Abstract
Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39–6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.
Highlights
Following the cardiovascular safety concerns raised during the clinical development of romosozumab, we performed a pharmacovigilance study in FAERS to study the events of interest in post-marketing safety reports
Our results identified higher than expected reports for the adjudicated outcome for major cardiovascular events (MACE), including the individual events of myocardial infarction (MI), stroke, and cardiovascular events with romosozumab compared to all other cases in the FAERs database
We identified higher than expected reports of MACE, which was elevated in reports originating from Japan
Summary
The clinical efficacy and safety of romosozumab were demonstrated in the two pivotal Phase 3 randomized controlled trials (RCTs), the active-controlled fracture study in postmenopausal women with osteoporosis (ARCH) and the fracture study in postmenopausal women with osteoporosis (FRAME) [1,2]. The United States (US) Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) denied the initial application for approval citing concerns of cardiovascular safety [4,5,6]. A safety warning for the risk of cardiovascular events was only recommended by the PMDA following a review of post-market case studies in September 2019 [10,11].
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