Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials.

Aim: Bevacizumab and ramucirumab are antiangiogenic monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, used in various cancers. Bleeding events have been described with these two agents. We conducted an up-to-date meta-analysis to determine the relative risk (RR) associated with the use of antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab. Methods: This meta-analysis of randomized controlled trials was performed after searching PubMed, American Society for Clinical Oncology Abstracts, European Society for Medical Oncology Abstracts, and the proceedings of major conferences for relevant clinical trials. RR and 95% CIs were calculated by random-effects or fixed-effects models for all-grade and high-grade bleeding events related to the angiogenesis inhibitors. Results: Eighty-five randomized controlled trials were selected for the meta-analysis, covering 46,630 patients. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade (RR: 2.38, 95% CI: 2.09-2.71, p<0.00001) and high-grade (RR: 1.71, 95% CI: 1.48-1.97, p<0.00001) bleeding compared with control arms. In the subgroup analysis, bevacizumab significantly increased the risk of all-grade (RR: 2.73, 95% CI: 2.24-3.33, p<0.00001) and high-grade bleeding (RR: 1.98, 95% CI: 1.68-2.34, p<0.00001), but ramucirumab only increased the risk of all-grade bleeding (RR: 1.94, 95% CI: 1.76-2.13, p<0.00001) and no difference was observed for the risk of high-grade bleeding (RR: 1.04, 95% CI: 0.78-1.39, p=0.79) compared with the control group. For lung cancer patients, bevacizumab significantly increased the risk of all-grade (RR: 4.72, 95% CI: 1.99-11.19, p=0.0004) and high-grade pulmonary hemorrhage (RR: 3.97, 95% CI: 1.70-9.29, p=0.001), but no significant differences in the risk of all-grade (RR: 1.09, 95% CI: 0.76-1.57, p=0.64) and high-grade (RR: 1.22, 95% CI: 0.35-4.21, p=0.75) pulmonary hemorrhage were observed for ramucirumab. The increased risk of all-grade and high-grade bleeding was also observed in colorectal cancer or non-colorectal tumors and low-dose or high-dose angiogenesis inhibitors. Conclusion: Antiangiogenic monoclonal antibodies are associated with a significant increase in the risk of all-grade and high-grade bleeding. Ramucirumab may be different from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients.