Macular Atrophy Incidence and Progression in Eyes with Neovascular Age-Related Macular Degeneration Treated with Vascular Endothelial Growth Factor Inhibitors Using a Treat-and-Extend or a Pro Re Nata Regimen: Four-Year Results of the MANEX Study

Wenlan (Wendy) Zhang, MD  |  January 24, 2021

January 2021

Spooner KL, Fraser-Bell S, Cozzi M, Staurenghi G, Invernizzi A, Monteduro D, Munk MR, Hong T, Chang AA. Macular Atrophy Incidence and Progression in Eyes with Neovascular Age-Related Macular Degeneration Treated with Vascular Endothelial Growth Factor Inhibitors Using a Treat-and-Extend or a Pro Re Nata Regimen: Four-Year Results of the MANEX Study. Ophthalmology 2020;127:1663-1673.

Anti-VEGF therapy is known to be effective against the leakage and bleeding of choroidal new vessels in neovascular AMD. However, there have been questions on whether the frequency or anti-VEGF therapy could accelerate the RPE, choriocapillaris, and photoreceptor loss characteristic of macular atrophy. Different postulates have been proposed as a mechanism of atrophy: atrophy in the setting of more sustained VEGF suppression in treat-and-extend (T&E) regimen eyes vs. atrophy in the setting of greater fluid fluctuations / CNV activity recurrence in PRN regimen eyes. Answers remain elusive as reports of the relationship between frequency of injections and macular atrophy incidence have been inconsistent in the literature.

The purpose of this study was to compare macular atrophy incidence and progression in treatment-naïve eyes with neovascular AMD treated with anti-VEGF agents using either a T&E or a PRN regimen in two real-world clinic settings over a period of 4 years.

This was a retrospective study in which the authors enrolled 264 consecutive patients from two retina clinics in Sydney, Australia (T&E patients, 163 patients) and Milan, Italy (PRN patients, 101 patients). Patients were enrolled and treated from January 2009 – January 2014. All patients underwent 3 monthly loading doses. PRN patients were followed at 4–8-week intervals and dosed according to changes in vision or signs of exudation on OCT/fluorescein. T&E patients were extended up to a maximum of 12 weeks. Notably, ranibizumab, bevacizumab, and aflibercept were all used. Medication switches were noted to happen in 130 (49%) eyes. Patients were enrolled if they were treatment-naïve at the initiation of treatment, had angiographically confirmed CNV, underwent recurrent and continuous anti-VEGF therapy in the study eye for a minimum of 4 years, and had Heidelberg fundus autofluorescence (FAF) imaging available at least yearly during the 4 years of follow up. Two masked graders independently delineated areas of MA from serial FAF images. Main outcome measures included macular atrophy incidence and progression over 4 years, and the association between treatment strategies and number of anti-VEGF injections.

Macular atrophy was found to be present in 24% of eyes in the T&E group and 20% of eyes in the PRN group (P=0.45). In these eyes, the mean square root area of atrophy progressed by a rate of 0.4±0.2 mm/year in the T&E group and 0.4±0.1 mm/year in the PRN group (P=0.23). Eyes without baseline macular atrophy showed detectable atrophy in 27% eyes in the T&E group and 25% of eyes in the PRN group at year 4. Multivariate analyses found that baseline predictors of greater macular atrophy progression were older age, poorer baseline visual acuity, and presence of retinal angiomatous proliferation (P=0.03). Regression analyses found no association between T&E and PRN treatment regimens with the risk of development of new macular atrophy over 4 years or the progression of pre-existing macular atrophy at year 4 (P=0.692). Eyes treated with T&E regimen received significantly more injections than those receiving PRN treatment and were noted to have significantly better visual outcomes at year 4. The authors concluded that neither macular atrophy incidence nor progression of macular atrophy was influenced by the treatment regimen or injection frequency.

There are some limitations to this study, including its retrospective nature as well as the limited generalizability of the findings to the cohorts in this study. Moreover, the authors measured atrophy using the Heidelberg Region Finder software. While this is a validated method to assess atrophy in the presence of CNV, there are limitations such as masking from fibrosis and disease activity. Lastly, the study is not powered to evaluate any possible differences between anti-VEGF agents. However, this study – with its number of enrolled eyes and the length of follow up data in a real-world setting – lends additional insight into whether anti-VEGF therapy may (or may not) impact macular atrophy development/progression in eyes with neovascular AMD.

Wenlan (Wendy) Zhang, MD

Retina Northwest
Portland, OR

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