Treatment of Inflammatory Bowel Disease with Biologics in Japan: A Single-Center, Retrospective Pharmacoeconomic Study.

Biologics are essential for treating inflammatory bowel disease (IBD); however, only a few studies have validated cost-effective treatment options and patient factors for biologic use using real-world data from Japanese patients with IBD. Here, we aimed to provide pharmacoeconomic evidence to support clinical decisions for IBD treatment using biologics. We assessed 183 cases (127 patients) of IBD treated with biologics between November 2004 and September 2021. Data on patient background, treatment other than biologics, treatment-related medical costs, and effectiveness index (ratio of the C-reactive protein-negative period to drug survival time) were analyzed using univariate and multivariate logistic regression analyses. Drug survival was determined using Kaplan-Meier survival curve analysis. The outcomes were to validate a novel assessment index and elucidate the following aspects using this index: the effectiveness-cost relationship of long-term biologic use in IBD and cost-effectiveness-associated patient factors. Body mass index ≥25 kg/m2 and duration of hypoalbuminemia during drug survival correlated significantly with the therapeutic effectiveness of biologics. There were no significant differences in surgical, granulocyte apheresis, or adverse-event costs per drug survival time. Biologic costs were significantly higher in the group showing lower effectiveness than in the group showing higher effectiveness. These findings hold major pharmacoeconomic implications for not only improving therapeutic outcomes through the amelioration of low albumin levels and obesity but also potentially reducing healthcare expenditure related to the use of biotherapeutics. To our knowledge, this is the first pharmacoeconomic study based on real-world data from Japanese patients with IBD receiving long-term biologic therapy.

A low prognostic nutritional index is associated with increased remote infections within 30 days of colorectal surgery: A retrospective cohort study.

OBJECTIVE: This study aimed to identify risk factors for remote infection (RI) within 30 days after colorectal surgery. METHODS: This retrospective study included 660 patients who underwent colorectal surgery at Yamaguchi University Hospital or Ube Kosan Central Hospital between April 2015 and March 2019. Using electronic medical records, we identified the incidence of surgical site infection and RI within 30 days after surgery and obtained information on associated factors. Univariate and multivariable analyses were performed to identify significant risk factors in 607 (median age, 71 years) patients. RESULTS: Seventy-eight (13%) and 38 (6.3%) patients had surgical site infection and RI, respectively. Of the 38 patients diagnosed with RI, 14 (36.8%) had a bloodstream infection, 13 (34.2%) had a urinary tract infection, 8 (21.1%) had a Clostridioides difficile infection, and 7 (18.4%) had respiratory tract infections. Multivariable analysis showed that a preoperative prognostic nutritional index of ≤40 (OR, 2.30; 95% CI, 1.07-4.92; P = .032), intraoperative blood transfusion (OR (odds ratio), 3.06; 95% CI, 1.25-7.47; P = .014), and concomitant stoma creation (OR, 4.13; 95% CI, 1.93-8.83; P = .0002) were significant RI predictors. CONCLUSIONS: Nutritional interventions prompted by low preoperative prognostic nutritional index in colorectal surgery may lead to decreases in postoperative RI.

Impact of the hospital volume and setting on postoperative complications of surgery for gastroenterological cancers in a regional area of Western Japan.

PURPOSE: A research subgroup was established by the Japanese Society of Gastroenterological Surgery to improve the health care quality in the Chushikoku area of Western Japan. METHODS: The records of four surgical procedures were extracted from the Japanese National Clinical Database and analyzed retrospectively to establish the association between hospital characteristics, defined using a combination of hospital case-volume and patients' hospital travel distance, and the incidences of perioperative complications of ≥ Grade 3 of the Clavien-Dindo classification after gastroenterological surgery. RESULTS: This study analyzed 11,515 cases of distal gastrectomy for gastric cancer, 4,705 cases of total gastrectomy for gastric cancer, 4,996 cases of right hemicolectomy for colon cancer, and 5,243 cases of lower anterior resection for rectal cancer, with composite outcome incidences of 5.6%, 10.2%, 5.5%, and 10.7%, respectively. After adjusting for patient characteristics and surgical procedures, no association was identified between the hospital category and surgical outcomes. CONCLUSION: The findings of our study of the Chushikoku region did not provide positive support for the consolidation and centralization of hospitals, based solely on hospital case volume. Our grouping was unique in that we included patient travel distance in the analysis, but further investigations from other perspectives are needed.

Pharmacoeconomic study of biologics for psoriasis treatment based on real-world drug survival.

The efficacy of biologics in psoriasis treatment is clinically proven; however, biologics are expensive. In this study, we assessed the real-world cost-effectiveness of biologics for psoriasis treatment by evaluating the relationship between biologic drug survival (DS) and total medical-treatment costs from a pharmacoeconomic viewpoint. Furthermore, the effects of patient factors on cost-effectiveness were investigated. We retrospectively reviewed the medical records of 135 cases who received either a tumor necrosis factor-alpha (TNF-α) monoclonal antibody (TNF-mab), interleukin (IL)-17 mab, or IL23p19-mab for psoriasis from January 2010 to June 2020 at Yamaguchi University Hospital. We compared the monthly medical-treatment costs according to biologic classification and found that costs of medical services, tests, and external preparations required for the treatment process were significantly higher in the TNF-mab group than in the other groups, and the total medical costs associated with TNF-mab treatment were significantly higher than those of IL17-mab treatment. The total monthly cost of medical care was lower in the long-term DS group than in the short-term group. The number of prescriptions for external preparations, comprising Vitamin D3 and corticosteroid, was significantly higher in the long-term DS group than in the short-term group; in the TNF-mab group, the proportion of patients without smoking habits was significantly higher in the long-term group as well. Our study indicated that when costly biologics are used for psoriasis treatment, the maintenance of long-term DS and appropriate patient guidance might improve the quality of medical care, thus allowing cost-effective medical care.

[Standardization of Hypnotic Agents for Prevention of Falls: A Pharmacoeconomic Study].

To reduce the number of falls caused by hypnotic agents, the standardization of insomnia treatment was carried out at Yamaguchi University Hospital from April 2019. There were concerns that medical costs would increase due to the selected medicines-suvorexant and eszopiclone-being more expensive than conventional benzodiazepines. In this study, the standardization of insomnia treatment was evaluated by pharmacoeconomics. The costs of the hypnotic agents was considered, as was the cost of examination/treatment following falls. Effectiveness was evaluated as the incidence of falls within 24 hours of taking hypnotic agents. This analysis took the public healthcare payer's perspective. Propensity score matching based on patient background, showed that, per hospitalization the medicine costs of the recommended group increased by 1,020 yen, however, the examination/treatment costs following falls decreased by 487 yen when compared with the non-recommended group. Overall, the recommended group incurred costs of 533 yen more per hospitalization for patients prescribed hypnotic agents compared to the non-recommended group, but the incidence of falls for the recommended group was significantly lower than that in the non-recommended group (1.9% vs. 6.3%; p<0.01). These results suggest that in order to prevent the incidence of falls by 1 case, it is necessary to increase costs by 12,086 yen which is the subthreshold cost for switching to the recommended medicine as standardization. The selection of recommended medicines may be a cost-effectiveness option compared with non-recommended medicines.

Exploration and time-serial validation of logistic regression models composed of multiple laboratory tests for early detection of HCV-associated hepatocellular carcinoma.

BACKGROUND: We developed a laboratory test-based regression model for early detection of hepatocellular carcinoma (HCC) associated with HCV in its surveillance. METHODS: This matched case-control study was conducted by enrolling 452 patients with chronic hepatitis and/or cirrhosis, including 129 patients complicated with HCC. One-to-one propensity score matching was performed by referring to sex, age, and fibrosis-4 index, which resulted in 102 patients each in HCC and non-HCC groups. Logistic regression models (LRM) for distinguishing the two groups were explored from variable combinations of laboratory tests. The model was validated by our new scheme of applying it retroactively to trimonthly previous datasets. RESULTS: Models with a practical level of diagnostic accuracy (C-statistic) were α-fetoprotein (AFP) alone (0.810), LRM3 comprising AFP, AST, and ALT (0.850), and LRM4 comprising AFP, AFP/(AST × ALT), and AST (0.862). After retroactive application of each model, LRM4 showed the highest distinction of the two groups at -12M, -6M, -3M with C-statistics of 0.654, 0.786, 0.834, respectively. LRM4 was accurate even after limiting cases to early-stage HCC. CONCLUSIONS: LRM4 was proved useful in prompting clinicians to perform timely image study in the surveillance. The retroactive validation scheme is applicable to assess diagnostic models of other neoplastic diseases.

Cost-effectiveness of a "treat-all" strategy using Direct-Acting Antivirals (DAAs) for Japanese patients with chronic hepatitis C genotype 1 at different fibrosis stages.

AIM: To evaluate the cost-effectiveness of therapeutic strategies initiated at different stages of liver fibrosis using three direct-acting antivirals (DAAs), sofosbuvir-ledipasvir (SL), glecaprevir-pibrentasvir (GP), and elbasvir plus grazoprevir (E/G), for Japanese patients with chronic hepatitis C (CHC) genotype 1. METHODS: We created an analytical decision model reflecting the progression of liver fibrosis stages to evaluate the cost-effectiveness of alternative therapeutic strategies applied at different fibrosis stages. We compared six treatment strategies: treating all patients regardless of fibrosis stage (TA), treating individual patients with one of four treatments starting at four respective stages of liver fibrosis progression (F1S: withholding treatment at stage F0 and starting treatment from stage F1 or higher, and three successive options, F2S, F3S, and F4S), and administering no antiviral treatment (NoRx). We adopted a lifetime horizon and Japanese health insurance payers' perspective. RESULTS: The base case analysis showed that the incremental quality-adjusted life years (QALY) gain of TA by SL, GP, and E/G compared with the strategies of starting treatments for patients with the advanced fibrosis stage, F2S, varied from 0.32 to 0.33, and the incremental cost-effectiveness ratios (ICERs) were US$24,320, US$18,160 and US$17,410 per QALY, respectively. On the cost-effectiveness acceptability curve, TA was most likely to be cost-effective, with the three DAAs at the willingness to pay thresholds of US$50,000. CONCLUSIONS: Our results suggested that administration of DAA treatment for all Japanese patients with genotype 1 CHC regardless of their liver fibrosis stage would be cost-effective under ordinary conditions.

Differences in healthcare expenditure estimates according to statistical approach: A nationwide claims database study on patients with hepatocellular carcinoma.

AIM: Disease-associated healthcare expenditures are generally calculated using matched comparisons or regression-based analyses, but little is known about their differences in estimates. This aim of this study was to compare the differences between disease-associated healthcare expenditures estimated using these 2 methods. METHODS: In this retrospective cohort study, a matched comparison was first conducted by matching cases with controls using sex, age, and comorbidities to estimate disease-associated expenditures. The cases were then used in a fixed-effects analysis that compared expenditures before and after disease occurrence. The subjects were adults (≥20 years) with primary hepatocellular carcinoma (HCC) who underwent treatment (including surgical resection, locoregional therapy, transcatheter arterial chemoembolization, and transarterial embolization) at a Japanese hospital between April 2010 and March 2018. We calculated the total healthcare expenditures per patient per month according to treatment and disease phase (initial, continuing, and terminal). RESULTS: There were 14,923 cases in the initial/continuing phases and 15,968 cases in the terminal phase. In the initial/continuing phases, 3,552 patients underwent surgical resection only, with HCC-associated expenditures of $5,555 according to the matched comparison and $5,889 according to the fixed-effects analysis (proportional difference: 94.3%). The initial phase expenditures were approximately 9% higher in the fixed-effects analysis, whereas the continuing phase expenditures were approximately 7% higher in the matched comparison. The expenditures in the terminal phase were 93.1% higher in the fixed-effects analysis. CONCLUSIONS: The 2 methods produced similar estimates of HCC-associated healthcare expenditures in the initial/continuing phases. However, terminal phase expenditures were substantially different between the methods.

Evaluation of the Anonymity and Utility of De-Identified Clinical Data Based on Japanese Anonymization Criteria.

We analyze the deterioration of clinical data quality due to anonymization. The result shows that data quality remained high with micro-aggregation and also verify the availability of noise addition to prevent illegal re-identification by matching another personal data.

The Inequality of Patient Profile Information in Japanese Hospitals.

A model dataset of patient profile information was created based on the items used at five Japanese university hospitals, the patient information data elements in Health Level 7 (HL7) v2.5, and the standard datasets for medical information exchange used in Japan. In order to check the validity of the model dataset, a cross-sectional survey was performed. A preliminary analysis of 20 Japanese hospitals found that most items were implemented at some hospitals, but the number of items implemented at many hospitals was rather small. This result strongly shows the necessity for a standardized dataset of patient profile information.

[Security Management in Clinical Laboratory Departments and Facilities: Current Status and Issues].

We conducted a questionnaire survey regarding the current activities for protecting patients' privacy and the security of information systems (IS) related to the clinical laboratory departments of university hospitals, certified training facilities for clinical laboratories, and general hospitals in Yamaguchi Prefecture. The response rate was 47% from 215 medical institutions, including three commercial clinical laboratory centers. The results showed that there were some differences in management activities among facilities with respect to continuing education, the documentation or regulation of operational management for paper records, electronic information, remaining samples, genetic testing, and laboratory information for secondary use. They were suggested to be caused by differences in functions between university and general hospitals, differences in the scale of hospitals, or whether or not hospitals have received accreditation or ISO 15189. Regarding the IS, although the majority of facilities had sufficiently employed the access control to IS, there was some room for improvement in the management of special cases such as VIPs and patients with HIV infection. Furthermore, there were issues regarding the login method for computers shared by multiple staff, the showing of the names of personnel in charge of reports, and the risks associated with direct connections to systems and the Internet and the use of portable media such as USB memory sticks. These results indicated that further efforts are necessary for each facility to continue self-assessment and make improvements.

[Evaluation of diagnostic performance of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) for HCV related hepatocellular carcinoma developed after long-term follow up].

PURPOSE: This study evaluated the diagnostic performance of two tumor markers, alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), a combination of these tests and other common tests for patients developing hepatocellular carcinoma (HCC) during long-term follow-up for HCV-related liver disease. METHODS: We reviewed the medical records of 144 patients who developed HCC after at least one-year follow up for HCV-related liver disease in Yamaguchi University Hospital or Tenri Hospital and demographic, clinical and laboratory data were collected retrospectively. To evaluate diagnostic test performance, we defined the oldest data collected from each patient at least one year before the diagnosis of HCC as negative control data. RESULTS: Sensitivity and specificity were 0.52, 0.61 for AFP with a cut-off of 20 ng/ml compared to 0.47 and 1.00 for DCP with a cut-off of 40 mAU/ml, respectively. Combination tests for AFP at 100 ng/ml and DCP at 40 mAU/ml yielded the best sensitivity at 0.84 with a specificity of 0.50. Multivariate logistic regression model using AFP, AST, LD, hemoglobin, prothrombin time and male ratio as variables showed significantly better diagnostic performance, i.e. sensitivity 0.85, specificity 0.74, than single test or combination test using AFP and DCP alone. CONCLUSIONS: AFP and DCP alone were not sufficient for detection of HCC developing during long-term follow-up of HCV-related cirrhosis. Logistic regression including AFP and commonly used laboratory tests showed superior diagnostic accuracy compared to that of tumor marker tests alone.

[Contributions of university hospitals to local health integration networks].

The use of ICT (Information and Communication Technology) has supported the widespread sharing of healthcare data. Collaboration among medical or health facilities in the community using a telemedicine infrastructure has been promoted by the Strategy of IT-related Structural Reform (the Acceleration and Advancement of e-Japan Priority Policy Program) of the Japanese government. Many university hospitals have been playing leading roles of facilitating collaboration with community healthcare. Through advances in broadband networking and security technology, we have made great progress from the trial stage to the practical stage in the electronic sharing of clinical data. Although many efforts are being made spread the cooperation areas or widen the scope of information sharing for utilization in disease prevention or clinical trials of newly developed drugs as well as medical information, university hospitals have to continue working on these areas to support patients and staff as core hospitals in the community.

Economic consequence of immediate testing for C-reactive protein and leukocyte count in new outpatients with acute infection.

BACKGROUND: There have been few well-designed studies that assess the cost-effectiveness of near-patient immediate testing. METHODS: We analyzed the economic outcome of immediate testing for C-reactive protein (CRP) and white blood cell count (WBC) in 305 new outpatients with acute infections. Patients were randomized into two groups: 147 patients were tested immediately for CRP and WBC before the physician's initial consultation (advance testing), and 154 patients were not subjected to advance testing. The subsequent prescribing decision and the drug/testing/personnel costs were compared between the groups. RESULTS: In the advance-testing group, the initial consultation was followed by a total of 84 prescriptions of oral antibiotics, against 158 in the other group. Comparing the total costs of oral and parenteral antibiotics between the two groups, a 30% reduction was achieved with advance testing ( yen105,830 vs. yen151,102). However, the savings were largely offset by frequent prescription of newer, expensive influenza neuraminidase inhibitors. Advance testing also significantly reduced additional laboratory use. More frequent urgent testing increased personnel costs in the non-advance-testing group. Overall, total cost was somewhat higher in the advance-testing group ( yen1,028,827 vs. yen984,105). CONCLUSIONS: The cost per antibiotic prescription reduced with advance testing was yen604 (approximately 5.8 US dollars) in our clinical setting. Judicious use of antivirals and introduction of a simple CRP test kit would improve cost-effectiveness.

Cost-effectiveness of ribavirin plus interferon alpha-2b for either interferon relapsers or non-responders in chronic hepatitis C: a Japanese trial.

The aim of this study was to examine the cost-effectiveness of combination therapy with ribavirin plus interferon alpha-2b compared with interferon monotherapy for hepatitis C-infected Japanese patients who had either temporarily responded or not responded to initial interferon treatment. Data from a recent randomized clinical trial among relapsed or non-responding patients comparing combination therapy to interferon alone were applied to a computer cohort simulation Markov process model to project lifelong clinical and economic outcomes. Combination therapy for 24 weeks should increase life expectancy by 1.6 quality-adjusted life years and should reduce discounted (3% per year) lifetime costs by yen 121,000 when compared to retreatment with interferon alone. For the subgroup of patients with genotype 1b and high viral load, combination therapy should be cost-effective ( yen 187,000 per QALY gained with a 3% annual discount rate) by well-accepted international standards. These results were robust with combination therapy remaining cost-effective or cost saving in sensitivity analysis involving reasonable variation in all parameters. For patients similar to those enrolled in the interferon alpha-2b and ribavirin trials in Japan, combination therapy should be considered cost-effective with the higher drug treatment costs nearly completely offset by future savings through reductions in future liver complications from hepatitis C.

[Searching for primary studies for inclusion in systematic reviews].

Searching for relevant literature is an important process when carrying out a systematic review. Although general-purpose literature databases such as MEDLINE contain a huge number of articles, only a small fraction of these report evidence applicable to a systematic review. Development of an optimal search strategy giving priority to minimizing the number of important articles not retrieved is thus desirable. The retrieval of relevant studies cited in literature databases can be substantially enhanced by selected combinations of indexing terms and textwords. In order to improve the likelihood of retrieving studies relevant to a specific clinical question, precise database search skills are required: creation of an explicit, well formulated question using PI (E) CO, and development of a list of optimal indexing terms such as MeSH and textwords. However, even a search strategy yielding maximum sensitivity could omit some relevant articles. Consequently, hand-searching for articles in key or unindexed journals is still necessary to identify all relevant studies.

[Special comments--problems in systematic review for diagnostic accuracy of high-sensitivity C-reactive protein assay in neonatal infection].

We conducted a systematic review for the diagnostic accuracy of high-sensitivity C-reactive protein assay for neonatal infection. In total, 558 relevant published reports were found in a search of MEDLINE and Igaku-Chuo-Shi. With our inclusion and exclusion criteria, we finally selected 30 primary studies for meta-analysis. We critically appraised the quality of selected clinical studies and then extracted sensitivity and specificity data from each article for meta-analysis. There was only one article that fulfilled our three major standards for quality assessment(rank A; high-quality), while 19 studies which fulfilled only one criterion were assigned to rank C(low-quality). Most studies neither took careful consideration of the blindness against the results of the index test nor described this methodological standard. Lack of qualified primary studies may have had substantial influence on the summary estimates. Insufficient number of primary studies for meta-analysis and their unsatisfactory quality would be improved by the addition of supplemental results retrieved from raw data, which the authors of clinical studies did not present in their articles.

Utilization of common inflammatory markers in new, symptomatic, primary care outpatients based on their cost-effectiveness.

Few studies have demonstrated the optimal usage of common inflammatory markers, alone or in combination, based on the cost-effectiveness. We analyzed the yield and cost of C-reactive protein (CRP), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), sialic acid, and protein fractionation in 177 new primary care outpatients with inflammation-related symptoms. A useful result (UR) was assigned if tests contributed to a change in physician's diagnosis or decision-making. Costs of testing were calculated based on either single or simultaneous measurement. Five inflammatory markers generated 147 URs in 123 patients. CRP showed the best contribution to generation of UR, followed by sialic acid, protein fractionation, WBC, and ESR. CRP demonstrated poor correlation with WBC (r = 0.458), while sialic acid strongly correlated with total absolute amount of alpha1 and alpha2 fractions in protein fractionation (r = 0.855) and moderately with ESR (r = 0.651). The combination of CRP and WBC produced the best cost-effectiveness at a cost of Yen 1169 (US dollars 9.6 or Euro 9.7)/additional UR against CRP testing alone. Sialic acid, an automated multichannel analyzer-based test, demonstrated the favorable cost-effectiveness over ESR or protein fractionation when combined with CRP (and WBC). Our results indicate that the optimal usage of these inflammatory markers should involve careful cost-effectiveness considerations.