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Retinal Physician

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CONTROVERSIES IN CARE: Examining the Evidence for Macular Atrophy as a Complication of Anti-VEGF Therapy for Wet AMD

By: Michael Colucciello, MD
Retinal Physician November 1, 2022 Vol 19, Issue November/December 2022 Page(s): 42-44, 46

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Historically, 90% of all legal blindness from age-related macular degeneration (AMD) has been attributed to the effects of the neovascular (wet) form as opposed to the dry form.1 However, the 2 forms frequently coexist in those with wet AMD. The dry, atrophic component can adversely impact quality of life and activities of daily living due to the resultant decrease in contrast sensitivity and visual field, especially if it occurs in or near the fovea.

A common therapeutic approach to wet AMD is a loading dose followed by long-term maintenance treatment with the intravitreal anti–vascular endothelial growth factor (anti-VEGF) agents aflibercept (Eylea; Regeneron), bevacizumab (Avastin; Genentech), ranibizumab (Lucentis; Genentech), and brolucizumab (Beovu; Novartis). Recently, a surgically administered port-delivery reservoir system (Susvimo; Genentech) was approved by the FDA. This device delivers anti-VEGF medication in a sustained fashion (rather than the “pulsed” kinetics characteristically delivered by serial anti-VEGF injections), with a typical refill every 6 months. In the future, intravitreal gene therapy may lead to constitutive expression of intraocular anti-VEGF protein.

Prior to a discussion about potential adverse effects from long-term intravitreal anti-VEGF administration, we must acknowledge the efficacy of anti-VEGF agents; vision loss can be avoided by treating macular neovascularization associated with AMD with anti-VEGF agents. Patients who receive monthly intravitreal anti-VEGF treatment have been shown to achieve greater improvements in visual acuity over 2 years than patients who are treated less frequently.2 Active wet AMD associated with bleeding, tears of the retinal pigment epithelium (RPE), or fibrosis with secondary photoreceptor loss often results from anti-VEGF undertreatment.3-6 Indeed, “real-world” evidence indicates that anti-VEGF undertreatment in patients with wet AMD leads to vision loss.7,8 However, there are signals that secondary macular atrophy (MA) may be an unwanted collateral effect with intraocular exposure of anti-VEGF (Figure 1).

Figure 1. Development of macular atrophy after serial anti-VEGF treatment of wet AMD. Clinical photo (A) and optical coherence tomography (B) on presentation showed cystoid macular edema associated with a retinal angiomatous proliferation lesion (type 3 macular neovascularization). Clinical photo (C) and optical coherence tomography (D) after 2 years of serial anti-VEGF administration, showing the resolution of edema and occurrence of extrafoveal macular atrophy in the region of the previously leaking retinal angiomatous proliferation lesion (temporal macula).
Figure 1. Development of macular atrophy after serial anti-VEGF treatment of wet AMD. Clinical photo (A) and optical coherence tomography (B) on presentation showed cystoid macular edema associated with a retinal angiomatous proliferation lesion (type 3 macular neovascularization). Clinical photo (C) and optical coherence tomography (D) after 2 years of serial anti-VEGF administration, showing the resolution of edema and occurrence of extrafoveal macular atrophy in the region of the previously leaking retinal angiomatous proliferation lesion (temporal macula).

CONSIDERING COLLATERAL DAMAGE WITH WET AMD TREATMENT

If associated with secondary MA or photoreceptor loss (usually following progressive atrophy and thinning of the RPE and choriocapillaris), long-term intensive treatment with anti-VEGF agents could result in irreversible vision loss for patients with wet AMD. In primary MA, the area of atrophy enlarges concentrically, and this ultimately manifests as a demarcation between the atrophic and nonatrophic retina that appears “geographic.” The older term “geographic atrophy” (GA) continues to be used by some to indicate primary MA. Conversely, secondary MA in the setting of wet AMD often lacks a sharp boundary.9,10

A direct cause-effect relationship between GA and use of anti-VEGF agents in wet AMD has not yet been proven. The 2 categories of evidence that indicate there may be an association are: (1) based on analysis of trial study results and (2) based on clinical characteristics.

TRIALS THAT SHOWED ASSOCIATION OF ATROPHY WITH ANTI-VEGF ADMINISTRATION

CATT Study

Retrospective analyses of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) suggested that receiving more anti-VEGF injections is associated with GA progression. Two years of treatment in CATT with monthly injections (mean of 22.5 injections) was associated with a 59% increase in risk of MA development in comparison with PRN treatment (mean of 13.1 injections).11 This proportion increased to 41% at 5 years, with an increase in foveal atrophy from 6% to 17%.12,13

Additional evidence that anti-VEGF dosing frequency may affect the development of MA comes from analysis of the cohort who switched frequency. Those who switched from monthly injections in year 1 to PRN treatment in year 2 had a lesser incidence of MA during their second year under PRN treatment (7%) than during the first year of monthly injections (12.7%). This lower second-year rate (7%) was similar to the second-year rate of GA development in the group that had received PRN for 2 years (8.8% in the PRN always group) and was lower than the second year rate of GA development in the patients who continued with monthly therapy in the second year of the study (12.4% in the monthly always group).11

An analysis of the 5-year follow-up, which included 647 patients from the original CATT group, showed that a high percentage of eyes treated for nAMD with anti-VEGF injections develop nongeographic MA in the area of CNV, with one-third having MA at year 1 and four-fifths by year 5. By 4 years after detection, approximately 50% of the eyes with nongeographic atrophy progressed to geographic-type atrophy.14

IVAN Study

The Inhibition of VEGF in the Age-related Choroidal Neovascularisation (IVAN) trial compared the efficacy of monthly or as-needed intravitreal injections of bevacizumab with ranibizumab in 610 patients with untreated wAMD. In this study, significantly more patients developed MA in the continuous monthly administration group (35%) than in the discontinuous “as needed” group (26%; P=.03).15

Meta-analysis

A recent meta-analysis of several studies found an association between frequency and number of anti-VEGF injections and the development of MA. The analysis included 31 articles covering 4,609 study eyes, each receiving a mean of 17.7 injections over 35.2 months. The authors found a positive correlation between number of injections and incidence of MA.16

TRIALS THAT SHOWED NO ASSOCIATION OF ATROPHY WITH ANTI-VEGF ADMINISTRATION

HARBOR Study

The HARBOR study was a phase 3 double-masked, multicenter, randomized, active-treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg ranibizumab administered monthly or on an as-needed basis in patients with subfoveal neovascular age-related macular degeneration. The study assessed 1,095 patients and reported no correlation between number of injections or ranibizumab dose on the development or rate of MA enlargement.17

SEVEN-UP Study

Patients originally treated with ranibizumab in the ANCHOR and MARINA studies for 2 years and the HORIZON study for an additional 2 years were evaluated in the SEVEN-UP study, with a total follow-up of 7 years. A progression rate of MA of 0.28 mm2/year was described in these patients. Macular atrophy was characterized as less severe in the study eyes than in fellow eyes with nAMD. The authors therefore concluded that monthly ranibizumab injections did not lead to atrophy progression over time.18 However, the study’s conclusion has been contested due to the relatively small cohort, possible selection bias, and heterogeneity of patients regarding their condition at baseline and treatment paradigms over the years. Also, these studies were not designed to evaluate the question of whether or not the anti-VEGF treatment was a risk factor for progression of the MA.

TREX-AMD Trial

The TREX-AMD study was the first prospective, randomized trial directly comparing monthly with treat-and-extend dosing for neovascular AMD. A post-hoc analysis of 60 patients with wet AMD from the TREX-AMD trial showed that the dosing regimen did not seem to influence the development or progression of MA.19

FLUID Study

In the FLUID study, patients treated with a ranibizumab treat-and-extend protocol who tolerated some subretinal fluid achieved VA that was comparable, with fewer injections (“relaxed” protocol), compared to that achieved when treatment aimed to resolve all SRF completely (“intensive” protocol). In the summary of the 24-month treatment results, no reported increased macular atrophy in the “intensive” or “relaxed” ranibizumab treatment cohorts occurred.20

TRIAL THAT ASSESSED ATROPHY WITHOUT CONTROLS OR DID NOT ASSESS ATROPHY

RIVAL Study

The RIVAL study, enrolling 281 patients with untreated wet AMD, specifically compared the development of MA in patients with wet AMD treated with either ranibizumab or aflibercept. These patients received either ranibizumab or aflibercept monthly for 3 months followed by a treat-and-extend regimen, during which disease activity was monitored.21 The RIVAL study found that the proportion of patients who developed MA increased in both groups over the 24-month treatment period (ranibizumab 5% to 37%; aflibercept 6% to 32%).22 The change in MA area at month 12 was found to be similar to that seen in natural history studies.23 Because there was no control group in the RIVAL study, the results from this study did not reflect on the potential role of these agents in MA progression.

TRIALS WITH NO ATROPHY ASSESSMENT

There are also studies that did not specifically address MA progression. These include the VIEW1 and VIEW2 studies (evaluating aflibercept),24 TENAYA/LUCERNE (evaluating faricimab),25 HAWK/HARRIER (evaluating brolucizumab),26 and ARCHWAY (ranibizumab port delivery system).27

ASSOCIATION OF MA WITH ANTI-VEGF BASED ON CLINICAL CHARACTERISTICS

Subretinal Fluid

It has been theorized that subretinal fluid (SRF) may be an indicator of milder or more benign wet AMD,28 or may contain neuroprotective factors that promote RPE and outer retina survival.29 Alternatively, the presence of residual SRF may be a marker for an incomplete blockade of VEGF, allowing preservation of choriocapillaris.

In the CATT and HARBOR studies, the presence of SRF was associated with a lower risk of MA and better visual acuity outcome. In the HARBOR trial, SRF was associated with a lower risk of MA incidence over 24 months.17 In the CATT study, the relative incidence of MA among treatment groups was similar to the relative incidence of residual fluid on OCT: the higher the rate of residual fluid on OCT, the lower the rate of MA. The CATT 5-year results show that the presence of subretinal fluid at the baseline visit was a protective factor against the conversion of nongeographic atrophy to MA during treatment (fluid not in fovea center: RR, 0.49 [95% CI, 0.32-0.73]; fluid in fovea center: RR, 0.38 [95% CI, 0.25-0.59]; P<.001).12

In the CATT study, patients treated with ranibizumab had a more complete resolution of fluid than those treated with bevacizumab. Treatment with ranibizumab, regardless of the dosing regimen, was associated with a 43% increase in risk of MA development in comparison with bevacizumab.11 In the IVAN trial, the presence of subretinal fluid (SRF) cut in half the probability of MA developing within a wet AMD lesion.15 The IVAN study found no difference in new MA between the eyes treated with ranibizumab and those treated with bevacizumab.

Intraretinal Fluid

The presence of intraretinal fluid was associated with MA in both the CATT and HARBOR studies.12,17

Choroidal Thinning

An important trophic factor for the choroid and choriocapillaris is VEGF derived from the RPE. Serial administration of intravitreal anti-VEGF agents can lead to thinning of the choroid,30,31 which is associated with increased MA area.32

Macular Neovascularization

Theoretically, type 1 macular neovascularization (MNV, located between Bruch membrane and the RPE) may be a compensatory form of slow-growing blood vessels elicited in response to an ischemic outer retina, recapitulating the choriocapillaris.33 This type I macular neovascularization may offer nutritional support and the associated shallow SRF may offer the protective benefits described above. Patients with type I MNV often have little or no vision loss and have a relatively low risk of secondary MA.34,35 Conversely, patients with type 3 MNV (retinal angiomatous proliferation) have the highest associated MA risk of all the MNV subtypes (with a hazard ratio of 2.5 in the Grunwald study).11,34

Subretinal Hyperreflective Material

A post-hoc analysis of the CATT study found that the presence of subretinal hyperreflective material (SHRM) at baseline was a significant predictor for the development of MA at 1 year, but there was no difference at week 104 for the development of MA with respect to SRHM persistence.36 In the TREX-AMD trial, eyes that had thicker SHRM did seem to develop more MA over the course of 18 months.19

Pigment Epithelial Detachment

In the TREX-AMD trial, eyes that had a thicker PED at baseline developed more MA over the course of 18 months.19

Hemorrhage

In the TREX-AMD trial, eyes that had hemorrhage at baseline developed more MA over the course of 18 months.19

THE CONTROVERSY

In a subsequent installment of “Controversies in Care,” our experts will opine on whether the evidence, as delineated above, is significant enough to support that serial administration of anti-VEGF agents contributes to secondary MA in the setting of wAMD. They will discuss what other investigations may be needed to further define the association, whether this should change the optimism associated with longer duration treatment strategies, and whether and how MA mitigation in this setting is appropriate. RP

Michael Colucciello, MD, FASRS, is a clinical associate at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, and a retina specialist with the South Jersey Eye Physicians Division of PRISM Vision Group in Moorestown, New Jersey. Editor’s note: Hear discussion of this article on the Retina Podcast at www.retinapodcast.com .

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