Cardiovascular events associated with CDK4/6 inhibitors based on randomized controlled trials or cohort trials: a safety meta-analysis

BackgroundCDK4/6 inhibitors is highly valued, but the incidence of cardiovascular events (CVAEs) associated with CDK4/6 inhibitors is not clear. MethodsEligible 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 FDA Adverse Event Reporting System database. Study heterogeneitywas assessed using the I2 statistic. Using Peto OR and inverse variance methods to calculate the risk and incidence of CVAEs associated with CDK4/6 inhibitors. Findings21 RCTs and cohort trials (n=24,331) were included. During the follow-up period of 8.4 to 34.0 months, CDK4/6 inhibitors significantly increased the risk of CVAEs (Peto OR, 1.64, 95% confidence interval, 1.23 - 2.21, P < 0.01). The rates of QT prolongation and deep vein thrombosis were 98.83 (89.6-100.1) and 6.41 (5.23-7.18) per 1000 patients, respectively. Moreover, we identified 11 CVAEs that were not reported in RCTs or cohort studies, acute coronary syndrome, atrial fibrillation, and mobile thrombophlebitis etc. were 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 patients treatment stage. InterpretationCDK4/6 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.