How to Judge Failure: Defining Treatment Resistance to Anti-VEGF Therapy in Exudative Maculopathies - A Systematic Scoping Review.

Topic: To evaluate the currently used definitions of treatment resistance in common retinal vascular diseases (neovascular age-related macular degeneration (nAMD), diabetic macula edema (DME) and retinal vein occlusion (RVO)) through a systematic scoping review of published studies.

Clinical relevance: A notable proportion of patients receiving therapy for retinal vascular diseases exhibit suboptimal responses to anti-vascular endothelial growth factor (anti-VEGF) therapy, however currently there are no well-recognized definitions of resistance to treatment in these conditions. Clear definitions of treatment-resistance would aid in developing treatment strategies and guiding research studies for these patients.

Methods: The online databases Pubmed, Embase and the Cochrane Database of Systemic Reviews were searched on January 5^thand August 16^th 2025 for articles relating to treatment resistance in all three conditions.

Results: 402 publications were identified, of which 88 met the eligibility criteria: 30 relating to nAMD (Table 1), 48 relating to DME (Table 2) and 10 relating to RVO (Table 3). Wide heterogeneity exists in the definition of treatment resistance for each condition. Persistent intraretinal fluid and/or subretinal fluid on optical coherence tomography (OCT) is the most commonly used criterion in each condition. Duration of prior treatment for defining resistance is commonly longest for nAMD, however treatment frequency of approximately ≤6-weekly injections for defining resistance was generally similar across all 3 conditions.

Conclusions: There is wide variability in the definitions used, however persistent intraretinal and/or subretinal fluid on OCT despite regular anti-VEGF therapy of approximately ≤6-weekly intervals are the most common criteria across all three conditions. Adoption of these definitions for future studies would help ensure consistency and may potentially improve patient outcomes by improving the validity of future studies and allowing for the development of treatment paradigms to manage this patient subgroup.