- Email: [email protected]
Incidence of Macular Atrophy after Untreated Neovascular Age-Related Macular Degeneration
Journal Pre-proof Incidence of macular atrophy following untreated neovascular age-related macular degeneration: Age-Related Eye Disease Study Report 40 Panos G. Christakis, MD, Elvira Agrón, MA, Michael L. Klein, MD, Traci E. Clemons, PhD, J. Peter Campbell, MD, MPH, Frederick L. Ferris, MD, Emily Y. Chew, MD, Tiarnan D. Keenan, BM BCh, PhD, for the Age-Related Eye Diseases Study Research Group PII:
S0161-6420(19)32297-3
DOI:
https://doi.org/10.1016/j.ophtha.2019.11.016
Reference:
OPHTHA 11008
To appear in:
Ophthalmology
Received Date: 21 August 2019 Revised Date:
29 October 2019
Accepted Date: 19 November 2019
Please cite this article as: Christakis PG, Agrón E, Klein ML, Clemons TE, Campbell JP, Ferris FL, Chew EY, Keenan TD, for the Age-Related Eye Diseases Study Research Group, Incidence of macular atrophy following untreated neovascular age-related macular degeneration: Age-Related Eye Disease Study Report 40, Ophthalmology (2019), doi: https://doi.org/10.1016/j.ophtha.2019.11.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology
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Incidence of macular atrophy following untreated neovascular age-related macular degeneration: Age-Related Eye Disease Study Report 40
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Panos G. Christakis, MD1,2, Elvira Agrón, MA1, Michael L. Klein, MD3, Traci E. Clemons, PhD4, J. Peter Campbell, MD, MPH3, Frederick L. Ferris, MD5, Emily Y. Chew, MD1, and Tiarnan D. Keenan, BM BCh, PhD1, for the Age-Related Eye Diseases Study Research Group6
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Institutions 1
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Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
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Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA Emmes Corporation, Rockville, Maryland, USA Ophthalmic Research Consultants, LLC, Waxhaw, NC, USA Appendix of the AREDS Research Group appears in the supplement
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Corresponding Author
Tiarnan D. Keenan, BM BCh, PhD NIH, Building 10, CRC, Room 10D45 10 Center Dr, MSC 1204 Bethesda, MD 20892-1204 Telephone: 301 451 6330 Fax: 301 496 7295
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Presented in part at:
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Association for Research in Vision and Ophthalmology Annual Meeting, Honolulu, Hawaii, 2018
Email:
[email protected]
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Financial support:
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This study was supported by the National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland (contract NOI-EY-0-2127 (EYC),
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P30EY10572 (MLK and JPC), and K12EY27720 (JPC)). The sponsor and funding organization participated in the design and conduct of the study, data collection, management, analysis, and interpretation, and preparation, review and approval of the manuscript. The study was also supported by unrestricted departmental funding (MLK and JPC) and a Career Development Award (JPC) from Research to Prevent Blindness.
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Conflict of interest:
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No conflicting relationship exists for any author.
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Running head:
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Macular atrophy following untreated neovascular AMD.
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Abbreviations
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AMD: age-related macular degeneration
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AREDS: Age-Related Eye Disease Study
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CATT: Comparison of Age-Related Macular Degeneration Treatments Trials
49
CFP: color fundus photograph
50
CI: confidence interval
51
FA: fluorescein angiography
52
GA: geographic atrophy
53
GRS: genetic risk score
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GWAS: genome-wide association study
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HR: hazard ratio
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IVAN: Inhibit VEGF in Age-Related Choroidal Neovascularization
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MARINA: Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration
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MPS: Macular Photocoagulation Study
60
NV: neovascular age-related macular degeneration
61
OCT: optical coherence tomography
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PDT: photodynamic therapy
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PRN: pro re nata
64
RPE: retinal pigment epithelium
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SD: standard deviation
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SE: standard error
67 68
SEVEN-UP: Seven-Year Observational Update of Macular Degeneration Patients Post-MARINA/ANCHOR and HORIZON Trials
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TAP: Treatment of Age-related macular degeneration with Photodynamic therapy study
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VEGF: vascular endothelial growth factor
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VIP: Verteporfin in Photodynamic Therapy study
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Abstract
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Purpose
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To report the natural history of untreated neovascular age-related macular degeneration (NV),
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concerning risk of subsequent macular atrophy.
77
Design
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Prospective cohort within a randomized, controlled trial of oral micronutrient supplements.
79
Participants
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Age-Related Eye Disease Study (AREDS) participants, aged 55-80 years, who developed NV
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during follow-up (1992-2005), prior to the advent of anti-VEGF therapy.
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Methods
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Stereoscopic color fundus photographs were collected at annual study visits and graded
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centrally for features of late AMD. Incident macular atrophy after NV was examined by
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Kaplan-Meier analysis and proportional hazards regression.
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Main outcome measures
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Incident macular atrophy following NV, including risk of central involvement.
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Results
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Of the 4,757 AREDS participants, 708 eyes (627 participants) developed NV during follow-up
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and were eligible for analysis. The cumulative risks of incident macular atrophy after untreated
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NV were 9.6% (standard error 1.2%), 31.4% (2.2%), 43.1% (2.6%), and 61.5% (4.3%) at two, five,
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seven, and 10 years, respectively. This corresponded to a linear risk of 6.5%/year. The
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cumulative risk of central involvement was 30.4% (3.2%), 43.4% (3.8%), and 57.0% (4.8%) at
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first appearance of atrophy, two years, and five years, respectively. Geographic atrophy (GA) in
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the fellow eye was associated with increased risk of macular atrophy after NV (HR 1.70,
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1.17-2.49; p=0.006). However, higher 52-SNP AMD Genetic Risk Score was not associated with
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increased risk of macular atrophy after NV (hazard ratio 1.03, 95% CI 0.90-1.17; p=0.67).
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Similarly, no significant differences were observed according to the SNPs CFH rs1061170, CFH
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rs10922109, ARMS2 rs10490924, or C3 rs2230199.
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Conclusions
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The rate of incident macular atrophy following untreated NV is relatively high, increasing
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linearly over time and affecting half of eyes by eight years. Hence, factors other than anti-VEGF
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therapy are involved in atrophy development, including natural progression to GA. Comparison
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with studies of treated NV suggests it may not be necessary to invoke a large effect of
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anti-VEGF therapy on inciting macular atrophy, though a contribution remains possible. Central
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involvement by macular atrophy is present in approximately one third of eyes at the time
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atrophy develops (similar to pure GA) and increases linearly to half of eyes at three years.
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Introduction
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Age-related macular degeneration (AMD) is the most common cause of legal blindness in
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developed countries and is predicted to affect 196 million people worldwide by 2020.1-3 Late
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AMD, the stage associated with severe visual loss, occurs in two forms, neovascular AMD (NV)
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and geographic atrophy (GA). Untreated NV has a very poor prognosis: 76% of eyes have
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20/200 or worse visual acuity three years after NV development.4 The advent of anti-VEGF
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therapy revolutionized NV treatment. In 2006, the Minimally Classic/Occult Trial of the
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Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular
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Degeneration (MARINA) demonstrated that eyes with NV treated with ranibizumab had a
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nearly 10-fold decreased risk of severe vision loss at two years, compared with eyes that
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received sham.5 The efficacy of anti-VEGF for NV was corroborated in many clinical trials and
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became the standard of care.6-8
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However, long-term follow-up of these clinical trial participants demonstrated that eyes with
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NV receiving anti-VEGF therapy had high rates of subsequent macular atrophy. The Comparison
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of AMD Treatments Trials (CATT) reported that the proportion of eyes with incident macular
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atrophy five years after starting anti-VEGF therapy for NV was 38%.9 In addition, using a
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different definition for macular atrophy, the Seven-Year Observational Update of Macular
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Degeneration Patients Post-MARINA/ANCHOR and HORIZON Trials (SEVEN-UP), which assessed
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eyes that were originally treated with ranibizumab in these trials, found the proportion of eyes
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with macular atrophy at seven years to be 98%; indeed, by this point, the macular atrophy had
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become the primary anatomic determinant of visual outcomes.10
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This led some authors to question whether anti-VEGF therapy itself might increase the
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tendency to develop macular atrophy, which would have potential implications for clinical
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practice. In the Inhibit VEGF in Age-Related Choroidal Neovascularization (IVAN) trial, the
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authors reported a possible increased risk of macular atrophy in eyes treated with anti-VEGF for
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two years with a monthly regimen compared with a pro re nata (PRN) regimen (odds ratio 1.47,
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95% CI 1.03-2.11).11 However, recent reanalyses using a specially designed grading protocol did
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not replicate these findings (odds ratio 1.01 per treatment cycle, 95% CI 0.91-1.13).12 Similarly,
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in the CATT, the authors observed increased risk of macular atrophy (hazard ratio 1.59,
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1.17-2.16) in eyes treated for two years with monthly versus PRN anti-VEGF13, though no
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significant difference was observed at five years (i.e., three years after the end of the two-year
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clinical trial).9 In post hoc analysis of the HARBOR study, monthly versus PRN anti-VEGF therapy
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for two years was not associated with a significant difference (hazard ratio 1.29, 95% CI
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0.99-1.68).14
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However, in these and similar studies of NV treated with anti-VEGF therapy, regarding macular
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atrophy following NV, it is extremely difficult to separate out the relative contributions of (i)
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natural progression to GA, as the final common pathway in AMD disease progression (i.e.,
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independent of NV presence), (ii) NV-associated macular atrophy (i.e., through
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NV/exudation-related damage to the retinal pigment epithelium (RPE) and nearby cells), and
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(iii) potential contribution of anti-VEGF therapy.
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The natural history of untreated NV would provide valuable information regarding the potential
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contribution of anti-VEGF therapy, since removing component (iii) would enable an
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understanding of the natural progression from NV to macular atrophy through components (i)
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and (ii) only. The Age-Related Eye Disease Study (AREDS) was a multicenter prospective study of
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the clinical course of AMD and age-related cataract, as well as a phase III RCT designed to
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assess the effects of nutritional supplements on AMD and cataract progression previously.15
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Since the AREDS occurred prior to the advent of anti-VEGF therapy, this study provided an
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opportunity to evaluate long-term natural history data.
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The primary aim of this study was to analyze the risk of incident macular atrophy following
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untreated NV. Secondary aims included examining the risk of central involvement by incident
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macular atrophy at first appearance of the atrophy, subsequent progression to central
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involvement over time, and potential risk factors for macular atrophy.
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Methods
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Study population and procedures for the Age-Related Eye Disease Study
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The study design for the AREDS has been described previously.15 In short, 4,757 participants
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aged 55 to 80 years were recruited between 1992 and 1998 at 11 retinal specialty clinics in the
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United States. Based on fundus photographic gradings, best-corrected visual acuity, and
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ophthalmoscopic evaluations, participants were enrolled into one of several AMD categories.
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Of the 4,757 participants, 3,640 took part in the AMD trial. The participants were randomly
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assigned to placebo, antioxidants, zinc, or the combination of antioxidants and zinc. The
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primary endpoint was progression to late AMD (defined as NV or central GA).
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Institutional review board approval was obtained at each clinical site and written informed
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consent for the research was obtained from all study participants. The research was conducted
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under the tenets of the Declaration of Helsinki and pre-dated the Health Insurance Portability
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and Accountability Act.
175
Questionnaires administered at the baseline and subsequent study visits collected information
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that included medications, adverse events and treatment compliance. At baseline and annual
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study visits, comprehensive eye examinations were performed by certified study personnel
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using standardized protocols, and stereoscopic color fundus photographs (CFP) were captured.
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Progression to late AMD was defined by the study protocol based on the grading of CFP, as
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described previously.15 Additional ‘event photographs’ were taken at any visit in which a ≥10
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letter reduction in best corrected visual acuity was noted, compared to the baseline visit, or
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when the clinical examination suggested NV or central GA. CFPs were graded using a
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standardized protocol by certified graders at a reading center (Fundus Photographic Reading
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Center, University of Wisconsin). GA/macular atrophy was defined as a sharply demarcated,
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usually circular zone of partial or complete depigmentation of the RPE, typically with exposure
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of underlying large choroidal blood vessels, that must be as large as circle I-1 (1/8 disk
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diameter, i.e., approximately 215µm). An area of RPE atrophy within or adjacent to a subretinal
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fibrous scar was not considered macular atrophy. The CFPs were deemed to be of gradable
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quality in 99.4% of the 48,998 sets of CFPs evaluated in the first 10 years of the study.16 All of
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the CFPs were graded independently, and the graders were masked to the grades from
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previous visits. Contemporaneous replicate grading exercises showed 96% exact agreement
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between graders, with weighted kappa values of 0.71-0.73 for GA suggesting precise grading.16
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The AREDS cohort was followed between 1992 and 2005, prior to the United States Food and
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Drug Administration approval of ranibizumab for NV. Hence, the participants were offered
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standard of care treatment for NV by their local retinal specialists. For the early years of the
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AREDS follow-up, this generally comprised no active treatment; rarely, participants might
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undergo laser photocoagulation, following the results of the Macular Photocoagulation Study
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(MPS).17 In the later years of follow-up, again, this normally meant no active treatment; in some
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rare cases, participants might receive photodynamic therapy (PDT), following publication of the
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Treatment of Age-related macular degeneration with Photodynamic therapy (TAP) and
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Verteporfin in Photodynamic Therapy (VIP) studies.18,19
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Eligibility criteria and statistical analysis
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The unit of analysis was at the eye level. In the AREDS participants, eyes that developed NV
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without prior/simultaneous GA during study follow-up were eligible for analysis. Hence, eyes
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that developed NV and GA/macular atrophy simultaneously (i.e., both NV and GA graded
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positive for the first time in the same CFP) were excluded from analysis (since the primary
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outcome was incident macular atrophy subsequent to NV). In addition, eyes that underwent
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macular laser photocoagulation and/or PDT for NV, prior to NV positive grading on CFP at an
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AREDS study visit, were also excluded.
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The rates of incident macular atrophy after NV were examined by Kaplan-Meier survival
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analysis. In addition, in these eyes with incident macular atrophy after NV, the rates of atrophy
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progression to central involvement were calculated by Kaplan-Meier survival analysis. Study
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eyes that underwent macular laser photocoagulation and/or PDT for NV were censored at the
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time of treatment to prevent confounding with respect to the development of macular atrophy.
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Further Kaplan-Meier survival analyses were performed with stratification by (i) AMD genotype
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and (ii) fellow eye GA status. Regarding AMD genotype, the following genetic characteristics
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were pre-specified for analysis: AMD Genetic Risk Score (GRS)20, CFH rs1061170 (Y402H) risk
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alleles, CFH rs10922109 protective alleles (the lead variant at this locus in a large genome-wide
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association study (GWAS) of late AMD20), ARMS2 rs10490924 risk alleles (the locus with highest
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attributable risk of late AMD), and C3 rs2230199 risk alleles. The AMD GRS is a weighted risk
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score for late AMD, based on 52 independent variants at 34 loci identified in a large GWAS20; it
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was calculated for each participant according to methods described previously.20 Participants
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can be divided into three groups (0-2); group 0 participants are those with a GRS below the
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mean GRS of a control population without late AMD, while group 1 and 2 participants are those
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with a higher GRS (below and above the median GRS of a large population with late AMD,
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respectively). Regarding fellow eye GA status, the analyses were limited to those participants
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with one but not both eyes in the current study; fellow eye GA status (present or absent) was
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defined at the time of incident NV in the study eye. In addition, the demographic characteristics
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of participants (age, sex, educational level, and smoking status, as well as AREDS treatment
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assignment) were analyzed separately according to presence/absence of progression to
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macular atrophy, as potential risk factors.
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For all of these variables, statistical testing was performed using proportional hazards
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regression. For analyses of the demographic characteristics, the full study population was used
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(n=708 eyes, taking into account correlation between the eyes of an individual); for those of the
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genetic characteristics, the study population was restricted to those participants with genotype
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data available (n=433 eyes, taking into account correlation between the eyes of an individual);
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for those of the fellow eye GA status, the analyses were limited to those participants with one
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but not both eyes in the current study (n=546 participants/eyes). All analyses were conducted
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using SAS version 9.4 (SAS Inc, Cary NC).
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Results
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A total of 1,042 eyes developed NV during the AREDS follow-up. Of these, 265 eyes (25.4%)
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were excluded because of prior or simultaneous GA/macular atrophy and an additional 69 eyes
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(6.6%) were excluded because of laser photocoagulation prior to NV detection. The remaining
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708 eyes (67.9%) of 627 participants were considered at risk of incident macular atrophy and
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eligible for subsequent analyses. The baseline characteristics of these eyes are shown in Table
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1. The number of study eyes censored during follow-up because of laser photocoagulation
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and/or PDT for NV was 239 (comprising 130 eyes with treatment at the same study visit as NV
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detection and 109 eyes with treatment after NV detection).
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During mean follow-up of 3.2 years (SD 3.4), of the 708 eyes at risk, 204 eyes (28.8%) developed
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incident macular atrophy, at a mean interval of 3.8 years (SD 2.4) from the time of NV
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detection. By Kaplan-Meier analysis, the cumulative risk of developing macular atrophy after
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untreated NV was 9.6% (standard error (SE) 1.2%), 31.4% (SE 2.2%), 43.1% (SE 2.6%), and 61.5%
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(SE 4.3%) at two, five, seven, and 10 years, respectively (Figure 1). The time point at which 50%
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of eyes were affected was 8.0 years (95% confidence interval (CI) 7.3-9.6). The cumulative
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progression to macular atrophy over time appeared strikingly linear. Considered in this way, the
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progression corresponded (by linear regression) to a linear risk of 6.5% per year.
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Of the 204 eyes with incident macular atrophy after NV, the proportion with central
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involvement at first appearance of the atrophy was 30.4% (62 eyes). Of the 142 eyes whose
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incident macular atrophy was non-central at first appearance, the proportion that progressed
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to central involvement (over mean follow-up of 7.6 years (SD 1.9)) was 22.5% (32 eyes). Hence,
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the total number of eyes that developed incident central macular atrophy at any point after
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untreated NV was 94 (representing 13.3% of all eyes at risk).
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By Kaplan-Meier analysis, out of the 204 eyes with incident macular atrophy after NV, the
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cumulative risk of developing central involvement by atrophy was 30.4% (SE 3.2%) at baseline
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(i.e., at first appearance of macular atrophy), 43.4% (SE 3.8%) at two years, and 57.0% (SE 4.8%)
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at five years (Figure 2). The time point at which 50% of eyes had central involvement was 3.1
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years (95% CI 2.0-5.1). Excluding those eyes with central involvement at baseline, this
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corresponded (by linear regression) to a linear risk of 8.8% per year. Finally, considering
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progression to macular atrophy and progression to central involvement simultaneously, the
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Kaplan-Meier analysis of the cumulative risk of incident central macular atrophy following NV is
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shown in Figure 3.
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Potential risk factors for the development of macular atrophy after untreated NV were analyzed
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by proportional hazards regression, including demographic characteristics, AREDS treatment
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assignment, AMD genotype, and fellow eye GA status (Table 2). No demographic characteristic
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was significantly associated with progression to macular atrophy: age (p=0.81), sex (p=0.66),
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smoking status (p=0.41), education level (p=0.37), or body mass index (0.20). Similarly, no
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significant difference was observed according to AREDS treatment assignment (p=0.66).
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Participants with a higher AMD GRS were not significantly more or less likely to develop
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macular atrophy after NV, compared to those with a lower GRS (Table 2). The hazard ratio
281
associated with higher GRS was 1.03 (95% CI 0.90-1.17, p=0.67). Similarly, no significant
282
differences were observed according to the individual loci examined: CFH rs1061170, CFH
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rs10922109, ARMS2 rs10490924, or C3 rs2230199.
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However, participants whose fellow eye had GA (at the time of incident NV in the study eye)
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were significantly more likely to progress to macular atrophy (Table 2; Figure 4). For example,
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the cumulative risk of developing macular atrophy by five years after NV was 43.9% (SE 6.8%)
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for participants whose fellow eye had GA, versus 26.8% (SE 2.6%) for participants whose fellow
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eye did not have GA. According to proportional hazards regression, the hazard ratio for macular
289
atrophy associated with GA in the fellow eye was 1.70 (1.17-2.49, p=0.006). In additional
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regression analyses that considered all variables simultaneously in the same model, the results
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were similar, i.e., fellow eye GA status was significant (p=0.01, hazard ratio 1.81, 1.13-2.91) and
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all other variables were non-significant (p>0.4 for each).
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Discussion
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The AREDS represents the largest cohort of prospective data on the natural history of untreated
296
NV, with respect to the development of macular atrophy, to our knowledge. Since anti-VEGF
297
therapy has become the standard of care for NV, future data on untreated NV are unlikely,
298
making this dataset potentially unique in history.
299
This study demonstrates that, without anti-VEGF therapy, incident macular atrophy occurs in
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approximately one third of eyes within five years of NV, and that one half of eyes are affected
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by eight years. Interestingly, the cumulative development of macular atrophy appears strikingly
302
linear over this long time period of a decade without NV treatment. This prolonged linearity
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may represent contributions from component (i) described above (i.e., natural progression to
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GA, as the final common pathway in AMD disease progression, independent of NV presence)
305
and perhaps also component (ii) (i.e., macular atrophy from NV/exudation-related damage to
306
RPE and nearby cells), though separating their contributions is very difficult.
307
However, the AREDS grading definitions did not consider areas of RPE atrophy within or
308
adjacent to subretinal fibrous scars as macular atrophy, and 131 of the 708 study eyes had a
309
positive grading for subretinal fibrous scars at the time of incident NV. Hence, it is possible that
310
these percentages are underestimates of the true proportions with macular atrophy. For these
311
reasons, we repeated the Kaplan-Meier analyses with censoring of eyes at the point of
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subretinal fibrosis formation. Of the 577 study eyes, 81 progressed to macular atrophy and 496
313
did not. The rates of progression to macular atrophy were much lower than in the original
314
analyses. Hence, many of the eyes with subretinal fibrosis did subsequently receive a positive
315
grade for macular atrophy, even though the area within or adjacent to the fibrosis was not
316
considered; for example, of the 131 eyes described above, 44 still received a subsequent grade
317
of macular atrophy. These considerations may also emphasize the contribution of component
318
(ii) to macular atrophy.
319
Additional findings in this study relate to central involvement, which is important for
320
determining visual potential. This study shows that central involvement is already present at
321
first occurrence of the atrophy in approximately one third of eyes. This is similar to the
322
proportion with central involvement by pure GA (i.e., without preceding NV), as observed in the
323
AREDS2 (i33% of eyes).21
324
Another point of comparison between these AREDS data (on macular atrophy after untreated
325
NV) with AREDS2 data (on pure GA without prior NV) is the speed of progression to central
326
involvement in eyes whose incident atrophy was non-central. In the current study, the rates of
327
central involvement were 18.7% (SE 4.0%) by two years and 35.1% (SE 5.8%) by four years. The
328
equivalent values for pure GA in AREDS2 were 32% and 57%.21 Although direct comparison
329
between the two datasets is difficult, the lower rate of progression to central involvement for
330
macular atrophy than pure GA might support the idea that enlargement of atrophy could be
331
slower in the presence of NV.21-23 However, alternative explanations include different
332
distribution of starting locations for the macular atrophy versus pure GA and the fact that, in
333
the AREDS, atrophy would not be graded as central in the presence of a central subretinal
334
fibrous scar.
335
An additional finding in this study was the increased risk of progression to macular atrophy
336
according to the presence of GA in the fellow eye. This is consistent with similar findings for
337
treated NV in the CATT9,13 and the HARBOR study14. This result, and its similarity to related
338
findings for treated NV, may emphasize the relative contribution of component (i).
339
However, the genetic analyses did not support the hypothesis that higher genetic load (as
340
regards risk of late AMD) is associated with increased risk of macular atrophy after untreated
341
NV. Together with the other results, this means that few risk factors are available to predict the
342
likelihood of atrophy. The genetic results might potentially argue against the contribution of
343
component (i) to the development of atrophy. However, all of the study eyes had already
344
demonstrated the capability of progressing to late AMD and the large majority (91%) were from
345
participants with a high GRS; this may help explain why AMD genotype is not a distinguishing
346
feature in predicting progression to macular atrophy after untreated NV but is for predicting
347
GA. We are not aware of previous studies that have analyzed the AMD GRS in this way. The
348
only study to have examined genotype in macular atrophy after (treated) NV was the CATT,
349
where the authors considered four SNPs; the data at five years suggested significant results for
350
ARMS2 (hazard ratio 1.8 (1.2-2.7) for TT versus GG) and TLR3 (hazard ratio 0.5 (0.3-0.9) for TT
351
versus CC).9
352
Comparison with literature
353
The purpose of comparing these findings with those in the literature (Table 3) was to examine
354
similarities and differences between the behavior of eyes with NV that is treated (with
355
anti-VEGF therapy) versus untreated (i.e., natural history). This should provide insights into the
356
question of whether anti-VEGF therapy may cause and/or contribute to macular atrophy.
357
The CATT randomized 1,185 participants with NV to either ranibizumab or bevacizumab,
358
administered either monthly or PRN, over two years.24 Masked graders at a reading center
359
assessed the presence of macular atrophy at two years and five years. The cumulative
360
proportions of eyes with incident macular atrophy were 17% and 38%, respectively (Table 3).9,13
361
These are higher than the equivalent values in the current study of 10% and 31%. However, the
362
proportions in the current study may have been underestimates for three reasons: first, the
363
AREDS grading definitions did not count atrophy that was within or adjacent to subretinal
364
fibrous scars. Second, the sensitivity of detection was likely higher in the CATT, which used both
365
fluorescein angiography (FA) and CFP.9,13 Third, eyes that underwent laser photocoagulation or
366
PDT for NV were censored in the current study. Overall, these considerations suggest that
367
anti-VEGF therapy may make a relatively minor contribution to the risk of macular atrophy after
368
NV. Alternatively, another possibility is that anti-VEGF therapy did make an important
369
contribution to macular atrophy incidence in the CATT, but the rates are similar to those in the
370
AREDS because, in the AREDS, the effect of removing component (iii) is compensated by
371
increased effects of component (ii), i.e., increased NV/exudation-related RPE damage.
372
Like the CATT, the IVAN was a controlled trial of different anti-VEGF drugs and regimens: 610
373
participants were randomized to ranibizumab or bevacizumab, administered monthly or PRN.11
374
Following recent regrading using a revised protocol12, the proportion of eyes with incident
375
macular atrophy at the primary endpoint of two years was 25% (Table 3). This is higher than the
376
proportion observed in the current study of untreated NV (10%). However, in the IVAN, the size
377
threshold for defining atrophy was much lower at 175 µm, and atrophy was defined using FA
378
and/or CFP, assisted by optical coherence tomography (OCT).
379
In the HARBOR study, a recent post hoc analysis reported rates of incident macular atrophy of
380
21% at one year and 29% at two years (Table 3).14 Again, this is higher than the equivalent rates
381
in the current study, though sensitivity for detecting atrophy was likely higher through the use
382
of FA.
383
In the SEVEN-UP study, post hoc analysis reported macular atrophy rates (combining
384
pre-existing and incident cases) as high as 98% of eyes at a mean of 7.3 years after
385
enrollment.10 However, important contributing factors to this high rate include the imaging
386
modality used (fundus autofluorescence) and the lower minimum size requirement (175 µm). In
387
addition, the sample size was small (60 eyes) and may not be representative of the original
388
study cohorts.
389
Strengths and limitations
390
The main strength of this study relates to its unique position in history, where a cohort of eyes
391
with NV was followed longitudinally, prior to the advent of anti-VEGF injections. The study
392
benefitted from large sample size and long follow-up time, permitting meaningful Kaplan-Meier
393
analyses over a long period. Additional strengths include comprehensive data collection at set
394
time-points and standardized reading center evaluation of images by masked graders using a
395
uniform definition of macular atrophy.
396
One important limitation was that macular atrophy was assessed on CFP only, rather than by
397
modern multimodal approaches including OCT and fundus autofluorescence. However, since
398
the widespread use of these imaging modalities post-dated the advent of anti-VEGF therapy,
399
we presume that no AMD dataset will ever achieve the combination of untreated NV and
400
multimodal imaging. Similarly, it would be ideal to compare treated and untreated NV in the
401
same cohort of participants, for more direct comparisons of macular atrophy formation. Again,
402
this is unlikely to occur. Finally, our dataset does not permit explicit considerations of
403
intralesional versus extralesional macular atrophy (since NV lesion boundaries can not be
404
assessed on CFP alone).
405
Conclusions
406
In summary, the AREDS demonstrates that the rate of incident macular atrophy in untreated
407
NV is relatively high, occurring in approximately one third of eyes within five years of NV and
408
one half by eight years. Hence, when the potential effect of anti-VEGF on progression to
409
macular atrophy is removed, a relatively high rate of progression to macular atrophy is still
410
observed. Factors other than anti-VEGF therapy are therefore involved in atrophy formation.
411
This includes natural progression to GA (as the final common pathway in AMD disease
412
progression, independent of NV presence); indeed, this study observed increased risk of
413
macular atrophy in participants with pure GA in the fellow eye.
414
The progression rates in this study may be underestimates owing to detection methods and
415
grading definitions. With this in mind, comparison with studies of treated NV suggests that it
416
may not be necessary to invoke a large effect of anti-VEGF therapy on the development of
417
macular atrophy. However, a smaller contribution of anti-VEGF therapy to macular atrophy
418
remains possible, particularly if, in the current study, the effect of removing anti-VEGF therapy
419
was exchanged for the effect of increased NV/exudation-associated RPE damage. Finally, in this
420
study, central involvement by macular atrophy was present at the outset in about one third of
421
eyes and rose to one half by three years. These data may be useful, since central macular
422
atrophy is increasingly likely to become the main determinant of visual acuity and legal
423
blindness following NV successfully treated by anti-VEGF therapy.
424
Figure legends
425
Figure 1. Kaplan-Meier curve of the progression of eyes to incident macular atrophy following
426
neovascular age-related macular degeneration, without treatment.
427
Figure 2. Kaplan-Meier curve of the progression of eyes with incident macular atrophy (after
428
neovascular AMD, without treatment) to central involvement.
429
Figure 3. Kaplan-Meier curve of the progression of eyes to incident central macular atrophy
430
following neovascular age-related macular degeneration, without treatment.
431
Figure 4. Kaplan-Meier curve of the progression of eyes to incident macular atrophy following
432
neovascular age-related macular degeneration, without treatment, stratified by the presence or
433
absence of geographic atrophy in the fellow eye (at the time of neovascular age-related
434
macular degeneration in the study eye).
435
436
References
437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479
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2. 3.
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Quartilho A, Simkiss P, Zekite A, Xing W, Wormald R, Bunce C. Leading causes of certifiable visual loss in England and Wales during the year ending 31 March 2013. Eye (Lond). 2016;30(4):602-607. Congdon N, O'Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477-485. Wong WL, 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(2):e106-116. Wong TY, Chakravarthy U, Klein R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115(1):116-126. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. Vedula SS, Krzystolik MG. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008(2):CD005139. Ip MS, Scott IU, Brown GC, et al. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(10):1837-1846. Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014(8):CD005139. Grunwald JE, 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(1):97-104. Bhisitkul RB, Mendes TS, Rofagha S, et al. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON studies: the SEVEN-UP study. Am J Ophthalmol. 2015;159(5):915-924 e912. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267. Bailey C, Scott LJ, Rogers CA, et al. Intralesional Macular Atrophy in Anti-Vascular Endothelial Growth Factor Therapy for Age-Related Macular Degeneration in the IVAN Trial. Ophthalmology. 2019;126(1):75-86. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014;121(1):150-161. Sadda SR, Tuomi LL, Ding B, Fung AE, Hopkins JJ. Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2018;125(6):878-886. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials. 1999;20(6):573-600. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6. Am J Ophthalmol. 2001;132(5):668-681.
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Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol. 1991;109(9):1220-1231. Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study G. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol. 2001;119(2):198-207. Verteporfin In Photodynamic Therapy Study G. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization--verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131(5):541-560. Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134-143. Keenan TD, Agron E, Domalpally A, et al. Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16. Ophthalmology. 2018;125(12):1913-1928. Dansingani KK, Freund KB. Optical Coherence Tomography Angiography Reveals Mature, Tangled Vascular Networks in Eyes With Neovascular Age-Related Macular Degeneration Showing Resistance to Geographic Atrophy. Ophthalmic Surg Lasers Imaging Retina. 2015;46(9):907-912. Capuano V, Miere A, Querques L, et al. Treatment-Naive Quiescent Choroidal Neovascularization in Geographic Atrophy Secondary to Nonexudative Age-Related Macular Degeneration. Am J Ophthalmol. 2017;182:45-55. Comparison of Age-related Macular Degeneration Treatments Trials Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
Table 1. Demographic and genetic characteristics of the study population
Age at neovascular AMD (years: mean, SD) Female (%) Education level (%) High school or less Some college College graduate Smoking status (%) Never Former Current Body mass index (%) ≤25 26-30 >30 AREDS treatment assignment (%) Placebo Antioxidants Zinc Antioxidants & zinc Follow-up time from neovascular AMD to last visit (years: mean, SD) AMD Genetic Risk Score (%) Group 0 Group 1 Group 2 CFH rs1061170 alleles (%) 0 1 2 CFH rs10922109 alleles (%) 0 1 2 ARMS2 rs10490924 alleles (%) 0 1 2 C3 rs2230199 alleles (%) 0 1 2
All eyes (n=708 for demographic characteristics; n=433 for genetic characteristics) 75.5 (5.7)
Eyes that did not progress to macular atrophy after neovascular AMD (n=504; n= 293) 76.3 (5.4)
Eyes that did progress to macular atrophy after neovascular AMD (n=204; n=140) 73.6 (5.8)
62.0
61.7
62.7
41.8 28.1 30.1
40.5 29.6 30.0
45.1 24.5 30.4
38.8 51.3 9.9
38.9 51.6 9.5
38.7 50.5 10.8
33.1 40.5 26.4
35.3 39.3 25.4
27.5 43.6 28.9
27.7 25.7 24.6 22.0 3.2 (3.4)
28.4 25.4 23.2 23.0 2.1 (2.8)
26.0 26.5 27.9 19.6 6.1 (3.1)
9.2 36.5 54.3
9.2 39.6 51.2
9.3 30.0 60.7
16.4 45.5 38.1
16.0 45.4 38.6
17.1 45.7 37.1
66.5 30.3 3.2
67.6 29.7 2.7
64.3 31.4 4.3
32.6 47.1 20.3
34.1 47.4 18.4
29.3 46.4 24.3
8.8 40.9 50.3
8.9 39.2 51.9
8.6 44.3 47.1
Abbreviations: AMD=age-related macular degeneration; AREDS=Age-Related Eye Disease Study; SD=standard deviation
Table 2. Potential risk factors for progression to macular atrophy following untreated neovascular agerelated macular degeneration: results of proportional hazards regression Hazard ratio
95% confidence interval
P
Age (per year)*
1.00
0.96-1.03
0.81
Male
0.93
0.69-1.27
0.66
0.84 0.86
0.59-1.19 0.61-1.20
0.33 0.37
0.96 1.23
0.70-1.32 0.75-2.04
0.79 0.41
1.22 1.28
0.85-1.74 0.88-1.88
0.28 0.20
1.03
0.90-1.17
0.67
0.89 0.88
0.57-1.39 0.56-1.41
0.62 0.60
1.02 0.81
0.71-1.47 0.42-1.53
0.92 0.51
0.99 0.97
0.67-1.47 0.60-1.55
0.98 0.89
0.98 0.78
0.54-1.78 0.42-1.45
0.94 0.44
1.70
1.17-2.49
0.006
Education level High school or less (reference) Some college College graduate Smoking status Never (reference) Former Current Body mass index ≤25 (reference) 26-30 >30 AMD Genetic Risk Score† CFH rs1061170 alleles 0 (reference) 1 2 CFH rs10922109 alleles 0 (reference) 1 2 ARMS2 rs10490924 alleles 0 (reference) 1 2 C3 rs2230199 alleles 0 (reference) 1 2 Geographic atrophy in fellow eye‡
Abbreviations: AMD=age-related macular degeneration * n=708 eyes for age and the other demographic characteristics, with all characteristics considered simultaneously in the same multivariable model † n=433 eyes for all genetic characteristics, with each considered separately in univariate models; the AMD Genetic Risk Score was treated as a continuous variable ‡ n=546 eyes for fellow eye analysis, including only those participants with one but not both eyes in the study population
Table 3. Proportion of study eyes with incident macular atrophy following neovascular age-related macular degeneration at specified time points: current study (of untreated neovascular disease) and comparison with literature (for neovascular disease treated with anti-VEGF therapy) Age-Related Eye Disease Study (no anti-VEGF therapy)
Comparison of AgeRelated Macular Degeneration Treatments Trials
Inhibit VEGF in AgeRelated Choroidal Neovascularization (revised grading 2019) Macular NV without central macular atrophy
HARBOR
Eligibility criteria
Macular NV. No pre-existing/ simultaneous macular atrophy (current study)
NV with subfoveal involvement and no central macular atrophy
Minimum size definition for macular atrophy
215 µm
250 µm
175 µm
250 µm
175 µm
Imaging modalities used to define macular atrophy
CFP
FA and CFP
FA and/or CFP, aided by OCT
FA
FAF and red-free/FA
17%
25%*
29%
-†
5 years 31.4%
38%
-
-
-
7 years 43.1%
-
-
-
98%†
10 years 61.5%
-
-
-
-
Proportion of study eyes with incident macular atrophy at specified time points from study baseline 2 years 9.6%
Subfoveal NV
SEVEN-UP openlabel extension study (following MARINA, ANCHOR, and HORIZON) Per MARINA, ANCHOR, and HORIZON trials
* Total of 35%, including macular atrophy that was already present at baseline † But, in the subset of eyes with fluorescein angiography available at two years and seven years, 95% (two years) and 100% (seven years) Abbreviations: CFP=color fundus photograph; FA=fluorescein angiography; FAF=fundus autofluorescence; NV=neovascular age-related macular degeneration; OCT=optical coherence tomography
Précis In the Age-Related Eye Disease Study, the incidence of macular atrophy following neovascular age-related macular degeneration was high at 31% (five years) and 62% (ten years), despite absence of anti-VEGF therapy.
S0161-6420(19)32297-3
DOI:
https://doi.org/10.1016/j.ophtha.2019.11.016
Reference:
OPHTHA 11008
To appear in:
Ophthalmology
Received Date: 21 August 2019 Revised Date:
29 October 2019
Accepted Date: 19 November 2019
Please cite this article as: Christakis PG, Agrón E, Klein ML, Clemons TE, Campbell JP, Ferris FL, Chew EY, Keenan TD, for the Age-Related Eye Diseases Study Research Group, Incidence of macular atrophy following untreated neovascular age-related macular degeneration: Age-Related Eye Disease Study Report 40, Ophthalmology (2019), doi: https://doi.org/10.1016/j.ophtha.2019.11.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology
1 2
Incidence of macular atrophy following untreated neovascular age-related macular degeneration: Age-Related Eye Disease Study Report 40
3 4 5 6
Panos G. Christakis, MD1,2, Elvira Agrón, MA1, Michael L. Klein, MD3, Traci E. Clemons, PhD4, J. Peter Campbell, MD, MPH3, Frederick L. Ferris, MD5, Emily Y. Chew, MD1, and Tiarnan D. Keenan, BM BCh, PhD1, for the Age-Related Eye Diseases Study Research Group6
7 8
Institutions 1
9 10
Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
11
2
12
3
13
4
14
5
15
6
Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA Emmes Corporation, Rockville, Maryland, USA Ophthalmic Research Consultants, LLC, Waxhaw, NC, USA Appendix of the AREDS Research Group appears in the supplement
16 17 18 19 20 21 22
Corresponding Author
Tiarnan D. Keenan, BM BCh, PhD NIH, Building 10, CRC, Room 10D45 10 Center Dr, MSC 1204 Bethesda, MD 20892-1204 Telephone: 301 451 6330 Fax: 301 496 7295
23 24 25 26 27
Presented in part at:
28
Association for Research in Vision and Ophthalmology Annual Meeting, Honolulu, Hawaii, 2018
Email:
[email protected]
29 30
Financial support:
31 32
This study was supported by the National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland (contract NOI-EY-0-2127 (EYC),
33 34 35 36 37
P30EY10572 (MLK and JPC), and K12EY27720 (JPC)). The sponsor and funding organization participated in the design and conduct of the study, data collection, management, analysis, and interpretation, and preparation, review and approval of the manuscript. The study was also supported by unrestricted departmental funding (MLK and JPC) and a Career Development Award (JPC) from Research to Prevent Blindness.
38 39
Conflict of interest:
40
No conflicting relationship exists for any author.
41 42
Running head:
43
Macular atrophy following untreated neovascular AMD.
44 45
Abbreviations
46
AMD: age-related macular degeneration
47
AREDS: Age-Related Eye Disease Study
48
CATT: Comparison of Age-Related Macular Degeneration Treatments Trials
49
CFP: color fundus photograph
50
CI: confidence interval
51
FA: fluorescein angiography
52
GA: geographic atrophy
53
GRS: genetic risk score
54
GWAS: genome-wide association study
55
HR: hazard ratio
56
IVAN: Inhibit VEGF in Age-Related Choroidal Neovascularization
57 58
MARINA: Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration
59
MPS: Macular Photocoagulation Study
60
NV: neovascular age-related macular degeneration
61
OCT: optical coherence tomography
62
PDT: photodynamic therapy
63
PRN: pro re nata
64
RPE: retinal pigment epithelium
65
SD: standard deviation
66
SE: standard error
67 68
SEVEN-UP: Seven-Year Observational Update of Macular Degeneration Patients Post-MARINA/ANCHOR and HORIZON Trials
69
TAP: Treatment of Age-related macular degeneration with Photodynamic therapy study
70
VEGF: vascular endothelial growth factor
71
VIP: Verteporfin in Photodynamic Therapy study
72
73
Abstract
74
Purpose
75
To report the natural history of untreated neovascular age-related macular degeneration (NV),
76
concerning risk of subsequent macular atrophy.
77
Design
78
Prospective cohort within a randomized, controlled trial of oral micronutrient supplements.
79
Participants
80
Age-Related Eye Disease Study (AREDS) participants, aged 55-80 years, who developed NV
81
during follow-up (1992-2005), prior to the advent of anti-VEGF therapy.
82
Methods
83
Stereoscopic color fundus photographs were collected at annual study visits and graded
84
centrally for features of late AMD. Incident macular atrophy after NV was examined by
85
Kaplan-Meier analysis and proportional hazards regression.
86
Main outcome measures
87
Incident macular atrophy following NV, including risk of central involvement.
88
Results
89
Of the 4,757 AREDS participants, 708 eyes (627 participants) developed NV during follow-up
90
and were eligible for analysis. The cumulative risks of incident macular atrophy after untreated
91
NV were 9.6% (standard error 1.2%), 31.4% (2.2%), 43.1% (2.6%), and 61.5% (4.3%) at two, five,
92
seven, and 10 years, respectively. This corresponded to a linear risk of 6.5%/year. The
93
cumulative risk of central involvement was 30.4% (3.2%), 43.4% (3.8%), and 57.0% (4.8%) at
94
first appearance of atrophy, two years, and five years, respectively. Geographic atrophy (GA) in
95
the fellow eye was associated with increased risk of macular atrophy after NV (HR 1.70,
96
1.17-2.49; p=0.006). However, higher 52-SNP AMD Genetic Risk Score was not associated with
97
increased risk of macular atrophy after NV (hazard ratio 1.03, 95% CI 0.90-1.17; p=0.67).
98
Similarly, no significant differences were observed according to the SNPs CFH rs1061170, CFH
99
rs10922109, ARMS2 rs10490924, or C3 rs2230199.
100
Conclusions
101
The rate of incident macular atrophy following untreated NV is relatively high, increasing
102
linearly over time and affecting half of eyes by eight years. Hence, factors other than anti-VEGF
103
therapy are involved in atrophy development, including natural progression to GA. Comparison
104
with studies of treated NV suggests it may not be necessary to invoke a large effect of
105
anti-VEGF therapy on inciting macular atrophy, though a contribution remains possible. Central
106
involvement by macular atrophy is present in approximately one third of eyes at the time
107
atrophy develops (similar to pure GA) and increases linearly to half of eyes at three years.
108
109
Introduction
110
Age-related macular degeneration (AMD) is the most common cause of legal blindness in
111
developed countries and is predicted to affect 196 million people worldwide by 2020.1-3 Late
112
AMD, the stage associated with severe visual loss, occurs in two forms, neovascular AMD (NV)
113
and geographic atrophy (GA). Untreated NV has a very poor prognosis: 76% of eyes have
114
20/200 or worse visual acuity three years after NV development.4 The advent of anti-VEGF
115
therapy revolutionized NV treatment. In 2006, the Minimally Classic/Occult Trial of the
116
Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular
117
Degeneration (MARINA) demonstrated that eyes with NV treated with ranibizumab had a
118
nearly 10-fold decreased risk of severe vision loss at two years, compared with eyes that
119
received sham.5 The efficacy of anti-VEGF for NV was corroborated in many clinical trials and
120
became the standard of care.6-8
121
However, long-term follow-up of these clinical trial participants demonstrated that eyes with
122
NV receiving anti-VEGF therapy had high rates of subsequent macular atrophy. The Comparison
123
of AMD Treatments Trials (CATT) reported that the proportion of eyes with incident macular
124
atrophy five years after starting anti-VEGF therapy for NV was 38%.9 In addition, using a
125
different definition for macular atrophy, the Seven-Year Observational Update of Macular
126
Degeneration Patients Post-MARINA/ANCHOR and HORIZON Trials (SEVEN-UP), which assessed
127
eyes that were originally treated with ranibizumab in these trials, found the proportion of eyes
128
with macular atrophy at seven years to be 98%; indeed, by this point, the macular atrophy had
129
become the primary anatomic determinant of visual outcomes.10
130
This led some authors to question whether anti-VEGF therapy itself might increase the
131
tendency to develop macular atrophy, which would have potential implications for clinical
132
practice. In the Inhibit VEGF in Age-Related Choroidal Neovascularization (IVAN) trial, the
133
authors reported a possible increased risk of macular atrophy in eyes treated with anti-VEGF for
134
two years with a monthly regimen compared with a pro re nata (PRN) regimen (odds ratio 1.47,
135
95% CI 1.03-2.11).11 However, recent reanalyses using a specially designed grading protocol did
136
not replicate these findings (odds ratio 1.01 per treatment cycle, 95% CI 0.91-1.13).12 Similarly,
137
in the CATT, the authors observed increased risk of macular atrophy (hazard ratio 1.59,
138
1.17-2.16) in eyes treated for two years with monthly versus PRN anti-VEGF13, though no
139
significant difference was observed at five years (i.e., three years after the end of the two-year
140
clinical trial).9 In post hoc analysis of the HARBOR study, monthly versus PRN anti-VEGF therapy
141
for two years was not associated with a significant difference (hazard ratio 1.29, 95% CI
142
0.99-1.68).14
143
However, in these and similar studies of NV treated with anti-VEGF therapy, regarding macular
144
atrophy following NV, it is extremely difficult to separate out the relative contributions of (i)
145
natural progression to GA, as the final common pathway in AMD disease progression (i.e.,
146
independent of NV presence), (ii) NV-associated macular atrophy (i.e., through
147
NV/exudation-related damage to the retinal pigment epithelium (RPE) and nearby cells), and
148
(iii) potential contribution of anti-VEGF therapy.
149
The natural history of untreated NV would provide valuable information regarding the potential
150
contribution of anti-VEGF therapy, since removing component (iii) would enable an
151
understanding of the natural progression from NV to macular atrophy through components (i)
152
and (ii) only. The Age-Related Eye Disease Study (AREDS) was a multicenter prospective study of
153
the clinical course of AMD and age-related cataract, as well as a phase III RCT designed to
154
assess the effects of nutritional supplements on AMD and cataract progression previously.15
155
Since the AREDS occurred prior to the advent of anti-VEGF therapy, this study provided an
156
opportunity to evaluate long-term natural history data.
157
The primary aim of this study was to analyze the risk of incident macular atrophy following
158
untreated NV. Secondary aims included examining the risk of central involvement by incident
159
macular atrophy at first appearance of the atrophy, subsequent progression to central
160
involvement over time, and potential risk factors for macular atrophy.
161 162
Methods
163
Study population and procedures for the Age-Related Eye Disease Study
164
The study design for the AREDS has been described previously.15 In short, 4,757 participants
165
aged 55 to 80 years were recruited between 1992 and 1998 at 11 retinal specialty clinics in the
166
United States. Based on fundus photographic gradings, best-corrected visual acuity, and
167
ophthalmoscopic evaluations, participants were enrolled into one of several AMD categories.
168
Of the 4,757 participants, 3,640 took part in the AMD trial. The participants were randomly
169
assigned to placebo, antioxidants, zinc, or the combination of antioxidants and zinc. The
170
primary endpoint was progression to late AMD (defined as NV or central GA).
171
Institutional review board approval was obtained at each clinical site and written informed
172
consent for the research was obtained from all study participants. The research was conducted
173
under the tenets of the Declaration of Helsinki and pre-dated the Health Insurance Portability
174
and Accountability Act.
175
Questionnaires administered at the baseline and subsequent study visits collected information
176
that included medications, adverse events and treatment compliance. At baseline and annual
177
study visits, comprehensive eye examinations were performed by certified study personnel
178
using standardized protocols, and stereoscopic color fundus photographs (CFP) were captured.
179
Progression to late AMD was defined by the study protocol based on the grading of CFP, as
180
described previously.15 Additional ‘event photographs’ were taken at any visit in which a ≥10
181
letter reduction in best corrected visual acuity was noted, compared to the baseline visit, or
182
when the clinical examination suggested NV or central GA. CFPs were graded using a
183
standardized protocol by certified graders at a reading center (Fundus Photographic Reading
184
Center, University of Wisconsin). GA/macular atrophy was defined as a sharply demarcated,
185
usually circular zone of partial or complete depigmentation of the RPE, typically with exposure
186
of underlying large choroidal blood vessels, that must be as large as circle I-1 (1/8 disk
187
diameter, i.e., approximately 215µm). An area of RPE atrophy within or adjacent to a subretinal
188
fibrous scar was not considered macular atrophy. The CFPs were deemed to be of gradable
189
quality in 99.4% of the 48,998 sets of CFPs evaluated in the first 10 years of the study.16 All of
190
the CFPs were graded independently, and the graders were masked to the grades from
191
previous visits. Contemporaneous replicate grading exercises showed 96% exact agreement
192
between graders, with weighted kappa values of 0.71-0.73 for GA suggesting precise grading.16
193
The AREDS cohort was followed between 1992 and 2005, prior to the United States Food and
194
Drug Administration approval of ranibizumab for NV. Hence, the participants were offered
195
standard of care treatment for NV by their local retinal specialists. For the early years of the
196
AREDS follow-up, this generally comprised no active treatment; rarely, participants might
197
undergo laser photocoagulation, following the results of the Macular Photocoagulation Study
198
(MPS).17 In the later years of follow-up, again, this normally meant no active treatment; in some
199
rare cases, participants might receive photodynamic therapy (PDT), following publication of the
200
Treatment of Age-related macular degeneration with Photodynamic therapy (TAP) and
201
Verteporfin in Photodynamic Therapy (VIP) studies.18,19
202
Eligibility criteria and statistical analysis
203
The unit of analysis was at the eye level. In the AREDS participants, eyes that developed NV
204
without prior/simultaneous GA during study follow-up were eligible for analysis. Hence, eyes
205
that developed NV and GA/macular atrophy simultaneously (i.e., both NV and GA graded
206
positive for the first time in the same CFP) were excluded from analysis (since the primary
207
outcome was incident macular atrophy subsequent to NV). In addition, eyes that underwent
208
macular laser photocoagulation and/or PDT for NV, prior to NV positive grading on CFP at an
209
AREDS study visit, were also excluded.
210
The rates of incident macular atrophy after NV were examined by Kaplan-Meier survival
211
analysis. In addition, in these eyes with incident macular atrophy after NV, the rates of atrophy
212
progression to central involvement were calculated by Kaplan-Meier survival analysis. Study
213
eyes that underwent macular laser photocoagulation and/or PDT for NV were censored at the
214
time of treatment to prevent confounding with respect to the development of macular atrophy.
215
Further Kaplan-Meier survival analyses were performed with stratification by (i) AMD genotype
216
and (ii) fellow eye GA status. Regarding AMD genotype, the following genetic characteristics
217
were pre-specified for analysis: AMD Genetic Risk Score (GRS)20, CFH rs1061170 (Y402H) risk
218
alleles, CFH rs10922109 protective alleles (the lead variant at this locus in a large genome-wide
219
association study (GWAS) of late AMD20), ARMS2 rs10490924 risk alleles (the locus with highest
220
attributable risk of late AMD), and C3 rs2230199 risk alleles. The AMD GRS is a weighted risk
221
score for late AMD, based on 52 independent variants at 34 loci identified in a large GWAS20; it
222
was calculated for each participant according to methods described previously.20 Participants
223
can be divided into three groups (0-2); group 0 participants are those with a GRS below the
224
mean GRS of a control population without late AMD, while group 1 and 2 participants are those
225
with a higher GRS (below and above the median GRS of a large population with late AMD,
226
respectively). Regarding fellow eye GA status, the analyses were limited to those participants
227
with one but not both eyes in the current study; fellow eye GA status (present or absent) was
228
defined at the time of incident NV in the study eye. In addition, the demographic characteristics
229
of participants (age, sex, educational level, and smoking status, as well as AREDS treatment
230
assignment) were analyzed separately according to presence/absence of progression to
231
macular atrophy, as potential risk factors.
232
For all of these variables, statistical testing was performed using proportional hazards
233
regression. For analyses of the demographic characteristics, the full study population was used
234
(n=708 eyes, taking into account correlation between the eyes of an individual); for those of the
235
genetic characteristics, the study population was restricted to those participants with genotype
236
data available (n=433 eyes, taking into account correlation between the eyes of an individual);
237
for those of the fellow eye GA status, the analyses were limited to those participants with one
238
but not both eyes in the current study (n=546 participants/eyes). All analyses were conducted
239
using SAS version 9.4 (SAS Inc, Cary NC).
240 241
Results
242
A total of 1,042 eyes developed NV during the AREDS follow-up. Of these, 265 eyes (25.4%)
243
were excluded because of prior or simultaneous GA/macular atrophy and an additional 69 eyes
244
(6.6%) were excluded because of laser photocoagulation prior to NV detection. The remaining
245
708 eyes (67.9%) of 627 participants were considered at risk of incident macular atrophy and
246
eligible for subsequent analyses. The baseline characteristics of these eyes are shown in Table
247
1. The number of study eyes censored during follow-up because of laser photocoagulation
248
and/or PDT for NV was 239 (comprising 130 eyes with treatment at the same study visit as NV
249
detection and 109 eyes with treatment after NV detection).
250
During mean follow-up of 3.2 years (SD 3.4), of the 708 eyes at risk, 204 eyes (28.8%) developed
251
incident macular atrophy, at a mean interval of 3.8 years (SD 2.4) from the time of NV
252
detection. By Kaplan-Meier analysis, the cumulative risk of developing macular atrophy after
253
untreated NV was 9.6% (standard error (SE) 1.2%), 31.4% (SE 2.2%), 43.1% (SE 2.6%), and 61.5%
254
(SE 4.3%) at two, five, seven, and 10 years, respectively (Figure 1). The time point at which 50%
255
of eyes were affected was 8.0 years (95% confidence interval (CI) 7.3-9.6). The cumulative
256
progression to macular atrophy over time appeared strikingly linear. Considered in this way, the
257
progression corresponded (by linear regression) to a linear risk of 6.5% per year.
258
Of the 204 eyes with incident macular atrophy after NV, the proportion with central
259
involvement at first appearance of the atrophy was 30.4% (62 eyes). Of the 142 eyes whose
260
incident macular atrophy was non-central at first appearance, the proportion that progressed
261
to central involvement (over mean follow-up of 7.6 years (SD 1.9)) was 22.5% (32 eyes). Hence,
262
the total number of eyes that developed incident central macular atrophy at any point after
263
untreated NV was 94 (representing 13.3% of all eyes at risk).
264
By Kaplan-Meier analysis, out of the 204 eyes with incident macular atrophy after NV, the
265
cumulative risk of developing central involvement by atrophy was 30.4% (SE 3.2%) at baseline
266
(i.e., at first appearance of macular atrophy), 43.4% (SE 3.8%) at two years, and 57.0% (SE 4.8%)
267
at five years (Figure 2). The time point at which 50% of eyes had central involvement was 3.1
268
years (95% CI 2.0-5.1). Excluding those eyes with central involvement at baseline, this
269
corresponded (by linear regression) to a linear risk of 8.8% per year. Finally, considering
270
progression to macular atrophy and progression to central involvement simultaneously, the
271
Kaplan-Meier analysis of the cumulative risk of incident central macular atrophy following NV is
272
shown in Figure 3.
273
Potential risk factors for the development of macular atrophy after untreated NV were analyzed
274
by proportional hazards regression, including demographic characteristics, AREDS treatment
275
assignment, AMD genotype, and fellow eye GA status (Table 2). No demographic characteristic
276
was significantly associated with progression to macular atrophy: age (p=0.81), sex (p=0.66),
277
smoking status (p=0.41), education level (p=0.37), or body mass index (0.20). Similarly, no
278
significant difference was observed according to AREDS treatment assignment (p=0.66).
279
Participants with a higher AMD GRS were not significantly more or less likely to develop
280
macular atrophy after NV, compared to those with a lower GRS (Table 2). The hazard ratio
281
associated with higher GRS was 1.03 (95% CI 0.90-1.17, p=0.67). Similarly, no significant
282
differences were observed according to the individual loci examined: CFH rs1061170, CFH
283
rs10922109, ARMS2 rs10490924, or C3 rs2230199.
284
However, participants whose fellow eye had GA (at the time of incident NV in the study eye)
285
were significantly more likely to progress to macular atrophy (Table 2; Figure 4). For example,
286
the cumulative risk of developing macular atrophy by five years after NV was 43.9% (SE 6.8%)
287
for participants whose fellow eye had GA, versus 26.8% (SE 2.6%) for participants whose fellow
288
eye did not have GA. According to proportional hazards regression, the hazard ratio for macular
289
atrophy associated with GA in the fellow eye was 1.70 (1.17-2.49, p=0.006). In additional
290
regression analyses that considered all variables simultaneously in the same model, the results
291
were similar, i.e., fellow eye GA status was significant (p=0.01, hazard ratio 1.81, 1.13-2.91) and
292
all other variables were non-significant (p>0.4 for each).
293 294
Discussion
295
The AREDS represents the largest cohort of prospective data on the natural history of untreated
296
NV, with respect to the development of macular atrophy, to our knowledge. Since anti-VEGF
297
therapy has become the standard of care for NV, future data on untreated NV are unlikely,
298
making this dataset potentially unique in history.
299
This study demonstrates that, without anti-VEGF therapy, incident macular atrophy occurs in
300
approximately one third of eyes within five years of NV, and that one half of eyes are affected
301
by eight years. Interestingly, the cumulative development of macular atrophy appears strikingly
302
linear over this long time period of a decade without NV treatment. This prolonged linearity
303
may represent contributions from component (i) described above (i.e., natural progression to
304
GA, as the final common pathway in AMD disease progression, independent of NV presence)
305
and perhaps also component (ii) (i.e., macular atrophy from NV/exudation-related damage to
306
RPE and nearby cells), though separating their contributions is very difficult.
307
However, the AREDS grading definitions did not consider areas of RPE atrophy within or
308
adjacent to subretinal fibrous scars as macular atrophy, and 131 of the 708 study eyes had a
309
positive grading for subretinal fibrous scars at the time of incident NV. Hence, it is possible that
310
these percentages are underestimates of the true proportions with macular atrophy. For these
311
reasons, we repeated the Kaplan-Meier analyses with censoring of eyes at the point of
312
subretinal fibrosis formation. Of the 577 study eyes, 81 progressed to macular atrophy and 496
313
did not. The rates of progression to macular atrophy were much lower than in the original
314
analyses. Hence, many of the eyes with subretinal fibrosis did subsequently receive a positive
315
grade for macular atrophy, even though the area within or adjacent to the fibrosis was not
316
considered; for example, of the 131 eyes described above, 44 still received a subsequent grade
317
of macular atrophy. These considerations may also emphasize the contribution of component
318
(ii) to macular atrophy.
319
Additional findings in this study relate to central involvement, which is important for
320
determining visual potential. This study shows that central involvement is already present at
321
first occurrence of the atrophy in approximately one third of eyes. This is similar to the
322
proportion with central involvement by pure GA (i.e., without preceding NV), as observed in the
323
AREDS2 (i33% of eyes).21
324
Another point of comparison between these AREDS data (on macular atrophy after untreated
325
NV) with AREDS2 data (on pure GA without prior NV) is the speed of progression to central
326
involvement in eyes whose incident atrophy was non-central. In the current study, the rates of
327
central involvement were 18.7% (SE 4.0%) by two years and 35.1% (SE 5.8%) by four years. The
328
equivalent values for pure GA in AREDS2 were 32% and 57%.21 Although direct comparison
329
between the two datasets is difficult, the lower rate of progression to central involvement for
330
macular atrophy than pure GA might support the idea that enlargement of atrophy could be
331
slower in the presence of NV.21-23 However, alternative explanations include different
332
distribution of starting locations for the macular atrophy versus pure GA and the fact that, in
333
the AREDS, atrophy would not be graded as central in the presence of a central subretinal
334
fibrous scar.
335
An additional finding in this study was the increased risk of progression to macular atrophy
336
according to the presence of GA in the fellow eye. This is consistent with similar findings for
337
treated NV in the CATT9,13 and the HARBOR study14. This result, and its similarity to related
338
findings for treated NV, may emphasize the relative contribution of component (i).
339
However, the genetic analyses did not support the hypothesis that higher genetic load (as
340
regards risk of late AMD) is associated with increased risk of macular atrophy after untreated
341
NV. Together with the other results, this means that few risk factors are available to predict the
342
likelihood of atrophy. The genetic results might potentially argue against the contribution of
343
component (i) to the development of atrophy. However, all of the study eyes had already
344
demonstrated the capability of progressing to late AMD and the large majority (91%) were from
345
participants with a high GRS; this may help explain why AMD genotype is not a distinguishing
346
feature in predicting progression to macular atrophy after untreated NV but is for predicting
347
GA. We are not aware of previous studies that have analyzed the AMD GRS in this way. The
348
only study to have examined genotype in macular atrophy after (treated) NV was the CATT,
349
where the authors considered four SNPs; the data at five years suggested significant results for
350
ARMS2 (hazard ratio 1.8 (1.2-2.7) for TT versus GG) and TLR3 (hazard ratio 0.5 (0.3-0.9) for TT
351
versus CC).9
352
Comparison with literature
353
The purpose of comparing these findings with those in the literature (Table 3) was to examine
354
similarities and differences between the behavior of eyes with NV that is treated (with
355
anti-VEGF therapy) versus untreated (i.e., natural history). This should provide insights into the
356
question of whether anti-VEGF therapy may cause and/or contribute to macular atrophy.
357
The CATT randomized 1,185 participants with NV to either ranibizumab or bevacizumab,
358
administered either monthly or PRN, over two years.24 Masked graders at a reading center
359
assessed the presence of macular atrophy at two years and five years. The cumulative
360
proportions of eyes with incident macular atrophy were 17% and 38%, respectively (Table 3).9,13
361
These are higher than the equivalent values in the current study of 10% and 31%. However, the
362
proportions in the current study may have been underestimates for three reasons: first, the
363
AREDS grading definitions did not count atrophy that was within or adjacent to subretinal
364
fibrous scars. Second, the sensitivity of detection was likely higher in the CATT, which used both
365
fluorescein angiography (FA) and CFP.9,13 Third, eyes that underwent laser photocoagulation or
366
PDT for NV were censored in the current study. Overall, these considerations suggest that
367
anti-VEGF therapy may make a relatively minor contribution to the risk of macular atrophy after
368
NV. Alternatively, another possibility is that anti-VEGF therapy did make an important
369
contribution to macular atrophy incidence in the CATT, but the rates are similar to those in the
370
AREDS because, in the AREDS, the effect of removing component (iii) is compensated by
371
increased effects of component (ii), i.e., increased NV/exudation-related RPE damage.
372
Like the CATT, the IVAN was a controlled trial of different anti-VEGF drugs and regimens: 610
373
participants were randomized to ranibizumab or bevacizumab, administered monthly or PRN.11
374
Following recent regrading using a revised protocol12, the proportion of eyes with incident
375
macular atrophy at the primary endpoint of two years was 25% (Table 3). This is higher than the
376
proportion observed in the current study of untreated NV (10%). However, in the IVAN, the size
377
threshold for defining atrophy was much lower at 175 µm, and atrophy was defined using FA
378
and/or CFP, assisted by optical coherence tomography (OCT).
379
In the HARBOR study, a recent post hoc analysis reported rates of incident macular atrophy of
380
21% at one year and 29% at two years (Table 3).14 Again, this is higher than the equivalent rates
381
in the current study, though sensitivity for detecting atrophy was likely higher through the use
382
of FA.
383
In the SEVEN-UP study, post hoc analysis reported macular atrophy rates (combining
384
pre-existing and incident cases) as high as 98% of eyes at a mean of 7.3 years after
385
enrollment.10 However, important contributing factors to this high rate include the imaging
386
modality used (fundus autofluorescence) and the lower minimum size requirement (175 µm). In
387
addition, the sample size was small (60 eyes) and may not be representative of the original
388
study cohorts.
389
Strengths and limitations
390
The main strength of this study relates to its unique position in history, where a cohort of eyes
391
with NV was followed longitudinally, prior to the advent of anti-VEGF injections. The study
392
benefitted from large sample size and long follow-up time, permitting meaningful Kaplan-Meier
393
analyses over a long period. Additional strengths include comprehensive data collection at set
394
time-points and standardized reading center evaluation of images by masked graders using a
395
uniform definition of macular atrophy.
396
One important limitation was that macular atrophy was assessed on CFP only, rather than by
397
modern multimodal approaches including OCT and fundus autofluorescence. However, since
398
the widespread use of these imaging modalities post-dated the advent of anti-VEGF therapy,
399
we presume that no AMD dataset will ever achieve the combination of untreated NV and
400
multimodal imaging. Similarly, it would be ideal to compare treated and untreated NV in the
401
same cohort of participants, for more direct comparisons of macular atrophy formation. Again,
402
this is unlikely to occur. Finally, our dataset does not permit explicit considerations of
403
intralesional versus extralesional macular atrophy (since NV lesion boundaries can not be
404
assessed on CFP alone).
405
Conclusions
406
In summary, the AREDS demonstrates that the rate of incident macular atrophy in untreated
407
NV is relatively high, occurring in approximately one third of eyes within five years of NV and
408
one half by eight years. Hence, when the potential effect of anti-VEGF on progression to
409
macular atrophy is removed, a relatively high rate of progression to macular atrophy is still
410
observed. Factors other than anti-VEGF therapy are therefore involved in atrophy formation.
411
This includes natural progression to GA (as the final common pathway in AMD disease
412
progression, independent of NV presence); indeed, this study observed increased risk of
413
macular atrophy in participants with pure GA in the fellow eye.
414
The progression rates in this study may be underestimates owing to detection methods and
415
grading definitions. With this in mind, comparison with studies of treated NV suggests that it
416
may not be necessary to invoke a large effect of anti-VEGF therapy on the development of
417
macular atrophy. However, a smaller contribution of anti-VEGF therapy to macular atrophy
418
remains possible, particularly if, in the current study, the effect of removing anti-VEGF therapy
419
was exchanged for the effect of increased NV/exudation-associated RPE damage. Finally, in this
420
study, central involvement by macular atrophy was present at the outset in about one third of
421
eyes and rose to one half by three years. These data may be useful, since central macular
422
atrophy is increasingly likely to become the main determinant of visual acuity and legal
423
blindness following NV successfully treated by anti-VEGF therapy.
424
Figure legends
425
Figure 1. Kaplan-Meier curve of the progression of eyes to incident macular atrophy following
426
neovascular age-related macular degeneration, without treatment.
427
Figure 2. Kaplan-Meier curve of the progression of eyes with incident macular atrophy (after
428
neovascular AMD, without treatment) to central involvement.
429
Figure 3. Kaplan-Meier curve of the progression of eyes to incident central macular atrophy
430
following neovascular age-related macular degeneration, without treatment.
431
Figure 4. Kaplan-Meier curve of the progression of eyes to incident macular atrophy following
432
neovascular age-related macular degeneration, without treatment, stratified by the presence or
433
absence of geographic atrophy in the fellow eye (at the time of neovascular age-related
434
macular degeneration in the study eye).
435
436
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Table 1. Demographic and genetic characteristics of the study population
Age at neovascular AMD (years: mean, SD) Female (%) Education level (%) High school or less Some college College graduate Smoking status (%) Never Former Current Body mass index (%) ≤25 26-30 >30 AREDS treatment assignment (%) Placebo Antioxidants Zinc Antioxidants & zinc Follow-up time from neovascular AMD to last visit (years: mean, SD) AMD Genetic Risk Score (%) Group 0 Group 1 Group 2 CFH rs1061170 alleles (%) 0 1 2 CFH rs10922109 alleles (%) 0 1 2 ARMS2 rs10490924 alleles (%) 0 1 2 C3 rs2230199 alleles (%) 0 1 2
All eyes (n=708 for demographic characteristics; n=433 for genetic characteristics) 75.5 (5.7)
Eyes that did not progress to macular atrophy after neovascular AMD (n=504; n= 293) 76.3 (5.4)
Eyes that did progress to macular atrophy after neovascular AMD (n=204; n=140) 73.6 (5.8)
62.0
61.7
62.7
41.8 28.1 30.1
40.5 29.6 30.0
45.1 24.5 30.4
38.8 51.3 9.9
38.9 51.6 9.5
38.7 50.5 10.8
33.1 40.5 26.4
35.3 39.3 25.4
27.5 43.6 28.9
27.7 25.7 24.6 22.0 3.2 (3.4)
28.4 25.4 23.2 23.0 2.1 (2.8)
26.0 26.5 27.9 19.6 6.1 (3.1)
9.2 36.5 54.3
9.2 39.6 51.2
9.3 30.0 60.7
16.4 45.5 38.1
16.0 45.4 38.6
17.1 45.7 37.1
66.5 30.3 3.2
67.6 29.7 2.7
64.3 31.4 4.3
32.6 47.1 20.3
34.1 47.4 18.4
29.3 46.4 24.3
8.8 40.9 50.3
8.9 39.2 51.9
8.6 44.3 47.1
Abbreviations: AMD=age-related macular degeneration; AREDS=Age-Related Eye Disease Study; SD=standard deviation
Table 2. Potential risk factors for progression to macular atrophy following untreated neovascular agerelated macular degeneration: results of proportional hazards regression Hazard ratio
95% confidence interval
P
Age (per year)*
1.00
0.96-1.03
0.81
Male
0.93
0.69-1.27
0.66
0.84 0.86
0.59-1.19 0.61-1.20
0.33 0.37
0.96 1.23
0.70-1.32 0.75-2.04
0.79 0.41
1.22 1.28
0.85-1.74 0.88-1.88
0.28 0.20
1.03
0.90-1.17
0.67
0.89 0.88
0.57-1.39 0.56-1.41
0.62 0.60
1.02 0.81
0.71-1.47 0.42-1.53
0.92 0.51
0.99 0.97
0.67-1.47 0.60-1.55
0.98 0.89
0.98 0.78
0.54-1.78 0.42-1.45
0.94 0.44
1.70
1.17-2.49
0.006
Education level High school or less (reference) Some college College graduate Smoking status Never (reference) Former Current Body mass index ≤25 (reference) 26-30 >30 AMD Genetic Risk Score† CFH rs1061170 alleles 0 (reference) 1 2 CFH rs10922109 alleles 0 (reference) 1 2 ARMS2 rs10490924 alleles 0 (reference) 1 2 C3 rs2230199 alleles 0 (reference) 1 2 Geographic atrophy in fellow eye‡
Abbreviations: AMD=age-related macular degeneration * n=708 eyes for age and the other demographic characteristics, with all characteristics considered simultaneously in the same multivariable model † n=433 eyes for all genetic characteristics, with each considered separately in univariate models; the AMD Genetic Risk Score was treated as a continuous variable ‡ n=546 eyes for fellow eye analysis, including only those participants with one but not both eyes in the study population
Table 3. Proportion of study eyes with incident macular atrophy following neovascular age-related macular degeneration at specified time points: current study (of untreated neovascular disease) and comparison with literature (for neovascular disease treated with anti-VEGF therapy) Age-Related Eye Disease Study (no anti-VEGF therapy)
Comparison of AgeRelated Macular Degeneration Treatments Trials
Inhibit VEGF in AgeRelated Choroidal Neovascularization (revised grading 2019) Macular NV without central macular atrophy
HARBOR
Eligibility criteria
Macular NV. No pre-existing/ simultaneous macular atrophy (current study)
NV with subfoveal involvement and no central macular atrophy
Minimum size definition for macular atrophy
215 µm
250 µm
175 µm
250 µm
175 µm
Imaging modalities used to define macular atrophy
CFP
FA and CFP
FA and/or CFP, aided by OCT
FA
FAF and red-free/FA
17%
25%*
29%
-†
5 years 31.4%
38%
-
-
-
7 years 43.1%
-
-
-
98%†
10 years 61.5%
-
-
-
-
Proportion of study eyes with incident macular atrophy at specified time points from study baseline 2 years 9.6%
Subfoveal NV
SEVEN-UP openlabel extension study (following MARINA, ANCHOR, and HORIZON) Per MARINA, ANCHOR, and HORIZON trials
* Total of 35%, including macular atrophy that was already present at baseline † But, in the subset of eyes with fluorescein angiography available at two years and seven years, 95% (two years) and 100% (seven years) Abbreviations: CFP=color fundus photograph; FA=fluorescein angiography; FAF=fundus autofluorescence; NV=neovascular age-related macular degeneration; OCT=optical coherence tomography
Précis In the Age-Related Eye Disease Study, the incidence of macular atrophy following neovascular age-related macular degeneration was high at 31% (five years) and 62% (ten years), despite absence of anti-VEGF therapy.