Broader perspective for the treatment approach on retinal neovascular diseases

Retinal disease treatment options have never been so diverse as they are today.

In our current era, anti–vascular endothelial growth factor (VEGF) use is mainstream. Suprathreshold laser is applicable only in advanced cases, otherwise doing more harm than good for many. Corticosteroids were almost never mainstream because of potential adverse effects, and subthreshold lasers are reserved for the avant-garde.

The largest and most influential clinical trials have aimed to demonstrate the efficacy and safety of a single modality. Recent academic debate is focused on the role of each therapy in isolation and the comparison of different anti-VEGF agents. But this perspective no longer accurately reflects the real-world complexity of retinal neovascular diseases.^1-5

Real clinical practice today is understood as the implementation of recommended guidelines for treatment. However, only a few countries are wealthy enough to implement guideline-based anti-VEGF protocols for treating retinal diseases.

Clinical practice is too often a hybrid strategy tailored to the realities of cost, access, and patient adherence, characterized by the variability of recommendations and the personalization of treatment. This is frequently not genuine personalization but compromise caused by system limitations rather than disease needs.

On the other side are neovascular retinal diseases, with diverse clinical presentations and stages. There are numerous clinical presentations, making it impossible for all of them to fit into a single, uniform treatment protocol, assuming homogeneity where none exists. Even when we have multiple molecules with different efficacies and durations, the push is towards replacing older therapies with newer ones, rather than enriching therapeutic plans with both.

We need genuine individualization. The initial fine-tuning of the staging relies on clinical signs, optical coherence tomography (OCT), and angiography, enabling us to distinguish different phenotypes that require a personalized treatment approach. That approach cannot and should not depend solely on anti-VEGF therapy, especially not on a single anti-VEGF agent and a single treat-and-extend protocol.

For example, today we can diagnose wet age-related macular degeneration (AMD) at an early stage, something that was not possible at the start of the anti-VEGF era. Conversely, we have advanced wet AMD with extensive fibrovascular proliferation and large intraretinal and subretinal fluid. How does the 8 mg aflibercept loading dose work equally well for both cases? Why are we not using 2 mg of aflibercept in early-stage wet AMD or starting with 8 mg and switching to 2 mg later?

For other neovascular retinal diseases, such as diabetic retinopathy, subthreshold laser remains an underutilized option; corticosteroids offer specific benefits in some instances, and even suprathreshold laser may reduce treatment burden.

The future of clinical trials must involve the integration of treatment options, with a greater focus on precise definitions of disease stages as a key parameter for differentiating treatments. Artificial intelligence (AI) offers a transformative opportunity.

By integrating OCT biomarkers, angiography, and clinical presentation, AI can help stratify patients far more effectively than human pattern recognition alone.⁶ Real personalized algorithms tailored not only to disease stage but also to individual response would replace the “one size fits all” protocol. Patients deserve treatment strategies as dynamic and adaptable as their diseases.

References

1. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-1806.

2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. doi:10.1056/NEJMoa054481

3. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. doi:10.1056/NEJMoa062655

4. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264

5. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. doi:10.1016/j.ophtha.2011.01.031

6. Schmidt-Erfurth U, Sadeghipour A, Gerendas BS, Waldstein SM, Bogunović H. Artificial intelligence in retina. Prog Retin Eye Res. 2018;67:1-29. doi:10.1016/j.preteyeres.2018.07.004