Enhancing the understanding of anti-VEGF treatment failure in retinal vascular diseases: a call for expanded analyses and threshold validation

Dear Editors,

We read with great interest the study by Fu et al. [1] on the visual and anatomical failure of anti-VEGF therapy for retinal vascular diseases, particularly diabetic macular edema (DMO) and retinal vein occlusions (RVO). This important contribution provides valuable insights into treatment outcomes in a real-world clinical setting. We would like to commend the authors for their thorough analysis and their efforts to better understand the factors contributing to anti-VEGF treatment failure. However, we would like to offer a few suggestions that could further enhance the robustness of the study.

Firstly, while the authors employed Kaplan–Meier survival analysis and Cox regression models, we believe these methods may inadvertently overestimate risk when competing risks are present. Secondary events, such as cataract progression or glaucoma, which may influence visual outcomes or treatment escalation, might not have been fully accounted for. In such scenarios, we suggest that a competing risks model would be more appropriate, as it would provide a more accurate assessment of the time to anti-VEGF failure by considering the impact of these secondary events. This approach could offer a more comprehensive understanding of the factors influencing treatment failure in real-world practice.

Secondly, the authors have adjusted for several demographic and clinical variables, which is commendable. However, we believe that expanding the scope of covariates to include systemic health conditions, such as hypertension or cardiovascular disease, may improve the analysis. Previous studies have demonstrated that these comorbidities can significantly affect the prognosis of retinal vascular diseases and the effectiveness of treatment [2, 3]. Additionally, considering socioeconomic factors such as income and education level might provide a more complete understanding of how these elements influence treatment outcomes, particularly in terms of access to care and adherence to therapy.

Thirdly, while the authors define treatment failure using both anatomical (central subfoveal thickness) and functional (visual acuity) measures, we feel that the specific thresholds for failure (CST > 325 µm and VA change < 5 ETDRS letters) might benefit from further validation. We suggest performing sensitivity analyses to explore how varying these thresholds might impact the findings. Additionally, it would be helpful for the authors to provide a clearer rationale for these particular threshold values and to discuss their applicability and validation in other clinical cohorts. Furthermore, macular ischemia and epiretinal membranes, which can contribute to treatment failure, were not directly addressed in the current analysis, and their inclusion might provide additional insight into treatment outcomes.

In conclusion, while Fu et al.’s study provides valuable contributions to our understanding of anti-VEGF treatment failure in retinal vascular diseases, addressing the points mentioned above could further strengthen the findings and improve their clinical applicability. We sincerely appreciate the authors’ efforts and look forward to seeing how their work evolves.

Author contributions

All authors contributed to the conception, design, and interpretation of the study’s results. CC conceived the overall project, designed the study, conducted the data analysis, and wrote the manuscript. HG contributed to drafting the manuscript and provided intellectual feedback on its content. XG contributed to the data analysis and helped refine the discussion section of the Letter. WW provided critical revisions to the manuscript for important intellectual content and approved the final version for publication.

Competing interests

The authors declare no competing interests.