs (aHR, 0.73; 95% CI, 0.56-0.97) or with >2.5 years' duration of type 2 diabetes (aHR, 0.77; 95% CI, 0.66-0.91) in the DPP-4 inhibitors versus glimepiride group.DPP-4 inhibitors did not increase cardiovascular risk compared with glimepiride regardless of CVD history and diabetes duration.

Health Care Utilization and Direct Costs in Mild, Moderate, and Severe Adult Asthma: A Descriptive Study Using the 2014 South Korean Health Insurance Database.

PURPOSE: Although asthma exacerbation comprises a large burden of the total asthma-related costs, few studies have examined the frequency and cost of acute exacerbation according to asthma severity. This study investigated asthma-related health care utilization and costs according to the severity of asthma. METHODS: We conducted a descriptive study using the national health insurance claims database between January 1 and December 31, 2014. We included adult patients with asthma (18 years of age and older) who had ≥2 claims with for an asthma diagnosis and were prescribed ≥1 asthma medications. They were classified into 3 asthma severity levels (level 1 = mild, level 2 = moderate, and level 3 = severe), based on individual medication prescriptions. Acute exacerbation was defined as having a corticosteroid burst, an emergency department visit, or hospitalization. Health care utilization, acute exacerbation, and direct costs associated with asthma were compared according to asthma severity levels. FINDINGS: Of the 36,687 adult asthma patients, level 1 had the largest proportion of patients (81.2%), followed by level 2 (18.2%), and level 3 (0.6%). The average number of asthma-related outpatient visits was 4.5 for level 1, 7.2 for level 2, and 11.9 for level 3 (P < 0.01). The estimated asthma-related direct cost per patient was $174 for level 1, $634 for level 2, and $1635 for level 3 (P < 0.01). The number of patients who experienced acute exacerbation increased as asthma severity increased: level 1, 22.6%; level 2, 26.0%; and level 3, 48.7% (P < 0.01). Direct costs associated with asthma exacerbation dramatically increased and accounted for 15.1% of the total cost in level 1 patients, 19.5% in level 2 patients, and 40.8% in level 3 patients (P < 0.01). IMPLICATIONS: The direct costs of acute exacerbation increased as asthma severity increased. In patients with severe asthma, acute exacerbation and the relative cost ratio in South Korea were higher than those in other countries. Proper management is required to avoid acute exacerbations and to reduce the burden of asthma, particularly in patients with severe asthma.

Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity.

Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and ß-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.

Assessment of the Price-Volume Agreement Program in South Korea.

The Price-Volume Agreement Program (PVAP) was promulgated in 2007 in South Korea as the first attempt to adjust drug pricing according to total consumption in order to contain drug expenditure. This study was designed to assess the impact of the PVAP on diabetes drug expenditure for a period of a 10-year period (2003-2012) using claims data from the National Health Insurance Service. We estimated a multilevel mixed-effects linear regression model by comparing the level of total monthly diabetes drug expenditure for drugs subject to PVAP and existing drugs after adjusting the average differences in drug expenditure before and after the PVAP. The monthly total expenditure for drugs that were newly listed through the PVAP (negotiation drugs) was 7.03% higher on average compared to that for existing drugs, controlling for the baseline differences in expenditure before and after the PVAP. This increase was observed in all four subgroups of diabetes drugs, including sitagliptin, vildagliptin, exenatide, and others. The growth rate of total diabetes drug expenditure was reduced after the PVAP despite the sustained escalation of expenditure levels, which may imply that the PVAP has the potential to be an effective tool for drug expenditure control in the long term.

Protective Effects of Quercetin Against HgCl2-Induced Nephrotoxicity in Sprague-Dawley Rats.

Mercury is a well-known environmental pollutant that can cause nephropathic diseases, including acute kidney injury (AKI). Although quercetin (QC), a natural flavonoid, has been reported to have medicinal properties, its potential protective effects against mercury-induced AKI have not been evaluated. In this study, the protective effect of QC against mercury-induced AKI was investigated using biochemical parameters, new protein-based urinary biomarkers, and a histopathological approach. A 250 mg/kg dose of QC was administered orally to Sprague-Dawley male rats for 3 days before administration of mercury chloride (HgCl2). All animals were sacrificed at 24 h after HgCl2 treatment, and biomarkers associated with nephrotoxicity were measured. Our data showed that QC absolutely prevented HgCl2-induced AKI, as indicated by biochemical parameters such as blood urea nitrogen (BUN) and serum creatinine (sCr). In particular, QC markedly decreased the accumulation of Hg in the kidney. Urinary excretion of protein-based biomarkers, including clusterin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and vascular endothelial growth factor (VEGF) in response to HgCl2 administration were significantly decreased by QC pretreatment relative to that in the HgCl2-treated group. Furthermore, urinary excretion of metallothionein and Hg were significantly elevated by QC pretreatment. Histopathological examination indicated that QC protected against HgCl2-induced proximal tubular damage in the kidney. A TUNEL assay indicated that QC pretreatment significantly reduced apoptotic cell death in the kidney. The administration of QC provided significant protective effects against mercury-induced AKI.

Use of injectable drugs with oral-formulation alternatives for outpatients in South Korea.

This study analyzed the use of injectable drugs with oral-formulation alternatives in the outpatient setting in South Korea. We conducted a retrospective cross-sectional data analysis using 2008 National Health Insurance claims data. All active ingredients were categorized into dual-formulation ingredients (DFIs) and single formulation ingredients (SFIs), and were identified by the type of healthcare service provider (HSP) and anatomical therapeutic chemical (ATC) group. 14.6 % (102/701) of total drugs were extracted as DFIs at about the same rate as that for drugs in the World Health Organization database (14.45 %), showing similar patterns by ATC group. The rate of injectable drug use varied more substantially for DFIs (range 0.94-4.54 %) than for SFIs (range 0.27-1.12 %) by the type of HSP. For DFIs, the highest proportion of injectable drug use was observed in group H (all hormonal preparations, 22.74 %) and group M (anti-inflammatory and anti-rheumatic preparations, 10.23 %) among ATC groups. The proportion of injectable drug use was higher in clinics and small hospitals than in tertiary hospitals and general hospitals where patients with more severe cases tend to visit. The results imply the potentially inappropriate or excessive use of injectable drugs and suggest the need to develop standard guidelines for injectable drug use and strategies to promote high-quality healthcare including education on rational prescribing.

A comparative analysis of the impact of a positive list system on new chemical entity drugs and incrementally modified drugs in South Korea.

BACKGROUND: Medical costs in South Korea have risen, in part due to increased demand and consumption of pharmaceutical products by an aging population and also because of the introduction of newer, more expensive drugs. In an effort to stabilize the financing of health insurance and alleviate the financial burden on individuals, the government implemented a policy changing the national health insurance drug-listing system from a negative list system to a positive list system (PLS). OBJECTIVES: The goal of this study was to compare differences in drug-listing rates for new chemical entities (NCEs) and incrementally modified drugs (IMDs) after South Korea introduced the PLS in December 2006. Parameters significantly affecting NCE and IMD listings were also identified. METHODS: New drug-listing data for 2007 and 2008 were obtained from the databases of the Health Insurance Review Agency and the Ministry of Health and Welfare. Descriptive analyses on the reimbursement rate and logistic regression analysis were conducted. Statistical significance was tested for all results, and P < 0.05 was considered statistically significant. RESULTS: A total of 150 reimbursement applications (79 for NCEs, 71 for IMDs) were examined for this study. The overall drug-listing rate was lower than before the introduction of the PLS. Drug reimbursement rates for NCEs (50.6%) were lower than those for IMDs (74.6%) (P = 0.0025). However, the price negotiation rate was 85.0% for NCEs compared with 73.6% for IMDs (P = 0.1847). The time required for both reimbursement and drug pricing was significantly longer for NCE than for IMD listings (P < 0.05). Cost-effectiveness and budget impact were 2 significant variables affecting the listing of NCEs. However, no significant variable was identified for IMDs. CONCLUSIONS: The PLS challenges the drug-listing system by decreasing the drug-listing rate and lengthening the period for reimbursement determinations. These effects were more pronounced for NCE listings than for IMD listings.