Thromboembolic and bleeding events associated with angiogenesis inhibitors in cancer patients

Angiogenesis inhibitors are associated with increased risk of thromboembolic events (TEEs) and hemorrhagic events. However, their clinical features are not well characterized in real-world studies. First, we conducted a pharmacovigilance study to investigate characteristics of TEEs and bleeding and compare vascular endothelial growth factor and its receptor inhibitors (VEGF/VEGFRIs) with other antiangiogenic agents. Second, we performed a retrospective analysis of lung cancer patients who received bevacizumab or anlotinib to assess the incidence of VEGF/VEGFRI-associated TEEs and bleeding. In the pharmacovigilance study, both VEGF/VEGFR-targeted biologics and VEGFR-tyrosine kinase inhibitors were associated with higher reporting of arterial thromboembolism (ATE) (reporting odd ratio (ROR) 2.91; ROR 1.25; respectively), and bleeding (ROR 2.56; ROR 2.35; respectively). Venous thromboembolism (VTE) was only associated with VEGF/VEGFR-targeted biologics (ROR 3.11). In the cohort study, bevacizumab, aflibercept, and ramucirumab showed the strongest associations with VTE, ATE, and bleeding, respectively. In the cohort study of 261 lung cancer patients treated with bevacizumab or anlotinib, 42.9% were older than 65 years, 62.1% were male, with TEEs occurred in 11.5%, and bleeding in 8.8%. All VEGF/VEGFRIs were associated with increased ATE and bleeding risk. VEGF/VEGFR-targeted biologics also significantly raise the risk of VTE.