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CONTROVERSIES IN CARE: Macular Atrophy Associated With Anti-VEGF Therapy for Wet AMD

Retina specialists discuss what might be an inconvenient truth.

By: Michael Colucciello, MD, Jayanth Sridhar, MD, Anton Kolomeyer, MD, PhD
Retinal Physician January 1, 2023 Vol 20, Issue January/February 2023 Page(s): 34-37

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The previous installment of “Controversies in Care,” which appeared in the November/December 2022 issue of Retinal Physician, reviewed the evidence for macular atrophy (MA) as a complication of anti-VEGF therapy for wet age-related macular degeneration (wet AMD, Figure 1).1 Several trials show an association with atrophy, including the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT),2-4 the IVAN Study,5 and a recent meta-analysis of several studies, covering 4,609 study eyes, that found a positive correlation between number of injections and incidence of MA.6 However, the evidence is inconclusive overall, as other trials either show no association of atrophy with anti-VEGF administration or do not specifically address MA progression.

Figure 1. Wet age-related macular degeneration (wet AMD) on optical coherence tomography angiography (OCTA)
Figure 1. Wet age-related macular degeneration (wet AMD) on optical coherence tomography angiography (OCTA). Mature, tangled 3.5 mm diameter, 9.5 mm2 area subfoveal type 1 macular neovascularization (MNV) in wet AMD visualized via OCTA (A). Associated structural B-scan OCT with superimposed flow signals (red) showing flow in the MNV (B). Is this new blood flow causing resistance to macular atrophy? Could suppression of this MNV flow with anti-VEGF agents lead to macular atrophy?

This follow-up installment includes expert commentary on this issue by Jay Sridhar, MD, FASRS, and Anton Kolomeyer, MD, PhD. They discuss whether the evidence is significant enough to support the hypothesis that serial administration of anti-VEGF agents contributes to secondary MA in the setting of wet AMD.

Adjustments to Treatment May Help

Jayanth Sridhar, MD, FASRS

Dr. Colucciello has done a comprehensive job delineating the mixed and often confusing evidence surrounding anti-VEGF therapy for wet AMD and its potential effect on MA. One of the biggest reasons that the data are contradictory is that MA can be a consequence of the natural progression of macular degeneration to the advanced dry form, or geographic atrophy (GA). Geographic atrophy development does often occur concurrently with wet AMD and thus it becomes near impossible to attribute atrophy solely to frequent anti-VEGF administration.

Still, studies such as CATT2,4 that illustrated higher rates of atrophy with more frequent anti-VEGF injection may not be totally off base. Perhaps the best explanation is disease heterogeneity; that is, anti-VEGF therapy may pose greater risk for more rapid atrophy progression in some eyes. As sophisticated as our diagnostic modalities, such as optical coherence tomography (OCT), have become, we still do not have perfect parameters to properly assess which wet AMD patients are higher risk to be “sensitive” to developing more atrophy with anti-VEGF therapy. Optical coherence tomography angiography (OCTA) has given some hints by suggesting that not all choroidal neovascular membranes (CNVMs) in AMD are pathologic. Rather, so-called nonexudative macular neovascularization (MNV) are often asymptomatic, do not always imply development of vision-threatening exudation, and may even have a protective effect in some eyes to slow progression of GA.7 Small series using OCTA have helped clarify which MNVs may be more prone to ultimately exude and cause vision loss,8 but the jury is still out on how to best identify which lesions carry more protective value rather than pathologic risk.

Implications to current day-to-day practice exist, but wet AMD is still generally treated with anti-VEGF to a sufficient extent to limit exudation, given the rapidity of vision loss with undertreated wet AMD when compared to vision loss from GA. One adjustment that many physicians in the field have made, including myself, is to be more tolerant of trace amounts of subretinal fluid (SRF) in eyes receiving anti-VEGF therapy for wet AMD when defining treatment patterns and extension intervals, whether using a pro re nata (PRN) or treat-and-extend (TREX) approach. The FLUID study and other similar reports have indicated similar to better visual acuity with greater tolerance for residual SRF on OCT in treated eyes with wet AMD.9,10 Currently, I generally halt extension and maintain an interval when new, asymptomatic SRF is observed on a visit during a TREX regimen, whereas before I would reduce the interval. If that SRF stays stable on a fixed interval for 2 to 3 more injections, I will gently extend by an additional week to see if the SRF alters significantly or not. My hope is perhaps minimizing anti-VEGF treatment in these cases offers little to no risk of exudative vision loss while theoretically assisting in slowing GA in those patients that may be more susceptible to anti-VEGF–associated atrophy.

Looking forward, several therapies, including gene therapy, are in the pipeline that will ideally result in long-term VEGF suppression without breaks. How these will affect GA rates in treated patients remains to be seen, but currently the practical and psychological burden of patients being tethered to frequent, fixed-interval intravitreal injections renders the discussion almost moot. The import of the unmet need of longer term therapeutic options for the blinding condition that is wet AMD far outweighs theoretical impacts on atrophy rates. Still, it is reassuring to see successes emerging in trials for complement-based therapies for GA.11,12 We still do not know how these treatments will interact with our well-known anti-VEGF treatments in eyes with concomitant wet AMD and GA. However, if we do observe increased atrophy in some of the gene therapy–treated wet AMD eyes, for example, having potential options on the horizon that could mitigate these effects is heartening.

Many Questions Must Still Be Answered

Anton Kolomeyer, MD, PhD

We are all biased by our idiosyncratic experiences. I have been seeing more patients with concurrent exudative AMD and extensive MA. These patients are either continuing to receive their “n-teenth” anti-VEGF injection or, after receiving dozens of injections, have now stopped due to significant, permanent loss of vision. Am I experiencing recency bias, or am I more primed to notice these types of patients now that we may soon have the first FDA-approved intravitreal therapy for patients with GA?13,14

It is interesting that studies of intravitreal anticomplement therapy for GA have definitively shown increased likelihood of exudative conversion in treated patients compared to controls.13,14 Yet, after decades of use and dozens of registration trials and post hoc analyses of anti-VEGF injections for exudative AMD, we still have not been able to fully ascertain the theoretical connection between MA and anti-VEGF injections.3-6,10,15-19 Perhaps a connection does not exist. The relationship between RPE cells, photoreceptors, choriocapillaris, VEGF levels, and pathogenesis of exudative AMD is intricate and incredibly complex. It is also not completely characterized, and that is why we have this “controversy” on which to opine.

Vascular endothelial growth factor is a critical trophic factor that is preferentially secreted toward the basal surface of RPE cells.20 Receptors of VEGF are present throughout the retina and the choroid, and are concentrated on RPE cells, Müller cells, and photoreceptors.21,22 Physiologic levels of VEGF are important for retinal/RPE homeostasis, as well as for preservation of the choriocapillaris.23 Atrophy of the choriocapillaris has been localized to the area of CNV formation. However, there is no consensus or definitive data on the physiologic concentration of VEGF in nonpathologic conditions. The amount of VEGF normally present and needed to maintain retinal homeostasis is not known.

In retinovascular/proliferative conditions, levels of VEGF are highly and sometimes persistently elevated.24 Vitreous VEGF sampling has shown that the concentration of VEGF plummets practically to zero after anti-VEGF injections.25 In areas of GA, there is co-localization of RPE cell loss and choriocapillaris degeneration, which may imply that lack or decreased production of VEGF by RPE cells contributes to the development of GA.23 It would make sense that persistent depletion/neutralization of free VEGF in the vitreous has a deleterious effect on viability of the retina, RPE, and the choriocapillaris, and that this would progress to or lead to development or worsening of MA.

On the other hand, data from the phase 2 Ladder study showed higher MA in the monthly ranibizumab (Lucentis; Genentech) injection arm compared to the 100 mg/mL implant arm in patients without MA at baseline, which contradicts the above.26 Another question is why we don’t commonly see MA developing in patients with DR/DME and RVO who are treated chronically with anti-VEGF injections as well.

There are preclinical data regarding the relationship between VEGF and retinal atrophy. For example, Saint-Geniez et al showed that VEGF neutralization negatively affected RPE cell, photoreceptor, and choriocapillaris viability and that Müller cell signaling resulted in overall retinal degeneration in the adult mouse.23 There are many other similar studies. These findings support the idea that VEGF is important in retinal homeostasis and suggest that VEGF depletion may result in deleterious effects on the retina, RPE, and choriocapillaris. These are the mechanisms that may contribute to the development of GA and MA.

Despite suggestive evidence from preclinical studies and clinical observations, data from post hoc analyses of anti-VEGF injection registration and extension trials are equivocal, and at times directly contradict regarding the association between anti-VEGF injections and development/progression of MA.3-6,10,15-19 The inconsistency of these data is likely multifactorial and relate to disease heterogeneity (ie, type of CNVM), presence of risk characteristics (ie, subretinal hyperreflective material or SRF), methodology (measurements performed on fundus photos vs OCT), treatment regimen (monthly vs TREX), and other factors in the clinical trial patient cohorts.

It is also possible that there are other yet unidentified factors driving the development of MA that may be preventing us from definitively determining if there is an association between anti-VEGF injections and development and/or progression of MA. There may be too many variables to keep track of and account for in the pathogenesis of MA. We know that type of CNV, several OCT biomarkers (eg, SRF, choriocapillaris thickness), and injection frequency/burden are important contributors to consider; however, we are unable to assign a “value” or “weight” of importance to each of these (eg, treatment frequency vs type of CNVM).

Genetics could also play a role. There are a number of GA single nucleotide polymorphisms (SNPs) such as CFH rs1061170, ARMS2 rs1049092, HTRA1 rs1120063, C3 rs2230199, and TLR3 rs377529.27,28 However, I do not believe that any study looked at the association of MA development with distribution of such SNPs.

There are likely other contributing factors that are yet to be identified. Perhaps with the increased utilization of artificial intelligence in ophthalmology, we may be able to “teach” a system to identify those patients who are most at risk for the development of MA before it is clinically evident and irreversibly damages our patient’s vision.29 Theoretically, upon identification of such patients, if approved, perhaps anti-complement injections may be used to modify the natural history of development of MA in patients receiving anti-VEGF injections.13,14 This is all speculation, however. There is much work to do and critical questions to answer before this controversy is settled. RP

Michael Colucciello, MD, FASRS, is a clinical associate at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, and a retina specialist with the South Jersey Eye Physicians Division of PRISM Vision Group in Moorestown, New Jersey. Jayanth Sridhar, MD, FASRS, is a vitreoretinal surgeon and associate professor of clinical ophthalmology at the University of Miami’s Bascom Palmer Eye Institute in Miami, Florida. He reports consultancy to Apellis, Genentech, and Regeneron. Anton Kolomeyer, MD, PhD, is an adjunct assistant professor of ophthalmology at the University of Pennsylvania’s Perelman School of Medicine and a retina specialist with PRISM Vision Group-NJ Retina Division in Vineland, New Jersey. He reports consultancy to Allergan/Abbvie, Genentech, and Regeneron, and consultancy to and speaking for Biogen.

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