A systematic review of eligibility criteria in randomized controlled trials of anti-VEGF therapy for retinal vein occlusion

ABSTRACT Purpose Randomized controlled trials (RCTs) of anti-vascular endothelial growth factor therapy (anti-VEGF) for retinal vein occlusion (RVO) outline treatment efficacy and aim to guide decisions in clinical practice. However, the strict eligibility criteria applied in registration trials may limit their representativeness and raise concerns about generalizability to real-world populations. This systematic review summarizes the eligibility criteria used in these studies. Design Systematic review. Methods We systematically searched in 12 scientific literature databases on 22 June 2025. RCTs of intravitreal anti-VEGF therapy for RVO in English were considered eligible for our study. Data on the eligibility criteria for visual function, disease definition and stage, ocular comorbidities, systemic comorbidities, demographics, and other factors not encompassed in other categories were extracted and summarized for a qualitative review. Due to the nature of the systematic review, neither a quantitative meta-analysis nor a formal risk-of-bias assessment was performed. Results We identified a total of 23 eligible studies, which in total included 4,883 eyes of 4,883 patients with RVO. We identified eligibility criteria on areas of visual function (minimum 6–24 ETDRS letters; maximum 70–78 ETDRS letters), disease definition and stage (criteria based on branch or central RVO, retinal features, and minimal central subfield thickness), ocular and systemic comorbidities, specific demographics, as well as a miscellaneous category (e.g., contraception use requirement). The most frequent exclusion criteria across studies were any history of prior intravitreal anti-VEGF (91.3%), ongoing ocular inflammation or infection (82.6%), intraocular surgery (78.3%), diabetic retinopathy (74%), cardiovascular disease (69.6%), laser photocoagulation (69.6%), age-related macular degeneration (56.5%), and glaucoma (52.2%) with percentages reflecting the proportion of the 23 included trials that applied each exclusion criterion. Some studies applied numerous eligibility criteria which, based on post-hoc qualitative comparisons with real-world RVO population, may limit generalizability. Conclusions RCTs of anti-VEGF treatments for RVO have used stringent eligibility criteria, which may limit the generalizability of their findings to real-world patients.