Evaluation of Risk of Cardiac or Cerebrovascular Events in Romosozumab Users Focusing on Comorbidities: Analysis of the Japanese Adverse Drug Event Report Database

Kotake, Kazumasa; Mitsuboshi, Satoru; Omori, Yuki; Kawakami, Yukio; Kawakami, Yoshimi

doi:10.1177/87551225221144960

Cited by 13 publications

(4 citation statements)

References 22 publications

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“…9 Similarly, a study using the Japanese adverse event reporting database indicated a relatively high number of cardiac and cerebrovascular events among romosozumab users (n=859) compared to other osteoporosis medications. 10 In contrast, the present study excludes selection bias by restricting the subjects to new users 15 and addresses confounding by indication through comparison of the presence or absence of CVD with the active comparator. 34 The latter is further minimized by instrumental variable analyses.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacovigilance studies using adverse event reporting databases in the United States and Japan indicated an increase in CVD with romosozumab compared to other medications. 9,10 However, these findings were derived from adverse event cases and may suffer from bias related to unmeasured underlying disease and reporting bias. 11 In addition, post-marketing surveillance of romosozumab by a pharmaceutical company lacks evidence from active comparator studies.…”

Section: Introductionmentioning

confidence: 99%

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Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses

Tominaga,

Ikenoue,

Ishii

et al. 2024

Preprint

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Importance Romosozumab, a novel anti-osteoporotic agent, confers marked improvement in bone mineral density; however, its cardiovascular safety remains a concern. Objective To compare the cardiovascular safety of romosozumab to bisphosphonates in patients with osteoporosis. Design A cohort study using a new-user, active comparator design. Setting Medical facilities, including clinics and hospitals, visited by a wide range of populations in Japan that are covered by a commercial administrative claims database, collected from March 4, 2019 to August 31, 2021. Participants Japanese adults aged ≥40 years who were diagnosed with osteoporosis or experienced a fragility fracture. Those who received romosozumab or bisphosphonates after the commercialization of romosozumab started in Japan (March 4, 2019) were included. Exposure A new prescription of romosozumab or bisphosphonate (based on verification of a 180-day washout period). Main Outcomes and Measures The primary outcome was the incidence rate of cardiovascular disease (consisting of myocardial infarction and stroke) within one year of prescription. Cardiovascular disease was identified by algorithms with a combination of diagnosis, medical procedure, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient's facility within 90 days prior to the index date. Results Of the 61,558 included prescriptions, 8,806 were for romosozumab and 52,752 were for bisphosphonates. The mean age of the romosozumab group was higher than that of the bisphosphonates group (80.5 vs. 78.3 years, respectively). The majority of patients were female (80.2 vs. 85.3%, respectively). The incidence of cardiovascular disease was 7.98 per 100 person-years for romosozumab versus 7.15 for bisphosphonates (unadjusted incidence rate ratio: 1.12 (95% confidence interval: 1.03-1.21)). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.09 (95% confidence interval: 0.79-1.76) for romosozumab compared to bisphosphonates over one year. Conclusions and Relevance In this large observational study, there was no definitive evidence of increased risk of cardiovascular disease associated with romosozumab use compared with bisphosphonates in patients with osteoporosis. These findings alleviate clinicians' excessive concerns about the potential cardiovascular safety of romosozumab in treatment decision-making for osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses

Tominaga,

Ikenoue,

Ishii

et al. 2024

Preprint

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“…First, the chi-square test was used to compare the frequency of herpes zoster between tofacitinib doses of 5 mg/day and 10 mg/day. The reporting odds ratio (ROR), which can be generally used to identify drug-associated adverse events [ 19 , 20 ], 95% confidence interval (CI), and P values were calculated. Second, multivariable logistic regression analysis was performed to identify the risk factors for herpes zoster in tofacitinib users, and the adjusted OR, 95% CI, and P values were calculated.…”

Section: Methodsmentioning

confidence: 99%

Association Between the Dose of Tofacitinib and Risk of Herpes Zoster in Patients With Rheumatoid Arthritis: Analysis of Japanese Adverse Drug Event Report Data

Kotake,

Mitsuboshi

2024

Cureus

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Background: Tofacitinib is one of the Janus kinase inhibitors approved for the treatment of rheumatoid arthritis. The major adverse event of this drug is herpes zoster, which can lead to death in severe cases. The risk of herpes zoster has been studied at 10 mg/day of tofacitinib; however, 5 mg/day, which is recommended in patients with chronic kidney disease, is unclear. Objective: To investigate whether 5 mg/day of tofacitinib reduced the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients. Methods: We analyzed the Japanese Adverse Drug Event Report Data (JADER) database and compared the frequency of herpes zoster in rheumatoid arthritis patients treated with tofacitinib 5 mg/day and 10 mg/day. Multivariable logistic regression analysis was performed to identify the risk factors for herpes zoster in tofacitinib users. Results: A total of 812 tofacitinib users with rheumatoid arthritis were identified, including 131 with herpes zoster. Disproportionality for herpes zoster was observed between 5 mg/day and 10 mg/day (reporting odds ratio (OR): 0.68, 95% confidence interval (CI): 0.47-0.98, P = 0.045). Multivariable logistic regression analysis showed that the risk of herpes zoster was significantly increased in female patients (OR: 1.87, 95% CI: 1.12-3.12, P = 0.016) and methotrexate users (OR: 1.69, 95% CI: 1.12-2.54, P = 0.013) and significantly decreased with tofacitinib 5 mg/day compared with 10 mg/day (OR: 0.62, 95% CI: 0.40-0.96, P = 0.032). Conclusion: We suggest that tofacitinib 5 mg/day may decrease the risk of herpes zoster compared with 10 mg/day in rheumatoid arthritis patients.

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“…Age, history of dementia, and history of cerebrovascular disease were investigated because these factors have been suggested to be associated with delirium. Dementia and cerebrovascular diseases were de ned as in previous reports (Table A2 in the Appendix) [32,33]. These diseases were collected from the DEMO and HIST categories.…”

Section: Data Collection and De Nitionsmentioning

confidence: 99%

Association of silodosin, tamsulosin, and naftopidil with delirium: analysis of the pharmacovigilance database in Japan

Kotake,

Noritake,

Kawakami

2023

Int J Clin Pharm

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Background: Tamsulosin, an α1-adrenoceptor antagonist, may increase the risk of dementia in older men with benign prostatic hyperplasia. An association between α1-adrenoceptor antagonists and delirium has been suggested, but the details are unclear.Aims: This study investigated the association between α1-adrenoceptor antagonists and delirium in patients with benign prostatic hyperplasia, using the Japanese Adverse Drug Event Report database.Method: First, disproportionality analysis compared the frequency of delirium in the α1-adrenoceptor antagonists silodosin, tamsulosin, and naftopidil. Next, multivariate logistic analysis was performed to examine the association between delirium and α1-adrenoceptor antagonists where disproportionality was detected.Results: A disproportionality in delirium was observed in patients who received tamsulosin (reporting odds ratio 1.85, 95% con dence interval 1.38-2.44, P < 0.01) and naftopidil (reporting odds ratio 2.23, 95% con dence interval 1.45-3.28, P < 0.01). Multivariate logistic analysis revealed that in addition to previously reported risk factors for delirium, delirium in patients who received tamsulosin was signi cantly increased with concomitant use of anticholinergics (odds ratio 2.73, 95% con dence interval 1.41-5.29, P < 0.01) and delirium in patients who received naftopidil was signi cantly increased with concomitant use of β3 adrenoceptor agonists (odds ratio 4.19, 95% con dence interval 1.66-10.6, P < 0.01). Conclusion:We found that concomitant use of anticholinergic or β3 adrenoceptor agonistsused to treat overactive bladder were strongly associated with delirium. Therefore, con rming the medical history and concomitant medications of patients who receive tamsulosin or naftopidil and providing preventive interventions for delirium may contribute to improved patient outcomes.

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Evaluation of Risk of Cardiac or Cerebrovascular Events in Romosozumab Users Focusing on Comorbidities: Analysis of the Japanese Adverse Drug Event Report Database

Cited by 13 publications

References 22 publications

Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses

Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses

Association Between the Dose of Tofacitinib and Risk of Herpes Zoster in Patients With Rheumatoid Arthritis: Analysis of Japanese Adverse Drug Event Report Data

Association of silodosin, tamsulosin, and naftopidil with delirium: analysis of the pharmacovigilance database in Japan

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