Long term outcome after anti-VEGF treatment—what do we know about the impact of morphological parameters?

Despite the initial positive effect of anti-VEGF treatment in eyes with neovascular AMD (nAMD), long-term results still remain un-satisfying (1-3). Five-year outcomes from the CATT study showed a mean decline of 11 letters from the 2-year follow-up visit, and 3 letters compared to the original baseline (3). This is similar to the long-term results from an observational study reported by Gillies et al. demonstrating a 2.6 letter loss of visual acuity (VA) at 7 years compared to baseline (2), as well as the results from the SEVEN-UP study which showed an even more dramatic 8.6 letter loss relative to baseline 7 years after the initiation of anti-VEGF therapy (1). Several explanations for these suboptimal lower outcomes may be considered, including undertreatment in a real-world environment leading to progressive exudation and scarring, as well as the development of retinal pigment epithelial (RPE) atrophy—both of which yielding progressive photoreceptor dysfunction and loss (1,4,5). However, the relationship between these various morphological parameters evident over time in eyes with nAMD and VA are not yet fully understood.

In their manuscript “Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)”, the authors report on a detailed analysis of morphological parameters and their association with VA in 523 patients with available morphological and VA data 5 years after entry into the CATT study (6). The results of this analysis indicate that the development of a new foveal scar, CNV, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM) and retinal thinning, development or worsening of foveal geographic atrophy (GA), and an increase in lesion size during follow-up are important contributors to the VA decline observed from year 2 to 5. Foveal SHRM demonstrated the biggest impact on VA, presumably due to overlying photoreceptor damage. This finding is in line with earlier reports (7,8) which highlighted the functional importance of SHRM. SHRM in the setting of AMD may correlate with CNV, fibrin, hemorrhage, pseudo-vitelliform material, or fibrotic scar; however, persistent SHRM during long-term follow-up after anti-VEGF therapy most likely represents scarred fibrovascular tissue. Although a higher proportion of eyes demonstrated retinal thinning at year 5 (36%) compared to year 1 (21%) and 2 (22%), the proportion of eyes with IRF increased steadily during follow-up and foveal IRF was associated with worse VA over the entire study duration. These findings support the hypothesis that IRF that persists despite anti-VEGF therapy may represent “cystoid degeneration” from tissue loss rather than a manifestation of active exudation.

Recently, subretinal hyporeflective fluid (SRF) has been associated with less atrophy and better VA outcomes (9). The underlying mechanism for this effect and the therapeutic relevance of this observation remains unknown. In the CATT study, foveal SRF was associated with better VA at both 2 and 5 years follow-up. However, this apparent positive effect was no longer observed on multivariate analysis at year 5 adjusting for IRF, SHRM and total CNV lesion size, indicating that other factors may be more relevant than SRF itself for the observed outcomes. It is also worth pointing out that in studies in which SRF was associated with better vision or less atrophy, patients with SRF were still being treated with anti-VEGF therapy (9). Thus, there is no evidence that not treating eyes with SRF leads to better outcomes, whereas there is ample evidence that leaving active exudation untreated leads to vision loss (10). It is possible that a small amount of SRF may represent a CNV membrane that is largely controlled, though not eliminated. Such a “controlled” CNV membrane, if confined below an intact RPE, may potentially have positive effects (11), though this needs to be confirmed in future studies. Regardless, treatment of active exudation remains the priority.

In conclusion, several morphological parameters could be identified that help to better understand the long-term results of anti-VEGF therapy in nAMD. The impact and therapeutic relevance of various parameters, in particular SRF, are not yet fully understood and warrant further investigation. There remains a significant unmet need to develop therapies that limit scar formation as well as the development and progression of atrophy.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes.2018.11.01). S Liakopoulos reports receiving fees for serving as a consultant for Novartis. SR Sadda reports fees for serving as a consultant for Genentech, Novartis, Allergan, Amgen, and Thrombogenics.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013;120:2292-9. [Crossref] [PubMed]
2. Gillies MC, Campain A, Barthelmes D, et al. Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study. Ophthalmology 2015;122:1837-45. [Crossref] [PubMed]
3. Maguire MG, Martin DF, Jaffe GJ, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology 2016;123:1751-61. [Crossref] [PubMed]
4. Grunwald JE, Pistilli M, Daniel E, et al. Incidence and Growth of Geographic Atrophy during 5 Years of Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology 2017;124:97-104. [Crossref] [PubMed]
5. Daniel E, Pan W, Ying GS, et al. Development and Course of Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology 2018;125:1037-46. [Crossref] [PubMed]
6. Jaffe GJ, Ying GS, Toth CA, et al. Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials. Ophthalmology 2018; [Epub ahead of print]. [Crossref] [PubMed]
7. Keane PA, Liakopoulos S, Chang KT, et al. Relationship between optical coherence tomography retinal parameters and visual acuity in neovascular age-related macular degeneration. Ophthalmology 2008;115:2206-14. [Crossref] [PubMed]
8. Ristau T, Keane PA, Walsh AC, et al. Relationship between visual acuity and spectral domain optical coherence tomography retinal parameters in neovascular age-related macular degeneration. Ophthalmologica 2014;231:37-44. [Crossref] [PubMed]
9. Sadda SR, Tuomi LL, Ding B, et al. Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration. Ophthalmology 2018;125:878-86. [Crossref] [PubMed]
10. Brown DM, Tuomi L, Shapiro H, et al. Anatomical measures as predictors of visual outcomes in ranibizumab-treated eyes with neovascular age-related macular degeneration. Retina 2013;33:23-34. [Crossref] [PubMed]
11. Christenbury JG, Phasukkijwatana N, Gilani F, et al. Progression Of Macular Atrophy In Eyes With Type 1 Neovascularization and Age-Related Macular Degeneration Receiving Long-Term Intravitreal Anti-Vascular Endothelial Growth Factor Therapy: An Optical Coherence Tomographic Angiography Analysis. Retina 2018;38:1276-88. [Crossref] [PubMed]