Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies

Background: Since the efficacy of ranibizumab (RBZ), bevacizumab (BVZ) and aflibercept (AFB) is comparable in neovascular age-related macular degeneration (AMD), we conducted a systematic review and meta-analysis to evaluate the long-term safety profiles of these agents, including ocular safety. Methods: Systematic review identifying randomized controlled trials (RCTs) comparing RBZ, BVZ and AFB directly published before March 2019. Serious ocular adverse events (SOAE) of special interest were endophthalmitis, pseudo-endophthalmitis, retinal pigment epithelium tear and newly identified macular atrophy. Results: Thirteen RCTs selected for meta-analysis (4952 patients, 8723 people-years follow-up): 10 compared RBZ vs. BVZ and three RBZ vs. AFB. There were no significant differences in almost all adverse events (systemic and ocular) between BVZ, RBZ and AFB in up to two years' follow-up. Macular atrophy was reported heterogeneously and not reported as SOAE in most trials. Conclusions: Direct comparison of RBZ, BVZ and AFB safety profiles in the RCT network meta-analytical setting have not revealed a consistent benefit of these three commonly used anti-vascular endothelial growth factor (anti-VEGF) agents in AMD. Network model ranking highlighted potential benefits of RBZ in terms of a systemic safety profile; however, this appears a hypothesis rather than a conclusion. Newly identified macular atrophy is underestimated in RCTs-future real-world data should be focused on SOAE.