Keiko Hosohata

Objective To evaluate the disproportionality, times to onset, and outcomes of cardiac adverse events (AEs) associated with axitinib, using data from the Japanese Adverse Drug Event Report (JADER) database. Methods We analyzed data for the period from April 2004 to December 2024. Those on cardiac AEs were extracted and the disproportionality of axitinib-associated AEs was assessed by calculating reporting odds ratios (RORs). Results Of the 2,988,681 reports with sex and age information, we identified 4788 reports of AEs associated with axitinib, including 508 cardiac AEs. Signals were detected for 16 cardiac AEs after adjustment for sex and age. Fatal outcomes were reported for five of these events with particularly high rates observed for cardiac failure, myocarditis, and immune-mediated myocarditis. Median times to onset indicated that cardiac AEs associated with axitinib occurred 14 to 420 days after administration. Weibull distributions showed that seven AEs (blood pressure increased, myocardial infarction, acute myocardial infarction, blood pressure systolic increased, oedema peripheral, oedema, and generalised oedema) occurred constantly throughout the exposure period (random failure type), and stress cardiomyopathy and immune-mediated myocarditis developed in a dose-dependent manner (wear-out failure-type). Conclusions We focused on cardiac AEs associated with axitinib as post-marketing AEs. Some with fatal outcomes may occur not only early in treatment but also later in the course. Continuous monitoring is essential to ensure timely detection and management of these potentially serious AEs in clinical practice.

Purpose To evaluate the disproportionality, time to onset, reporting frequency, and outcomes of hematologic AEs associated with trastuzumab deruxtecan (T-DXd) using data from the Japanese Adverse Drug Event Report database (JADER). Methods We analyzed data for the period from April 2004 to December 2024. Data on hematologic AEs were extracted, and the disproportionality of T-DXd-associated AEs was assessed by calculating reporting odds ratios. Results Among the 3,221,393 reports analyzed, 1561 were associated with T-DXd, including 433 hematologic AEs. Signals were detected for six AEs, including febrile neutropenia, anaemia, neutrophil count decreased, neutropenia, platelet count decreased, and myelosuppression. All had fatal cases, with particularly high fatality rates observed for febrile neutropenia and platelet count decreased. A histogram of median times to onset showed that febrile neutropenia and platelet count decreased typically occurred within 8 to 10.5 days after administration. Weibull distribution analysis indicated that febrile neutropenia showed an early-onset tendency (early failure type), whereas platelet count decreased occurred in a dose-dependent manner (wear-out failure type). Conclusions Some hematologic AEs associated with T-DXd can be fatal and may occur not only early in treatment but also later in the course. Continuous monitoring is essential for their timely detection and appropriate management.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are often used in hypertensive patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, binds the ACE2 receptor on the cell surface. This study aimed to identify the risk factors influencing COVID-19 infection in hypertensive patients. Methods: This is a part of a single-center, retrospective, observational study investigating patients ≥ 20 years old at Kenwakai Hospital (Nagano, Japan). COVID-19 was diagnosed by polymerase chain reaction. All patients received antihypertensive drugs. Results: Among 316 patients (mean age, 75.0 ± 13.4 years; men, 55.1%), COVID-19 was diagnosed in 39 (12.3%). Multiple logistic regression analysis after adjustment for age, sex, and smoking status identified increased serum creatinine (Scr) as a significant risk factor for COVID-19 (odds ratio [OR] 1.10; 95% confidence interval [CI] 1.00–1.20; p = 0.046). Conversely, lower serum chloride was associated with COVID-19 (OR 0.92; 95% CI 0.85–0.99; p = 0.047). There was no significant association between COVID-19 and the use of ACEIs and ARBs. Conclusions: Scr was independently associated with COVID-19 risk, whereas ACEI/ARB use was not associated with COVID-19 risk in Japanese hypertensive patients, suggesting that these users need not discontinue or change their treatment. The study population included a very high proportion of patients with advanced chronic kidney disease, which makes the cohort substantially different from the general hypertensive population. However, our results can help guide targeted treatment strategies, improving patient outcomes in healthcare settings.

Background/Aim: This study aimed to evaluate the disproportionality, times to onset, incidence rates, and outcomes of gastrointestinal adverse events (AEs) associated with trastuzumab deruxtecan (T-DXd), using data from the Japanese Adverse Drug Event Report database (JADER). Patients and Methods: We analyzed data for the period from April 2004 to December 2024. Those on gastrointestinal AEs were extracted and the disproportionality of T-DXd-associated AEs was assessed by calculating reporting odds ratios (RORs). Results: Of the 3,221,393 reports analyzed, we identified 1,561 reports of AEs associated with T-DXd, including 264 gastrointestinal AEs. Signals were detected for seven gastrointestinal AEs: nausea, decreased appetite, vomiting, diarrhoea, ascites, dehydration, and enterocolitis. Fatal outcomes were reported for six of these events, excluding ascites, with particularly high fatality rates observed for diarrhoea, dehydration, and enterocolitis. A histogram of median times to onset indicated that gastrointestinal AEs associated with T-DXd occurred 3 to 84 days after administration. Weibull distributions showed that nausea, decreased appetite, and vomiting occurred constantly throughout the exposure period (random failure type), and diarrhoea and dehydration developed in a dose-dependent manner (wear-out failure-type). Conclusion: Gastrointestinal adverse events associated with T-DXd can arise early or later in treatment and may lead to serious or fatal outcomes. These findings underscore the importance of continuous post-marketing surveillance and proactive clinical management to detect and mitigate these potentially severe AEs.

Aim This study was conducted to examine disproportionality, times to onset, incidence rates, and outcomes of trastuzumab deruxtecan-associated pulmonary adverse events (AEs) using the Japanese Adverse Drug Event Report database. Methods We analyzed data for the period from April 2004 to December 2024. Data on pulmonary AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs). Results Of the 3,221,393 reports analyzed, we identified 1561 reports of AEs associated with trastuzumab deruxtecan, including 505 pulmonary AEs. Only 474 reports were identified as signal-positive: interstitial lung disease, pulmonary toxicity, pneumonitis, and Pneumocystis jirovecii pneumonia. Among these, interstitial lung disease was the most frequently reported (26.6%) and included several fatal cases. Histograms of median times to onset for the four detected pulmonary AE signals showed that AEs occurred at a median of 7–27.5 days after trastuzumab deruxtecan administration. Weibull distributions showed that interstitial lung disease occurred early after administration (early failure type), but pulmonary toxicity occurred constantly throughout the exposure period (random failure type). Conclusions We focused on pulmonary AEs associated with trastuzumab deruxtecan as postmarketing AEs. Serious outcomes can arise after trastuzumab deruxtecan administration. Patients should be monitored for signs of onset of these AEs not only at the start of administration but also over an extended period.

Background: The P2Y12 receptor inhibitors clopidogrel and prasugrel are widely used. Clopidogrel and prasugrel have different metabolic pathways, but whether their adverse event (AE) profiles differ significantly is unclear. Objective: This study aimed to compare the possible AEs induced by clopidogrel and prasugrel and to assess the rank-order of their AEs submitted to a spontaneous reporting database. Materials and Methods: Data were extracted from the Japanese Adverse Drug Event Report database (JADER). Reports of AEs associated with clopidogrel and prasugrel were analyzed to calculate the reporting odds ratios (RORs) and 95% confidence intervals (CIs). Results: Based on 5869 reports for clopidogrel (69.6%, men) and 513 reports for prasugrel (74.1%, men), 703 and 135 different AEs were identified, respectively. Bleeding complications including hemorrhage were commonly reported for both clopidogrel and prasugrel. As for AEs related to clopidogrel, unexpected AEs such as interstitial lung disease (227 reports; ROR, 1.77; 95% CI, 1.49– 2.10), abnormal hepatic function (137 reports; ROR, 1.27; 95% CI, 1.07– 1.51), and hepatocellular injury (96 reports; ROR, 120.0; 95% CI, 94.9– 151.8) ranked at relatively high positions based on the number of occurrences, unlike prasugrel. Conclusion: This analysis of the national pharmacovigilance database highlights distinct AE profiles for clopidogrel and prasugrel. Unexpected AEs associated with clopidogrel were identified, providing valuable insights for clinical monitoring and patient safety.

Purpose: The aim of the study was to determine the association between coronavirus disease 2019 (COVID-19) infection and diabetes management indices in patients with type 2 diabetes mellitus. Patients and Methods: A single-center, retrospective, observational study of patients with type 2 diabetes mellitus at Kenwakai Hospital (Nagano, Japan) was conducted. Data of 95 patients (mean age, 72 ± 12 years; men, 67.4%) who visited between March 1, 2019 and February 28, 2022 were obtained from the hospital’s electronic information system. COVID-19 was diagnosed by a chemiluminescent enzyme immunoassay (CLEIA). Results: There was no association between COVID-19 infection and age, sex, hemodialysis treatment status, or the Charlson Comorbidity Index. After adjustment for possible confounding factors, the incidence of COVID-19 infection was significantly correlated with HbA1c ≥ 7.0% (odds ratio [OR], 5.51; 95% confidence interval [CI], 1.30– 23.26). Conclusion: The results suggest an association between high HbA1c levels and COVID-19 infection in patients with type 2 diabetes mellitus. Appropriate management of diabetes mellitus, focusing on HbA1c levels, may help prevent COVID-19 infection and severe disease after infection.

Purpose: The aim of the study was to identify the characteristics of patients infected with coronavirus disease 2019 (COVID-19) and to determine risk factors for COVID-19 infection in Japanese patients. Patients and Methods: We conducted a single-center retrospective observational study in Japanese adult patients (≥ 20 years) who visited Kenwakai Hospital (Nagano Japan). We analyzed data of 378 patients (mean age, 75 ± 14 years; men, 54%) from the hospital’s electronic information system. COVID-19 was diagnosed by polymerase-chain reaction. Patients were divided into 2 groups based on diagnosis of COVID-19. Results: Patients infected with COVID-19 showed significantly higher rates of men (69.8 vs 51.6%, P = 0.025) than uninfected control patients. After adjustment for possible confounding factors, COVID-19 infection was significantly associated with BUN (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01– 1.03) and serum creatinine (Scr) (OR, 1.14; 95% CI, 1.05– 1.24). This association was observed in men (BUN, P = 0.012; Scr, P = 0.012), but not in women (BUN, P = 0.43; Scr, P = 0.54). Conclusion: BUN and Scr are potential risk factors for infection of COVID-19 in Japanese patients, particularly in men. Our results suggest that renal parameters might be important in Japanese male patients for the early detection of COVID-19 infection.

Purpose: Clinically, glaucoma is a serious problem because it is asymptomatic until a relatively late stage in most cases, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of glaucoma with the causative drugs using a spontaneous reporting system database. Methods: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on reports of glaucoma caused by all drugs, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for glaucoma. Results: Among 609 reports of adverse events corresponding to glaucoma (46%, women), the most frequently implicated drug were steroids (prednisolone, betamethasone sodium phosphate, triamcinolone acetonide, and fluorometholone), pregabalin, ranibizumab, crizotinib, tacrolimus hydrate, darbepoetin alfa, and foscarnet sodium hydrate. Among 207 reports involved in angle-closure glaucoma (86%, women), anticholinergic drug and antidepressants ranked high and showed signals. Signals were also detected in bromazepam (ROR, 69.7; 95% CI, 30.9– 157.5), oral brotizolam (ROR, 16.6; 95% CI, 6.18– 44.8), and oral milnacipran hydrochloride (ROR, 22.8; 95% CI, 8.46– 61.4) for angle-closure glaucoma. Conclusion: A national pharmacovigilance database enabled us to identify the drugs that frequently induce glaucoma. The likelihood of the reporting of glaucoma varied among the drugs, which should be used carefully in clinical practice to avoid it.