Japanese Clinical Practice Research Articles

Efficacy of rifaximin against covert hepatic encephalopathy and hyperammonemia in Japanese patients.

Covert hepatic encephalopathy (CHE) impairs patient quality of life and occurs in approximately 30% of liver cirrhosis (LC) cases. Japanese clinical practice guidelines recommend rifaximin to treat overt HE (OHE). However, the usefulness of rifaximin against CHE is not thoroughly investigated in Japanese patients. We aimed to investigate the efficacy of rifaximin against hyperammonemia and CHE in Japan. We observed 102 patients with HE showing hyperammonemia secondary to LC and examined various biochemical and behavioral parameters following rifaximin treatment. CHE was diagnosed when the patients exhibited two or more abnormal neuropsychological test (NPT) scores but did not indicate OHE symptoms. In the 102 cases, a significant therapeutic effect of rifaximin on hyperammonemia was observed from 2 to 48 weeks after starting treatment. Excluding 10 patients diagnosed with OHE upon starting rifaximin treatment, 12 of the 92 remaining patients (11.8%) transitioned to OHE within 1 year. The 1 year cumulative OHE transition rate was 14.5%. Among the 24 patients with CHE diagnosed by the NPT for whom NPT results could be evaluated at 4 and 12 weeks after starting treatment, 10 (41.6%) had recovered from CHE at 12 weeks. When the factors contributing to recovery from CHE were examined by multivariate analysis, an ammonia level <129 μg/dL was a significant factor. Rifaximin was thus significantly effective against both hyperammonemia and CHE in Japanese patients.

Japanese clinical practice guidelines for aspiration and pharyngeal residual assessment during eating and swallowing for nursing care.

This clinical practice guideline aims to provide and recommend methods of assessing aspiration and pharyngeal residue during eating and swallowing and methods of selecting and implementing nursing care for adults to prevent the development of aspiration pneumonia through early and appropriate management of oropharyngeal dysphagia. In April 2018, the Japan Academy of Nursing Science established the Supervisory Committee in Nursing Care Development/Standardization Committee to develop clinical practice guidelines for aspiration and pharyngeal residual assessment during eating and swallowing for nursing care. This clinical practice guideline was developed according to the Minds Manual for Guideline Development 2017, with the aim of providing a specific pathway for nurses to determine the policy for selecting management for oropharyngeal dysphagia based on research evidence and multifaceted factors including the balance of benefits and harms and patients' values. Based on the 10 clinical questions related to assessment by physical assessment, the Repetitive Saliva Swallowing Test, Modified Water Swallowing Test, Food Test, cervical auscultation, observation using an ultrasound diagnostic device, and an endoscope, 10 recommendations have been developed. Eight recommendations have been evaluated as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) 2C, and the other two have been evaluated as no GRADE. The first reliable clinical practice guideline has been produced from an academic nursing organization that focuses on assessment for nursing care and incorporates the latest findings.

Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection

Toxigenic culture and cytotoxicity assays are standard tests for detecting C. difficile infection (CDI). Others include immunochromatographic strips, a rapid diagnostic test that detects glutamate dehydrogenase (GDH and toxins simultaneously, and the nucleic acid amplification test (NAAT) that detects C. difficile toxin-producing genes. NAAT may not be available in some facilities, so a 2-step method can be adopted where GDH-positive and toxin-negative specimens are selected first, and then toxigenic culture is performed for these specimens.

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Symptom Improvement of ulceRative colitis after an Induction dose of UStekinumab in Japanese clinical practice (SIRIUS), measured using patient-reported outcomes: a prospective observational study

IntroductionUlcerative colitis (UC) is an idiopathic, chronic inflammatory disease of the large intestine. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23 and has proven efficacy...

Observational study of rebiopsy in EGFR-TKI-resistant patients with EGFR mutation-positive advanced NSCLC

The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20–87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

Effectiveness of Pembrolizumab in Patients with HNSCC in Japanese Real-World Clinical Practice

Effectiveness of Pembrolizumab in Patients with HNSCC in Japanese Real-World Clinical Practice

Recent Advances in Medical Therapy for Urological Cancers.

The mainstay of medical treatment has been tyrosine kinase inhibitors (TKIs) for renal cell cancer (RCC), cytotoxic chemotherapy for urothelial cancer (UC), and androgen deprivation therapy for prostate cancer. These therapeutic modalities still play important roles in these malignancies. However, immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 or CTLA-4 are being rapidly introduced for the treatment of metastatic urological cancers, just as they have been for other malignancies. Currently, the paradigm of medical treatment for patients with metastatic urological cancer is dramatically changing. Accordingly, we need to organize and summarize the new therapeutic tools, which include immune checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs). This review provides an overview of agents and regimens that have just launched or will be launched in the near future in Japan. Based on the promising anti-tumor efficacy and manageable safety profiles being demonstrated in clinical trials, these new agents and therapies are expected to be rapidly introduced in Japanese clinical practice. Additionally, the newly designed ADC, enfortumab vedotin, which comprises a fully human monoclonal antibody conjugated to an anti-cancerous agent via a protease-cleavable linker, has just been launched in Japan. In order to provide the optimal treatment for our patients, we need to completely understand these new therapeutic tools.

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: final results of a 3-year post-marketing surveillance study

ABSTRACT Background Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, was licensed for treating type 2 diabetes (T2D) in Japan and elsewhere in recent years. We conducted a post-marketing surveillance study of empagliflozin in Japan. Research design and methods This was a 3-year, prospective, multicenter, observational study of the safety and effectiveness of empagliflozin in T2D patients in Japanese clinical practice who had not previously received this medication. The primary endpoint was the incidence of adverse drug reactions (ADRs). Results Of 8145 patients enrolled from 1103 sites, 7931 received ≥1 dose of empagliflozin. Mean age was 58.7 years (10.5% aged ≥75), glycated hemoglobin (HbA1c) 8.0%, body mass index 28.1 kg/m2 (<20 kg/m2 in 2.1%); 63.0% were male and most had comorbidities (renal impairment in ~62%). Median treatment duration was 36.5 months. ADRs occurred in 1024 (12.91%) patients overall (serious ADRs in 2.09%) and 120 patients aged ≥75 years (14.46%). ADRs of special interest included hypoglycemia (0.44% of patients), urinary tract infections (1.07%), genital infections (0.66%), volume depletion (0.50%), diabetic ketoacidosis (0%), and lower limb amputation (0.04%). Overall mean change in HbA1c from baseline was –0.75%. Conclusions Empagliflozin is effective and generally well tolerated in Japanese patients, and ADRs are consistent with its known safety profile.

Quality assessment of Japanese clinical practice guidelines including recommendations for acupuncture

BackgroundThe quality of clinical practice guidelines (CPGs) should be extensively evaluated. This study aimed to evaluate Japanese CPGs that include recommendations for acupuncture. MethodsIn a literature search, CPGs including recommendations for acupuncture published in Japan until October 2021 were sought. We assessed (1) whether the CPGs were developed in accordance with the Grading Recommendations Assessment, Development and Evaluation (GRADE) system, (2) the quality of the CPGs using the Appraisal of Guidelines for Research and Evaluation (AGREE) II, and (3) whether the strength of the recommendations for acupuncture was consistent with each CPG's predefined procedure. ResultsSeventeen CPGs including 23 recommendations in total were identified and assessed. (1) Three CPGs were in accordance with the GRADE system. (2) The mean score of overall assessment using AGREE II was 4.5 on a 7-point Likert scale. The mean domain scores were 77% for domain 1 (scope and purpose), 54% for domain 2 (stakeholder involvement), 48% for domain 3 (rigor of development), 78% for domain 4 (clarity of presentation), 20% for domain 5 (applicability), and 51% for domain 6 (editorial independence). (3) The strength of the recommendations for acupuncture in two CPGs was judged to be underestimated. Some of the CPGs contained elementary problems that were not considered in AGREE II. ConclusionThe methodological quality of Japanese CPGs including recommendations for acupuncture was not necessarily high. Since technical issues exist in each field of therapy, the respective experts should be involved in developing and reviewing CPGs to disseminate accurate health information.

Comparison of Cryoballoon and Contact Force-Sensing Radiofrequency Ablation for Persistent Atrial Fibrillation in Clinical Practice.

Outcomes of cryoballoon ablation for persistent atrial fibrillation (AF) are unclear, especially in Japanese patients, so the effectiveness and safety of cryoballoon ablation in clinical practice were retrospectively compared with those of contact force-sensing radiofrequency (CFRF) ablation including the high-power protocol.Methods and Results:Consecutive patients with persistent AF were reviewed, and 253 and 265 patients who underwent cryoballoon and CFRF ablation, respectively, were enrolled. The primary endpoint was atrial arrhythmia recurrence. The secondary endpoints were periprocedural complications and repeat ablation. The rate of additional left atrial (LA) ablation after pulmonary vein isolation (PVI) was similar between groups (68.8% cryoballoon vs. 74.0% CFRF, P=0.19). Freedom from atrial arrhythmia recurrence was comparable between groups over a follow-up of 25.5±12.5 months (72.3% cryoballoon vs. 69.8% CFRF; adjusted hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.59-1.21, P=0.36). Outcomes were similar in the subgroups of PVI alone and PVI plus additional LA ablation. LA posterior wall isolation, absence of defragmentation, and low creatine clearance, but not catheter selection, were associated with the primary endpoint. Periprocedural complications (adjusted HR 0.73, 95% CI 0.34-1.54, P=0.41) and repeat ablation (adjusted HR 1.11, 95% CI 0.71-1.74, P=0.64) were similar for both procedures. Cryoballoon ablation for persistent AF in Japanese clinical practice had acceptable outcomes comparable to those of advanced CFRF ablation.

Multicenter, retrospective, observational study for the Treatment Pattern of systemic corticoSTERoids for relapse of non-infectious uveitis accompanying Vogt-Koyanagi-Harada disease or sarcoidosis.

Non-infectious uveitis associated with Vogt-Koyanagi-Harada (VKH) disease or sarcoidosis is commonly treated with systemic corticosteroids (SCS). We assessed the use of SCS for non-infectious uveitis relapses in Japanese clinical practice. Multicenter, retrospective chart review (UMIN Clinical Trial Registry; UMIN000032390). One hundred fifty-seven patients (15- ≤ 75years; 103 VKH disease, 54 sarcoidosis) given SCS to treat a relapse of non-infectious intermediate, posterior, or panuveitis accompanying VKH disease or sarcoidosis were studied (August 2011-December 2018). SCS dose and duration, concomitant medications, subsequent relapses, and steroid-related adverse drug reactions (ADRs) were analyzed for 12months after target relapse treatment. Relationships between background factors and total SCS dose were analyzed (logistic regression). Mean (± SD) total SCS dose over 12months after target relapse treatment was 3874 ± 2775mg, and was higher in patients with immunosuppressants than in those without (4575mg vs 3496mg). Immunosuppressant use was the only factor significantly associated with higher total SCS dose (p = 0.0196). Mean duration of SCS treatment for relapse was 318.7 ± 89.3days. Only 29.3% of patients were steroid-free after 12months; the percentage was higher in patients without immunosuppressants (36.3% vs 16.4%). Subsequent relapse was experienced by 39.5% of patients, and 13.4% had a steroid-related ADR (mostly glaucoma or diabetes). In Japanese clinical practice, many patients with recurrent uveitis accompanying VKH disease or sarcoidosis received SCS for relapse for ≥ 300days, suggesting that reducing corticosteroids is challenging in patients with difficulty suppressing inflammation.

Synopsis of a clinical practice guideline for pancreatic ductal adenocarcinoma with peritoneal dissemination in Japan; Japan Peritoneal Malignancy Study Group.

Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000‐2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels (“strong”, “medium”, “weak”, “very weak”). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. These guidelines address three subjects: diagnostic, chemotherapeutic, and surgical approaches. They include nine clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one “column”. This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020)

摂食嚥下時の誤嚥・咽頭残留アセスメントに関する看護ケアガイドライン

摂食嚥下時の誤嚥・咽頭残留アセスメントに関する看護ケアガイドライン

The revised recommendation for administering vitamin C in septic patients: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020.

The revised recommendation for administering vitamin C in septic patients: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022).

BackgroundCoronavirus disease (COVID‐19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J‐SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID‐19 using the experience of creating the J‐SSCG.MethodsThe Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of recommendations. The first edition of this guideline was released on September 9, 2020, and this is the revised edition (version 5.0; released on July 15, 2022). Clinical questions (CQs) were set for the following 10 drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), casirivimab/imdevimab (CQ9‐1), sotrovimab (CQ9‐2), molnupiravir (CQ10), and nirmatrelvir/ritonavir (CQ11).RecommendationsFavipiravir is not suggested for all patients with COVID‐19 (GRADE 2C). Remdesivir is suggested for patients with mild COVID‐19 who do not require oxygen, and patients with moderate COVID‐19 requiring supplemental oxygen/hospitalization (both GRADE 2B). Corticosteroids are recommended for moderate and severe COVID‐19 (GRADE 1B, 1A). However, their administration is not recommended for mild COVID‐19 (GRADE 1B). Tocilizumab is suggested for moderate and severe COVID‐19 (GRADE 2B, 2C). Anticoagulant administration is recommended for moderate and severe COVID‐19 (Good Practice Statement). Baricitinib is suggested for moderate and severe COVID‐19 (both GRADE 2C). Casirivimab/imdevimab and sotrovimab are recommended for mild COVID‐19 (both GRADE 2C). Molnupiravir and nirmatrelvir/ritonavir are recommended for mild COVID‐19 (both GRADE 2C). SARS‐CoV‐2 mutant strains emerge occasionally, and each time, the treatment policy at clinics is forced to change drastically. We ask health‐care professionals in the field to refer to the recommendations in these guidelines and use these to keep up to date with COVID‐19 epidemiological information.

Deciphering the clinical features of heterogeneous stage III non-small cell lung cancer in Japanese real-world clinical practice: Expanded cohort of the SOLUTION study

ObjectivesTo evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. Materials and methodsPatients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. ResultsThe study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18–20 and 12–14 weeks in the CRT and RT cohorts, respectively. ConclusionPatients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC.

Incidence and Clinical Features of Venous Thromboembolism in Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan.

Coronavirus disease 2019 (COVID-19) reportedly causes venous thromboembolism (VTE), but the status of this complication in Japan was unclear. The VTE and COVID-19 in Japan Study is a retrospective, multicenter cohort study enrolling hospitalized patients with COVID-19 who were evaluated with contrast-enhanced computed tomography (CT) examination at 22 centers in Japan between March 2020 and October 2020. Among 1,236 patients with COVID-19, 45 (3.6%) were evaluated with contrast-enhanced CT examination. VTE events occurred in 10 patients (22.2%), and the incidence of VTE in mild, moderate, and severe COVID-19 was 0%, 11.8%, and 40.0%, respectively. COVID-19 patients with VTE showed a higher body weight (81.6 vs. 64.0 kg, P=0.005) and body mass index (26.9 vs. 23.2 kg/m2, P=0.04), and a higher proportion had a severe status for COVID-19 compared with those without. There was no significant difference in the proportion of patients alive at discharge between patients with and without VTE (80.0% vs. 88.6%, P=0.48). Among 8 pulmonary embolism (PE) patients, all were low-risk PE. Among a relatively small number of patients undergoing contrast-enhanced CT examination in Japanese real-world clinical practice, there were no VTE patients among those with mild COVID-19, but the incidence of VTE seemed to be relatively high among severe COVID-19 patients, although all PE events were low-risk without significant effect on mortality risk.

Abstract 10141: Outcomes in Elderly Patients with Hospitalized Heart Failure Stratified by Left Ventricular Ejection Fraction

Introduction: The prevalence of heart failure (HF) has increased markedly with age. Given the influence of age and left ventricular ejection fraction (LVEF) on the mortality in HF, the assessment of clinical outcomes in elderly patients stratified LVEF categories may provide better care decisions in clinical settings. Methods: Between 2006 and 2017, 3558 consecutive patients enrolled in a prospective multicenter registry in Japan (the West Tokyo Heart Failure registry) were analyzed. We divided the patients into three age groups: &lt;65 years (younger), 75-84 years (elderly), and ≥85 years (very-elderly) by each LVEF subgroup (HF with preserved ejection fraction [HFpEF, LVEF ≥50%] or non-HFpEF [LVEF &lt;50%]). The primary endpoint was all-cause mortality after discharge. We performed a multivariate cox proportional hazards analysis to identify the risk factors for all-cause death using several covariates. Results: Overall, 1505 HFpEF (younger: n=182, elderly: n=894, very-elderly: n=429) and 2053 non-HFpEF (younger: n=575, elderly: n=1159, very-elderly: n=319) were included in this study. During the median follow-up period of 2.0 years, the incidence of all-cause death was almost similar in both HFpEF and non-HFpEF groups (19.2% vs. 20.3%, p=0.60 for log-rank test). The mortality increased substantially with increasing age categories, and also differed by LVEF categories (Figure). After multivariable adjustments, age (per 1-year increase) and LVEF (per 1% decrease) were the significant predictors of all-cause death (age: hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.05, p&lt;0.001; LVEF: HR 1.01, 95% CI 1.01-1.02, p&lt;0.01). Conclusions: In contemporary Japanese clinical practice with aging, age was closely associated with higher risks for all-cause death, and the mortality was stratified by LVEF categories.