Patients In Japan Research Articles

Increased national critical care demands were associated with a higher mortality of intubated COVID-19 patients in Japan: a retrospective observational study

BackgroundThere was no study to investigate the association between the national surge of Coronavirus disease 2019 (COVID-19) patients and the mortality of mechanically ventilated COVID-19 patients. The aim of this study was to assess the association between mortality in mechanically ventilated COVID-19 patients and two distinct national COVID-19 surge indices: (1) the daily number of newly confirmed COVID-19 cases, representing overall medical demands and (2) the total number of critically ill COVID-19 patients, reflecting critical care demands.MethodsWe analyzed the patient data registered in a national database of mechanically ventilated COVID-19 patients between February 6, 2020, and May 16, 2023, combined with the data officially published by the Japanese government. Multivariable logistic regression analysis was performed to evaluate the association of these two indices with COVID-19 mortality. A generalized linear mixed effect model was used to examine the relationships between the variation in the impact of critical care demands across hospitals and the variation in baseline risk across hospitals.ResultsThe data of 8327 patients from 264 centers in Japan were analyzed. The overall mortality rate was 24% (1990/8327). The critical care demands, but not overall medical demands, were independently associated with the mortality (OR, 1.11; 95% CI 1.07–1.16; p < 0.001). This effect of critical care demands on the mortality was more pronounced in hospitals with higher baseline risk (r = 0.67).ConclusionsThe national critical care demands were independently associated with the mortality of COVID-19 patients requiring mechanical ventilation. This effect was more pronounced in hospitals with higher baseline risk.

Evaluation of self-stigma in patients with epilepsy: Validation of the self-stigma scale to Spanish (ESSS-S).

The Epilepsy Self-Stigma Scale (ESSS) has been developed in Japan for patients with epilepsy (PWE). We aimed to validate the scale in Spanish and examine its validity and reliability. The transcultural adaptation of the ESSS was conducted using translation and back-translation, along with pilot testing and an expert panel review. An online questionnaire was used to assess construct validity, criterion validity, and internal consistency. A total of 260 out of 628 participants completed the questionnaires. We found a two-factor structure that explained 61.3% of the total variance: factor 1 "self-perceived discrimination" with a Cronbach's alpha of 0.80, and factor 2 "social isolation" with a Cronbach's alpha of 0.75. The reliability of overall ESSS-S 8-item scores was high (Cronbach's alpha = 0.74). Convergent validity was tested and demonstrated a significant correlation. P. Self-perceived discrimination scores were associated with higher anxiety and depression scores (r = 0.53/0.54; p < 0.001), lower self-esteem (-0.53; p < 0.001), and lower quality of life (r = -0.66; p < 0.001). Social isolation scores were associated with higher anxiety and depression scores (r = 0.41/0.33; p < 0.001), lower self-esteem (-0.34; p < 0.001), and lower quality of life (r = -0.35; p < 0.001). Temporal reliability was also tested, showing a test-retest ICC of 0.87. The mean self-stigma score in the Spanish population was 17.68 ± 5.45 out of 32 points. Invariance across gender and age groups indicated that there are no systematic response biases by gender or age, so stratified scores could be related to other constructs. The Spanish version of ESSS (ESSS-S) is a valid and reliable tool for the assessment of self-stigma in PWE among Spanish speakers. This study aimed to validate the Epilepsy Self-Stigma Scale (ESSS) for Spanish speakers (ESSS-S). We conducted transcultural adaptation of the scale. ESSS-S showed high reliability and strong validity, correlating with higher anxiety and depression, lower self-esteem, and quality of life. ESSS-S is a reliable and valid tool for assessing self-stigma in Spanish-speaking people with epilepsy.

Patient and family burden in pediatric atopic dermatitis and its treatment pattern in Japan.

This study evaluated the level of burden in pediatric and adolescent atopic dermatitis (AD) patients in Japan, the associated burden on caregivers/families, and whether this burden varied with age. Data were drawn from the Adelphi Pediatric AD Disease Specific Programme (DSP)™, a cross-sectional survey of physicians and their patients conducted in Japan between July and December 2022. Physicians reported patient demographics, clinical characteristics, disease burden, and current/previous therapies. Patients and/or caregivers reported perceived disease severity and impact of AD, including the Children's Dermatology Life Quality Index (CDLQI) and Dermatitis Family Impact questionnaire (DFI). Overall, 55 physicians provided data for 537 AD patients aged ≤17. Mean (SD) overall scores for CDLQI, POEM, and DFI were 9.3 (6.3), 8.3 (6.8), and 11.7 (7.2), respectively. Age was associated with higher patient and/or caregiver-reported CDLQI scores, which increased by 0.543 points per year of age (P = 0.01). Patients with severe disease reported a more significant impact on quality of life factors compared with mild patients (P < 0.001). Age was associated with higher caregiver-reported burden, with DFI scores increasing by 0.325 per year (P = 0.01). Physician-reported impact on caregivers showed that age was significantly associated with increased burden on sleep, daily activities, work, and mood (P < 0.05), with disease severity associated with impact across all factors (P < 0.01). Both increasing age and disease severity were associated with the increased impact of AD on patients and their caregivers. Disease control/modification through appropriate therapeutic intervention at a younger age may relieve the burden of pediatric AD on patients and their families.

A cost-effectiveness analysis of three surgical options for treating displaced femoral neck fractures in active older patients in Japan: A full economic evaluation.

For older patients with displaced femoral neck fractures, in which primary osteosynthesis is usually not indicated, there are three primary prosthetic options-bipolar hemiarthroplasty (BHA), single-bearing total hip arthroplasty (SB-THA), and dual-mobility THA (DM-THA). However, the optimal choice for managing displaced femoral neck fractures remains controversial. Accordingly, this study aimed to evaluate the cost-effectiveness of BHA, SB-THA, and DM-THA in active older patients with displaced femoral neck fractures. A decision tree combined with a Markov model was employed to analyze the cost and quality-adjusted life years (QALYs) of BHA, SB-THA, and DM-THA for the management in the Japanese healthcare system. By simulating the five-year trajectory of a 75-year-old woman treated for a displaced femoral neck fracture, the cost-effectiveness of the three surgical options was evaluated. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were used to assess parameter uncertainty. Additionally, two scenario analyses were conducted for other settings. The treatment was considered to be cost-effective when the incremental cost-effectiveness ratio (ICER) was below the 5,000,000 yen/QALY threshold. Compared with BHA, SB-THA exhibited higher costs but greater health benefits, resulting in an ICER of 1,499,440 yen/QALY. DM-THA offered additional health benefits compared with SB-THA, with an ICER of 4,145,777 yen/QALY. One-way sensitivity analysis revealed some influential parameters. PSA indicated that the probability of DM-THA, SB-THA, and BHA being cost-effective was 40.1%, 38.5%, and 21.4%, respectively. SB-THA was more cost-effective than BHA in patients aged 65-85 years, while DM-THA was more cost-effective than SB-THA in patients aged 65-75 years. The results suggest that SB-THA is a cost-effective alternative to BHA for displaced femoral neck fractures in active older patients, whereas DM-THA is more cost-effective than SB-THA in relatively younger patients. It is, therefore, recommended that orthopedic surgeons select the most appropriate surgical option based on the individual patient's physiological age.

Contemporary description of cardiac manifestations in ATTR amyloidosis: results from the multi-country OverTTuRe study

Abstract Background In transthyretin (ATTR) amyloidosis, amyloid fibrils accumulate in the myocardium, resulting in cardiac manifestations that can ultimately be fatal. The diverse presentation of this condition often results in prolonged diagnostic journeys for patients before they receive a definitive diagnosis of ATTR amyloidosis and treatment. Purpose To delineate the demographic and clinical characteristics of patients diagnosed with ATTR amyloidosis by cardiac manifestations, and to examine the duration from the first recorded cardiac manifestation to diagnosis. Methods OverTTuRe is a multi-country study generating real-world evidence from a cohort of patients identified as having ATTR amyloidosis between 2017-2022. Data were extracted from the US (Optum’s de-identified Clinformatics Data Mart Database) and Japan (Medical Data Vision Database). Additional analyses from European countries are ongoing. Patients aged ≥18 years with a recorded ICD-10 diagnosis code for ATTR amyloidosis (all phenotypes) or record for an ATTR-specific treatment were included. The index date was defined as first recorded date of diagnosis or ATTR-specific treatment. Patients with a diagnostic code or treatment indicative of secondary (AA) amyloidosis or light chain (AL) amyloidosis were excluded. Results 17,720 patients (median age: 75 years; 48.3% males) with ATTR amyloidosis were identified from the US and 4,690 from Japan (median age: 77 years; 57.0% males). Among individuals with 5 years of any available data prior to ATTR amyloidosis diagnosis (US: 9,147 [51.6%]; Japan: 2,600 [55.4%]), the most frequent initial cardiac manifestation ahead of ATTR amyloidosis was heart failure (US: 30.3%; Japan: 42.0%) followed by atrial fibrillation (21.9%) and cardiomyopathy (21.7%) in the US, and angina (21.6%) and atrial fibrillation (18.7%) in Japan. Among patients with 5 years of any available data before diagnosis plus cardiac manifestations, there were higher proportions of males than females and older individuals (Table). Median time from the earliest recording of any cardiac manifestation to the diagnosis of ATTR amyloidosis was 2.4 years (IQR: 0.9, 3.9) in the US and 1.2 years (IQR: 0.1, 3.2) in Japan. Median time to diagnosis increased with age and was similar across sexes in the US, whilst females in Japan had longer median time to diagnosis. Among the cardiac manifestations (heart failure, atrial fibrillation, cardiomyopathy, angina, aortic valve stenosis), 52.5% of patients in Japan had at least 2 manifestations, whilst in the US 59.4% of patients had more than 2 manifestations. Conclusions These findings highlight the prevalence of cardiac manifestations such as heart failure, in patients identified as having ATTR amyloidosis, particularly among men and elderly individuals. The observed delay in diagnosis of ATTR amyloidosis illustrates the importance of increased awareness to support early recognition and treatment to limit adverse clinical outcomes.

Real world evidence of Sacubitril/Valsartan in octogenarian patients with heart failure. Results From the PARACHUTE-HF Study

Abstract Introduction The beneficial effects of Angiotensin Receptor Neprilysin Inhibitors (ARNI) on heart failure (HF) patients, particularly those with reduced left ventricular ejection fraction (LVEF), have been highlighted in several randomized controlled trials. Since 2020, ARNI has been available for HF treatment in Japan, a country known for its aging population. However, the inclusion of octogenarians in previous trials has been limited, leaving a gap in evidence regarding ARNI's effectiveness in the elderly. Objective This study aims to explore the real-world efficacy and safety of ARNI treatment among octogenarian HF patients in Japan, reflecting its status as a leading aging society. Methods The Prospective Area Registry of ARNI for Congestive Heart failUre in Tokyo East (PARACHUTE) trial, a multicenter registry, was conducted. It involved patients newly prescribed ARNI for chronic HF regardless of LVEF between 2020 and 2021. We compared patient backgrounds, changes in NT-proBNP levels at 6 months, and the rate of ARNI discontinuation between groups aged below and above 80 years. Results The study enrolled 105 patients, with an average age of 75 years. Forty-six patients (44%) were over 80 years old, and the majority (72%) were male. Among the younger group, 50% had preserved LVEF, compared to 32% in the octogenarian group (p=0.01). Median NT-proBNP levels across all patients decreased significantly from 2,540 pg/mL at baseline to 998 pg/mL at 6 months. The reduction in NT-proBNP was similar between the two age groups, with no significant interaction (p=0.46). Discontinuation rates due to any cause were not significantly different between younger and older patients (7% vs. 13%, p=0.28). Conclusion ARNI treatment resulted in significant reductions in NT-proBNP levels in HF patients, both under and over 80 years of age, with comparable discontinuation rates. These findings highlight the effectiveness and safety of ARNI in the management of chronic HF in the elderly, offering valuable real-world evidence from Japan's unique demographic context.

The prognostic impact of renal dysfunction and anemia in japanese heart failure patients stratified by left ventricular ejection fraction

Abstract Background Renal dysfunction and anemia have been reported to be important prognostic factors in heart failure (HF) patients, but the differences in their effects stratified by left ventricular ejection fraction (LVEF) are not clear. Therefore, we investigated the prognostic impact of renal dysfunction and anemia in Japanese HF patients stratified by LVEF. Methods We combined two registry studies of acute HF patients in Japan and examined major events and associated factors during 2-year observation period. The primary endpoint was defined as all-cause mortality or HF hospitalization. Renal dysfunction was defined as eGFR &amp;lt;60 mL/min/1.73 m2, and anemia was defined as hemoglobin &amp;lt;13 g/dl in men and 12 g/dl in women. Two groups were also analyzed by LVEF (LVEF &amp;gt;50% and LVEF &amp;lt;49%). Results A total of 2142 patients were enrolled and analyzed. The mean observation period was 623±244 days. Mean age was 78.7 years. Forty-nine percent were male. Coronary artery disease and atrial fibrillation were present in 31% and 44% of patients, respectively. Medications included beta-blockers in 61% of patients and RAS inhibitors in 53%. Renal dysfunction was present in 1676 patients (74%) and anemia in 1523 patients (67%). Combination of both was observed in 1190 patients (53%). The primary endpoint was observed in 1015 patients, with 563 deaths and 737 HF hospitalizations. Multivariate analysis in a Cox proportional hazards model showed that renal dysfunction alone (HR: 1.39, 95%CI:1.06-1.81, p=0.02) and combination of renal dysfunction and anemia (HR 1.72, 95%CI:1.34-2.21, p&amp;lt;0.01) were independent prognostic factors in all patients. In patients with LVEF &amp;lt;49%, renal dysfunction alone (HR: 1.50, 95%CI:1.04-2.16, p=0.03) and combination of renal dysfunction and anemia (HR: 1.90, 95%CI:1.34-2.68, p&amp;lt;0.01) were predictive factors. On the other hand, in patients with LVEF &amp;gt;50%, only the combination of renal dysfunction and anemia were independent predictors (HR: 1.46, 95%CI:1.01-2.10, p=0.04). Conclusion We identified differences in the prognostic impact of anemia and renal dysfunction by LVEF.

Thirty days clinical outcomes following stent implantation with aspirin-free prasugrel monotherapy in non-ST segment elevation myocardial infarction. Interim report from ASET-Japan pilot study

Abstract Background Dual antiplatelet therapy with a P2Y12 inhibitor, in addition to aspirin, is the standard therapy after percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) to prevent ischemic cardiovascular events. The Acetyl-Salicylic Elimination Trial (ASET) pilot studies conducted in Japan in patients with NSTE-ACS investigated the safety and feasibility of a low-dose prasugrel monotherapy after PCI. Purpose To ensure the safety of the patients, enrolment in the study was implemented only after confirmation of a successful procedure. The abstract reports our interim analysis, aimed at evaluating preliminary safety and feasibility. Methods The ASET-Japan pilot study was designed to explore the feasibility and safety of a low dose of prasugrel monotherapy (3.75mg/day), without adjunctive aspirin, after optimal PCI using Everolimus eluting stent (EES) in Japanese patients with non-ST-segment elevation acute coronary syndromes. The primary endpoint in the ASET-Japan NSTE-ACS (Phase 2) is a 12-month clinical outcome. The study is currently in the follow-up phase. All the target lesions were treated with a platinum-chromium everolimus-eluting stent. The primary ischemic endpoint was the composite of cardiac death, spontaneous target vessel myocardial infarction, or definite stent thrombosis, and the primary bleeding endpoint was Bleeding Academic Research Consortium types 3 and 5 bleeding up to 12-month. If more than 3 events occurred, trial enrollment would have to be terminated by the data and safety monitoring board. Results One hundred one patients were enrolled after successful index PCI and completed a 30 days follow-up. The mean age was 69.1±12.3 years and 75.2% was male. The mean anatomical SYNTAX score was 7.9±4.7. Unstable angina (UAP) and NSTEMI were seen in 24.8% (25/101) and 75.2% (75/101) patients, respectively. According to the Braunwald classification, 8 percent of the patients were categorised as Class IA UAP, 48% as Class IB, 20% as Class IIB, 4% as Class IIIA and 20% as Class IIIB. In NSTEMI patients, the median (IQR) pre-procedural troponin value (cardiac Troponin T or I) was 2.79 (1.12 – 22.27) times the Upper Limit of Normal. According to the PRECISE DAPT score, 36.6% of patients were categorised as High Bleeding Risk (HBR) with scores above 25. At one month, the primary ischemic endpoints of cardiac death, target-vessel spontaneous MI or definite Stent thrombosis did not occur. Two patients (2.0%) had BARC type 3a bleeding. Conclusion Prasugrel monotherapy in the first 30 days following platinum-chromium everolimus-eluting stent deployment is a feasible and safe strategy in NSTE-ACS patients with simple anatomy and successful PCI.

An increasing trend of overweight and obesity in the Japanese incident end-stage kidney disease population.

The global prevalence of overweight/obesity has been rising, and this trend is apparent in US and European incident end-stage kidney disease (ESKD) populations. We aimed to examine temporal trends in the prevalence of overweight/obesity and underweight among adult incident ESKD patients in Japan by year of dialysis initiation between 2006 and 2019 in comparison with those observed in the Japanese adult population during the same period. Using data from the Japanese Society of Dialysis Therapy Renal Data Registry and the National Health and Nutrition Survey, the sex-specific prevalence of overweight/obesity and that of underweight (BMI ≥ 25 kg/m2 and <18.5 kg/m2, respectively) were calculated, adjusted for age according to the 2019 Population Census via the direct method. Average annual percentage changes (AAPCs) and corresponding 95% confidence intervals (CIs) were calculated to examine trends. From 2006 to 2019, the age-adjusted prevalence of overweight/obesity in the incident ESKD population increased for males (AAPC 3.36 [95% CI, 2.70 to 4.09]) and females (AAPC 2.86 [95% CI, 1.65 to 4.19]). The age-adjusted prevalence of overweight/obesity in the general population increased for males (AAPC 0.87 [95% CI, 0.26 to 1.42]) but not for females (AAPC 0.01 [95% CI, -0.55 to 0.57]). The age-adjusted prevalence of underweight in the incident ESKD population significantly decreased but was higher than that in the general population for both sexes. An increasing trend of overweight/obesity was observed in the incident ESKD population in Japan. There is a pressing need to address both underweight and overweight/obesity in the incident ESKD population.

Primary Adjunctive Corticosteroids in the Acute Management of High-Risk Kawasaki Disease in a North American Cohort.

Primary adjunctive therapy with corticosteroids have been shown to reduce coronary artery abnormalities in high-risk Kawasaki Disease (KD) patients in Japan (RAISE study). We evaluated their effect on outcomes in North American patients with high-risk KD. We performed a single-center retrospective review of high-risk KD patients between 2010 - 2023. From 2017-2023, adjunctive corticosteroids in a modified RAISE regimen (mRAISE) were given to high-risk patients as primary adjunctive therapy with intravenous gammaglobulin (IVIG) and aspirin. We compared CA outcomes in these patients and those presenting from 2010-2016, when mRAISE therapy was not administered. A total of 221 high-risk KD patients were treated at our institution between 2010-2023. Among these, 83 received the mRAISE regimen and 138 did not (no corticosteroid, n=82, corticosteroid in a non-mRAISE regimen, n=56). There were no significant differences in coronary artery outcomes in the mRAISE and non-mRAISE groups. Patients receiving the mRAISE regimen were significantly less likely to receive more than one dose of IVIG when compared to those who did not receive this regimen (11% vs 33%, p<0.001). Use of adjunctive primary therapy with corticosteroids in a mRAISE regimen in high-risk KD patients resulted in significantly decreased IVIG retreatment.

Delays in Cardiopulmonary Resuscitation, Defibrillation, and Epinephrine Administration in Out-of-Hospital Cardiac Arrest - Composite Time-Dependent Effects of Prehospital Interventions on 30-Day Favorable Neurological Outcomes and Social Implications From a Prospective Nationwide Population-Based Cohort Study.

Our study investigated the prognostic impacts of the interval between collapse and the initiation of cardiopulmonary resuscitation (CPR), and subsequent intervals to defibrillation or epinephrine administration, on 30-day favorable neurological outcomes following out-of-hospital cardiac arrest (OHCA). This nationwide population-based cohort study used the All Japan Utstein Registry, encompassing OHCA patients in Japan between January 2006 and December 2021. The primary outcome was 30-day favorable neurological outcomes, defined as Cerebral Performance Category 1 or 2. Three-dimensional plots and multivariable logistic regression models were used to assess the time-dependent prognostic impacts of prehospital CPR interventions. In all, 184,731 OHCA patients (86,246 with shockable rhythm and 98,485 with non-shockable rhythm) were included in the study. Three-dimensional plots revealed that the interval between collapse and initiation of CPR, and subsequent intervals to defibrillation or epinephrine, were independently associated with 30-day favorable neurological outcomes in the groups with shockable and non-shockable rhythms, respectively (P<0.05 for all). Among patients with witnessed OHCA, there was a dose-response relationship between delays in the collapse-CPR initiation interval, and subsequent intervals to defibrillation or epinephrine administration, and 30-day favorable neurological outcomes. Our findings provide valuable insights into OHCA management.

Perioperative complications in patients aged ≥85 years undergoing spinal surgery: a retrospective comparative study of pre-old and old patients in Japan.

A retrospective comparative study. To compare the characteristics of perioperative complications in patients aged ≥85 years with those of younger patients undergoing similar spine surgery and examine factors associated with perioperative complications and clinical outcomes among patients aged ≥85 years. The risk factors for perioperative complications and their effect on outcomes in patients aged ≥85 years remain unclear. Furthermore, no study has compared younger patients with similar surgeries and condition with those aged ≥85 years. The study included patients aged ≥65 years who underwent spinal surgeries. The patients aged ≥85, 75-84, and 65-74 years were categorized into the super-old, old, and pre-old groups, respectively. The differences in perioperative age-related complications were compared among the three groups while matching for surgical procedures and general conditions (study 1). Furthermore, preoperative and intraoperative factors were examined for perioperative complications in the super-old group (study 2). Complications were categorized into surgical site and systemic complications. The analysis included 44 patients from each group. In study 1, the total complication rates were 40.9%, 25%, and 18.2% of the super-old, old, and pre-old groups, respectively. Differences in complication rates were observed between the super-old and pre-old groups (p=0.011). In study 2, 58 patients from the super-old group were analyzed. Surgical site complications were significantly associated with longer surgical duration (p=0.02) and more estimated blood loss (p=0.003). Systemic complications were significantly associated with previous cerebrovascular disease (p=0.014), preoperative motor deficit (p=0.023), and emergency case (p=0.006) and negatively associated with diabetes mellitus (p=0.048). Perioperative complications increased with advancing age in the super-old, old, and pre-old groups. The complication type is associated with specific background factors; therefore, determining them may help prevent perioperative complications.

Decision regret after curative treatment and its association with the decision-making process and quality of life for prostate cancer patients.

To determine how the treatment decision-making process and posttreatment health-related quality of life (HRQOL) are related to regret about treatment choice for prostate cancer patients in Japan. We invited a total of 614 patients who were treated with radiation therapy (RT), radical prostatectomy (RP), or active surveillance/watchful waiting (AS/WW) from April 2007 to March 2021. Posttreatment regret was evaluated by the Decision Regret Scale. HRQOL was evaluated by the Expanded Prostate Cancer Index Composite and the 12-item Short Form Survey. The decision-making process was assessed by patient evaluation of the decision-making process. We compared the decision regret scale scores across treatment types, HRQOL, and decision-making processes. Data from 371 patients were analyzed (RT: 202, RP: 149, AS/WW: 20). The median length of time since treatment was 64 (IQR: 43-93) months. The decision regret scale scores were not significantly different among the treatment groups but were significantly greater (strong regret) in patients with poor urinary summary scores, bowel summary scores, and hormonal summary scores. The decision regret scale scores were significantly lower (less regret) for patients who reported being adequately informed at the time of the treatment decision and who had adequately communicated their questions and concerns to physicians than for patients who reported less adequate communication. This result was also observed among patients who reported low HRQOL scores. These findings underline the important influence of posttreatment HRQOL and decision-making as an interactive process between physicians and their patients on posttreatment regret in prostate cancer patients.

Drug-drug interactions between letermovir and tacrolimus in Japanese renal transplant recipients simulated using a physiologically based pharmacokinetic model.

Letermovir (LET) is a novel antiviral agent recently approved for cytomegalovirus (CMV) prophylaxis of renal transplant patients in Japan. However, its interactions with tacrolimus (TAC), an important immunosuppressant, remain ambiguous, warranting careful evaluation considering the unique genetic and physiological characteristics of Japanese patients. Therefore, in this study, we aimed to investigate the drug-drug interactions between LET and extended-release TAC (ER-TAC) in Japanese renal transplant patients via physiologically based pharmacokinetic (PBPK) modeling. We developed PBPK models for LET and TAC, including a new model for ER-TAC, using the Simcyp simulator. We also created a virtual Japanese post-transplant population by incorporating physiological parameters specific to Japanese patients, including CYP3A5 genotypes. Our model accurately predicted the pharmacokinetics of both immediate-release and ER-TAC co-administered with LET. In the Japanese population, LET significantly increased ER-TAC exposure, with the effect varying by CYP3A5 genotype. For CYP3A5*1 carrier, the area under the curve ratio ranged from 2.33 to 2.53, while for CYP3A5*3/*3 carriers, it ranged from 2.82 to 2.86. The maximum concentration ratio was approximately 1.50 across all groups. Our findings suggest reducing the ER-TAC dose by approximately 57-60% for CYP3A5*1 carrier and 65% for CYP3A5*3/*3 carriers when co-administered with LET for Japanese renal transplant patients. Moreover, the developed model incorporating population-specific factors, such as hematocrit values and CYP3A5 genotype frequencies, is a valuable tool to evaluate complex drug interactions and guide the dosing strategies for LET and TAC in Japanese patients. Overall, this study expands the application of PBPK modeling in transplant pharmacology, contributing to the development of effective immunosuppressive strategies for Japanese renal transplant patients.

Long-term safety and efficacy of ropeginterferon alfa-2b in Japanese patients with polycythemia vera.

Ropeginterferon alfa-2b (ropegIFN), a new-generation interferon-based agent, has been approved in Japan for patients with polycythemia vera (PV) who are ineligible for or respond inadequately to conventional treatment. However, long-term outcomes with ropegIFN in Japanese patients have not been reported. This extension of a phase2 study of ropegIFN in Japanese patients with PV aimed to determine its long-term safety/efficacy, and changes over time in JAK2 V617F allele burden. Here, we report data from the phase2 study and subsequent extension over a period of 36months. The primary endpoint was the complete hematologic response (CHR) maintenance rate without phlebotomy (hematocrit value < 45% without phlebotomy during the previous 12weeks, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L). The CHR maintenance rates were 8/27 (29.6%), 18/27 (66.7%), and 22/27 (81.5%) at 12, 24, and 36months, respectively. No thrombotic or hemorrhagic events occurred. The median allele burden change from baseline was - 74.8% at 36months. All patients experienced adverse events; 25/27 (92.6%) experienced adverse drug reactions (ADRs), but no serious ADRs or deaths occurred. This interim analysis demonstrated the safety and efficacy of ropegIFN over 36months in Japanese patients with PV.

Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: A retrospective claims database study.

Treatment trends for newly diagnosed multiple myeloma (NDMM) are not fully evaluated in real-world settings in the Japanese population. Triple-class exposed (TCE) patients with relapsed or refractory MM have a poor prognosis and limited treatment options. To clarify characteristics, treatment trends, and TCE status in Japanese patients with MM, we conducted a retrospective, non-interventional study. Data from patients with MM were extracted from a Japanese claims database between 2015 and 2022: this study identified patients with NDMM prescribed daratumumab (D), lenalidomide (R), and/or bortezomib (V) as 1st-line treatment. The patient characteristics and treatment trends were analyzed for non-transplant and transplant groups. Of 1,784 patients, non-transplant patients (n = 1,656, median age 75 years [range: 37-94]) received R+dexamethasone (Rd) (24.7%), Vd (23.8%), and RVd (15.6%) and transplant patients (n = 128, median age 61 years [range: 35-73]) received RVd (49.5%), Vd (18.7%), and DVd (8.4%) in 1st line. In the non-transplant group, the commonly prescribed treatment regimens were Rd for patients aged ≥75 years, Vd for patients aged 65-74 years, and RVd for patients aged <65 years. Patients with renal or cardiac dysfunction commonly received Vd or Rd, respectively. In the transplant group, 107 (83.6%) and 20 (15.6%) patients received transplantation in the 1st and 2nd lines, respectively. The top three regimens as induction therapy before stem cell transplantation were RVd (49.5%), Vd (18.7%), or DVd (8.4%) in 1st line. Cumulative TCE patients by 5th line were 351 (21.2%) and 56 (43.8%) for non-transplant and transplant patients, respectively. TCE ratio at each line gradually increased from 1st to 5th line (11.1-69.2% in the non-transplant group and 21.1-100% in the transplant group, respectively). Of 184 TCE patients in the non-transplant group, 89.7% received sequencing treatments including DRd, RVd, and DVd, and 10.3% received D-RVd in 1st line.

Low remission rates and high incidence of adverse events in a prospective VEXAS syndrome registry.

We aimed to gather real-world clinical evidence of detailed disease activity, treatments, remission rates, and adverse events (AEs) associated with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome in a prospective study. Patients in Japan suspected of having VEXAS syndrome were enrolled in a registry study. A novel disease activity measure (VEXASCAF) assessing 11 symptoms associated with VEXAS syndrome was evaluated at enrolment and after 3 months. AEs, survival, CRP levels, and treatments were also recorded at enrolment and 3 months after enrolment. All exons of UBA1 were sequenced using a next-generation sequencer to determine the variant allele frequencies of pathogenic variants in the peripheral blood of all patients. Of the 55 registered patients, 30 patients were confirmed to have pathogenic variants of UBA1. All patients were male, with a median age of 73.5 years. VEXASCAF and CRP levels decreased significantly at 3 months post-enrolment, but the oral prednisolone dose did not change. Only two patients achieved complete remission according to FRENVEX at 3 months after enrolment. During the observation period of 6 months, 28 AEs were observed, including 3 deaths, 4 malignancies from two cases, 2 thromboses, and 13 infections (including 4 mycobacterial infections). Inflammation of the lung and cervical region (i.e. parotid and submandibular gland swelling, tonsillitis, cervical swelling, and pain) were the most common AEs. Patients with VEXAS syndrome required high-dose glucocorticoids to achieve remission, and complications-such as malignancy, thrombosis, and infection-occurred frequently within a short observation period.

One-year seizure freedom and quality of life in patients with drug-resistant epilepsy receiving adjunctive vagus nerve stimulation in Japan.

Amount of seizure-free days is a critical determinant of quality of life (QoL) in patients with drug-resistant epilepsy (DRE). The fractions of patients experiencing prolonged periods of seizure freedom with adjunctive vagus nerve stimulation (VNS) have yet to be assessed on a large scale. Retrospective analysis of patients in the Japanese VNS prospective observational registry who experienced at least 1 year of seizure freedom from all seizures, focal seizures, or tonic-clonic seizures (TCS), as well as patient-reported change in QoL in these groups. The study included 362 patients with DRE, 147 were female (40.6%), and the median age at VNS implant was 23.0 years (range: 1.0-73.0). A total of 225 patients reported focal seizures and 184 patients reported TCS. After 36 months of adjunctive VNS, the cumulative proportion of patients experiencing at least 1 year of complete seizure freedom was 11% (38/356) with an average duration of seizure freedom of 19.4 months. In patients with focal seizures, 25% (n = 57/225) experienced at least 1 year of freedom from focal seizures with an average duration of 24.8 months. Higher cumulative rates of freedom from TCS were observed: 55% (n = 101/184) experienced at least 1 year without TCS with an average duration of TCS-free periods of 28.9 months. 82.1% of patients with 12-month complete seizure freedom reported markedly improved or improved QoL compared with 51.9% of patients who were not seizure-free. QoL changes in patients with 12-month seizure freedom from TCS and focal seizures were similar: 61.8% and 63% of respective patients reported either markedly improved or improved QoL at 36 months. Complete seizure freedom is rare in patients treated with VNS; however, this analysis found approximately half of patients who experienced TCS prior to VNS experienced prolonged periods of freedom from TCS with adjunctive VNS. We studied patients in Japan with epilepsy that is difficult to treat. To understand if adding vagus nerve stimulation (VNS) helps such patients, we looked at which patients stopped having all seizures or stopped having a specific seizure type (such as tonic-clonic seizures or focal seizures), and how long these periods lasted. With VNS treatment, about 2 out of 4 patients with tonic-clonic seizures and 1 out of 4 patients with focal seizures had more time without these seizure types. Without seizures, patients felt better about their daily lives. Even patients who still had seizures felt better about their daily lives after 3 years of VNS treatment. The clinical trial registry number is UMIN000014728.

Characteristics, Treatment, and Prognosis in Octogenarian and Older Patients With Acute Heart Failure in Japan - Prospective Observational Study on Acute Pharmacotherapy and Prognosis in Management of Acute Heart Failure (POPEYE-AHF Registry).

The number of older people in Japan is increasing more quickly than in other countries; with this aging of society, the number of elderly patients hospitalized for acute heart failure (HF) is also increasing. The treatment and prognosis of acute HF may be changing, but there are insufficient recent data, especially for octogenarian and older patients. This study investigated the characteristics and treatment of acute HF patients in Japan. From 2018 to 2020, 1,146 patients from 7 Tokai area hospitals were followed for at least 1 year. The mean age was 78 years. Compared with patients aged <80 years, those aged ≥80 years were more likely to be female (57.4% vs. 34.2%), have a lower body mass index (22.2 vs. 24.9 kg/m2), and have HF with preserved ejection fraction (43.1% vs. 21.4%), and less likely to have HF with reduced ejection fraction (38.9% vs. 61.7%). During hospitalization, 6.5% died. After discharge, patients faced high risks of rehospitalization for HF and death (27.6 and 14.2 per 100 patient-years, respectively). Notably, prescription rates of HF medications have declined over time for all patients, but especially for those aged ≥80 years. Guideline-directed medical therapy should be provided based on a thorough understanding of an individual's background rather than withheld simply because of clinical inertia due to a patient's advanced age.

Characteristics and outcomes of heart failure in Japan: A hospital-based administrative database analysis.

Epidemiological and outcome studies on patients in Japan with heart failure (HF) categorized by left ventricular ejection fraction (LVEF) are currently limited. The aim of this non-interventional database study was to provide further information on these patients. Administrative claims data and electronic medical records from hospitals participating in the Voluntary Hospitals in Japan (VHJ) organization were used. Patients hospitalized with a primary diagnosis of HF between 1 April 2017 and 30 March 2020 were categorized by baseline LVEF on echocardiogram: HF with reduced EF (HFrEF, LVEF <40%); HF with preserved EF (HFpEF, LVEF ≥50%); and HF with mildly reduced EF (HFmrEF, 40% to <50% LVEF). Patients were evaluated for baseline characteristics, pre-admission diagnosis, prescription drugs, length of hospitalization, HF treatment cost, overall cost of hospitalization, and in-hospital prescription. An exploratory analysis compared post-hospitalization mortality and re-hospitalization rates. In total, 10646 hospitalized patients from 17 VHJ hospitals were enrolled. Of these, 7212 were included in the analysis set and categorized into HFpEF (3183, 44.1%), HFmrEF (1280, 17.7%), and HFrEF (2749, 38.1%) groups based on baseline LVEF. Beta-blocker use increased during hospitalization, with a mean (95% confidence interval [CI]) of 23.3% (22.3-24.3) of patients receiving these agents before admission versus 69.4% (68.3-70.5) at discharge. Administration of diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) showed a similar trend. Differences in treatments were observed between HF categories at discharge, with a higher proportion (95% CI) of ACE inhibitor use in the HFrEF group (40.6% [38.7-42.4]) versus HFmrEF (27.5% [25.1-30.0]) and HFpEF (20.6% [19.2-22.1]) groups (P<0.0001), and more ARB use in the HFmrEF and HFpEF groups (32.5% [29.9-35.1] and 31.2% [29.6-32.9], respectively) versus HFrEF (25.1% [23.5-26.8]; P<0.0001). Mean (standard deviation [SD]) length of hospitalization was 22.2 (23.3) days, and the median (interquartile range) was 17 (11-25) days. Estimated average cost of HF treatment per patient during index hospitalization was 300090 yen with HFrEF treatment costing the most. Average total healthcare expenditure during hospitalization was 1225650 yen per index hospitalization per patient, with HFrEF also the most expensive. During a mean (SD) observation period of 324 (304) days, ~21% of patients in each group required re-hospitalization for HF, and 625 patients (8.7%) died. The proportion of patients in each HF category was largely consistent with existing data. Discharge medications indicated high prescription of guideline-directed therapy. This study provides real-world data on patients with HF in Japan that can help inform future clinical decision-making.