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Effectiveness of bevacizumab step therapy for neovascular age-related macular degeneration



To determine the effectiveness of bevacizumab step therapy for neovascular age-related macular degeneration (nAMD) in routine clinical practice.


In this retrospective case series, eyes initiating treatment for nAMD at an academic medical centre from 2011–2019 were included. Exclusion criteria included previous intravitreal anti-VEGF injections, prior non-cataract intraocular surgery, <1 year of treatment, and not starting on monthly bevacizumab therapy. Of 895 eligible eyes, 548 were excluded, yielding 347 eyes in the study population.

These eyes were treated for nAMD under the bevacizumab step therapy protocol with an option to switch to another agent in the event of predefined treatment failure. Treatment failure was defined as losing 15 or more Early Treatment Diabetic Retinopathy Study letters or switching to an alternative anti-VEGF agent. Eyes that did not meet these criteria were deemed treatment successes. Annual change in mean VA from baseline (ΔVA) was the primary outcome. Secondary outcomes included treatment success rate, medication switch rate, and post-switch ΔVA.


After 1 year, mean ΔVA was +8.4 letters (95% CI: +6.1 to +10.6 letters). 86% had treatment success, and 6% of eyes had switched to aflibercept. In years 2–7, ΔVA ranged from +7.0 to −0.7 letters, and treatment success rates ranged from 68 to 82%. 11% (n = 38) of eyes were switched to aflibercept. The post-switch ΔVA in these eyes was −7.1 letters (95% CI: −13.3 to −0.1) after a mean of 17.7 ± 12.6 injections over an average of 2.7 ± 2.0 years.


A bevacizumab step therapy protocol in routine clinical practice is effective for long-term treatment of nAMD.

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Fig. 1: Secondary outcomes for 1 and 5 year analyses.

Data availability

The datasets analysed during the current study are not publicly available due to use of protected health information but are available from the corresponding author on reasonable request.


  1. Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N. Engl J Med. 2004;351:2805–16.

    Article  CAS  Google Scholar 

  2. Stone TW, ed. ASRS 2018 Preferences and Trends Membership Survey. Chicago, IL: American Society of Retina Specialists; 2018.

  3. CATT Research Group, Martin DF, Maguire MG, Ying G-S, Grunwald JE, Fine SL, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl J Med. 2011;364:1897–908.

    Article  Google Scholar 

  4. Comparison of Age-related Macular Degeneration Treatments Trials Research Group, Martin DF, Maguire MG, Fine SL, Ying G-S, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388–98.

    Article  Google Scholar 

  5. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382:1258–67.

    Article  CAS  Google Scholar 

  6. Krebs I, Schmetterer L, Boltz A, Told R, Vécsei-Marlovits V, Egger S, et al. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol. 2013;97:266–71.

    Article  Google Scholar 

  7. Kodjikian L, Souied EH, Mimoun G, Mauget-Faÿsse M, Behar-Cohen F, Decullier E, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120:2300–9.

    Article  Google Scholar 

  8. Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122:146–52.

    Article  Google Scholar 

  9. Heier JS, Brown DM, Chong V, Korobelnik J-F, Kaiser PK, Nguyen QD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537–48.

    Article  Google Scholar 

  10. Schmidt-Erfurth U, Kaiser PK, Korobelnik J-F, 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;121:193–201.

    Article  Google Scholar 

  11. Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD. Bevacizumab for neovascular age-related macular degeneration using a treat-and-extend regimen: clinical and economic impact. Am J Ophthalmol. 2012;153:468–73.e1.

    Article  CAS  Google Scholar 

  12. Schmid MK, Bachmann LM, Fäs L, Kessels AG, Job OM, Thiel MA. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol. 2015;99:141–6.

    Article  Google Scholar 

  13. Jiang S, Park C, Barner JC. Ranibizumab for age‐related macular degeneration: a meta‐analysis of dose effects and comparison with no anti‐VEGF treatment and bevacizumab. J Clin Pharm Ther. 2014;39:234–9.

    Article  CAS  Google Scholar 

  14. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127:72–84.

    Article  Google Scholar 

  15. Patel S. Medicare spending on anti-vascular endothelial growth factor medications. Ophthalmol Retin. 2018;2:785–91.

    Article  Google Scholar 

  16. Where the newest anti-VEGF agent fits in the exudative-disease toolbox: Retina Specialist; 2019 Available from:

  17. Berkowitz ST, Sternberg P, Feng X, Chen Q, Patel S. Analysis of anti–vascular endothelial growth factor injection claims data in US medicare part B beneficiaries from 2012 to 2015. JAMA Ophthalmol. 2019;137:921–8.

    Article  Google Scholar 

  18. Rosenfeld PJ, Windsor MA, Feuer WJ, Sun SJ, Frick KD, Swanson EA, et al. Estimating medicare and patient savings from the use of bevacizumab for the treatment of exudative age-related macular degeneration. Am J Ophthalmol. 2018;191:135–9.

    Article  Google Scholar 

  19. Parikh R, Ross JS, Sangaralingham LR, Adelman RA, Shah ND, Barkmeier AJ. Trends of anti-vascular endothelial growth factor use in ophthalmology among privately insured and medicare advantage patients. Ophthalmology. 2017;124:352–8.

    Article  Google Scholar 

  20. Hutton D, Newman-Casey PA, Tavag M, Zacks D, Stein J. Switching to less expensive blindness drug could save Medicare Part B $18 billion over a ten-year period. Health Aff. 2014;33:931–9.

    Article  Google Scholar 

  21. Medicare Advantage Prior Authorization and Step Therapy for Part B Drugs Centers for Medicare & Medicaid Services; 2018 Available from:

  22. New Step Therapy Policy Threatens Medicare Advantage Patients’ Timely Access to Sight-Saving Treatments [press release]. American Academy of Ophthalmology 2019.

  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;355:1432–44.

    Article  CAS  Google Scholar 

  24. 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;355:1419–31.

    Article  CAS  Google Scholar 

  25. Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina. 2010;30:1046–50.

    Article  Google Scholar 

  26. Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121:2181–92.

    Article  Google Scholar 

  27. Bhandari S, Nguyen V, Arnold J, Young S, Banerjee G, Gillies M, et al. Treatment outcomes of ranibizumab versus aflibercept for neovascular age-related macular degeneration: data from the fight retinal blindness! registry. Ophthalmology. 2020;127:369–76.

    Article  Google Scholar 

  28. Singer MA, Awh CC, Sadda S, Freeman WR, Antoszyk AN, Wong P, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119:1175–83.

    Article  Google Scholar 

  29. Comparison of Age-related Macular Degeneration Treatments Trials Research Group, Maguire MG, Martin DF, Ying G-S, Jaffe GJ, Daniel E, et al. Five-year outcomes with anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123:1751–61.

    Article  Google Scholar 

  30. Gillies MC, Campain A, Barthelmes D, Simpson Judy M, Arnold JJ, Guymer RH, et al. Long-term outcomes of treatment of neovascular age-related macular degeneration: data from an observational study. Ophthalmology. 2015;122:1837–45.

    Article  Google Scholar 

  31. 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;120:2292–9.

    Article  Google Scholar 

  32. Wykoff CC, Ou WC, Brown DM, Croft DE, Wang R, Payne JF, et al. Randomized trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: 2-year results of the TREX-AMD study. Ophthalmol Retin. 2017;1:314–21.

    Article  Google Scholar 

  33. Kiss S, Campbell J, Almony A, Shih V, Serbin M, LaPrise A, et al. Management and outcomes for neovascular age-related macular degeneration: analysis of United States Electronic Health Records. Ophthalmology 2020;127:1179–88.

    Article  Google Scholar 

  34. CMS Office of Enterprise Data and Analytics. Medicare Part B Drug Spending Dashboard Centers for Medicare & Medicaid Services; Available from:

  35. Goldberg RA, Flynn HW, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153:204–8.

    Article  CAS  Google Scholar 

  36. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133:1159–64.

    Article  Google Scholar 

  37. Yu JH, Gallemore E, Kim JK, Patel R, Calderon J, Gallemore RP. Silicone oil droplets following intravitreal bevacizumab injections. Am J Ophthalmol Case Rep. 2018;10:142–4.

    Article  Google Scholar 

  38. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123:1351–9.

    Article  Google Scholar 

  39. Glasser DB, Parikh R, Lum F, Williams GA. Intravitreal anti-vascular endothelial growth factor cost savings achievable with increased bevacizumab reimbursement and use [published online ahead of print June 13, 2020]. Ophthalmology.

  40. Christoforidis JB, Briley K, Binzel K, Bhatia P, Wei L, Kumar K, et al. Systemic biodistribution and intravitreal pharmacokinetic properties of bevacizumab, ranibizumab, and aflibercept in a nonhuman primate model. Invest Ophthalmol Vis Sci. 2017;58:5636–45.

    Article  CAS  Google Scholar 

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The study was supported in part by a Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organization had no role in the design or conduct of this research

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SP confirms that he has had full access to the data in the study and final responsibility for the decision to submit for publication. Conceived and/or designed the work that led to the submission, acquired data, and/or played an important role in interpreting the results: JS, SJK, PS, SP. Drafted or revised the manuscript: JS, SJK, PS, SP. Approved the final version: JS, SJK, PS, SP. Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JS, SJK, PS, SP.

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Correspondence to Shriji Patel.

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Siktberg, J., Kim, S.J., Sternberg, P. et al. Effectiveness of bevacizumab step therapy for neovascular age-related macular degeneration. Eye (2022).

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