Cardiovascular Events Associated with CDK4/6 Inhibitors: A Safety Meta-Analysis of Randomized Controlled Trials and a
Chengrong Zhang1, Guoshuang Shen1, Shengmei Li1
1Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
Insights
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors increase cardiovascular adverse events (CVAEs), including hypertension and QT prolongation. Early recognition and management of these events are crucial for patient safety.
Area of Science:
- Oncology
- Cardiology
- Pharmacovigilance
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are crucial in cancer therapy.
- The incidence and spectrum of cardiovascular adverse events (CVAEs) linked to CDK4/6 inhibitors require clarification.
Purpose of the Study:
- To systematically assess the risk of CVAEs associated with CDK4/6 inhibitors.
- To analyze pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) database.
- To conduct a meta-analysis of randomized controlled trials (RCTs).
Main Methods:
- Systematic literature search of multiple databases and ClinicalTrials.gov registry.
- Disproportionality analysis of FAERS data (Q1 2013 - Q1 2023).
- Meta-analysis using Peto odds ratio and inverse variance methods to quantify CVAE risk.
Main Results:
- 17 RCTs (23,437 patients) revealed CDK4/6 inhibitors significantly increase CVAE risk (Peto OR, 1.86).
- Common CVAEs include hypertension (68.07/1000) and QT prolongation (57.15/1000).
- Nine novel CVAEs (e.g., acute coronary syndrome, arrhythmia) were identified and strongly correlated with CDK4/6 inhibitors.
Conclusions:
- CDK4/6 inhibitors are associated with an increased risk of CVAEs, some potentially severe.
- Risk varies based on the specific inhibitor, combination therapy, and treatment stage.
- Prompt identification and management of CVAEs are essential in clinical practice.
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 I2 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.
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