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

Abstract

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.

Keywords: aflibercept; anti-vascular endothelial growth factor; bevacizumab; meta-analysis; neovascular age-related macular degeneration; randomized controlled trials; ranibizumab.

Figure 1

Study flow diagram Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) showing number of trials identified, included, excluded and reason for exclusion.* -.

Figure 2

Node graph of the network meta-analytic model developed. Richness of the line means a number of studies available. Solid line—head-to-head RCTs are available. Dotted line means no head-to-head RCTs are available and an indirect comparison in the frame of the network meta-analysis is performed.

Figure 3

Forest plot with direct and indirect comparison of RBZ, BVZ and AFB in the frame of the network meta-analytic model. Systemic serious adverse event (SAE) rate differs significantly between BVZ and RBZ, whereas the other safety parameters’ difference was recognized as statistically insignificant, both direct and indirect. *—significantly higher systemic SAE rate in BVZ vs. RBZ. R-ranibizumab; B-bevacizumab; A-aflibercept; CVD-cardiovascular diseases, Oc SAE–ocular serious adverse events; Sys SAE-systemic serious adverse events; tau2-between-study variance; I²–percentage of variance related to between-study heterogenicity; LOW CI–lower limit of confidence interval; UPP CI–upper limit of confidence interval; IRR–incidence rate ratio; vs.–versus.

Figure 4

Safety profile of three anti-VEGF interventions based on the p-score values estimated using the frequentist network meta-analytic model. SUCRA - surface under the cumulative ranking curve. P-scores are similar to SUCRA values in the Bayesian network model and the means probability of being the best treatment option.