Initial Triple Combination Therapy Including Intravenous Prostaglandin I2 for the Treatment of Patients with Severe Pulmonary Arterial Hypertension.

Upfront combination therapy including intravenous prostaglandin I2 (PGI2-IV) is recognized as the most appropriate treatment for patients with severe pulmonary arterial hypertension (PAH). This retrospective study aimed to determine reasons why this therapy is not used for some patients with severe PAH and describe the hemodynamic and clinical prognoses of patients receiving initial combination treatment with (PGI2-IV+) or without (PGI2-IV-) PGI2-IV.Data for patients with severe PAH (World Health Organization Functional Class III/IV and mean pulmonary arterial pressure [mPAP] ≥ 40 mmHg) were extracted from the Japan Pulmonary Hypertension Registry. Overall, 73 patients were included (PGI2-IV + n = 17; PGI2-IV- n = 56). The PGI2-IV+ cohort was younger than the PGI2-IV- cohort (33.8 ± 10.6 versus 52.6 ± 18.2 years) and had higher mPAP (58.1 ± 12.9 versus 51.8 ± 9.0 mmHg), greater prevalence of idiopathic PAH (88% versus 32%), and less prevalence of connective tissue disease-associated PAH (0% versus 29%). Hemodynamic measures, including mPAP, showed improvement in both cohorts (post-treatment median [interquartile range] 38.5 [17.0-40.0] for the PGI2-IV + cohort and 33.0 [25.0-43.0] mmHg for the PGI2-IV - cohort). Deaths (8/56) and lung transplantation (1/56) occurred only in the PGI2-IV - cohort.These Japanese registry data indicate that older age, lower mPAP, and non-idiopathic PAH may influence clinicians against using upfront combination therapy including PGI2-IV for patients with severe PAH. Early combination therapy including PGI2-IV was associated with improved hemodynamics from baseline, but interpretation is limited by the small sample size.

Assessment of coding-based frailty algorithms for long-term outcome prediction among older people in community settings: a cohort study from the Shizuoka Kokuho Database.

OBJECTIVES: To assess the applicability of Electronic Frailty Index (eFI) and Hospital Frailty Risk Score (HFRS) algorithms to Japanese administrative claims data and to evaluate their association with long-term outcomes. STUDY DESIGN AND SETTING: A cohort study using a regional government administrative healthcare and long-term care (LTC) claims database in Japan 2014-18. PARTICIPANTS: Plan enrollees aged ≥50 years. METHODS: We applied the two algorithms to the cohort and assessed the scores' distributions alongside enrollees' 4-year mortality and initiation of government-supported LTC. Using Cox regression and Fine-Gray models, we evaluated the association between frailty scores and outcomes as well as the models' discriminatory ability. RESULTS: Among 827,744 enrollees, 42.8% were categorised by eFI as fit, 31.2% mild, 17.5% moderate and 8.5% severe. For HFRS, 73.0% were low, 24.3% intermediate and 2.7% high risk; 35 of 36 predictors for eFI, and 92 of 109 codes originally used for HFRS were available in the Japanese system. Relative to the lowest frailty group, the highest frailty group had hazard ratios [95% confidence interval (CI)] of 2.09 (1.98-2.21) for mortality and 2.45 (2.28-2.63) for LTC for eFI; those for HFRS were 3.79 (3.56-4.03) and 3.31 (2.87-3.82), respectively. The area under the receiver operating characteristics curves for the unadjusted model at 48 months was 0.68 for death and 0.68 for LTC for eFI, and 0.73 and 0.70, respectively, for HFRS. CONCLUSIONS: The frailty algorithms were applicable to the Japanese system and could contribute to the identifications of enrollees at risk of long-term mortality or LTC use.

Real-World Evidence of the Incidence of and Risk Factors for Type 1 Diabetes Mellitus and Hypothyroidism as Immune-Related Adverse Events Associated With Programmed Cell Death-1 Inhibitors.

OBJECTIVE: The incidence of type 1 diabetes mellitus (T1DM) and hypothyroidism as immune-related adverse events (irAEs) after programmed cell death-1 inhibitor (PD-1i) administration has not yet been sufficiently evaluated in a real clinical setting. To assess the incidence of T1DM and hypothyroidism among PD-1is and to identify the risk factors associated with hypothyroidism using a large claims database. METHODS: This cohort study used the Shizuoka Kokuho database in Japan from 2012 to 2018, including approximately 2.2 million people. We enrolled 695 PD-1i-treated patients. T1DM and hypothyroidism as irAEs were identified using International Classification of Diseases 10th Revision and Anatomical Therapeutic Chemical classification codes. Risk factors for hypothyroidism were explored using the multivariable Fine and Gray regression model after adjusting for age group and sex, treating death as a competing risk. RESULTS: The cumulative incidences of T1DM and hypothyroidism were 0.3% and 8.3%, respectively. We described the detailed onset timing of irAEs in patients with T1DM and hypothyroidism; hypothyroidism was observed evenly within 1 year of the PD-1i prescription. Sex and certain cancer types, such as lung and urothelial cancers, were significantly associated with subdistribution hazard ratio (sHR) (female: sHR, 2.04 [95% CI, 1.20-3.47]; lung cancer: sHR, 0.55 [95% CI, 0.32-0.95]; and urothelial carcinoma: sHR, 2.40 [95% CI, 1.05-5.49]). CONCLUSION: The incidence of T1DM and hypothyroidism as irAEs and associated risk factors identified in this analysis were comparable to those found in previous studies. The use of a large claims database to detect irAEs, such as T1DM and hypothyroidism, may lead to safer use of PD-1is.

Risk prediction models in patients undergoing percutaneous coronary intervention: A collaborative analysis from a Japanese administrative dataset and nationwide academic procedure registry.

BACKGROUND: Contemporary guidelines emphasize the importance of risk stratification in improving the quality of care for patients undergoing percutaneous coronary intervention (PCI). We aimed to investigate whether adding information from a procedure-based academic registry to administrative claims data would improve the performance of risk prediction model. METHODS: We combined two nationally representative administrative and clinical databases. The study cohort comprised 43,095 patients; 18,719 and 23, 525 with acute [ACS] and chronic [CCS] coronary syndrome, respectively. Each population was randomly divided into the logistic regression model (derivation cohort, 80%) and model validation (validation cohort, 20%) groups. The performances of the following models were compared using C-statistics: (1) variables restricted to baseline claims data (model #1), (2) clinical registry data (model #2), and (3) expanded to both claims and clinical registry data (model #3). The primary outcomes were in-hospital mortality and bleeding. RESULTS: The primary outcomes occurred in 3.7% (in-hospital mortality)/5.0% (bleeding) of patients with ACS and 0.21%/0.95% of CCS patients. For each event, the model performance was 0.65 (95% confidence interval [CI], 0.60-0.69) /0.67 (0.63-0.71) in ACS and 0.52 (0.35-0.76) /0.62 (0.54-0.70) for CCS patients in model #1, 0.83 (0.80-0.87) /0.77 (0.74-0.81) in ACS and 0.76 (0.60-0.92) /0.67 (0.59-0.75) in CCS for model #2, and 0.83 (0.79-0.86) /0.78 (0.75-0.81) in ACS and 0.76 (0.61-0.92) /0.67 (0.58-0.74) in CCS for model #3. CONCLUSIONS: Combining clinical information from the academic registry with claims databases improved its performance in predicting adverse events.

Frailty and subsequent adverse outcomes in older patients with atrial fibrillation treated with oral anticoagulants: The Shizuoka study.

Background: In older patients with atrial fibrillation (AF), frailty is frequently prevalent. However, the prognostic value of frailty for adverse events after initiation of oral anticoagulants (OACs) is unclear. Objectives: We assessed whether frailty at the time of OAC initiation is associated with subsequent bleeding or embolic events. Methods: We extracted patients aged ≥65 years with nonvalvular AF in whom OACs were initiated from a universal administrative claims database incorporating primary and hospital care records in Shizuoka, Japan, between 2012 and 2018. Frailty was assessed using the electronic frailty index (eFI). The association of frailty with bleeding events and ischemic stroke/transient ischemic attack were evaluated using the Fine-Gray model and restricted cubic spline model. Results: Among 12,585 patients with AF, 7.8% were categorized as fit, 31.5% as mildly frail, 34.8% as moderately frail, and 25.9% as severely frail. The risk of bleeding was associated with a higher eFI (adjusted subdistribution hazard ratio [95% CI] for fit or mild frailty: 1.15 [1.02-1.30]; moderate frailty: 1.42 [1.24-1.61]; and severe frailty: 1.86 [1.61-2.15]), whereas the association was weaker for ischemic stroke/transient ischemic attack. The spline models demonstrated that the relative hazard for bleeding increased steeply with increasing eFI. Conclusion: Patients with frailty in whom OAC therapy is initiated have higher risk of bleeding, highlighting the importance of discussing this increased risk with patients with AF who have frailty and assessing frailty at the time of OAC initiation.

Persistence of tolvaptan medication for autosomal dominant polycystic kidney disease: A retrospective cohort study using Shizuoka Kokuho Database.

Autosomal dominant polycystic kidney disease (ADPKD) is a rare hereditary disease leading to end-stage renal failure in approximately half of patients by seventy years of age. It is important to continuously take tolvaptan to control disease progression. However, adherence to tolvaptan in a real-world setting, rather than randomized controlled trials (RCTs), has not been sufficiently reported. We aimed to investigate tolvaptan persistence among patients with ADPKD using a large claims database. Using the Shizuoka Kokuho Database, we identified patients diagnosed with ADPKD who were prescribed tolvaptan from March 2014-September 2018 in Japan. The persistence rate of tolvaptan medication was estimated by Kaplan-Meier analysis, and patient background factors associated with treatment discontinuation were exploratively evaluated with log-rank tests. We identified 1714 eligible patients with ADPKD, and among them, 25 patients used tolvaptan medication. We followed up these patients, whose median treatment duration was 21 months. The persistence rates at 12, 24, and 36 months were estimated to be 70.8% (95% confidence interval: 48.2-93.4), 46.5% (23.2-66.9), and 38.7% (16.4-60.8), respectively. In the exploratory analysis, there were no factors that were obviously associated with tolvaptan discontinuation. The persistence rate of tolvaptan in patients with ADPKD in a real-world setting may be lower than that in previous RCTs. Our innovative method, particularly in Japan, to analyze adherence using large claims data should change the way clinical epidemiological research and health policies of rare diseases are designed in the future.

Cost reduction associated with transradial access in percutaneous coronary intervention: A report from a Japanese nationwide registry.

Background: Percutaneous coronary intervention (PCI) is increasingly performed via transradial access (TRA). This study aimed to investigate the clinical and economic benefits of TRA compared with transfemoral access (TFA) under universal healthcare coverage system in Japan. Methods: A total of 36,153 patients (acute coronary syndrome [ACS], 15,266; stable ischemic heart disease [SIHD], 20,052) across 714 institutions in the Japanese nationwide PCI registry (J-PCI) in 2015 were analyzed (mean age 69.9 ± 11.1 years and 23.6% female). Cost was defined as the total amount of healthcare resources used to care for the patient during hospitalization. Propensity score matching analysis was conducted to balance the baseline characteristics of patients undergoing TRA and TFA. Findings: The median total cost of PCI was JPY 1,341,176 (interquartile range, 959,052), with higher expenses for ACS (JPY 1,772,116 [1,117,107]) compared with SIHD (JPY 1,119,153 [540,440]) patients. Most patients underwent PCI via TRA (73.8%), and after propensity score matching, TRA was associated with a reduced risk of in-hospital death and bleeding (0.88% vs. 1.91% [P < 0.0001] and 2.18% vs. 4.53% [P < 0.0001] in ACS, and 0.10% vs. 0.28% [P = 0.070] and 0.53% vs. 1.72% [P < 0.0001] in SIHD, respectively), which led to lower costs in both ACS (JPY 1,699,279 [1,164,554] for TRA vs. JPY 1,931,255 [1,070,222] for TFA; P < 0.0001), and SIHD (JPY 1,102,352 [505,904] for TRA vs. JPY 1,311,525 [706,450] for TFA; P < 0.0001) patients. Interpretation: In this direct cost analysis of a nationwide registry, the use of TRA was associated with cost saving for both ACS and SIHD patients. Funding: This study was funded by the Japan Society for the Promotion of Science (grant nos. 20H03915, 16H05215, 16KK0186, 20K22883, and 21K08064), Japan Agency for Medical Research and Development [AMED] (grant number 16lk1010004h0002), and the National Clinical Database. The J-PCI registry is led and supported by the Japanese Association of Cardiovascular Intervention and Therapeutics.

Changes in the Characteristics and Initial Treatments of Pulmonary Hypertension Between 2008 and 2020 in Japan.

Background: Pulmonary arterial hypertension (PAH) is a rare, progressive disease. The treatment landscape for PAH in Japan has evolved considerably in recent years, but there is limited knowledge of the changes in treatment practices or patient characteristics. Objectives: The aim of this study was to evaluate the changes in characteristics and initial treatments for PAH in Japan over time. Methods: This study used data from the Japan Pulmonary Hypertension Registry (JAPHR) to compare patient characteristics and treatment practices between 2008-2015 (n = 316) and 2016-2020 (n = 315). Results: The mean ± standard deviation age at diagnosis increased from 47.9 ± 16.7 years in 2008-2015 to 52.7 ± 16.9 years in 2016-2020. The mean pulmonary arterial pressure decreased from 45.4 ± 15.0 to 38.6 ± 13.1 mm Hg. Idiopathic/hereditary PAH was the most common etiology in both periods (50.0% and 51.1%, respectively). The proportion of patients prescribed oral/inhaled combination therapies increased from 47.8% to 57.5%. Oral/inhaled combination therapies were frequently prescribed to patients with congenital heart disease-related PAH (81.8%). There was no significant trend in prescribing practices based on French low-risk criteria: among patients with 0, 1, 2, 3, or 4 criteria, 53.8%, 68.8%, 52.8%, 66.7%, and 39.4% were prescribed oral/inhaled combination therapies, and 0%, 16.7%, 27.0%, 17.3%, and 15.2% were prescribed oral/inhaled monotherapies. Macitentan, tadalafil, selexipag, and epoprostenol were the most frequently prescribed drugs. Conclusions: The severity of PAH decreased over time in Japan. Oral/inhaled combination therapies were generally preferred. Physicians generally prescribed therapies after considering the patients' hemodynamics and clinical severity. (Japan Pulmonary Hypertension Registry [JAPHR]; UMIN000026680).

Incidence of adverse cardiovascular events in type 2 diabetes mellitus patients after initiation of glucose-lowering agents: A population-based community study from the Shizuoka Kokuho database.

AIMS/INTRODUCTION: Increased incidence of hospitalization for heart failure (HHF) among patients with diabetes is increasingly being reported. We investigated the incidence of adverse cardiovascular events including HHF among patients with type 2 diabetes mellitus, and the potential clinical improvement with sodium-glucose cotransporter 2 inhibitors (SGLT2i) using a contemporary administrative claims database from a large governmental district of Japan. MATERIALS AND METHODS: We included initiators of any oral glucose-lowering drugs between 2013 and 2018. We estimated the 5-year cumulative incidence of hospitalization for HF, myocardial infarction and stroke, treating death as a competing risk. We evaluated the possible impact of introducing SGLT2i to the potential recipients of the drug, using the inclusion criteria from Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trials, assuming the same risk reduction as theirs. RESULTS: Among 23,340 drug initiators (54.0% men, and 6.4% aged >85 years), the 5-year cumulative incidence was 5.4% (95% confidence interval 4.9-5.9%) for HHF, 1.9% (95% confidence interval 1.7-2.2%) for myocardial infarction admission and 6.1% (95% confidence interval 5.7-6.6%) for stroke admission. Among 6,192 patients with laboratory test data, 651 (10.5%) and 2,680 (43.3%) patients met the EMPA-REG-like and DECLARE-like criteria, respectively. The 5-year cumulative incidence among the 2,849 patients meeting either of the criteria was estimated to decrease from 97.1 to 75.6 events through 75% adoption of SGLT2i. CONCLUSIONS: The incidence of HHF was similar to that of stroke. A significant portion of our cohort met the inclusion criteria for major randomized clinical trials for SGLT2i, and estimated reduction in the HHF events was substantial.

Use of oral antidiabetic drugs in Japanese working-age patients with type 2 diabetes mellitus: dosing pattern for metformin initiators.

Objective: To determine the pattern of antidiabetic drug use, with a particular focus on the metformin dose, among patients with type 2 diabetes mellitus (T2DM) in a Japanese working population.Methods: We used an administrative claims database linked to yearly health check-up data from large corporations. Data were collected for T2DM patients who began using an antidiabetic drug between 2014 and 2017 (n = 20,401). We evaluated the type of antidiabetic drug used and the characteristics of the patients using each type of drug. Among the metformin users, we assessed the titration in its dose or treatment during the 12 month period after initiation at 3 month intervals.Results: Among 20,401 new antidiabetic users, the most frequently used agents during the study period were dipeptidyl peptidase-4 inhibitors (DPP4is; 47.4%), followed by biguanides (18.5%) and sodium glucose cotransporter-2 inhibitors (SGLT2is; 6.7%). Most patients who initiated with metformin were prescribed 500 mg or less daily (72.9%); only 2.0% were prescribed a daily dose of >1000 mg. Moreover, 27% remained on the same daily dose during the 1 year follow-up, whereas another 29.9% discontinued their antidiabetic treatment altogether.Conclusions: A unique pattern of prescription was observed amongst Japanese patients with T2DM, and DPP4is, rather than metformin, were predominantly used as the first-line treatment. SGLT2is were infrequently prescribed. Metformin was prescribed at a daily dose of ≤500 mg in many patients. Greater efforts are needed to assess the comparative effectiveness of these treatment strategies.

Adherence to antihypertensive medication and its predictors among non-elderly adults in Japan.

Nonadherence to antihypertensive drugs is a primary reason for suboptimal clinical outcomes among hypertensive patients. We assessed adherence to newly initiated antihypertensive medications in non-elderly Japanese patients and examined which patient and facility characteristics were associated with low adherence. We selected new oral antihypertensive drug users, aged 30-74 years, between 2014 and 2016 from a large administrative claims database. We measured adherence as the proportion of days covered (PDC) during a 1-year follow-up and divided patients into three groups of low (PDC < 40%), intermediate (PDC ≥ 40% to <80%), and high (PDC ≥ 80%) adherence. Factors associated with low adherence were assessed by logistic regression analysis with generalized estimating equations. Among 31,592 patients (mean age, 51.7 years; 41.2% female), the median 1-year PDC was 88.5% (IQR: 41.9-98.1%). In total, 59.2%, 16.6%, and 24.2% of patients were categorized as having high, intermediate, and low adherence, respectively. Female sex (odds ratio [OR] 1.15, 95% confidential interval [95% CI] 1.08-1.22), younger age, and the initiation of angiotensin-converting enzyme inhibitors (OR 1.37, 95% CI 1.12-1.66), beta-blockers and thiazide diuretics (OR 4.82, 95% CI 4.34-5.36 and OR 3.91, 95% CI 2.79-5.46, respectively; compared with angiotensin II receptor blockers) were associated with low adherence. Patients initiating antihypertensives at larger hospitals (≥200 beds) were more likely to be adherent. While adherence to antihypertensive drugs in non-elderly Japanese patients was relatively high compared with that reported in previous studies in Western countries, patients with intermediate-low adherence may benefit from targeted interventions.

[Process of "aseri" as experienced in the daily life of young adults].

"Aseri" is a Japanese term referring to an emotional state of "being impatient" or "feeling time urgency" that is experienced in everyday life. This study explored how people in early adulthood experienced aseri in their daily lives. Interviews were conducted with twenty young adults who recalled events or situations involving aseri. Grounded theory was referred in collection and analysis of data. The results showed that aseri developed in situations where there were several competing thoughts. Regarding the process in which aseri changed, two patterns were found: (a) when aseri was strongly experienced in the short term, it settled down easily; (b) when aseri was felt mildly in the long term, it gradually became latent. The theme of latent aseri reflected the developmental tasks of early adulthood that were considered significant for the participants including developmental tasks typically achieved in adolescence that were put off until early adulthood. Implications for aseri and directions for further research are discussed.