Defining response to anti-VEGF therapies in neovascular AMD

In the paper

“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]”

What the sources say

• Partly supported

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

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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]”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not matched

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

  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.

In the paper

“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.”

What the sources say

• Supported

  The Discussion says month 3 VA may indicate VA at months 6, 12, and 24, while cautioning that it can underestimate later gains. The Results report further gains with continued fixed monthly dosing and higher baseline VA among delayed than early 15-letter responders in ANCHOR and MARINA. The better-VA observation concerns baseline VA, not specifically VA at month 3. (LLM, conf=0.88)

  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

In the paper

“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”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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.

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Amoaku W . Ranibizumab: the clinician's guide to commencing, continuing, and discontinuing treatment. Eye 2009; 23: 2140–2142. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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]”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [55] Falavarjani KG, Modarres M . Bevacizumab tachyphylaxis. Ophthalmology 2009; 116: 1016–1017 author reply 1017. source
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Non-clinical factors for less frequent treatment in NHS care in England include poor access to services, appointment delays and other systems failures.66”

What the sources say

• Supported

  The Results (page unavailable) identify delays in referral, treatment, and follow-up among anti-VEGF safety incidents. The Discussion (page unavailable) says hospital eye-service capacity was sometimes problematic and describes organizational problems, supporting the claim’s account of non-clinical barriers to timely treatment in NHS care. (LLM, conf=0.86)

  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

In the paper

“Another option is to 'treat and extend' to aim for a persistent dry retina.28,29”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“Morphological 'failures' may or not be associated with a loss of VA.”

In the paper

“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.”

In the paper

“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);”

In the paper

“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.”

In the paper

“non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes.”

In the paper

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

In the paper

“This may not be detectable on OCT, but on fundoscopy or colour fundus photographs.”

In the paper

“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”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“Tachyphylaxis was thought to occur in 2% when treatment was given for recurrent CNV.60”

What the sources say

• ?Not checked — no full text of the sourcecites [60] Eghoj MS, Sorenson TL . Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2012; 96: 21–23. source

In the paper

“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]”

What the sources say

• ?Not checked — no full text of the sourcecites [46] Ellis LM, Hicklin DJ . Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res 2008; 14: 6371–6375. source
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“A true clinical decreased response to therapy may be metabolic, cellular or genetic.”

In the paper

“It has been reported to occur with drugs such as salmeterol, 51 alpha agonists including apraclonidine and brimonidine, 52 and infliximab.53”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“However, some cases of alleged tachyphylaxis may represent poor or suboptimal response to treatment, rather than true tachyphylaxis.”

In the paper

“Higher gain in acuity is often a function of poor starting vision and reflects a ceiling effect of BCVA measurements in n-AMD.16”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Amoaku W . Ranibizumab: the clinician's guide to commencing, continuing, and discontinuing treatment. Eye 2009; 23: 2140–2142. source

In the paper

“ICGA is necessary to make a definitive diagnosis of IPCV.”

In the paper

“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.”

In the paper

“Cellular mechanisms include the reduction in the number or concentration of, or binding to drug receptors.”