Liu Wensheng, Gao Feifei, Song Xue, Chen Hao, She Youjun, Liu Jiyong, Du Qiong
Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Front Pharmacol. 2025 May 30;16:1558128. doi: 10.3389/fphar.2025.1558128. eCollection 2025.
Despite the unprecedented advancement of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in the treatment paradigm for hormone-dependent breast cancer, reports of cardiovascular adverse events (CVAEs) in both pivotal trials and real-world settings have garnered concerns.
we aim to profile the incidence, clinical characteristics and risk factors of CVAEs associated CDK4/6i to provide a vigilant reference for cancer management.
The global disproportionality study was conducted by utilizing safety reports submitted to the FDA adverse event reporting system (FAERS) during the period from January 2015 to September 2024. Reporting odds ratio (ROR) was employed to identify and evaluate emerging CVAEs related to CDK4/6i. Multivariable logistic regression analysis was utilized to explore factors associated with CVAEs following CDK4/6i treatment. Parametric and cumulative distribution was used for the reported time-to-onset analysis.
A total of 4,709 reports of CVAEs were identified with CDK4/6i, of which 4264 (90.5%) were classified as serious and 12.0% were fatal situation. The median onset time of CVAEs with CDK4/6i was 102 days (interquartile range [IQR], 25-374 days). Disproportionality analysis revealed that Abemaciclib was significantly increased signal of venous thromboembolism (ROR = 2.57 [2.24-2.96]), whereas cardiac arrhythmia (ROR = 2.51 [2.13-2.96]) and torsade de pointes/QT prolongation (ROR = 5.7 [5-6.5]) were showed significantly disproportionate for ribociclib. Meanwhile, cerebrovascular accident and thrombosis were showed significant associated with Abemaciclib ribociclib or palbociclib treatment. Some emerging potential CVAEs, such as myocardial infarction and pulmonary edema, were found to be significantly associated with ribociclib and palbociclib. Additionally, age exceeding 65 years and types of CDK4/6i were significant risk factors for the incidence of CDK4/6i-related CVAEs.
CVAEs might occur with a greater frequency in the context of CDK4/6i than had been previously acknowledged. Our study provide an overview of the incidence, characteristics and risk factors of CDK4/6i-related CVAEs, and also uncovered potential CVAEs that were not identified in the clinical trials.
尽管细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）在激素依赖性乳腺癌治疗模式中取得了前所未有的进展，但关键试验和现实环境中关于心血管不良事件（CVAEs）的报告引发了关注。
我们旨在剖析与CDK4/6i相关的CVAEs的发生率、临床特征和危险因素，为癌症管理提供警惕性参考。
利用2015年1月至2024年9月期间提交给美国食品药品监督管理局不良事件报告系统（FAERS）的安全报告进行全球不成比例性研究。采用报告比值比（ROR）来识别和评估与CDK4/6i相关的新出现的CVAEs。多变量逻辑回归分析用于探索CDK4/6i治疗后与CVAEs相关的因素。参数和累积分布用于报告的发病时间分析。
共识别出4709份与CDK4/6i相关的CVAEs报告，其中4264份（90.5%）被归类为严重事件，12.0%为致命情况。CDK4/6i相关CVAEs的中位发病时间为102天（四分位间距[IQR]，25 - 374天）。不成比例性分析显示，阿贝西利显著增加了静脉血栓栓塞信号（ROR = 2.57 [2.24 - 2.96]），而对于瑞博西尼，心律失常（ROR = 2.51 [2.13 - 2.96]）和尖端扭转型室速/QT间期延长（ROR = 5.7 [5 - 6.5]）显示出显著的不成比例性。同时，脑血管意外和血栓形成与阿贝西利、瑞博西尼或哌柏西利治疗显著相关。一些新出现的潜在CVAEs，如心肌梗死和肺水肿，被发现与瑞博西尼和哌柏西利显著相关。此外，年龄超过65岁和CDK4/6i的类型是CDK4/6i相关CVAEs发生率的显著危险因素。
CDK4/6i背景下CVAEs的发生频率可能比之前认识到的更高。我们的研究概述了CDK4/6i相关CVAEs的发生率、特征和危险因素，还发现了临床试验中未识别的潜在CVAEs。
