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Cited by 355Retinal Diseases and TreatmentsOcular Diseases and Behçet’s SyndromeRetinal Imaging and Analysis

Defining response to anti-VEGF therapies in neovascular AMD

Open access
Amoaku, W M, Chakravarthy, U, Gale, R, Gavin, M, Ghanchi, F, Gibson, J, Harding, S, Johnston, R L +8 more·2015·Eye
DOI 10.1038/eye.2015.48PMC PMC4469673
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Abstract

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

Integrity signals

Registry

Crossref · 10.1038/eye.2015.48

Cites

81 of 81 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 94 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Anti-VEGF therapies have substantially reduced severe visual loss and disability from neovascular age-related macular degeneration at the population level in several developed economies.

    “The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD).”
    • Also stated in: § Introduction · plain
      “Importantly reductions in the rates of disability from n-AMD are now being observed at a population level in various developed economies such as Denmark, 1 Israel 2 and in regions of the United Kingdom where such data has been tracked or audited.3,4”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [1] Bloch SB, Larsen M, Munch IC . Incidence of legal blindness from age-related macular degeneration in Denmark: year 2000 to 2010. Am J Ophthalmol 2012; 153: 209–213. source
    • cites [2] Skaat A, Chetrit A, Belkin M, Kinori M, Kalter-Leibovici O . Time trends in the incidence and causes of blindness in Israel. Am J Ophthalmol 2012; 153: 214–221. source
    • cites [3] Rostron E, McKibbin M . Visual impairment certification secondary to ARMD in Leeds, 2005–2010: is the incidence falling? Eye (Lond) 2012; 26: 933–936. source

      The Abstract and Discussion report that certification for visual impairment due to neovascular ARMD fell in Leeds after ranibizumab was introduced. But the Discussion explicitly says the study cannot determine whether treatment caused the decrease, and the Conclusion calls for research on its relevance to larger populations. The paper therefore does not establish a treatment-driven reduction across several developed economies. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [4] Keenan TD, Kelly SP, Sallam A, Mohamed Q, Tufail A, Johnston RL et al. Incidence and baseline clinical characteristics of treated neovascular age-related macular degeneration in a well-defined region of the UK. Br J Ophthalmol 2013; 97: 1168–1172. source
  • Premisecitation

    In the ANCHOR and MARINA studies, 8-14% of eyes gained at least 15 letters during months 4 to 12.

    “In the ANCHOR and MARINA studies, 8-14% of eyes gained 415 letters during months 4 to 12. [22][23][24]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [22] Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–1431. source

      The Primary and Secondary End Points section reports that approximately one quarter to one third of ranibizumab-treated patients gained at least 15 letters at 12 months. It does not report an 8–14% gain during months 4 to 12, and this paper reports the MARINA study, not ANCHOR. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [23] Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432–1444. source
    • cites [24] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116: 57–65. source
  • Premisecitation

    Morphological outcomes may vary from complete resolution of the lesion to a fibrovascular scar despite presumed adequate monitoring of the disease.

    “Similarly, the morphological outcomes may also vary from complete resolution of the lesion to a fibrovascular scar despite presumed adequate monitoring of the disease.14”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Jaffe GJ, Martin DF, Toth CA, Daniel E, Maguire MG, Ying GS et alFor The CATT Research Group. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2013; 120: 1860–1870. source
  • Premisecitation

    The overall effectiveness of anti-VEGF therapies in n-AMD is unquestionable.

    “The overall effectiveness of anti-VEGF therapies in n-AMD is unquestionable.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [1] Bloch SB, Larsen M, Munch IC . Incidence of legal blindness from age-related macular degeneration in Denmark: year 2000 to 2010. Am J Ophthalmol 2012; 153: 209–213. source
    • cites [2] Skaat A, Chetrit A, Belkin M, Kinori M, Kalter-Leibovici O . Time trends in the incidence and causes of blindness in Israel. Am J Ophthalmol 2012; 153: 214–221. source
    • cites [3] Rostron E, McKibbin M . Visual impairment certification secondary to ARMD in Leeds, 2005–2010: is the incidence falling? Eye (Lond) 2012; 26: 933–936. source

      The Introduction says ranibizumab stabilises visual acuity in the majority of neovascular ARMD cases. However, the paper addresses one anti-VEGF treatment rather than therapies overall, and the Discussion says it cannot determine whether the decline in certifications was a direct consequence of its introduction. The claim’s unqualified certainty goes beyond the source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Keenan TD, Kelly SP, Sallam A, Mohamed Q, Tufail A, Johnston RL et al. Incidence and baseline clinical characteristics of treated neovascular age-related macular degeneration in a well-defined region of the UK. Br J Ophthalmol 2013; 97: 1168–1172. source
  • Premisecitation

    Patient expectations of successful treatment differ among patients, carers, and clinicians.

    “The expectations of patients, carers and clinicians on what constitutes successful treatment are different.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [5] Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K SEVEN-UP Study Group.. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013; 120: 2292–2299. source
    • cites [6] Rasmussen A, Bloch SB, Fuchs J, Hansen LH, Larsen M, Lacour M et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2013; 120: 2630–2636. source

      The Visual Acuity section describes why some patients stopped treatment, and the Discussion describes a clinical threshold for discontinuation. Neither compares what patients, carers, and clinicians consider successful treatment. Searches for differing expectations and perceptions of treatment success found no such comparison in our copy; page numbers were not provided. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 25

  • May combine two claims.

    Premisecitation

    The best outcomes with anti-VEGF therapies in n-AMD are achieved with regular dosing at specific intervals, usually monthly, as shown in pivotal ranibizumab trials, and sometimes two-monthly in the first year with aflibercept after three monthly initiation doses.

    “It is now accepted that the best outcomes with anti-VEGF therapies in n-AMD are achieved with regular dosing at specific intervals, usually monthly, as demonstrated in the pivotal trials of ranibizumab, and sometimes two monthly in the first year with aflibercept after the ' three monthly initiation doses'.[22][23][24][25]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [22] Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–1431. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [23] Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432–1444. source
    • cites [24] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116: 57–65. source

  • May combine two claims.

    Premisecitation

    Response to anti-VEGF therapy depends on factors including patient age, lesion characteristics, lesion duration, baseline visual acuity, and the presence of particular genotype risk alleles.

    “The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles.”
    • Also stated in: § General recommendations on optimal management of patients with n-AMD · hedged
      “Despite the evolution of several regimens for the monitoring of disease activity while on anti-VEGF therapy, the visual outcomes vary significantly from individual to individual, and may be dependent on the lesion type, genetic profile and the starting visual acuity.[13][14][15][16][17][18]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [13] Francis PJ . The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: The Lucentis Genotype Study (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc 2011; 109: 115–156.

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

    • cites [14] Jaffe GJ, Martin DF, Toth CA, Daniel E, Maguire MG, Ying GS et alFor The CATT Research Group. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2013; 120: 1860–1870. source

      The Results (Correlation of Morphology with VA; page not specified) identify lesion size and foveal pathology as predictors of visual acuity after anti-VEGF treatment, supporting the lesion-characteristics portion. The paper does not establish patient age, lesion duration, baseline visual acuity, or genotype risk alleles as determinants of treatment response; measuring baseline acuity and setting an age eligibility criterion do not establish those relationships. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Kitchens JW, Kassem N, Wood W, Stone TW, Isernhagen R, Wood E et al. A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration. Clin Ophthalmol 2013; 7: 1987–1993.

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

  • May combine two claims.

    Premisecitation

    Hariprasad et al reported that long-term visual gain may be predicted by visual acuity at month 3, but some eyes, especially those with better visual acuity, had continuing gain when continued dosing was maintained.

    “Hariprasad et al 34 have reported that although long-term visual gain may be predicted by VA at month 3 of treatment, some eyes especially those with better VA had a continuing or further gain in their vision when the continued dosing was maintained.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Hariprasad SM, Morse LS, Shapiro H, Wong P, Tuomi L . Fixed monthly versus less frequent ranibizumab dosing and predictors of visual response in exudative age-related macular degeneration. J Ophthalmol 2012; 2012: 690641. source

  • May combine two claims.

    Premisecitation

    Initial response at month 4 is not always predictive of long-term visual acuity gains, because a proportion of eyes continue to accrue gains after month 4.

    “However, this initial response at month 4 is not always predictive of long-term VA gains, as a proportion of such eyes continue to accrue gains in vision even after month 4 as in the ANCHOR and MARINA studies, 22,24 HARBOR study 30 and subsequent case series.31”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [22] Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–1431. source

      Figure 2 and the Primary and Secondary End Points section show that mean visual acuity in ranibizumab-treated groups improved early and remained improved at 12 and 24 months; the plotted group means indicate some further gain after the early months. The paper does not assess whether an individual eye’s month-4 response predicts its long-term gain or report the proportion of eyes that continued to gain after month 4. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [24] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116: 57–65. source
    • cites [30] Dreyer R, Kokame GT, Stoller G et al. Early vs delayed 15-Letter responders to ranibizumab treatment in year 1 of the Phase III HARBOR Trial. Invest Ophthalmol Vis Sci 2013; 54: 3829.

  • Classified as probably not a substantial claim.

    Premisecitation

    The Royal College of Ophthalmologists guidelines recommend using both visual function and morphological parameters to guide diagnosis and management of n-AMD with anti-VEGF therapy.

    “The RCOphth guidelines for the management of n-AMD with anti-VEGF therapy recommend the use of both visual function and morphological parameters to guide the diagnosis and management of this disease.7,8”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Amoaku W . Ranibizumab: the clinician's guide to commencing, continuing, and discontinuing treatment. Eye 2009; 23: 2140–2142. source
    • cites [8] Chakravarthy U, Williams M The AMD Guidelines Group.. The Royal College of Ophthalmologists Guidelines on AMD: Executive Summary. Eye 2013; 27: 1429–1431. source

      The Diagnosis passage (Classification and epidemiology; page unavailable) describes loss or distortion of central vision and recommends imaging to diagnose neovascular changes. The Treatment passage says the guidelines cover criteria for starting and continuing anti-VEGF therapy, but this executive summary does not say that both visual function and morphological parameters guide those treatment decisions. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patient expectations are influenced by fellow-eye status, the duration of treatment, and the burden of multiple attendances, investigations, and invasive treatment delivery.

    “Patient expectations are influenced by fellow-eye status, the longevity of the course of treatment and the consequential burden of multiple attendances, investigations and invasive treatment delivery.5,6”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [5] Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K SEVEN-UP Study Group.. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013; 120: 2292–2299. source
    • cites [6] Rasmussen A, Bloch SB, Fuchs J, Hansen LH, Larsen M, Lacour M et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2013; 120: 2630–2636. source

      The Visual Acuity section reports that some patients stopped attending because of trouble with transportation and monthly visits or a lack of trust in treatment. This supports a link between repeated visits and willingness to continue, but the paper does not establish that fellow-eye status, treatment duration, investigations, or invasive delivery influenced patient expectations. The Fellow-Eye Choroidal Neovascularization section reports fellow-eye outcomes, not expectations (page numbers unavailable). (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Predictors for poor response at 12 months include older age, better baseline acuity, larger CNV size, angiographic lesion type, absence of RAP, presence of GA, higher foveal thickness, PED, or elevation on OCT.

    “It has been reported that predictors for poor response at 12 months include: older age, better baseline acuity, larger CNV size, angiographic lesion type, the absence of RAP and the presence of GA, in addition to higher foveal thickness, PED or elevation on OCT.21”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Ying GS, Huang J, Maguire MG, Jaffe GJ, Grunwald JE, Toth C et alCATT Research Group. Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration. Ophthalmology 2013; 120: 122–129. source

      The Abstract Conclusion identifies older age, better baseline acuity, larger CNV area, classic lesion type, absence of RAP, GA, greater foveal thickness, and RPE elevation as predictors of less visual-acuity improvement at one year. The Methods mention PED as a component of tissue measured on OCT, but the Discussion identifies foveal thickness and RPE elevation—not PED separately—as the independent OCT predictors. The Results also describe the relationship with foveal thickness as nonmonotonic, so ‘higher’ thickness is an oversimplification. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Reduced response, presumed tachyphylaxis, may occur as early as after 2 anti-VEGF injections, while others occurred after 10 injections.

    “It has been suggested that reduced response, presumed 'tachyphylaxis' may occur as early as after 2 anti-VEGF injections while others occurred after 10 injections.45,[55][56][57][58][59]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [45] Schaal S, Kaplan JG, Tezel TH . Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008; 115: 2199–2205. source
    • cites [55] Falavarjani KG, Modarres M . Bevacizumab tachyphylaxis. Ophthalmology 2009; 116: 1016–1017 author reply 1017. source
    • cites [56] Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT . Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009; 29: 723–731. source

      The Results report tachyphylaxis after as many as 10 intravitreal bevacizumab treatments, supporting the upper end of the cited range. They do not report onset after 2 injections: the lowest count given is 3 treatments when counting only the affected eye. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In NHS care in England, non-clinical factors for less frequent treatment include poor access to services, appointment delays, and other systems failures.

    “Non-clinical factors for less frequent treatment in NHS care in England include poor access to services, appointment delays and other systems failures.66”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [66] Kelly SP, Barua A . A review of safety incidents in England and Wales for vascular endothelial growth factor inhibitor medications. Eye (Lond) 2011; 25: 710–716. source

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

    Premisecitation

    A treat-and-extend regimen aiming for a persistent dry retina is another treatment option.

    “Another option is to 'treat and extend' to aim for a persistent dry retina.28,29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD et al. Treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 2010; 117: 2134–2140. source
    • cites [29] Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD et al. Bevacizumab for neovascular age-related macular degeneration using a treat-and-extend regimen: clinical and economic impact. Am J Ophthalmol. 2012; 153: e1. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Treatment given before permanent destruction of neural and supporting cells will result in the best outcomes.

    “It is intuitive to suppose that treatment given when the disease has not caused permanent destruction of the neural and supporting cells will result in best outcomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Clinical factors contributing to suboptimal or poor response include chronicity with associated change in cytokine profile, chronic inflammation, or high VEGF levels requiring more frequent therapy.

    “Clinical factors include chronicity, with associated change of cytokine profile of the disease, chronic inflammation or high levels of VEGF requiring more frequent therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    There are large inter-individual differences in response to anti-VEGF agents, and this is made more complex by the availability of multiple agents with different molecular configurations.

    “There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations.”
    • Also stated in: § Introduction · plain
      “However, not all patients benefit in an identical manner and, as such, there have been multiple attempts to group and characterise patients' responses based on both functional and morphological outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the United Kingdom, indocyanine green angiography is not available in all units and is usually reserved for cases suspicious of polypoidal choroidopathy or retinal angiomatous proliferation or when response to anti-VEGF therapy is suboptimal.

    “In the United Kingdom, ICGA is not available in all units and is usually reserved for cases presenting with clinical features suspicious of polypoidal choroidopathy (IPCV) or retinal angiomatous proliferation (RAP) or when response to anti-VEGF therapy is suboptimal.11,12”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H et al. EVEREST study: efficacy and safety of verteporfin PDT in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 2012; 32: 1453–1464. source
    • cites [12] Koh AH, Chen LJ, Chen SJ, Chen Y, Giridhar A et alExpert PCV Panel. Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment. Retina 2013; 33: 686–716. source

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

    Premisereasoning

    Optical coherence tomography provides objective quantification of fluid and aids diagnosis and classification of lesion morphology and activity.

    “In addition, it aids in the diagnosis and classification of the lesion morphology and activity as depicted by the presence or absence of fluid in the various compartments of the retina-choroidal interface including intraretinal, subretinal and sub-RPE fluid.The tomogram also provides an objective quantification of the amount of fluid.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The group with increasing intraretinal cysts, IRF, or SRF compared with baseline likely represents the majority of patients over the very long term, and disease progression in the form of dry AMD may also occur and contribute to deteriorating visual function.

    “This group is likely to represent the majority of patients over the very long-term; however, disease progression in the form of 'dry' AMD may also occur and contribute to deteriorating visual function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    A proportion of eyes with n-AMD show a decline in acuity or morphology despite therapy or require very frequent re-treatment.

    “Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    As with primary failures, the development of other retinal disease may contribute to worsening visual acuity or symptoms and requires specific investigation.

    “As with primary failures, the development of other retinal disease may also contribute to worsening VA/symptoms and requires specific investigation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Morphological failures may or may not be associated with a loss of visual acuity.

    “Morphological 'failures' may or not be associated with a loss of VA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    In a particular eye, secondary response does not mirror and cannot be predicted from the primary response.

    “In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase.”
    • Also stated in: § Response based on change in VA in terms of ETDRS letters · hedged
      “The response in the primary phase does not necessarily mirror that in the secondary phase.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing, increased dosing intervals, treatment initiation at an advanced or chronic stage, cellular mechanisms, lesion type, genetic variation, and potential tachyphylaxis.

    “Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis);”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The mechanisms contributing to reduced efficacy are likely multifactorial, with drug-specific factors relevant in only a small proportion of cases.

    “The mechanisms contributing to reduced efficacy are also likely to be multifactorial with drug specific factors (for example, the development of neutralising antibodies, increased clearance from the eye, tachyphylaxis, reflux of drug following injectionand so on) likely to be relevant in only a small proportion of cases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Non-clinical factors such as poor access to clinics or delayed appointments may also lead to poor treatment outcomes.

    “non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The appearance of new retinal or subretinal haemorrhage indicates disease activity at any stage of treatment.

    “The appearance of new retinal or subretinal haemorrhage indicates disease activity at any stage of the treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    New haemorrhage may not be detectable on OCT but can be seen on fundoscopy or colour fundus photographs.

    “This may not be detectable on OCT, but on fundoscopy or colour fundus photographs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Fixed dosing at extended intervals from 6 months onwards (e.g., 2-3 months) is supported by post hoc analysis of the EXCITE data and VIEW studies.

    “Some clinicians may prefer fixed dosing at extended intervals from 6 months onwards from treatment initiation, for example, 2-3 months intervals as shown by post hoc analysis of the EXCITE data 73 and VIEW studies.74”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Amoaku WM, Yang Y, Chong V, Brittain C, Alsop J, Osborne A et al Durability of visual acuity responses to ranibizumab in wet age-related macular degeneration patients of the EXCITE Study. EURETINA Congress: Hamburg, Germany, 2013.

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

    • cites [74] Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V . Intravitreal Aflibercept injection for neovascular age-related macular degeneration: Ninety-Six-Week results of the VIEW Studies. Ophthalmology 2014; 121: 193–201. source

  • May combine two claims.

    Interpretationreasoning

    Labeling a lack of response at CNV reactivation as tachyphylaxis may be incorrect because a single anti-VEGF injection is unlikely to produce an optimal response.

    “Thus such a designation as tachyphylaxis may be incorrect as it is unlikely that a single injection of anti-VEGF would provide an optimum response.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Tachyphylaxis was estimated to occur in 2% of cases when treatment was given for recurrent choroidal neovascularization.

    “Tachyphylaxis was thought to occur in 2% when treatment was given for recurrent CNV.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Eghoj MS, Sorenson TL . Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2012; 96: 21–23. source

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

    Premisecitation

    Resistance to anti-VEGF therapies in cancer therapy is well recognised and is thought to be due to compensatory angiogenic signalling, which may be specific to the particular tissue environment.

    “Resistance to anti-VEGF therapies in cancer therapy is well recognised 46 and are thought to be due to compensatory angiogenic signalling, which may be specific to the particular tissue environment.[46][47][48]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Ellis LM, Hicklin DJ . Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res 2008; 14: 6371–6375. source
    • cites [47] Casanovas O, Hicklin DJ, Bergers G, Hanahan D . Drug resistance by evasion of antiangiogenic targeting of VEGF signalling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8: 299–309. source
    • cites [48] Batchelor TT, Sorenson AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalises tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11: 83–95. source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    A true clinical decrease in response to therapy may have metabolic, cellular, or genetic causes.

    “A true clinical decreased response to therapy may be metabolic, cellular or genetic.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Tachyphylaxis has been reported to occur with drugs such as salmeterol, alpha agonists including apraclonidine and brimonidine, and infliximab.

    “It has been reported to occur with drugs such as salmeterol, 51 alpha agonists including apraclonidine and brimonidine, 52 and infliximab.53”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Tsagaraki V, Amfilochiou A, Markantonis SL . Evidence of tachyphylaxis associated with salmeterol treatment of chronic obstructive pulmonary disease patients. Int J Clin Pract 2006; 60: 415–421. source
    • cites [52] Brown SM, Khanani AM, McCartney DL . The effect of daily use of brimonidine tartrate on the dark-adapted pupil diameter. Am J Ophthalmol 2004; 138: 149–151. source
    • cites [53] Svenson M, Geborek P, Saxne T, Bendtzen K . Monitoring patients treated with anti-TNFalpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology 2007; 46: 1828–1834. source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Some cases of alleged tachyphylaxis may represent poor or suboptimal response to treatment rather than true tachyphylaxis.

    “However, some cases of alleged tachyphylaxis may represent poor or suboptimal response to treatment, rather than true tachyphylaxis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Higher gain in acuity is often a function of poor starting vision and reflects a ceiling effect of BCVA measurements in n-AMD.

    “Higher gain in acuity is often a function of poor starting vision and reflects a ceiling effect of BCVA measurements in n-AMD.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Tufail A, Zarranz-Ventura J, Liew G, Johnston RL, Xing W, Akerele T et alWriting Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections. teport 1: visual acuity. Ophthalmology 2014; 121: 1092–1101. source

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Recalcitrant CNV suggests poor or suboptimal response to the anti-VEGF therapy administered.

    “Such 'recalcitrant' CNV suggests poor or suboptimal response to the anti-VEGF therapy administered.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Intraretinal cystoid oedema, subretinal fluid, diffuse foveal thickening, expanding serous PED, new sub- or intraretinal haemorrhage, and BCVA loss attributable to other signs of lesion activity are indicators of disease activity.

    “The presence of intraretinal cystoid oedema, subretinal fluid, diffuse thickening of the fovea, expanding serous PED, new subor intraretinal haemorrhage, BCVA loss attributable to other signs of lesion activity are all considered as indicators of disease activity, which therefore merit re-treatment.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Amoaku W . Ranibizumab: the clinician's guide to commencing, continuing, and discontinuing treatment. Eye 2009; 23: 2140–2142. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    ICGA is necessary to make a definitive diagnosis of IPCV.

    “ICGA is necessary to make a definitive diagnosis of IPCV.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Metabolic causes of reduced response may be alterations in drug absorption, distribution, or metabolism that decrease the effective concentration of the drug.

    “Metabolic causes of reduced response may be the result of alterations in drug absorption, distribution or metabolism, which decreases the effective concentration of the drug.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Cellular mechanisms of reduced response include a reduction in the number or concentration of drug receptors or in drug binding to receptors.

    “Cellular mechanisms include the reduction in the number or concentration of, or binding to drug receptors.”
    Quote in the paperNot a substantial claim
38 of 38

  • The paper relies on this without support.

    There is currently no consensus on how to classify optimal response or lack of response to anti-VEGF therapies for n-AMD.

    “There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies.”

  • The paper relies on this without support.

    There is confusion over terms such as responder status after treatment for n-AMD, tachyphylaxis, and recalcitrant n-AMD.

    “There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD.”

  • The paper relies on this without support.

    Morphological and functional responses to anti-VEGF treatments do not necessarily correlate and may be dissociated in an individual eye.

    “Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye.”
    “As function and morphology do not correlate, these responses may sometimes be mutually exclusive.”

  • The paper relies on this without support.

    Morphological changes precede the loss of visual function.

    “Morphological changes precede the loss of visual function.”

  • The paper relies on this without support.

    At present there is no consensus on what constitutes responsiveness to treatment, and whether pre-existing ocular or genetic characteristics or bio-therapeutic interactions such as tachyphylaxis have any role in determining outcome.

    “At present there is no consensus on what constitutes responsiveness to treatment, and whether pre-existing characteristics such as ocular and or genetic make up and, or bio-therapeutic interactions such as tachyphylaxis have any role in determining outcome.”

  • The paper relies on this without support.

    Clinical trial reports often do not include data on fellow or second eyes and are not designed to emphasise the importance of potential visual loss in this group.

    “Clinical trial reports often do not include data on fellow or second eyes and are not designed to emphasise the importance of potential visual loss in this group.”

  • The paper relies on this without support.

    Retinal atrophy or thinning and subretinal fibrosis do not indicate poor response but confound visual acuity.

    “Retinal atrophy/thinning and/or subretinal fibrosis do not imply poor response, but confound VA.”

  • The paper relies on this without support.

    Minimal change of fluid over scar tissue may not indicate poor response and may result from longstanding disease rather than treatment outcomes.

    “Similarly, minimal change of fluid over scar tissue etc may not imply poor response.These may resultfrom longstanding disease, rather than treatment outcomes.”

  • The paper relies on this without support.

    Outer retinal tubulations do not represent active fluid leakage.

    “Outer retinal tubulations (ORT) do not represent active fluid leakage.”

  • The paper relies on this without support.

    Evidence to date does not indicate that flattening of PED determines outcomes.

    “evidence to date does not indicate that flattening of PED determines outcomes”

  • The paper relies on this without support.

    PED progression indicates active disease and requires ICGA to exclude IPCV and/or consideration of treatment change.

    “PED progression indicates active disease and requires ICGA to exclude IPCV, and/orconsideration of treatment change.”

  • The paper relies on this without support.

    Morphological and functional features of response may not correlate.

    “Morphological and functional features (responses) may not correlate.”
12 of 12

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Unchanged fluid is inconsistently classified as non-response

    Major

    The abstract defines non-response by increased fluid, increased haemorrhage, or visual loss. Table 1 also classifies unchanged thickness or fluid as non-response, so its morphological criterion includes eyes without the deterioration specified in the abstract.

  • Good and partial responses share the same thickness-reduction range

    Minor

    The prose calls a reduction in central retinal thickness of up to 75% a good morphological response, while Table 1 assigns reductions between 25% and 75% to partial response. Eyes in that overlapping range therefore receive different classifications.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Hageman GS . Genetics in AMD. Vision Research Day. Novartis: Zurich, 2014 in press.
  2. Awad M, Amoaku W, Yang Y, Chong V, Alsop J . Early visual acuity (VA) gains with ranibizumab are predictive of good long-term VA outcomes in wet age-related macular degeneration (wAMD) —a sub-analysis of the EXCITE study. EURETINA Congress: Hamburg, Germany, 2013.
  3. Amoaku WM, Yang Y, Chong V, Brittain C, Alsop J, Osborne A et al Durability of visual acuity responses to ranibizumab in wet age-related macular degeneration patients of the EXCITE Study. EURETINA Congress: Hamburg, Germany, 2013.

Cited by

Sorted by citations

Related

Authors
Amoaku, W. M., Chakravarthy, U., Gale, R., Gavin, M., Ghanchi, F., Gibson, J., Harding, S., Johnston, R. L., Kelly, S., Lotery, A., Mahmood, S., Menon, G., Sivaprasad, S., Talks, J., Tufail, A., & Yang, Y.
Affiliations
  • Nottingham University Hospitals NHS Trust (GB)
  • Queen's University Belfast (GB)
  • York Hospital (GB)
  • Gartnavel General Hospital (GB)
  • Bradford Teaching Hospitals NHS Foundation Trust (GB)
  • Aston University (GB)
  • University of Liverpool (GB)
  • Gloucestershire Hospitals NHS Foundation Trust (GB)
  • Bolton NHS Foundation Trust (GB)
  • University of Southampton (GB)
  • Manchester Royal Eye Hospital (GB)
  • Frimley Park Hospital (GB)
  • NIHR Moorfields Biomedical Research Centre (GB)
  • Newcastle University (GB)
  • New Cross Hospital (GB)
Corresponding author
Amoaku, W M
ORCID
Venue
Eye
Publisher
Springer Science and Business Media LLC
Published
2015-04-17
Volume
29
Issue
6
Pages
721-731
ISSN
  • 0078-5334 (ISSN-L)
  • 0950-222X
  • 1476-5454
DOI
10.1038/eye.2015.48
PMC
PMC4469673
OpenAlex
W2093646832
Cited by
355
References
80
Citations by year
2026: 32 · 2025: 37 · 2024: 60 · 2023: 36 · 2022: 28 · 2021: 38 · 2020: 26 · 2019: 21 · 2018: 27 · 2017: 25 · 2016: 17 · 2015: 7
FWCI
4.71
Type
journal article
Language
en
Update notices
erratum (2015-10-08)
Open access
Licence
Locations
  • Eye (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Aston Publications Explorer (Aston University) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
Keywords
neovascular age-related macular degeneration, anti-VEGF therapy, treatment response classification, tachyphylaxis, central retinal thickness, intraretinal fluid, subretinal fluid, visual acuity, ceiling effect, lesion duration, lesion characteristics
MeSH terms
Humans, Visual Acuity, Treatment Outcome, Practice Guidelines as Topic, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor A, Wet Macular Degeneration, Intravitreal Injections

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.

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