CoChat
Sign Up
Cited by 335Retinal Diseases and TreatmentsRetinal and Macular SurgeryRetinal Imaging and Analysis

Risk of Scar in the Comparison of Age-related Macular Degeneration Treatments Trials

Open access
Daniel, Ebenezer, Toth, Cynthia A., Grunwald, Juan E., Jaffe, Glenn J., Martin, Daniel F., Fine, Stuart L., Huang, Jiayan, Ying, Gui-shuang +3 more·2014·Ophthalmology
DOI 10.1016/j.ophtha.2013.10.019PMC PMC3943618
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective To describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). Design Prospective cohort study within a randomized clinical trial. Participants Patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Methods Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation. Main outcome measures Scar formation. Results Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars. Conclusions Approximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar.

Integrity signals

Registry

Crossref · 10.1016/j.ophtha.2013.10.019

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 21 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    An earlier CATT paper reported that worse visual acuity at one year was linked to intraretinal fluid on OCT, but not to subretinal or sub-RPE fluid.

    “In a previous CATT report, we described a strong association between decreased visual acuity at the end of 1 year and the presence of intraretinal fluid but not subretinal or sub-RPE fluid on OCT.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Jaffe, 2013, Macular morphology and visual acuity in the Comparison of Age-related Macular Degeneration Treatments Trials, Ophthalmology source
  • Premisecitation

    Anti-VEGF injections for proliferative diabetic retinopathy can lead to more fibrosis due to an imbalance between connective tissue growth factor and VEGF.

    “Paradoxically, in eyes with proliferative diabetic retinopathy treated with anti-VEGF injections, there is increased fibrosis caused by imbalances between connective tissue growth factor and VEGF.32,33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Van Geest, 2012, A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy, Br J Ophthalmol source
    • cites [33] Kuiper, 2006, Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye, Arch Ophthalmol source
  • Findingown data

    The cumulative incidence rate of fibrotic scar at 2 years was 0.26 (95% CI 0.24-0.29).

    “The cumulative incidence rates of fibrotic scar at 1 and 2 years were 0.19 (95% CI, 0.17–0.22) and 0.26 (95% CI, 0.24–0.29), respectively.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Eyes with subretinal hyperreflective material had a greater risk of scarring than eyes without it (adjusted hazard ratio 1.7; 95% CI 1.3-2.3).

    “Risk was greater for eyes with SHRM (aHR, 1.7; 95% CI, 1.3–2.3)”
    • Also stated in: § Results · plain
      “subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3–2.3) versus no SHRM”
    Quote in the paperSubstantial claim
  • Findingown data

    At 1 year, 339 eyes (32.0%) had developed a scar.

    “At the end of 1 year, 339 eyes (32.0%) had developed a scar”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 15

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Scar formation after radiotherapy for neovascular age-related macular degeneration has been reported.

    “Scar that develops after radiotherapy for nvAMD has been described.6,7”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] 2004, The Age-Related Macular Degeneration Radiotherapy Trial (AMDRT): one year results from a pilot study, Am J Ophthalmol source
    • cites [7] Trikha, 2011, Ten-year follow-up of eyes treated with stereotactic fractionated external beam radiation for neovascular age-related macular degeneration, Retina source

  • May combine two claims.

    Premisecitation

    Subretinal and retinal scarring are linked to severe vision loss and are natural outcomes of neovascular age-related macular degeneration.

    “Subretinal and retinal scarring are associated with profound vision loss and are natural outcomes of neovascular age-related macular degeneration (nvAMD).1–4”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [1] Jaffe, 2013, Macular morphology and visual acuity in the Comparison of Age-related Macular Degeneration Treatments Trials, Ophthalmology source

      The Results report that eyes with foveal scar had the lowest mean visual acuity and that scar developed in 18.6% of eyes after 52 weeks of anti-VEGF treatment (page not available in our copy). The Discussion describes fibrosis as a treatment-emergent adverse effect associated with the greatest reduction in visual acuity. These passages support the vision-loss association, but do not establish scarring as a natural outcome of untreated neovascular AMD. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [2] Bressler, 1988, Natural course of poorly defined choroidal neovascularization associated with macular degeneration, Arch Ophthalmol source
    • cites [3] Wong, 2008, The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis, Ophthalmology source
    • cites [4] Pauleikhoff, 2005, Neovascular age-related macular degeneration: natural history and treatment outcomes, Retina source

  • May combine two claims.

    Findingown data

    Mean subretinal tissue complex thickness at the foveal center was greatest for eyes with fibrotic scars (168 μm; SE 8.7), intermediate for nonfibrotic scars (148 μm; SE 14.5), and least for eyes with no scar (119 μm; SE 4.1) (P < 0.0001).

    “The mean thickness of the subretinal tissue complex at the foveal center was greatest (168 μm; standard error [SE], 8.7) for eyes with fibrotic scars, less (148 μm; SE, 14.5) for eyes with nonfibrotic scars, and least (119 μm; SE, 4.1) for eyes with no scar at the foveal center (P < 0.0001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After one year of anti-VEGF treatment, roughly one third of eyes had developed scar, and by two years about half had developed scar.

    “After 1 year, scar developed in one third of the eyes treated with anti-VEGF drugs, and by 2 years, approximately half the eyes developed scar.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Classic CNV phenotype at baseline predicted scar formation, with risk doubling when occult CNV was admixed with classic and tripling when the phenotype was predominantly classic.

    “The type of CNV, as determined by FA at baseline, predicted scar formation. Scars were least likely to develop in eyes with occult CNV only. When occult CNV is admixed with the classic type, the risk doubles. The risk triples when the angiographic phenotype subset is composed predominantly of classic CNV.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a minimally classic lesion, the small classic CNV changed into a fibrotic scar at 2 years, while the larger occult portion did not transform into a CFP-visible scar.

    “The greater propensity for classic CNV to transform into a scar is illustrated in Figure 1C, where the minimally classic lesion’s small, centrally located classic CNV changes into a fibrotic scar in the CFP at 2 years, whereas the larger occult portion of the CNV lesion, although active, does not transform to a CFP-visible scar.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Eyes with subretinal hyperreflective material were at higher risk of both fibrotic and nonfibrotic scar.

    “Eyes with classic CNV and eyes with SHRM were at higher risk of both types of scar.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 926 patients without a fibrotic scar in the fellow eye at baseline, fibrotic scar developed in 226 (24%), nonfibrotic scar in 201 (22%), and no scar in 499 (54%) (P = 0.06).

    “In contrast, among 926 patients who did not have a fibrotic scar in the fellow eye at baseline, fibrotic scar developed in 226 (24%), nonfibrotic scar developed in 201 (22%), and no scar developed in 499 (54%; P = 0.06).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A larger area of choroidal neovascularization was associated with an increased risk of fibrotic scar but a decreased risk of nonfibrotic scar.

    “Although a larger area of CNV was associated with increased risk of fibrotic scar, it was associated with decreased risk of nonfibrotic scar.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither the choice of anti-VEGF agent nor the dosing schedule had a strong effect on whether scar developed.

    “The type of anti-VEGF therapy and dosing regimen did not strongly influence scar development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Eyes with classic choroidal neovascularization were at higher risk of both fibrotic and nonfibrotic scar.

    “Eyes with classic CNV and eyes with SHRM were at higher risk of both types of scar.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 133 patients with a scar in the fellow eye at baseline, at 2 years 36 (27%) had a fibrotic scar, 17 (13%) had a nonfibrotic scar, and 80 (60%) had no scar in the study eye.

    “At 2 years, among 133 patients with a scar in the fellow eye at baseline, 36 (27%) had a fibrotic scar, 17 (13%) had a nonfibrotic scar, and 80 (60%) had no scar in the study eye.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The CATT trial was registered with ClinicalTrials.gov under NCT00593450.

    “The CATT was registered with ClinicalTrials.gov (NCT00593450).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Almost all patients with neovascular age-related macular degeneration now receive intravitreal anti-VEGF drugs.

    “nearly all patients now receive treatment with intravitreal injections of drugs that target vascular endothelial growth factor (VEGF).8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Curtis, 2012, Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 Medicare beneficiaries, Am J Ophthalmol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    P values in the genetic analysis were adjusted to control the false discovery rate.

    “P values for the genetic analysis were adjusted to control for the false discovery rate.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J R Stat Soc Series B (Methodol) source

  • May combine two claims.

    Interpretationown data

    Because large fibrotic scars were uncommon in CATT, the authors suggest that anti-VEGF treatment may halt or postpone extensive fibrosis.

    “The rarity of large fibrotic scars in CATT suggests that extensive fibrosis is aborted or delayed by anti-VEGF therapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This finding might reflect that RAP lesions are smaller or often accompany occult CNV, which is less scar-forming than classic CNV.

    “This observation could be related to the relatively smaller RAP lesions or their common association with occult CNV, which forms fewer scars than classic CNV.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bevacizumab is reported to reduce scarring after glaucoma filtration surgery through antifibrotic effects.

    “Bevacizumab is reported to have antifibrotic activity that reduces scar formation in glaucoma filtration surgery.29–31”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] O'Neill, 2010, Antifibrotic activity of bevacizumab on human Tenon's fibroblasts in vitro, Invest Ophthalmol Vis Sci source
    • cites [30] Li, 2009, Inhibition of vascular endothelial growth factor reduces scar formation after glaucoma filtration surgery, Invest Ophthalmol Vis Sci source
    • cites [31] Memarzadeh, 2009, Postoperative use of bevacizumab as an antifibrotic agent in glaucoma filtration surgery in the rabbit, Invest Ophthalmol Vis Sci source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The blocked fluorescence might have come from deep sub-RPE hemorrhage or fibrosis that color photographs could not reveal.

    “The blocked fluorescence could have been the result of deep sub-RPE hemorrhage or deep fibrosis not visible on color photographs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In murine wound-healing models, lower VEGF levels are associated with scar-free fetal wounds, and adding exogenous VEGF converts a scar-free phenotype to a scar-forming one; neutralizing VEGF in adult wounds reduces vascularity and scar formation.

    “In a study that used fetal and adult wound-healing murine models, scar-free fetal wounds had lower VEGF levels and were less vascular than fibrotic fetal wounds, and the scar-free phenotype was converted to a scar-forming phenotype when exogenous VEGF was added.28 When VEGF was neutralized in adult wounds, vascularity was reduced, and scar formation was decreased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Wilgus, 2000, Regulation of scar formation by vascular endothelial growth factor, Lab Invest

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A phase II trial found that combining therapies improved visual acuity and cleared SHRM better than monotherapy.

    “The results showed that combination therapy more effectively than monotherapy improved visual acuity and better eliminated SHRM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dugal PU, Reichel E, Boyer DS, et al.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    One possibility is that anti-VEGF injections reduce scarring in occult-only lesions by keeping the CNV within the sub-RPE space and preventing its progression to classic CNV.

    “It is possible that intravitreal anti-VEGF treatment decreases scar formation in purely occult lesions by confining the CNV to the sub-RPE space, thereby stopping progression to classic CNV.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If followed longer, subretinal fluid might influence visual acuity by causing scar.

    “It is possible that with a longer period of observation, subretinal fluid also could affect visual acuity through scar formation.”
    Quote in the paperSubstantial claim
23 of 23

  • The paper relies on this without support.

    The factors associated with scarring after anti-VEGF therapy had not been described before this study.

    “The factors associated with scarring after anti-VEGF therapy have not been described.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • During the first two years of anti-VEGF treatment for nAMD, baseline risk factors for scar included predominantly classic CNV, blocked fluorescence, thicker retina, larger foveal subretinal tissue complex thickness, foveal subretinal fluid, and subretinal hyperreflective material.

    “We had shown earlier that during the first two years of treatment of nAMD with anti-VEGF drugs, the risk factors present at baseline for developing a scar included predominantly classic type of CNV, blocked fluorescence, thicker retina, larger foveal subretinal tissue complex thickness, foveal subretinal fluid and subretinal hyperreflective material.16”

    From Development and Course of Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials (2018) · cites this paper as [16]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Daniel, E., Toth, C. A., Grunwald, J. E., Jaffe, G. J., Martin, D. F., Fine, S. L., Huang, J., Ying, G.-S., Hagstrom, S. A., Winter, K., & Maguire, M. G.
Affiliations
  • University of Pennsylvania (US)
  • Duke University (US)
  • Cleveland Clinic (US)
  • University of Colorado Anschutz (US)
ORCID
Venue
Ophthalmology
Publisher
Elsevier BV
Published
2014-03
Volume
121
Issue
3
Pages
656-666
ISSN
0161-6420 (ISSN-L)
DOI
10.1016/j.ophtha.2013.10.019
PMC
PMC3943618
OpenAlex
W2063028754
Cited by
335
References
43
Citations by year
2026: 28 · 2025: 42 · 2024: 32 · 2023: 28 · 2022: 28 · 2021: 34 · 2020: 39 · 2019: 21 · 2018: 29 · 2017: 19 · 2016: 13 · 2015: 13 · 2014: 8 · 2013: 1
FWCI
11.49
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Ophthalmology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Pfizer
  • Regeneron Pharmaceuticals
  • Heidelberg Engineering
  • National Institutes of Health
  • Genentech
  • National Eye Institute (U10EY017825, U10EY017826, U10EY017823, U10EY017828)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal and Macular Surgery
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
Keywords
scar formation, neovascular age-related macular degeneration, ranibizumab, bevacizumab, anti-VEGF therapy, choroidal neovascularization, fibrotic scar, risk factors, subretinal hyperreflective material, retinal pigment epithelium elevation, dosing regimen, color fundus photography
MeSH terms
Bevacizumab, Ranibizumab, Cicatrix, Female, Fibrosis, Fluorescein Angiography, Genotype, Humans, Male, Middle Aged, Postoperative Complications, Prospective Studies, Retina, Risk Factors, Visual Acuity, Cohort Studies, Incidence, Angiogenesis Inhibitors, Tomography, Optical Coherence, Vascular Endothelial Growth Factor A, Wet Macular Degeneration, Intravitreal Injections, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-29.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-29.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review