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Meta-Analysis
. 2019 Mar 4;3(3):CD005139.
doi: 10.1002/14651858.CD005139.pub4.

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Sharon D Solomon  1 , Kristina Lindsley, Satyanarayana S Vedula, Magdalena G Krzystolik, Barbara S Hawkins
Affiliations
Meta-Analysis

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Sharon D Solomon et al. Cochrane Database Syst Rev. .

Abstract

Background: Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to AMD accounts for most cases of AMD-related severe vision loss. Intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision.

Objectives: • To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti-VEGF treatment for patients with neovascular AMD• To compare the relative effects of one of these anti-VEGF agents versus another when administered in comparable dosages and regimens SEARCH METHODS: To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (searched January 31, 2018); MEDLINE Ovid (1946 to January 31, 2018); Embase Ovid (1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number (ISRCTN) Registry (www.isrctn.com/editAdvancedSearch - searched January 31, 2018); ClinicalTrials.gov (www.clinicaltrials.gov - searched November 28, 2018); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en - searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials.

Selection criteria: We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year.

Data collection and analysis: Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by Cochrane.

Main results: We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively.When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti-VEGF agents had gained 15 letters or more of visual acuity (risk ratio [RR] 4.19, 95% confidence interval [CI] 2.32 to 7.55; moderate-certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high-certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95% CI 4.4 to 9.0 in one pegaptanib trial; mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate-certainty evidence) after one year of follow-up. Participants treated with anti-VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti-VEGF agents (moderate-certainty evidence). No trial directly compared pegaptanib versus another anti-VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib.Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95% CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95% CI 0.98 to 1.02; high-certainty evidence); results showed similar mean improvement in visual acuity (mean difference [MD] -0.5 letters, 95% CI -1.5 to 0.5; high-certainty evidence) after one year of follow-up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -11.6 μm, 95% CI -21.6 to -1.7; high-certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful.Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low- to moderate-certainty). Investigators rarely measured and reported data on visual function, quality of life, or economic outcomes.

Authors' conclusions: Results of this review show the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision-threatening complications with intravitreous injection of anti-VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti-VEGF agents, effects of long-term use, use of combination therapies (e.g. anti-VEGF treatment plus photodynamic therapy), and other methods of delivering these agents.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 2 Ranibizumab versus control, outcome: 2.1 Gain of 15 or more letters visual acuity at 1 year.
4
4
Forest plot of comparison: 2 Ranibizumab versus control, outcome: 2.2 Gain of 15 or more letters visual acuity at 2 years.
5
5
Forest plot of comparison: 4 Bevacizumab versus ranibizumab, outcome: 4.1 Gain of 15 or more letters visual acuity at 1 year.
6
6
Forest plot of comparison: 4 Bevacizumab versus ranibizumab, outcome: 4.2 Gain of 15 or more letters visual acuity at 2 years.
1.1
1.1. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 1 Gain of 15 or more letters visual acuity at 1 year.
1.2
1.2. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 2 Gain of 15 or more letters visual acuity at 2 years.
1.3
1.3. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 3 Loss of fewer than 15 letters visual acuity at 1 year.
1.4
1.4. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 4 Loss of fewer than 15 letters visual acuity at 2 years.
1.5
1.5. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 5 Loss of fewer than 30 letters visual acuity at 1 year.
1.6
1.6. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 6 Loss of fewer than 30 letters visual acuity at 2 years.
1.7
1.7. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 7 Visual acuity better than 20/200 at 1 year.
1.8
1.8. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 8 Visual acuity better than 20/200 at 2 years.
1.9
1.9. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 9 Maintenance of visual acuity at 1 year.
1.10
1.10. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 10 Maintenance of visual acuity at 2 years.
1.11
1.11. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 11 Mean change in visual acuity at 1 year (number of letters).
1.12
1.12. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 12 Mean change in visual acuity at 2 years (number of letters).
1.13
1.13. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 13 Reduction in size of CNV at 1 year (mean number of disc areas).
1.14
1.14. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 14 Reduction in size of lesion at 1 year (mean number of disc areas).
1.15
1.15. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 15 Reduction in size of lesion at 1 year (mean number of disc areas).
1.16
1.16. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 16 Reduction in size of lesion at 2 years (mean number of disc areas).
1.17
1.17. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 17 Mean change in quality of life scores at 1 year.
1.18
1.18. Analysis
Comparison 1 Anti‐VEGF treatment versus control, Outcome 18 Mean change in quality of life scores at 2 years.
2.1
2.1. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 1 Gain of 15 or more letters visual acuity at 1 year.
2.2
2.2. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 2 Gain of 15 or more letters visual acuity at 2 years.
2.3
2.3. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 3 Loss of fewer than 15 letters visual acuity at 1 year.
2.4
2.4. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 4 Loss of fewer than 15 letters visual acuity at 2 years.
2.5
2.5. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 5 Visual acuity better than 20/200 at 1 year.
2.6
2.6. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 6 Visual acuity better than 20/200 at 2 years.
2.7
2.7. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 7 Mean change in visual acuity at 1 year (number of letters).
2.8
2.8. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 8 Mean change in visual acuity at 2 years (number of letters).
2.9
2.9. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 9 Reduction in central retinal thickness at 1 year.
2.10
2.10. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 10 Reduction in central retinal thickness at 2 years.
2.11
2.11. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 11 No problems in quality of life domain at 1 year.
2.12
2.12. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 12 No problems in quality of life domain at 2 years.
2.13
2.13. Analysis
Comparison 2 Bevacizumab versus ranibizumab, Outcome 13 Loss of fewer than 30 letters visual acuity at 1 year.
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References

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References to studies excluded from this review

ADVANCE 2008 {unpublished data only}
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ARMAST 2008 {unpublished data only}
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Bashshur 2007 {published data only}
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    1. Brown DM, Ingerman A, Shearn SP, Slakter JS. CNV lesion characteristics as a predictor of visual outcome in wet AMD patients receiving combination therapy of intravitreal anti‐VEGF therapy and topical Squalamine lactate ophthalmic solution. Investigative Ophthalmology and Visual Science 2016;57(12):4419.
Cohen 2008 {published data only}
    1. Cohen SY, Bremond‐Gignac D, Quentel G, Mimoun G, Citterio T, Bisot‐Locard S, et al. Cost‐effectiveness sequential modeling of ranibizumab versus usual care in age‐related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology 2008;246(11):1527‐34. - PubMed
Costagliola 2010 {published data only}
    1. Costagliola C, Romano MR, Rinaldi M, dell'Omo R, Chiosi F, Menzione M, Semeraro F. Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age‐related macular degeneration. British Journal of Ophthalmology 2010;94(2):180‐4. - PubMed
Csaky 2015 {published data only}
    1. Csaky KG, Dugel PU, Pierce AJ, Fries MA, Kelly DS, Danis RP, et al. Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age‐related macular degeneration. Ophthalmology 2015;122(3):579‐88. - PubMed
Earnshaw 2007 {published data only}
    1. Earnshaw SR, Moride Y, Rochon S. Cost‐effectiveness of pegaptanib compared to photodynamic therapy with verteporfin and to standard care in the treatment of subfoveal wet age‐related macular degeneration in Canada. Clinical Therapeutics 2007;29(9):2096‐106. - PubMed
Eibenberger 2015 {published data only}
    1. Eibenberger K, Sulzbacher F, Rezar S, Roberts PK, Sacu S, Schmidt‐Erfurth U. Randomized comparison of anterior chamber inflammatory activity in eyes treated with intravitreal aflibercept or ranibizumab. Investigative Ophthalmology and Visual Science 2015;56(7):1517.
EMERGE 2016 {published data only}
    1. Christmas NJ. A phase 2 study (EMERGE) evaluating repeated intravitreal administration of ICON‐1 in patients with choroidal neovascularization (CNV) secondary to age‐related macular degeneration (AMD). Investigative Ophthalmology and Visual Science 2016;57(12):4434.
    1. NCT02358889. Study evaluating intravitreal hl‐con1TM in patients with ehoroidal neovascularization secondary to age‐related macular degeneration (EMERGE). ClinicalTrials.gov (accessed 24 August 2018).
    1. Wells JA, Gonzale CR, Berger BB, Gonzalez VH, Sippy BD, Burian G. A phase I, open‐label, dose‐excalation trial to investigate safety and tolerability of single intravitreous injections of ICON‐1 targeting tissue factor in wet AMD. Ophthalmic Surgery, Lasers and Imaging Retina 2018;49:336‐45. [DOI 10.3928/23258160‐20180501‐07; PUBMED: PMID 29772044] - PubMed
Erdokur 2009 {published data only}
    1. Erdokur O, Tetikoglu M, Ozturk M, Elcioglu M. Results of comparison in use to alternative therapy methods for subfoveal choroidal neovascularization secondary to age‐related macular degeneration. Retina‐Vitreus 2009;17(4):245‐50.
EXTEND‐I 2008 {published data only}
    1. Tano Y. The safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age‐related macular degeneration: 12‐month results from the phase I/II EXTEND‐I study. Investigative Ophthalmology and Visual Science 2008;49:ARVO E‐Abstract 272.
    1. Tano Y, Ohji M, EXTEND‐I Study Group. EXTEND‐I: safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age‐related macular degeneration. Acta Ophthalmologica 2010;88(3):309‐16. - PubMed
Eyetech Study 2003 {published data only}
    1. Eyetech Study Group. Anti‐vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age‐related macular degeneration: phase II study results. Ophthalmology 2003;110(5):979‐86. - PubMed
Falkenstein 2007 {published data only}
    1. Falkenstein IA, Cheng L, Morrison VL, Kozak I, Tammewar AM, Freeman WR. Standardized visual acuity results associated with primary versus secondary bevacizumab (Avastin®) treatment for choroidal neovascularization in age‐related macular degeneration. Retina 2007;27(6):701‐6. - PMC - PubMed
Fletcher 2008 {published data only}
    1. Fletcher EC, Lade RJ, Adewoyin T, Chong NV. Computerized model of cost‐utility analysis for treatment of age‐related macular degeneration. Ophthalmology 2008;115(12):2192‐8. - PubMed
FOCUS 2006 {published and unpublished data}
    1. Antoszyk AN, Tuomi L, Chung CY, Singh A, FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age‐related macular degeneration (FOCUS): year 2 results. American Journal of Ophthalmology 2008;145(5):862‐74. - PubMed
    1. Heier JS, Boyer DS, Ciulla TA, Ferrone PJ, Jumber MJ, Gentile RC, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age‐related macular degeneration: year 1 results of the FOCUS study. Archives of Ophthalmology 2006;124(11):1532‐42. - PubMed
    1. Heier JS, FOCUS Study Group. Intravitreal ranibizumab with verteporfin photodynamic therapy for neovascular age‐related macular degeneration: year one results. Program and abstracts of the American Society of Retina Specialists 23rd Annual Meeting; 2005 July 16‐20; Montreal. 2005.
GALATIR 2014 {unpublished data only}
    1. NCT02036723. Multicentre double blind randomized clinical study evaluating the efficacy and safety of BCD‐021 (CJSC BIOCAD, Russia) and Lucentis® (Novartis Pharmaceuticals Canada Inc.) in patients with neovascular wet age‐related macular degeneration (GALATIR). clinicaltrials.gov/show/NCT02036723 (accessed 5 February 2017).
Gallemore 2016 {published data only}
    1. Gallemore RP, Elman MJ, Milton M, Zamiri P, Grosskreutz CL. A proof of concept study of intravitreal (IVT) LFG316 in patients with neovascular age related macular degeneration (NAMD). Investigative Ophthalmology and Visual Science 2016;57(12):4985.
Hahn 2007 {published data only}
    1. Hahn R, Sacu S, Michels S, Varga A, Weigert G, Geitzenauer W, et al. Intravitreal bevacizumab versus verteporfin and intravitreal triamcinolone acetonide in patients with neovascular age‐related macula degeneration. Der Ophthalmologe 2007;104(7):588‐93. - PubMed
Hatta 2010 {published data only}
    1. Hatta Y, Ishikawa K, Nishihara H, Ozawa S, Ito Y, Terasaki H. Effect of photodynamic therapy alone or combined with posterior subtenon triamcinolone acetonide or intravitreal bevacizumab on choroidal hypofluorescence by indocyanine green angiography. Retina 2010;30(3):495‐502. - PubMed
HAWK 2018 {published data only}
    1. Dugel PU, Warburton J, Weichselberger A, Sallstig P. A 2‐year study comparing the efficacy and safety of brolucizumab vs aflibercept in subjects with neovascular age‐related macular degeneration: testing an alternative treatment regimen. Investigative Ophthalmology and Visual Science 2016;57(12):5018.
Heier 2006 {published data only}
    1. Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, et al. Ranibizumab for treatment of neovascular age‐related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology 2006;113(4):642. e1‐4. - PubMed
Hernandez‐Pastor 2008 {published data only}
    1. Hernandez‐Pastor LJ, Ortega A, Garcia‐Layana A, Giraldez J. Cost‐effectiveness of ranibizumab compared with photodynamic treatment of neovascular age‐related macular degeneration. Clinical Therapeutics 2008;30(12):2436‐51. - PubMed
Hernandez‐Pastor 2010 {published data only}
    1. Hernandez‐Pastor LJ, Ortega A, Garcia‐Layana A, Giraldez J. Cost‐effectiveness of ranibizumab compared with pegaptanib in neovascular age‐related macular degeneration. Investigative Ophthalmology and Visual Science 2010;248(4):467‐76. - PubMed
Holz 2016 {published data only}
    1. Holz FG, Dugel PU, Weissgerber G, Hamilton R, Silva R, Bandello F, et al. Single‐chain antibody fragment VEGF inhibitor RTH258 for neovascular age‐related macular degeneration: a randomized controlled study. Ophthalmology 2016;123(5):1080‐9. - PubMed
Javitt 2008 {published data only}
    1. Javitt JC, Zlateva GP, Earnshaw SR, Pleil AM, Graham CN, Brogan AJ, et al. Cost‐effectiveness model for neovascular age‐related macular degeneration: comparing early and late treatment with pegaptanib sodium based on visual acuity. Value in Health 2008;11(4):563‐74. - PubMed
Kralinger 2014 {published data only}
    1. Kralinger MT, Zehetner C, Waltl I, Kirchmayr R, Kieselbach GF. VEGF Plasma levels after intravitreal injection of aflibercept and ranibizumab. Investigative Ophthalmology and Visual Science 2014;55(13):4965.
Lai 2009 {published data only}
    1. Lai TY, Liu DT, Chan KP, Luk FO, Pang CP, Lam DS. Visual outcomes and growth factor changes of two dosages of intravitreal bevacizumab for neovascular age‐related macular degeneration: a randomized, controlled trial. Retina 2009;29(9):1218‐26. - PubMed
Lazic 2007 {published data only}
    1. Lazic R, Gabric N. Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age‐related macular degeneration. Ophthalmology 2007;114(6):1179‐85. - PubMed
Li 2012 {published data only}
    1. Fang K, Tian J, Qing X, Li S, Hou J, Li J, et al. Predictors of visual response to intravitreal bevacizumab for treatment of neovascular age‐related macular degeneration. Journal of Ophthalmology 2013;2013:676049. - PMC - PubMed
    1. Li X, Hu Y, Sun X, Zhang J, Zhang M, Neovascular Age‐Related Macular Degeneration Treatment Trial Using Bevacizumab (NATTB). Bevacizumab for neovascular age‐related macular degeneration in China. Ophthalmology 2012;119(10):2087‐93. - PubMed
Li 2013 {published data only}
    1. Li J, Zhang H, Sun P, Gu F, Liu ZL. Bevacizumab vs ranibizumab for neovascular age‐related macular degeneration in Chinese patients. International Journal of Ophthalmology 2013;6(2):169‐73. - PMC - PubMed
Matthe 2011 {published data only}
    1. Matthe E, Sandner D. Monotherapy of exudative age‐related macular degeneration with ranibizumab in patients at cardiovascular risk. Advantages of ranibizumab compared to a combination with pegaptanib. Der Ophthalmologe 2011;108(4):337‐41. - PubMed
MIRA‐1 2005 {published data only}
    1. Pulido JS, Anderson WB Jr, Flynn JT, Lichter PR, Sanders D. Multicenter prospective, randomized, double‐masked, placebo‐controlled study of rheopheresis to treat neovascular age‐related macular degeneration: interim analysis. Transactions of the American Ophthalmological Society 2002;100:85‐107. - PMC - PubMed
    1. Pulido JS, Sanders D, Klingel R. Rheopheresis for age‐related macular degeneration: clinical results and putative mechanism of action. Canadian Journal of Ophthalmology 2005;40(3):332‐40. - PubMed
Modarres 2009 {published data only}
    1. Modarres M, Naseripour M, Falavarjani KG, Nikeghbali A, Hashemi M, Parvaresh MM. Intravitreal injection of 2.5 mg versus 1.25 mg bevacizumab (Avastin®) for treatment of CNV associated with AMD. Retina 2009;29(3):319‐24. - PubMed
NCT00087763 {unpublished data only}
    1. NCT00087763. A phase II prospective, randomized, double‐masked, sham‐controlled, dose‐ranging, multi‐center trial to assess the effect of pegaptanib sodium on foveal thickening in patients with exudative subfoveal age‐related macular degeneration (AMD). clinicaltrials.gov/show/NCT00087763 (accessed 5 February 2017).
NCT01494805 {published data only}
    1. Constable IJ, Pierce CM, Lai CM, Magno AL, Degli‐Esposti MA, French MA, et al. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT‐1 for wet age‐related macular degeneration. EBioMedicine 2016;14:168‐75. - PMC - PubMed
    1. Lai CM, Magno A, Pierce C, Samulski RJ, Chalberg TW, Blumenkranz MS, et al. Results from a phase I/II clinical trial on anti‐vascular endothelial growth factor gene therapy in patients with exudative age‐related macular degeneration. Journal of Gene Medicine 2013;15(8‐9):319.
    1. Lai CM, Magno AL, Barone SB, Schwartz SD, Blumenkranz MS, Constable IJ, et al. Optical coherence tomography profiles, visual acuity and ranibizumab usage during 3‐year follow‐up in a rAAV.sFLT‐1 gene therapy clinical trial for wet age‐related macular degeneration. Molecular therapy. Conference: 20th Annual Meeting of the American Society of Gene and Cell Therapy, ASGCT 2017. United States 2017;25:315.
    1. Rakoczy EP, Lai CM, Magno A, French M, Barone SB, Schwartz SD, et al. Association of serum neutralizing antibodies with safety and efficacy outcomes in a Phase 2a trial of rAAV.sFlt‐ 1 in the treatment of wet AMD. Investigative Ophthalmology and Visual Science 2016;57(12):526.
NCT01796964 {published data only}
    1. Dugel PU, Jaffe GJ, Salistig P, Warburton J, Weichselberger A, Wieland M, et al. Brolucizumab versus aflibercept in participants with neovascular age‐related macular degeneration: a randomized trial. Ophthalmology 2017;124(9):1296‐304. - PubMed
    1. Dugel PU, Jaffe GJ, Sallstig P, Warburton J, Weichselberger A, Wieland M, et al. Brolucizumab versus aflibercept in participants with neovascular age‐related macular degeneration: a randomized trial. Ophthalmology 2017;124(9):1296‐304. - PubMed
Neubauer 2007 {published data only}
    1. Neubauer AS, Holz FG, Schrader W, Back EI, Kuhn T, Hirneiss C, et al. Cost‐utility analysis of ranibizumab (Lucentis®) in neovascular macular degeneration. Klinische Monatsblatter fur Augenheilkunde 2007; Vol. 224, issue 9:727‐32. - PubMed
Nguyen 2006 {published data only}
    1. Nguyen QD, Shah SM, Hafiz G, Quinlan E, Sung J, Chu K, et al. A phase I trial of an IV‐administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age‐related macular degeneration. Ophthalmology 2006;113(9):1522. - PubMed
Nowak 2012 {published data only}
    1. Nowak MS, Jurowski P, Grzybowski A, Goś R, Pastuszka M, Kapica A, et al. A prospective study on different methods for the treatment of choroidal neovascularization. The efficacy of verteporfin photodynamic therapy, intravitreal bevacizumab and transpupillary thermotherapy in patients with neovascular age‐related macular degeneration. Medical Science Monitor 2012;18(6):CR374‐80. - PMC - PubMed
Nunes 2014 {published data only}
    1. Nunes RP, Rodrigues E, Hirai FE, Barroso LF, Novais E, Badaro E, et al. Efficacy and cost‐effectiveness of anti‐VEGF treatments for age‐related macular degeneration (AMD). Investigative Ophthalmology and Visual Science 2014;55(13):4939.
OSPREY 2014 {published data only}
    1. Singerman LJ, Weichselberger A, Sallstig P. OSPREY trial: randomized, active‐controlled, phase II study to evaluate safety and efficacy of RTH258, a humanized single chain anti‐VEGF antibody fragment, in patients with neovascular AMD. Investigative Ophthalmology and Visual Science 2015;56(7):4801.
Parodi 2012 {published data only}
    1. Parodi MB, Cascavilla M, Papayannis A, Kontadakis DS, Bandello F, Iacono P. Intravitreal bevacizumab in advanced‐stage neovascular age‐related macular degeneration with visual acuity lower than 20/200. Archives of Ophthalmology 2012;130(7):934‐5. - PubMed
PERSPECTIVES 2012 {published data only}
    1. Chakravarthy U, Staurenghi G, Kwok K, Tressler CS, Buggage R, PERSPECTIVES Study Group. Treating early choroidal neovascularisation with pegaptanib sodium in patients with neovascular age‐related macular degeneration: findings of the PERSPECTIVES study. British Journal of Ophthalmology 2012;96(10):1351‐4. - PubMed
PrONTO Study 2009 {published data only}
    1. Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, Feuer W, et al. A variable‐dosing regimen with intravitreal ranibizumab for neovascular age‐related macular degeneration: year 2 of the PrONTO study. American Journal of Ophthalmology 2009;148(1):43‐58.e1. [10.1016/j.ajo.2009.01.024.Epub 2009 Apr 18] - PubMed
Raftery 2007 {published data only}
    1. Raftery J, Clegg A, Jones J, Tan SC, Lotery A. Ranibizumab (Lucentis®) versus bevacizumab (Avastin®): modelling cost effectiveness. British Journal of Ophthalmology 2007;91(9):1244‐6. - PMC - PubMed
RATE 2011 {unpublished data only}
    1. NCT01319188. Ranibizumab for age‐related macular degeneration and the risk of arterial thromboembolic events (RATE). clinicaltrials.gov/show/NCT01319188 (accessed 5 February 2017).
RIVAL 2017 {published data only}
    1. Gillies MC, Hunyor AP, Arnold JJ, Pecheur F, Underhill K, Guymer RH, et al. Comparison of ranibizumab and aflibercept in patients with neovascular age‐related macular degeneration treated following a 'treat and extend' protocol: efficacy variables from the pre‐specified 12‐month interim analysis of the rival study. Clinical and Experimental Ophthalmology. Conference: 49th Annual Scientific Congress of the Royal Australian and New Zealand College of Ophthalmologists. Australia 2017;45(1):29.
SAILOR 2009 {published data only}
    1. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age‐related macular degeneration. Ophthalmology 2009;116(9):1731‐9. - PubMed
    1. Reichel E, Francom S, Rubio R. Ranibizumab (Lucentis®) safety in previously treated and newly diagnosed patients with neovascular age‐related macular degeneration (AMD): the SAILOR study. The Macula Society. 2008:168.
Schmid‐Kubista 2011 {published and unpublished data}
    1. Schmid‐Kubista KE, Krebs I, Ansari‐Shahrezaei S, Haas P, Hagen S, Binder S. Comparing treatment of neovascular age‐related macular degeneration with sequential intravitreal Avastin and Macugen versus intravitreal mono‐therapy ‐ a pilot study. Current Eye Research 2011;36(10):958‐63. - PubMed
Sengul 2017 {published data only}
    1. Sengul A, Rasier R, Ciftci C, Artunay O, Kockar A, Bahcecioglu H, et al. Short‐term effects of intravitreal ranibizumab and bevacizumab administration on 24‐h ambulatory blood pressure monitoring recordings in normotensive patients with age‐related macular degeneration. Eye (London, England) 2017;31(5):677‐83. - PMC - PubMed
SIGHT 2014 {published data only}
    1. Li X, Chen Y, Zhang J, Xu X, Zhang F, Cheung CMG, et al. Intravitreal aflibercept versus photodynamic therapy in Chinese patients with neovascular age‐related macular degeneration: outcomes of the sight study. Journal of Ocular Pharmacology and Therapeutics 2017;33(6):435‐44.
SUMMIT 2007 {published data only}
    1. Slakter JS, DENALI Study Group. Combination therapy with verteporfin PDT and ranibizumab for subfoveal choroidal neovascularization due to AMD. Investigative Ophthalmology and Visual Science 2007;48:E‐Abstract 1817.
Suñer 2009 {published data only}
    1. Suñer IJ, Kokame GT, Yu E, Ward J, Dolan C, Bressler NM. Responsiveness of NEI VFQ‐25 to changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials. Investigative Ophthalmology and Visual Science 2009;50(8):3629‐35. - PubMed
Tano 2008 {published data only}
    1. Tano Y, Pegaptanib Sodium Multi‐center Study Group. Pegaptanib sodium one‐year treatment study for neovascular age‐related macular degeneration. Nippon Ganka Gakkai Zasshi 2008;112(7):590‐600. - PubMed
Vallance 2010 {published data only}
    1. Vallance JH, Johnson B, Majid MA, Banerjee S, Mandal K, Bailey CC. A randomised prospective double‐masked exploratory study comparing combination photodynamic treatment and intravitreal ranibizumab vs intravitreal ranibizumab monotherapy in the treatment of neovascular age‐related macular degeneration. Eye 2010;24(10):1561‐7. - PubMed
VERITAS 2006 {published data only}
    1. Mieler WF, The VERITAS trial. VERITAS ‐ The rationale and design of a combination therapy trial for wet AMD. Investigative Ophthalmology and Visual Science 2006;47:E‐Abstract 5232.
VIEW 2014 {published data only}
    1. Marcus DM. Long‐term follow‐up of intravitreal aflibercept injection (IAI) for neovascular age‐related macular degeneration (nAMD) in an open‐label extension of the VIEW1 study. Investigative Ophthalmology and Visual Science. 2014; Vol. 55(13):3943.
    1. Schmidt‐Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, et al. Intravitreal aflibercept injection for neovascular age‐related macular degeneration: ninety‐six‐week results of the VIEW studies. Ophthalmology 2014;121(1):193‐201. - PubMed
Weigert 2008 {published data only}
    1. Weigert G, Michels S, Sacu S, Varga A, Prager F, Geitzenauer W, et al. Intravitreal bevacizumab (Avastin) versus photodynamic therapy plus intravitreal triamcinolone for neovascular age‐related macular degeneration: 6‐month results of a prospective, randomized controlled clinical trial. British Journal of Ophthalmology 2008;92(3):356‐8. [PUBMED: PMID: 18201136] - PubMed
Wolowacz 2007 {published data only}
    1. Wolowacz SE, Roskell N, Kelly S, Maciver FM, Brand CS. Cost effectiveness of pegaptanib for the treatment of age‐related macular degeneration in the UK. Pharmacoeconomics 2007;25(10):863‐79. - PubMed
Zehetner 2013 {published data only}
    1. Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age‐related macular degeneration, and in patients with diabetic macular oedema. British Journal of Ophthalmology 2013;97(4):454‐9. - PubMed

References to ongoing studies

NCT00559715 {unpublished data only}
    1. NCT00559715. Prevention of vision loss in patients with age‐related macular degeneration (AMD) by intravitreal injection of bevacizumab and ranibizumab (VIBERA). clinicaltrials.gov/show/NCT00559715 (accessed 22 August 2018).

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