Signal detection is essential for identifying potential safety issues with drugs and medical devices. Change point analysis (CPA) detects changes in longitudinal data for a medical device without incorporating comparisons with other devices. This study investigated the temporal relationship between endoleak reports for aortic stent grafts identified using CPA and the issuance of the “Pharmaceuticals and Medical Devices Agency (PMDA) Alert for Proper Use of Medical Devices” in Japan. Device malfunction and adverse event reports for aortic stent grafts submitted to the PMDA between April 2008 and September 2022 were analyzed. The reports were mapped to the Medical Device Problem Terminology from the Japan Federation of Medical Devices Associations. CPA was used to identify temporal changes in report counts, with change points having confidence levels ≥ 90

ABSTRACTPurposeTo assess adverse neurological risks following influenza vaccination in older adults.MethodsUsing a linked database of healthcare administrative claims data and vaccination records from an urban city in Japan (April 1, 2014, to March 31, 2020), we conducted an observational study utilizing a self‐controlled case series design. We identified individuals aged ≥ 65 years who experienced adverse neurological outcomes, defined as hospitalizations related to epilepsy, paralysis, facial paralysis, neuralgia, neuritis, optic neuritis, migraine, extrapyramidal disorders, Guillain–Barre syndrome, or narcolepsy. We used conditional Poisson regression to analyze within‐subject incidence rate ratios, comparing the risk of these outcomes during risk periods following influenza vaccination (0–6 days and 7–29 days after each vaccination) with nonvaccination periods. Our analysis was adjusted for age and season groups as time‐varying covariates.ResultsWe enrolled 3283 eligible individuals (men: 1643; mean [standard deviation] age: 76 [7.3] years). The incidence rate ratio for the outcome during the risk periods was 0.93 (95% confidence interval, 0.66–1.30) in risk period 1 (0–6 days after vaccination) and 1.14 (0.96–1.35) in risk period 2 (7–29 days after vaccination), respectively.ConclusionsWe found no evidence that the risk of adverse neurological events was increased after influenza vaccination in older adults. These results may help reassure older adults who are hesitant to receive influenza vaccination because of concerns regarding adverse neurological outcomes.

Tumor necrosis factor-α inhibitors (TNFis) are associated with a risk of paradoxical psoriasis, but quantitative data remain limited. One proposed mechanism is the induction of interferon (IFN) production following TNFi administration. Etanercept and certolizumab pegol, which contain immunoglobulin fragments in their structures, reportedly induce IFN production in T cells more than monoclonal antibody (mAb) TNFi agents. Based on this, we hypothesized that non-mAb TNFi agents might carry a higher risk of paradoxical psoriasis than mAb agents. This study compared the risk of paradoxical psoriasis between mAb and non-mAb TNFi agents in rheumatoid arthritis (RA) patients. Using a claims database, we identified 1577 subjects in the mAb group and 1517 in the non-mAb group. Patient characteristics, including sex, age, and prior RA treatment, were extracted, and the onset of psoriasis was identified. Multivariable Cox regression analysis showed the hazard ratio (HR) for psoriasis onset in the mAb group versus the non-mAb group was 1.66 (95% confidence interval [CI]: 0.79-3.48). Subgroup analyses revealed that compared to etanercept, the HR for adalimumab was 1.43 (95% CI: 0.49-4.19), and compared to certolizumab pegol, it was 0.67 (95% CI: 0.19-2.39). These findings suggest that our hypothesis was not supported and that the risk of paradoxical psoriasis may vary even among non-mAb agents, as indicated by differences observed between etanercept and certolizumab pegol.

This study aimed to investigate whether the approved sequence of vedolizumab and ustekinumab impacts the results of previous observational studies conducted in the European Union (EU), comparing the effectiveness of these drugs in Crohn's disease (CD) patients who failed anti-tumor necrosis factor-alpha (TNF alpha) treatment. We conducted this study in Japan, where the approved sequence of drugs is different from that of the EU. We extracted 256 patients diagnosed with CD, who had a history of anti-TNF alpha treatment and were prescribed either vedolizumab or ustekinumab, from JMDC claims database. The patients' backgrounds were adjusted by inverse probability of treatment weighting using propensity score. The primary outcome was treatment persistence. Secondary outcomes were a steroid-free period, time to hospitalization, and time to CD-related surgery. The hazard ratios (HR) for survival times were estimated using the Cox proportional hazard model. The treatment persistence (primary endpoint) was significantly longer for ustekinumab than vedolizumab (HR, 0.32; 95% confidence interval (CI), 0.15-0.72). The results of the secondary endpoints were as follows: steroid-free period (HR, 0.38; 95% CI, 0.10-1.48), time to hospitalization (HR, 1.07; 95% CI, 0.60-1.91), or time to CD-related surgery (HR, 0.33; 95% CI, 0.11-0.97). There were no outcomes indicating the superiority of vedolizumab. Our findings suggest that ustekinumab is a more effective treatment option than vedolizumab for CD patients who failed to anti-TNF alpha treatment, and this finding remains consistent across both Japan and the EU.

PURPOSE:The Database Task Force of the Japan Society for Pharmacoepidemiology began its annual surveys of databases available for clinico and pharmacoepidemiological studies in 2010. In this report, we summarize the characteristics of the databases available in Japan based on the results of our 2021 survey to illustrate the recent developments in the infrastructure for database research in Japan.METHODS:We included 20 major databases from the academia, government, or industry that were accessible to third parties. We used a web-based questionnaire to ask the database providers about their characteristics, such as their organization, data source(s), numbers of individuals enrolled, age distribution, code(s) used, and average follow-up periods.RESULTS:We received responses from all 20 databases approached: eight hospital-based databases, six insurer-based databases, four pharmacy-based databases, and two in the "other" category. Among them, 17 contained information from medical claims, pharmacy claims, and/or Diagnosis Procedure Combination data. Most insurer databases contained health check-up data that could be attached to the claims component. Some hospital-based databases had data from electronic medical records. Most insurer-based databases collected data from the insurers of working-age employees and therefore had limited coverage of older people. Most databases coded their medication data using the Japanese reimbursement codes, and many provided Anatomical Therapeutic Chemical Classification codes.CONCLUSIONS:The number of databases available for clinico and pharmacoepidemiological research and the proportion of the population they cover are increasing in Japan. The differences in their characteristics mean that the appropriate database must be selected for a particular study purpose.

Aims The purpose of this study is to utilize patient-reported outcomes to determine the percentage of patients concerned about mild to moderate bleeding side effects of anticoagulants. Methods and results We consecutively enrolled 3312 newly diagnosed or referred patients for atrial fibrillation (AF) management from 11 sites within the Keio interhospital Cardiovascular Studies-Atrial Fibrillation registry between September 2012 and May 2018. Of these patients, 2636 (79.5%) were taking oral anticoagulants at enrollment. Using the Atrial Fibrillation Effect on Quality-of-life questionnaire (AFEQT), the patients who responded ‘1: not at all bothered’ or ‘2: hardly bothered’ on the seven-point scale regarding bleeding side effects were classified as the ‘no OAC concern’ group while those responding ‘3: a little bothered’ to ‘7: extremely bothered’ were classified as the ‘OAC concern’ group. On baseline analysis, 29.3% (n = 772) were ‘concerned’ about bleeding side effects. The proportion of women and patients with AF-related symptoms was higher in the oral anticoagulant (OAC) concern vs. no OAC concern group (36.9% vs. 29.8%, P < 0.0004 and 66.2% vs. 56.7%, P < 0.0001, respectively). The CHADS2 scores ≥ 2 were comparable between groups. Of the 430 patients in the 1-year follow-up analysis, the proportion of the continued OAC concern group (1 year from enrollment) was 41.6%. The dabigatran, rivaroxaban, and apixaban usage rates were comparable between the two groups in baseline and 1-year follow-up analysis. Conclusion Approximately one-third of all patients with AF on anticoagulant therapy were concerned regarding bleeding from short- and long-term anticoagulant use.

Background: Real-world data (RWD) and real-world evidence (RWE) are playing increasingly important roles in clinical research and health care decision-making. To leverage RWD and generate reliable RWE, data should be well defined and structured in a way that is semantically interoperable and consistent across stakeholders. The adoption of data standards is one of the cornerstones supporting high-quality evidence for the development of clinical medicine and therapeutics. Clinical Data Interchange Standards Consortium (CDISC) data standards are mature, globally recognized, and heavily used by the pharmaceutical industry for regulatory submissions. The CDISC RWD Connect Initiative aims to better understand the barriers to implementing CDISC standards for RWD and to identify the tools and guidance needed to more easily implement them. Objective: The aim of this study is to understand the barriers to implementing CDISC standards for RWD and to identify the tools and guidance that may be needed to implement CDISC standards more easily for this purpose. Methods: We conducted a qualitative Delphi survey involving an expert advisory board with multiple key stakeholders, with 3 rounds of input and review. Results: Overall, 66 experts participated in round 1, 56 in round 2, and 49 in round 3 of the Delphi survey. Their inputs were collected and analyzed, culminating in group statements. It was widely agreed that the standardization of RWD is highly necessary, and the primary focus should be on its ability to improve data sharing and the quality of RWE. The priorities for RWD standardization included electronic health records, such as data shared using Health Level 7 Fast Health care Interoperability Resources (FHIR), and the data stemming from observational studies. With different standardization efforts already underway in these areas, a gap analysis should be performed to identify the areas where synergies and efficiencies are possible and then collaborate with stakeholders to create or extend existing mappings between CDISC and other standards, controlled terminologies, and models to represent data originating across different sources. Conclusions: There are many ongoing data standardization efforts around human health data-related activities, each with different definitions, levels of granularity, and purpose. Among these, CDISC has been successful in standardizing clinical trial-based data for regulation worldwide. However, the complexity of the CDISC standards and the fact that they were developed for different purposes, combined with the lack of awareness and incentives to use a new standard and insufficient training and implementation support, are significant barriers to setting up the use of CDISC standards for RWD. The collection and dissemination of use cases, development of tools and support systems for the RWD community, and collaboration with other standards development organizations are potential steps forward. Using CDISC will help link clinical trial data and RWD and promote innovation in health data science.

BACKGROUND:This retrospective observational study validated case-finding algorithms for malignant tumors and serious infections in a Japanese administrative healthcare database.METHODS:Random samples of possible cases of each disease (January 2015-January 2018) from two hospitals participating in the Medical Data Vision Co., Ltd. (MDV) database were identified using combinations of ICD-10 diagnostic codes and other procedural/billing codes. For each disease, two physicians identified true cases among the random samples of possible cases by medical record review; a third physician made the final decision in cases where the two physicians disagreed. The accuracy of case-finding algorithms was assessed using positive predictive value (PPV) and sensitivity.RESULTS:There were 2,940 possible cases of malignant tumor; 180 were randomly selected and 108 were identified as true cases after medical record review. One case-finding algorithm gave a high PPV (64.1%) without substantial loss in sensitivity (90.7%) and included ICD-10 codes for malignancy and photographing/imaging. There were 3,559 possible cases of serious infection; 200 were randomly selected and 167 were identified as true cases after medical record review. Two case-finding algorithms gave a high PPV (85.6%) with no loss in sensitivity (100%). Both case-finding algorithms included the relevant diagnostic code and immunological infection test/other related test and, of these, one also included pathological diagnosis within 1 month of hospitalization.CONCLUSIONS:The case-finding algorithms in this study showed good PPV and sensitivity for identification of cases of malignant tumors and serious infections from an administrative healthcare database in Japan.

Background Guidelines recommend against all codeine use in children for its common indications of analgesia and cough suppression because of uncertain benefits and potential risk of death. However, because of its rarity, the occurrence of severe respiratory depression associated with codeine-containing antitussives has been poorly investigated. The objective of this study was to investigate the association between codeine-containing antitussives and severe respiratory depression in children. Methods We retrospectively identified Japanese children who were prescribed antitussives for respiratory diseases from a large Japanese administrative claims database (JMDC, Tokyo, Japan). We collected data on baseline characteristics including age, sex, and comorbidity. Each case was matched with four controls with the same sex and age in the same year from the same type of medical institution. We then examined the association between codeine-containing antitussives and subsequent severe respiratory depression using multivariable conditional logistic regression analysis. Results Of 164,047 children, 18,210 (11.1%) were prescribed codeine-containing antitussives. Of the children who took codeine-containing drugs, seven experienced severe respiratory depression. After adjusting for confounding factors, there was no significant difference in the proportion of severe respiratory depression between children with and without codeine-containing antitussives (odds ratio 1.15; 95% confidence interval, 0.48–2.78). Conclusion Occurrence of respiratory depression was very rare, and the association of codeine with respiratory depression was insignificant, even in a large sample of children in Japan.

Backgrounds Current guidelines recommend routine nephropathy monitoring, including microalbuminuria or proteinuria testing, for people with diabetes mellitus; however, its effect in terms of preserving renal function remains unclear. We conducted this study to examine the impact of routine nephropathy monitoring on subsequent changes in estimated glomerular filtration rate. Methods We retrospectively identified non-elderly individuals with diabetes mellitus based on the prescription of hypoglycemic agents from a large Japanese database (JMDC, Tokyo, Japan) of screening for lifestyle diseases linked with administrative claims data. We collected data on baseline characteristics including age, sex, comorbidity, and laboratory data. We then examined the association between routine nephropathy monitoring results and change in estimated glomerular filtration rate using a propensity-score inverse probability of treatment weighting method. Results Among 1,602 individuals who started taking hypoglycemic agents between 2005 and 2016, 102 (6.0%) underwent routine nephropathy monitoring during the first year of medication for diabetes mellitus. After adjusting for multiple confounding factors, there was no significant difference in subsequent estimated glomerular filtration rate changes between individuals with and without routine nephropathy monitoring (difference in percent change 0.11; 95% confidence interval −2.74 to 2.95). Conclusion Routine nephropathy monitoring was not associated with preserved renal function. Current recommendations for the universal application of nephropathy monitoring may have limited value to prevent renal dysfunction in non-elderly individuals with diabetes mellitus.

Recently, lipoprotein(a) (Lp(a)) levels have been reported to be associated with a risk of HF with preserved ejection fraction (HFpEF) in white ethnicity. However, the association between Lp(a) and echocardiographic parameters has not been clarified. Therefore, we examined Lp(a) distribution in

過去の薬害など薬の問題の究明に疫学手法が適用され，薬剤疫学という学問が誕生したが，薬剤疫学の第 1 回国際会議は 1985 年に開催され，国内でも 1995 年から開催されているように，比較的新しい学問である．今日においては米国のセンチネルや国内でも厚生労働省の懇談会による提言や改正 GPSP 省令を受けて医療データベースによる疫学的手法を適用した解析がなされるようになり，薬剤疫学が大きく注目されるようになった．その薬剤疫学の未来としては，さらに医療データベースの質と内容が充実され，また IoX や AI の進展によりシグナル検出は精度が増すと思われる．加えてゲノムデータも一層利用可能となりゲノム疫学との近接化や疾患登録などとのデータリンケージが可能となること，解析手法の高度化などが考えられる．そして単にビッグデータということで注目されるのではなく，そこから新たなエビデンスとして特に薬の安全性に関する Knowledge (知識) が生み出されていくことを期待したい．

BACKGROUND:Anticoagulant therapy is recommended in patients with atrial fibrillation (AF) but remains underused. The proper use of anticoagulants has been encouraged in guidelines frequently published over the past two decades.MATERIALS AND METHODS:In this study, we used insurance claims data collected from 2005 to 2014 to investigate the prevalence and incidence of non-valvular AF (NVAF) patients aged 20 to 74 years standardized to the Japanese population in 2012 and subdivided by stroke prevention drug type. We estimated the frequency of coagulation monitoring in patients with incident NVAF undergoing warfarin therapy in 2011 and later.RESULTS:From 2005 to 2014, the standardized prevalence of NVAF increased from 117/100,000 to 278/100,000 and the proportion of anticoagulant users increased from 38.4% to 58.0%, while that of antiplatelet monotherapy decreased from 32.3% to 12.0%. The standardized incidence of NVAF was stable at ~40/100,000 patient-years. The proportion of those patients who started anticoagulant soon after the initial diagnosis increased from 19.9% to 49.1% from 2006 to 2013. Among patients who started warfarin, switchers to DOAC had more frequent coagulation monitoring than non-switchers.CONCLUSION:The use of anticoagulant therapy has gradually increased in patients with NVAF in Japan during the study period from 2005 to 2014.

BackgroundIn Japan, several large healthcare databases have become available for research since the early 2000's. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims.MethodsWe selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI.ResultsIn a random sample of 200 patients, the average age was 67.7years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%.ConclusionThe PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke.