Cardiovascular adverse events with cdk4/6 inhibitors:a meta-analysis of randomized controlled trials

Importance In an era marked by the expanding indications of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), from being the standard first-line treatment for hormone receptor-positive, HER2-negative locally advanced and metastatic breast cancer (ABC)—representing over 65% of ABC cases—to their inclusion in adjuvant therapy strategies, it is critical to better understand their potential cardiovascular adverse events (CVAE) to ensure patient safety. Objective To assess the risk of 16 different CVAEs associated with CDK4/6i compared to control treatments (placebo or non-placebo) through a systematic review and meta-analysis of phase 2 and 3 randomized controlled trials (RCTs). This study focuses on adult cancer patients treated with CDK4/6i, analyzing cardiovascular risks using Peto odds-ratios (Peto-ORs) and incidence rates. Data Sources: A systematic search of ClinicalTrials.gov, MEDLINE, and Cochrane databases was conducted for RCTs up to April 6, 2024. Study Selection: Thirty-six RCTs (n=21,014 patients) were included in the safety meta-analysis. Trials were selected based on their comparison of CDK4/6i with control treatments and the availability of CVAE data. Risk of bias assessments were conducted for each included study. Data Extraction and Synthesis: Data extraction followed PRISMA guidelines, and random-effects meta-analysis was used to calculate Peto-ORs with 95% confidence intervals (95% CIs). Results CDK4/6i significantly significantly increased the risk of torsade de pointes / QT prolongation (TdP/QTprol) (Peto-OR=2.35; CI [1.66; 3.32]; I²=0%), venous thromboembolic events (VTE) (Peto-OR=1.85; CI [1.14; 3.02]; I²=26%), heart failure (HF) (Peto-OR=1.85; CI [1.14; 3.00]; I²=1%) and ischemic stroke (Peto-OR=1.69; CI [1,06; 2.70]; I²=0%) compared to control arms. The annualized incidence rates of CVAE in CDK4/6i group were 22.73 (95% CI: 4.94-104.52) for TdP/QTprol, 15.97 (95% CI: 7.99-31.90) for VTE, 6.02 (95% CI: 3.47-10.45) for HF and 10.37 (95% CI: 4.87-22.08) for ischemic stroke per 1000 person-years. The median median follow-up was 28 months. Conclusions and Relevance CDK4/6i are associated with a significantly increased risk of CVAEs, particularly TdP/QT prolongation, VTE, heart failure, and ischemic stroke. These findings are crucial for clinicians as the use of CDK4/6i continues to expand.