Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: A meta-analysis of approximately 29,000 cancer patients

Background Targeted therapy with tyrosine kinase inhibitors with anti-vascular endothelial growth factor activity improves survival of cancer patients. Cardiovascular complications are critical and it is unknown whether these require specific treatment strategies. We aimed to clarify the associated risk of cardiovascular adverse events in patients treated with tyrosine kinase inhibitors. Design The design of this study was a meta-analysis of randomised controlled trials. Methods We searched PubMed, Cochrane, EMBASE and Web of Science databases for randomised controlled trials published until January 2017 that assessed patients with different types of cancer treated with or without tyrosine kinase inhibitors in addition to standard chemotherapy. Results A total of 29,252 patients from 71 randomised controlled trials were included. Tyrosine kinase inhibitor treatment was associated with a higher cardiac ischaemia relative risk (relative risk=1.69; 95% confidence interval: 1.12-2.57; p=0.01), with the highest risks observed for sorafenib and patients with renal cancer. Risk of thrombocytopaenia (relative risk=2.2; 95% confidence interval: 1.73-2.79; p<0.001) was highest for regorafenib and patients with breast cancer. Left ventricular systolic dysfunction was increased after tyrosine kinase inhibitor therapy (relative risk=2.53; 95% confidence interval:1.79 - 3.57; p<0.001), with the highest risks reported for sunitinib and hepatocellular cancer. QT corrected interval prolongation (relative risk=6.25; 95% confidence interval: 3.44-11.38; p<0.001) and arterial hypertension (relative risk=3.78; 95% confidence interval: 3.15-4.54; p<0.001) were reported. The relative risks of arterial adverse events, cerebral ischaemia, venous adverse events and pulmonary embolism were similar across groups. Conclusion Tyrosine kinase inhibitors increase the risk of severe cardiovascular and particularly thrombotic adverse events. Specific treatment regimens when prescribing tyrosine kinase inhibitor therapies appear desirable.