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Quantitative response of macular neovascularisation to loading phase of aflibercept in neovascular age-related macular degeneration

Eye volume 37, pages 3648–3655 (2023)Cite this article

Subjects

Abstract

Purpose

To evaluate quantitative morphological changes in macular neovascularisation (MNV) network after aflibercept therapy in neovascular age-related macular degeneration (nAMD) patients.

Methods

Consecutive treatment-naïve patients with optical coherence tomography (OCT) angiography confirmed MNV due to nAMD who completed a loading phase of intravitreal aflibercept injections. A quantitative analysis of the vascular network remodelling was performed using a computational software (Angiotool).

Results

A total of 53 eyes of 52 patients were included in the analysis. The total MNV area decreased significantly after three aflibercept injections (p = 0.003). Total vessel area and vessel density decreased respectively of 20% and 12% at V3 (p < 0.001 in both cases). Other parameters that reduced significantly were total vessel length, average vessel length and density of vascular junctions (p = 0.018, p = 0.002, and p = 0.044, respectively). The number of vascular endpoints (p = 0.001) and lacunarity (p = 0.011) increased significantly, whilst the number of vascular junctions did not vary significantly (p = 0.068). Changes in vascular metrics were predominantly driven by MNV type 1 and 2. No clear relationship was observed between any of the vascular metrics and the macular fluid status.

Conclusion

Although objective quantification of vascular parameters showed a significant remodelling of the MNV post-loading phase of aflibercept in type 1 and 2 MNV subtypes, none of the quantified vascular metrics correlated to the macular fluid response. These findings highlight a dissociation of anti-angiogenic and anti-permeability properties of aflibercept therapy during the loading phase.

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Fig. 1: Images processing and analysis.
Fig. 2: Box plot analysis of macular neovascularisation metrics variation over time.
Fig. 3: Example of MNV remodelling over the aflibercept loading dose.

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Data availability

The dataset generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Sarwar S, Clearfield E, Soliman MK, Sadiq MA, Baldwin AJ, Hanout M, et al. Aflibercept for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2016;2:CD011346.

    PubMed  Google Scholar 

  2. Spaide RF, Jaffe GJ, Sarraf D, Freund KB, Sadda SR, Staurenghi G, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: consensus on neovascular age-related macular degeneration nomenclature study group. Ophthalmology. 2020;127:616–36. https://doi.org/10.1016/j.ophtha.2019.11.004.

    Article  PubMed  Google Scholar 

  3. Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98:1144–67. https://pubmed.ncbi.nlm.nih.gov/25136079.

    Article  PubMed  Google Scholar 

  4. Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res. 2018;64:1–55.

    Article  PubMed  Google Scholar 

  5. Lupidi M, Cerquaglia A, Chhablani J, Fiore T, Singh SR, Cardillo Piccolino F, et al. Optical coherence tomography angiography in age-related macular degeneration: the game changer. Eur J Ophthalmol. 2018;28:349–57.

    Article  PubMed  Google Scholar 

  6. Told R, Reiter GS, Schranz M, Reumueller A, Hacker V, Mittermueller TJ, et al. Correlation of retinal thickness and swept-source optical coherence tomography angiography derived vascular changes in patients with neovascular age-related macular degeneration. Curr Eye Res. 2021;46:1002–9.

    Article  CAS  PubMed  Google Scholar 

  7. Told R, Reiter GS, Mittermüller TJ, Schranz M, Reumueller A, Schlanitz FG, et al. Profiling neovascular age-related macular degeneration choroidal neovascularization lesion response to anti-vascular endothelial growth factor therapy using SSOCTA. Acta Ophthalmol. 2021;99:e240–e246.

    Article  CAS  PubMed  Google Scholar 

  8. Choi M, Kim S-W, Yun C, Oh J-H, Oh J. Predictive role of optical coherence tomography angiography for exudation recurrence in patients with type 1 neovascular age-related macular degeneration treated with pro-re-nata protocol. Eye (Lond). 2023;37:34–41. https://doi.org/10.1038/s41433-021-01879-2.

    Article  CAS  PubMed  Google Scholar 

  9. Takeuchi J, Kataoka K, Ito Y, Takayama K, Yasuma T, Kaneko H, et al. Optical coherence tomography angiography to quantify choroidal neovascularization in response to aflibercept. Ophthalmologica. 2018;240:90–98.

    Article  CAS  PubMed  Google Scholar 

  10. von der Emde L, Thiele S, Pfau M, Nadal J, Meyer J, Möller PT, et al. Assessment of exudative activity of choroidal neovascularization in age-related macular degeneration by OCT angiography. Ophthalmologica. 2020;243:120–8. https://www.karger.com/DOI/10.1159/000503609.

    Article  PubMed  Google Scholar 

  11. Cabral D, Coscas F, Pereira T, Français C, Geraldes C, Laiginhas R, et al. Quantitative optical coherence tomography angiography biomarkers in a treat-and-extend dosing regimen in neovascular age-related macular degeneration. Transl Vis Sci Technol. 2020;9:18 https://pubmed.ncbi.nlm.nih.gov/32714644.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Scharf J, Corradetti G, Corvi F, Sadda S, Sarraf D. Optical coherence tomography angiography of the choriocapillaris in age-related macular degeneration. J Clin Med. 2021;10:751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Al-Sheikh M, Iafe NA, Phasukkijwatana N, Sadda SR, Sarraf D. Biomarkers of neovascular activity in age-related macular degeneration using optical coherence tomography angiography. Retina. 2018;38. https://journals.lww.com/retinajournal/Fulltext/2018/02000/BIOMARKERS_OF_NEOVASCULAR_ACTIVITY_IN_AGE_RELATED.2.aspx.

  14. Coscas GJ, Lupidi M, Coscas F, Cagini C, Souied EH. Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related macular degeneration: a new diagnostic challenge. Retina. 2015;35:2219–28.

    Article  PubMed  Google Scholar 

  15. Rocholz R, Teussink MM, Dolz-Marco R, Holzhey C, Dechent JF, Tafreshi, et al. SPECTRALIS optical coherence tomography angiography (OCTA): principles and clinical applications. https://www.heidelbergengineering.com/media/e-learning/Totara/Dateien/pdf-tutorials/210111-001_SPECTRALIS%20OCTA%20-%20Principles%20and%20Clinical%20Applications_EN.pdf.

  16. Zudaire E, Gambardella L, Kurcz C, Vermeren S. A computational tool for quantitative analysis of vascular networks. PLoS One. 2011;6:e27385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu J, Song S, Yu X. Predicting lesion shrinkage in eyes with myopic choroidal neovascularization from features on optical coherence tomography angiography. Retina. 2022;42:1665–1672. https://doi.org/10.1097/IAE.0000000000003526.

    Article  CAS  PubMed  Google Scholar 

  18. Roberts PK, Nesper PL, Gill MK, Fawzi AA. Semiautomated quantitative approach to characterize treatment response in neovascular age-related macular degeneration: a real-world study. Retina. 2017;37. https://journals.lww.com/retinajournal/Fulltext/2017/08000/SEMIAUTOMATED_QUANTITATIVE_APPROACH_TO.8.aspx.

  19. Popovic N, Radunovic M, Badnjar J, Popovic T. Fractal dimension and lacunarity analysis of retinal microvascular morphology in hypertension and diabetes. Microvasc Res. 2018;118:36–43. https://www.sciencedirect.com/science/article/pii/S0026286218300104.

    Article  PubMed  Google Scholar 

  20. Lumbroso B, Rispoli M, Savastano MC, Jia Y, Tan O, Huang D. Optical coherence tomography angiography study of choroidal neovascularization early response after treatment. Dev Ophthalmol. 2016;56:77–85.

    Article  PubMed  Google Scholar 

  21. Lumbroso B, Rispoli M, Savastano MC. Longitudinal optical coherence tomography-angiography study of type 2 naive choroidal neovascularization early response after treatment. Retina. 2015;35:2242–51.

    Article  CAS  PubMed  Google Scholar 

  22. Miere A, Butori P, Cohen SY, Semoun O, Capuano V, Jung C, et al. Vascular remodeling of choroidal neovascularization after anti-vascular endothelial growth factor therapy visualized on optical coherence tomography angiography. Retina. 2019;39:548–57.

    Article  CAS  PubMed  Google Scholar 

  23. Papadopoulou DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009;116:1755–61. https://www.sciencedirect.com/science/article/pii/S0161642009002814.

    Article  PubMed  Google Scholar 

  24. Siemerink MJ, Klaassen I, van Noorden CJF, Schlingemann RO. Endothelial tip cells in ocular angiogenesis: potential target for anti-angiogenesis therapy. J Histochem Cytochem. 2013;61:101–15.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Norton K-A, Popel AS. Effects of endothelial cell proliferation and migration rates in a computational model of sprouting angiogenesis. Sci Rep. 2016;6:36992 https://doi.org/10.1038/srep36992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ishibashi T, Miller H, Orr G, Sorgente N, Ryan SJ. Morphologic observations on experimental subretinal neovascularization in the monkey. Invest Ophthalmol Vis Sci. 1987;28:1116–30.

    CAS  PubMed  Google Scholar 

  27. Spaide RF. Optical coherence tomography angiography signs of vascular abnormalization with antiangiogenic therapy for choroidal neovascularization. Am J Ophthalmol. 2015;160:6–16.

    Article  PubMed  Google Scholar 

  28. Faatz H, Rothaus K, Ziegler M, Book M, Heimes-Bussmann B, Pauleikhoff D, et al. Vascular analysis of type 1, 2, and 3 macular neovascularization in age-related macular degeneration using swept-source optical coherence tomography angiography shows new insights into differences of pathologic vasculature and may lead to a more personal understanding. Biomedicines. 2022;10:694.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Phasukkijwatana N, Tan ACS, Chen X, Freund KB, Sarraf D. Optical coherence tomography angiography of type 3 neovascularisation in age-related macular degeneration after antiangiogenic therapy. Br J Ophthalmol. 2017;101:597–602.

    Article  PubMed  Google Scholar 

  30. Ahmed M, Syrine BM, Nadia BA, Anis M, Karim Z, Mohamed G, et al. Optical coherence tomography angiography features of macular neovascularization in wet age-related macular degeneration: a cross-sectional study. Ann Med Surg. 2021;70:102826 https://www.sciencedirect.com/science/article/pii/S2049080121007767.

    Article  Google Scholar 

  31. Querques G, Miere A, Souied EH. Optical coherence tomography angiography features of type 3 neovascularization in age-related macular degeneration. Dev Ophthalmol. 2016;56:57–61.

    Article  PubMed  Google Scholar 

  32. Coscas F, Cabral D, Pereira T, Geraldes C, Narotamo H, Miere A, et al. Quantitative optical coherence tomography angiography biomarkers for neovascular age-related macular degeneration in remission. PLoS One. 2018;13:e0205513.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sacconi R, Fragiotta S, Sarraf D, Sadda SR, Freund KB, Parravano M, et al. Towards a better understanding of non-exudative choroidal and macular neovascularization. Prog Retin Eye Res. 2022;92:101113.

    Article  PubMed  Google Scholar 

  34. Arrigo A, Aragona E, Bandello F. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med. 2022;54:1089–111. https://doi.org/10.1080/07853890.2022.2064541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Y, Baccouche B, Olayinka O, Serikbaeva A, Kazlauskas A. The role of the Wnt pathway in VEGF/Anti-VEGF-dependent control of the endothelial cell barrier. Invest Ophthalmol Vis Sci. 2021;62:17 https://doi.org/10.1167/iovs.62.12.17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schranz M, Told R, Hacker V, Reiter GS, Reumueller A, Vogl W-D, et al. Correlation of vascular and fluid-related parameters in neovascular age-related macular degeneration using deep learning. Acta Ophthalmol. 2022. https://doi.org/10.1111/aos.15219.

  37. Ablonczy Z, Dahrouj M, Marneros AG. Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. FASEB J. 2014;28:2369–79. https://doi.org/10.1096/fj.13-248021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sarkar A, Jayesh Sodha S, Junnuthula V, Kolimi P, Dyawanapelly S. Novel and investigational therapies for wet and dry age-related macular degeneration. Drug Discov Today. 2022. https://www.sciencedirect.com/science/article/pii/S135964462200160X.

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Authors and Affiliations

  1. NIHR Moorfields Biomedical Research Centre and Clinical Research Facility, Moorfields Eye Hospital NHS Foundation Trust, 162, City Road, London, EC1V 2PD, UK

    Andrea Montesel, Ahmed M. Hagag, Shruti Chandra, Raheeba Pakeer Muhammed, Sridevi Thottarath, Swati Chandak & Sobha Sivaprasad

  2. Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK

    Ahmed M. Hagag, Shruti Chandra & Sobha Sivaprasad

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Contributions

AM, AMH and SS designed the study, analysed data, wrote and reviewed the paper. AM, AMH, SC, RPM, ST, SC collected the data. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sobha Sivaprasad.

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Competing interests

SS received consultancy fees from Bayer, Allergan, Novartis Pharma AG, Roche, Boehringer Ingelheim, Optos, Apellis, Oxurion, Oculis and Heidelberg Engineering. SS is Editor-in-Chief for the journal Eye. All the other authors declare no competing interests.

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Montesel, A., Hagag, A.M., Chandra, S. et al. Quantitative response of macular neovascularisation to loading phase of aflibercept in neovascular age-related macular degeneration. Eye 37, 3648–3655 (2023). https://doi.org/10.1038/s41433-023-02574-0

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