与CDK4/6抑制剂相关的心血管事件：随机对照试验的安全性荟萃分析及FAERS数据库的药物警戒研究
Cardiovascular Events Associated with CDK4/6 Inhibitors: A Safety Meta-Analysis of Randomized Controlled Trials and a Pharmacovigilance Study of the FAERS Database.
作者信息
Zhang Chengrong, Shen Guoshuang, Li Shengmei, Ma Fei, Li Huihui, Tang Yuyao, Li YongXin, Li Zhoujuan, Zhu Zijun, Qiu Tianlei, Liu Zhilin, Zhao Yi, Huang Shifeng, Zhao Fuxing, Kong Fanzhen, Zhao Jiuda
机构信息
Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出版信息
Am J Cardiovasc Drugs. 2025 May;25(3):373-388. doi: 10.1007/s40256-024-00709-6. Epub 2024 Dec 18.
BACKGROUND
CDK4/6 inhibitors are highly valued, but the incidence of cardiovascular adverse events (CVAEs) associated with CDK4/6 inhibitors is not clear.
OBJECTIVE
Our aim was therefore to assess the risk of developing CVAEs associated with CDK4/6 inhibitors, by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs), along with a pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS) database.
METHODS
Eligible CVAEs were extracted from the ClinicalTrials.gov registry. A systematic search of electronic databases (PubMed, Embase, Cochrane Library, and important meetings) until 3 September 2023 was conducted. A disproportionality analysis was performed from the first quarter (Q1) of 2013 to Q1 of 2023 using data from the FAERS database. Study heterogeneity was assessed using the I statistic. Using Peto odds ratio (Peto OR) and inverse variance methods to calculate the risk and incidence of CVAEs associated with CDK4/6 inhibitors.
RESULTS
In total, 17 RCTs with 23,437 patients were included in our meta-analysis. During the follow-up period of 8.4-34.0 months, CDK4/6 inhibitors significantly increased the risk of CVAEs (Peto OR, 1.86, 95% confidence interval, 1.30-2.68, P < 0.01). The rates of hypertension and QT prolongation were 68.07 (62.87-73.27) and 57.15 (50.83-63.48) per 1000 patients, respectively. Moreover, we identified nine CVAEs that were not reported in RCTs. These included acute coronary syndrome, arrhythmia, lymphoedema, hot flush, vein rupture, thrombophlebitis migrans, embolism venous, angiopathy and intracardiac thrombus, which were found to be strongly correlated with CDK4/6 inhibitors. Furthermore, the risk of CVAEs varied depending on the specific CDK4/6 inhibitors used, its combination with different endocrine therapies, and the patient's treatment stage.
CONCLUSION
CDK4/6 inhibitors increase the risk of CVAEs, some of which may lead to serious consequences. Early recognition and management of CVAEs is of great importance in clinical practice.
REGISTRATION
PROSPERO registration number CRD42023462059.
背景
细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂备受关注，但其相关心血管不良事件（CVAEs）的发生率尚不清楚。
目的
因此，我们旨在通过对随机对照试验（RCTs）进行系统评价和荟萃分析，以及对美国食品药品监督管理局不良事件报告系统（FAERS）数据库进行药物警戒研究，评估与CDK4/6抑制剂相关的CVAEs发生风险。
方法
从ClinicalTrials.gov注册库中提取符合条件的CVAEs。对电子数据库（PubMed、Embase、Cochrane图书馆和重要会议）进行系统检索，直至2023年9月3日。利用FAERS数据库2013年第一季度（Q1）至2023年Q1的数据进行不成比例分析。使用I统计量评估研究异质性。采用Peto比值比（Peto OR）和逆方差法计算与CDK4/6抑制剂相关的CVAEs的风险和发生率。
结果
我们的荟萃分析共纳入17项RCTs，涉及23437例患者。在8.4 - 34.0个月的随访期内，CDK4/6抑制剂显著增加了CVAEs的风险（Peto OR，1.86；95%置信区间，1.30 - 2.68；P < 0.01）。每1000例患者中高血压和QT间期延长的发生率分别为68.07（62.87 - 73.27）和57.15（50.83 - 63.48）。此外，我们还发现了9种在RCTs中未报告的CVAEs。这些包括急性冠状动脉综合征、心律失常、淋巴水肿、潮热、静脉破裂、游走性血栓性静脉炎、静脉栓塞、血管病和心内血栓，它们与CDK4/6抑制剂密切相关。此外，CVAEs的风险因所用的特定CDK4/6抑制剂、其与不同内分泌治疗的联合应用以及患者的治疗阶段而异。
结论
CDK4/6抑制剂增加了CVAEs的风险，其中一些可能导致严重后果。在临床实践中，早期识别和处理CVAEs非常重要。
注册信息
PROSPERO注册号CRD42023462059。
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