Anti–Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration
Authors: SriniVas R. Sadda, Robyn Guymer, Jordi M. Monés, Adnan Tufail, Glenn J. Jaffe
Journal: Ophthalmology (2019)

TopicTo summarize the rates of atrophy, risk factors, and atrophy-associated visual outcomes in patients with neovascular age-related macular degeneration (nAMD) who received anti–vascular endothelial growth factor (VEGF) treatment for macular neovascularization (MNV).Clinical RelevanceAge-related macular degeneration is a leading cause of vision loss worldwide, and VEGF inhibitors are the primary treatment for nAMD. However, atrophy is observed frequently in eyes treated with anti-VEGF therapy, prompting questions regarding a causative role for these therapies in atrophy development.MethodsPubMed was searched for articles published in the past 5 years (January 1, 2014, through January 10, 2019). Studies including atrophy outcome(s) in patients with age-related macular degeneration who received anti-VEGF treatment were included. Review articles, retrospective studies, case reports or studies, preclinical studies, prevalence data reports, and non-English studies were excluded. Randomization was not required.ResultsOverall, 145 studies were identified; 29 publications were included, with cohorts ranging from 8 to 1185 eyes. Imaging methods used to assess atrophy varied across studies. All studies confirmed the occurrence of atrophy, and when available, longitudinal data from the included studies demonstrated an increase in atrophy incidence over time. Key risk factors or phenotypes associated with atrophy were fellow eye atrophy, reticular pseudodrusen, increased injections, and type 3 lesion. In addition, visual acuity loss was noted with foveal atrophy.DiscussionAll studies demonstrated that atrophy occurs in the context of MNV treated with anti-VEGF therapy; however, it is not clear whether anti-VEGF treatment is causative of atrophy versus being associated with atrophy development. The included studies were not designed or powered to assess atrophy as a primary outcome. In addition, it is difficult to determine whether prognostic factors directly affect atrophy. Furthermore, patient populations in clinical trials do not necessarily represent real-world patients. Although phenotypes and risk factors may help to identify those at greater risk of atrophy developing, it is important to recognize that adequately treating exudative MNV remains the best option to optimize vision outcomes in patients with nAMD, particularly given the risk of vision loss with undertreatment observed in the real world. To summarize the rates of atrophy, risk factors, and atrophy-associated visual outcomes in patients with neovascular age-related macular degeneration (nAMD) who received anti–vascular endothelial growth factor (VEGF) treatment for macular neovascularization (MNV). Age-related macular degeneration is a leading cause of vision loss worldwide, and VEGF inhibitors are the primary treatment for nAMD. However, atrophy is observed frequently in eyes treated with anti-VEGF therapy, prompting questions regarding a causative role for these therapies in atrophy development. PubMed was searched for articles published in the past 5 years (January 1, 2014, through January 10, 2019). Studies including atrophy outcome(s) in patients with age-related macular degeneration who received anti-VEGF treatment were included. Review articles, retrospective studies, case reports or studies, preclinical studies, prevalence data reports, and non-English studies were excluded. Randomization was not required. Overall, 145 studies were identified; 29 publications were included, with cohorts ranging from 8 to 1185 eyes. Imaging methods used to assess atrophy varied across studies. All studies confirmed the occurrence of atrophy, and when available, longitudinal data from the included studies demonstrated an increase in atrophy incidence over time. Key risk factors or phenotypes associated with atrophy were fellow eye atrophy, reticular pseudodrusen, increased injections, and type 3 lesion. In addition, visual acuity loss was noted with foveal atrophy. All studies demonstrated that atrophy occurs in the context of MNV treated with anti-VEGF therapy; however, it is not clear whether anti-VEGF treatment is causative of atrophy versus being associated with atrophy development. The included studies were not designed or powered to assess atrophy as a primary outcome. In addition, it is difficult to determine whether prognostic factors directly affect atrophy. Furthermore, patient populations in clinical trials do not necessarily represent real-world patients. Although phenotypes and risk factors may help to identify those at greater risk of atrophy developing, it is important to recognize that adequately treating exudative MNV remains the best option to optimize vision outcomes in patients with nAMD, particularly given the risk of vision loss with undertreatment observed in the real world. Age-related macular degeneration (AMD) is a leading cause of severe and irreversible vision loss worldwide.1Wong W.L. Su X. Li X. et al.Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e106-e116Abstract Full Text Full Text PDF PubMed Scopus (2158) Google Scholar,2Schmidt-Erfurth U. Chong V. Loewenstein A. 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: 1144-1147Crossref PubMed Scopus (350) Google Scholar Vascular endothelial growth factor (VEGF), a critical mediator of neovascular AMD (nAMD), is associated with pathologic vascular permeability and proliferation.3Miller J.W. Le Couter J. Strauss E.C. et al.Vascular endothelial growth factor A in intraocular vascular disease.Ophthalmology. 2013; 120: 106-114Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar,4Chappelow A.V. Kaiser P.K. Neovascular age-related macular degeneration: potential therapies.Drugs. 2008; 68: 1029-1036Crossref PubMed Scopus (131) Google Scholar Phase 3 clinical trials of VEGF inhibitors validated intravitreal VEGF-A as a therapeutic target for nAMD treatment.5Heier J.S. Brown D.M. Chong V. et al.Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.Ophthalmology. 2012; 119: 2537-2548Abstract Full Text Full Text PDF PubMed Scopus (1546) Google Scholar, 6Rosenfeld P.J. Brown D.M. Heier J.S. et al.Ranibizumab for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1419-1431Crossref PubMed Scopus (4634) Google Scholar, 7Brown D.M. Kaiser P.K. Michels M. et al.Ranibizumab versus verteporfin for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1432-1444Crossref PubMed Scopus (2931) Google Scholar Studies in mice lacking retinal pigment epithelium (RPE)–derived soluble VEGF demonstrated normal choriocapillaris development; however, an atrophy-like phenotype emerged, with areas of photoreceptor apoptosis and RPE loss.8Saint-Geniez M. Kurihara T. Sekiyama E. et al.An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris.Proc Natl Acad Sci U S A. 2009; 106: 18751-18756Crossref PubMed Scopus (389) Google Scholar In clinical research, observation of eyes with untreated intermediate AMD revealed that atrophy develops in a certain proportion of eyes.9Christenbury J.G. Folgar F.A. O'Connell R.V. et al.Progression of intermediate age-related macular degeneration with proliferation and inner retinal migration of hyperreflective foci.Ophthalmology. 2013; 120: 1038-1045Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar In addition, an association between anti-VEGF treatment and atrophy development has been observed,10Chakravarthy U. Harding S.P. Rogers C.A. et al.A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to inhibit VEGF in age-related choroidal neovascularisation (IVAN).Health Technol Assess. 2015; 19: 1-298Crossref PubMed Scopus (51) Google Scholar, 11Grunwald J.E. Daniel E. Huang J. et al.Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2014; 121: 150-161Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 12Sadda S.R. Tuomi L.L. Ding B. et al.Macular atrophy in the HARBOR study for neovascular age-related macular degeneration.Ophthalmology. 2018; 125: 878-886Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar prompting questions regarding a causative role for these therapies in atrophy development. The potential relationship between atrophy and VEGF inhibition—the natural history of atrophy development, anti-VEGF causation of atrophy, or whether atrophy worsens the natural history of AMD—is unclear. Therefore, understanding the evidence behind the potential association between anti-VEGF treatment and atrophy is valuable. The objective of this systematic literature review was to summarize atrophy outcomes in patients with nAMD who received anti-VEGF treatment for macular neovascularization (MNV). Population, intervention, and outcome characteristics (Table 1) were used to search PubMed for articles published in the past 5 years (from January 1, 2014, through January 10, 2019). Review articles, retrospective studies, case reports or studies, preclinical studies, prevalence data reports, and non-English studies were excluded. Studies were required to report atrophy outcome(s), to include patients with AMD, and to include an anti-VEGF agent currently used to treat AMD (including bevacizumab). Randomization was not required. Abstracts were screened to determine which would undergo full-text review by a single reviewer (A.R.). The selected studies were further screened by an additional reviewer (J.S.) using the inclusion and exclusion criteria. The study adhered to the tenets set forth in the Declaration of Helsinki.Table 1Population, Intervention, Comparison, Outcome, and Setting Approach for Defining Eligibility CriteriaItemSearch TermsPopulation DiseaseNeovascular age-related macular degeneration, age-related macular degeneration, or choroidal neovascularizationIntervention Anti-VEGF therapyAnti-VEGF, ranibizumab, aflibercept, or bevacizumabComparison Not searchedOutcome AtrophyAtrophy, macular atrophy, or geographic atrophySetting Study designPhase 2, phase 3, and phase 4 RCTs; single-arm trials; prospective studiesRCT = randomized controlled trial; VEGF = vascular endothelial growth factor. Open table in a new tab RCT = randomized controlled trial; VEGF = vascular endothelial growth factor. The principal summary measures were atrophy outcomes and risk or predisposing factors for atrophy development or progression. Overall, 145 publications were assessed (Fig 1). After screening, 29 publications were included in the final analysis; the cohorts ranged from 8 to 1185 eyes.10Chakravarthy U. Harding S.P. Rogers C.A. et al.A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to inhibit VEGF in age-related choroidal neovascularisation (IVAN).Health Technol Assess. 2015; 19: 1-298Crossref PubMed Scopus (51) Google Scholar, 11Grunwald J.E. Daniel E. Huang J. et al.Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2014; 121: 150-161Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 12Sadda S.R. Tuomi L.L. Ding B. et al.Macular atrophy in the HARBOR study for neovascular age-related macular degeneration.Ophthalmology. 2018; 125: 878-886Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 13Ying G.S. Kim B.J. Maguire M.G. et al.Sustained visual acuity loss in the Comparison of Age-Related Macular Degeneration Treatments Trials.JAMA Ophthalmol. 2014; 132: 915-921Crossref PubMed Scopus (67) Google Scholar, 14Lee J.Y. Folgar F.A. Maguire M.G. et al.Outer retinal tubulation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2014; 121: 2423-2431Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 15Ciulla T.A. Ying G.S. Maguire M.G. et al.Influence of the vitreomacular interface on treatment outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 16Grunwald J.E. Pistilli M. Ying G.S. et al.Growth of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 809-816Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 17Willoughby A.S. Ying G.S. Toth C.A. et al.Subretinal hyperreflective material in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1846-1853.e5Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 18Maguire M.G. Martin D.F. et al.Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research GroupFive-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: 1751-1761Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 19Daniel E. Shaffer J. Ying G.S. et al.Outcomes in eyes with retinal angiomatous proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2016; 123: 609-616Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Sharma S. Toth C.A. 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Garweg J.G. et al.Pre-existing RPE atrophy and defects in the external limiting membrane predict early poor visual response to ranibizumab in neovascular age-related macular degeneration.Ophthalmic Surg Lasers Imaging Retina. 2017; 48: 326-332Crossref PubMed Scopus (9) Google Scholar, 37Mantel I. Dirani A. Zola M. et al.Macular atrophy incidence in anti-vascular endothelial growth factor-treated neovascular age-related macular degeneration: risk factor evaluation for individualized treatment need of ranibizumab or aflibercept according to an observe-and-plan regimen.Retina. 2019; 39: 906-917Crossref PubMed Scopus (16) Google Scholar, 38Mantel I. Zola M. De Massougnes S. et al.Factors influencing macular atrophy growth rates in neovascular age-related macular degeneration treated with ranibizumab or aflibercept according to an observe-and-plan regimen.Br J Ophthalmol. 2019; 103: 900-905Crossref PubMed Scopus (10) Google Scholar Study designs are summarized within the tables. Atrophy was described using nomenclature from the respective trial; the lexicon is addressed in the "Discussion." Thirteen publications from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT; ClinicalTrials.gov identifier; NCT00593450) assessed atrophy using color fundus photography (CFP) and fluorescein angiography (FA; Table 2).11Grunwald J.E. Daniel E. Huang J. et al.Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2014; 121: 150-161Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar,13Ying G.S. Kim B.J. Maguire M.G. et al.Sustained visual acuity loss in the Comparison of Age-Related Macular Degeneration Treatments Trials.JAMA Ophthalmol. 2014; 132: 915-921Crossref PubMed Scopus (67) Google Scholar, 14Lee J.Y. Folgar F.A. Maguire M.G. et al.Outer retinal tubulation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2014; 121: 2423-2431Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 15Ciulla T.A. Ying G.S. Maguire M.G. et al.Influence of the vitreomacular interface on treatment outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 16Grunwald J.E. Pistilli M. Ying G.S. et al.Growth of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 809-816Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 17Willoughby A.S. Ying G.S. Toth C.A. et al.Subretinal hyperreflective material in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1846-1853.e5Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 18Maguire M.G. Martin D.F. et al.Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research GroupFive-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: 1751-1761Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 19Daniel E. Shaffer J. Ying G.S. et al.Outcomes in eyes with retinal angiomatous proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2016; 123: 609-616Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Sharma S. Toth C.A. Daniel E. et al.Macular morphology and visual acuity in the second year of the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2016; 123: 865-875Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 21Daniel E. Grunwald J.E. Kim B.J. et al.Visual and morphologic outcomes in eyes with hard exudate in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmol Retina. 2017; 1: 25-33Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 22Grunwald J.E. 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: 97-104Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 23Daniel E. Ying G.S. Kim B.J. et al.Five-year follow-up of nonfibrotic scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2019; 126: 743-751Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 24Jaffe G.J. Ying G.S. Toth C.A. et al.Macular morphology and visual acuity in year five of the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2019; 126: 252-260Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar In the CATT, this atrophy was termed geographic atrophy (GA), although atrophy was associated with MNV. Among the 1185 participants, GA was present already in 86 (7.3%) at baseline and developed in an additional 120 (10.1%) and 36 (3.0%) eyes during years 1 and 2, respectively (Table 3).16Grunwald J.E. Pistilli M. Ying G.S. et al.Growth of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 809-816Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Among eyes with no GA at enrollment (n = 1024), 10.6% demonstrated GA by the end of year 1; this rate of incident GA increased to 18.3% by the end of year 2.11Grunwald J.E. Daniel E. Huang J. et al.Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2014; 121: 150-161Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar Among those who demonstrated GA at year 2, 83% showed extrafoveal GA and 17% showed foveal GA. Among gradable eyes, 41.4% demonstrated GA after 5 years; 16.5% of gradable eyes showed subfoveal GA.18Maguire M.G. Martin D.F. et al.Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research GroupFive-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: 1751-1761Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar The overall GA growth rate was 0.43 mm/year.16Grunwald J.E. Pistilli M. Ying G.S. et al.Growth of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 809-816Abstract Full Text Full Text PDF PubMed Scopus (158) Google ScholarTable 2Studies Identified by the Systematic Literature Review and Methods Used for Assessing Atrophy in the Included StudiesStudyMethods for Assessing AtrophyCATT11Grunwald J.E. Daniel E. Huang J. et al.Risk of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2014; 121: 150-161Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar,13Ying G.S. Kim B.J. Maguire M.G. et al.Sustained visual acuity loss in the Comparison of Age-Related Macular Degeneration Treatments Trials.JAMA Ophthalmol. 2014; 132: 915-921Crossref PubMed Scopus (67) Google Scholar, 14Lee J.Y. Folgar F.A. Maguire M.G. et al.Outer retinal tubulation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2014; 121: 2423-2431Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 15Ciulla T.A. Ying G.S. Maguire M.G. et al.Influence of the vitreomacular interface on treatment outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 16Grunwald J.E. Pistilli M. Ying G.S. et al.Growth of geographic atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 809-816Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 17Willoughby A.S. Ying G.S. Toth C.A. et al.Subretinal hyperreflective material in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2015; 122: 1846-1853.e5Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 18Maguire M.G. Martin D.F. et al.Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research GroupFive-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: 1751-1761Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 19Daniel E. Shaffer J. Ying G.S. et al.Outcomes in eyes with retinal angiomatous proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Ophthalmology. 2016; 123: 609-616Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Sharma S. Toth C.A. Daniel E. et al.Macular morphology and visual acuity in the second year of the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2016; 123: 865-875Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 21Daniel E. Grunwald J.E. Kim B.J. et al.Visual and morphologic outcomes in eyes with hard exudate in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmol Retina. 2017; 1: 25-33Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 22Grunwald J.E. 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: 97-104Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 23Daniel E. Ying G.S. Kim B.J. et al.Five-year follow-up of nonfibrotic scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2019; 126: 743-751Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 24Jaffe G.J. Ying G.S. Toth C.A. et al.Macular morphology and visual acuity in year five of the Comparison of Age-Related Macular Degeneration Treatments Trials.Ophthalmology. 2019; 126: 252-260Abstract Full Text Full Text PDF PubMed Scopus (102) Google ScholarColor fundus photography and fluorescein angiography∗The study by Lee et al11 also reported using SD OCT.HARBOR12Sadda S.R. Tuomi L.L. Ding B. et al.Macular atrophy in the HARBOR study for neovascular age-related macular degeneration.Ophthalmology. 2018; 125: 878-886Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar,25Sarraf D. London N.J. Khurana R.N. et al.Ranibizumab treatment for pigment epithelial detachment secondary to neovascular age-related macular degeneration: post hoc analysis of the HARBOR study.Ophthalmology. 2016; 123: 2213-2224Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,26Rebhun C.B. Moreira-Neto C. Gune S. et al.Macular atrophy in neovascular age-related macular degeneration: a pilot post hoc analysis of patients with pigment epithelial detachments.Retina. 2018 Dec 24; ([Epub ahead of print])https://doi.org/10.1097/IAE.0000000000002402Crossref Scopus (4) Google ScholarColor fundus photography and fluorescein angiographyIVAN10Chakravarthy U. Harding S.P. Rogers C.A. et al.A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to inhibit VEGF in age-related choroidal neovascularisation (IVAN).Health Technol Assess. 2015; 19: 1-298Crossref PubMed Scopus (51) Google Scholar,27Bailey C. Scott L.J. Rogers C.A. et al.Intralesional macular atrophy in anti-vascular endothelial growth factor therapy for age-related macular degeneration in the IVAN trial.Ophthalmology. 2019; 126: 75-86Abstract Full Text Full Text PDF PubMed Scopus (