Abstract
Purpose
The recent introduction of anti-VEGF drugs has widely changed the prognosis of exudative age-related macular degeneration (AMD), even if a variable percentage of patients showed an insufficient response. Aflibercept is a new anti-VEGF drug approved by FDA for the treatment of exudative AMD with a wider binding capacity than either bevacizumab or ranibizumab. Therefore, the purposes were as follows: (i) to report anatomical and functional outcomes of switching from bevacizumab/ranibizumab to aflibercept previously described in the scientific literature, (ii) to hypothesize the possible pathophysiological mechanisms of the resistance and tachyphylaxis to anti-VEGF drugs, and (iii) to suggest possible clinical actions to increase the chances of success for such difficult cases.
Methods
We reviewed the available scientific literature in Medline, Cochrane database, Current Contents, PubMed, and cross-referencing from identified articles, regarding the treatment of exudative AMD patients refractory to bevacizumab and/or ranibizumab and switched to aflibercept monotherapy. We included in this review all the cases in which the diagnosis of refractory or resistant exudative AMD was properly made, and the results of at least one aflibercept injection were described.
Findings
We reported the outcomes of 21 papers for a total of 1066 eyes affected by exudative AMD resistant to previous anti-VEGF drug injections and switched to aflibercept. Enrolled reports were divided into two groups: 5 prospective reports and 16 retrospective reports. All the reported papers conclude their analysis, stating that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients.
Implications
Analysis of the papers reported in this review demonstrates that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients. The mechanism for these effects is not yet completely understood.
Similar content being viewed by others
References
Friedman DS, O’Colmain BJ, Munoz B et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564–572
Khandhadia S, Cherry J, Lotery AJ (2012) Age-related macular degeneration. Adv Exp Med Bio 724:15–36
Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431
Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG et al (2012) Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 119:1388–1398
CATT Research Group (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364:1897–1908
Heier JS, Brown DM, Chong V et al (2012) VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 119:2537–2548
Dorrell M, Uusitalo-Jarvinen H, Aguilar E et al (2007) Ocular neovascularization: basic mechanisms and therapeutic advances. Surv Ophthalmol 52(suppl 1):S3–S19
Stewart MW, Rosenfeld PJ (2008) Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 92:667–668
Stewart MW (2012) Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol 6:1175–1186
Papadopoulos N, Martin J, Ruan Q et al (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185
Schmidt-Erfurth U, Kaiser PK, Korobelnik JF et al (2014) Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 121:193–201
Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, SEVEN-UP Study Group (2013) Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 120:2292–2299
Binder S (2012) Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol 96:1–2
Eghøj MS, Sørensen TL (2012) Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 96:21–23
Schaal S, Kaplan HJ, Tezel TH (2008) Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 115:2199–2205
Fooroghian F, Cukras C, Meyerle CB et al (2009) Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 29:723–731
Hoffman BB, Taylor P (2001) Neurotransmission: the autonomic and somatic motor nervous systems. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New York, pp 115–154
Tranos P, Vacalis A, Asteriadis S et al (2013) Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration. Drug Des Devel Ther 7:485–490
Gasperini JL, Fawzi AA, Khondkaryan A et al (2012) Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularization. Br J Ophthalmol 96:14–20
Brown DM, Chen E, Mariani A et al (2013) Super-dose anti-VEGF (SAVE) trial: 2.0 mg intravitreal ranibizumab for recalcitrant neovascular macular degeneration: primary end point. Ophthalmology 120:349–354
Fung AT, Kumar N, Vance SK et al (2012) Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study). Eye 26:1181–1187
Chaikitmongkol V, Bressler NM (2013) Dramatic resolution of choroidal neovascular abnormalities after single aflibercept injection following years of ranibizumab use. JAMA Ophthalmol 131:260–262
Miura M, Iwasaki T, Goto H (2013) Intravitreal aflibercept for polypoidal choroidal vasculopathy after developing ranibizumab tachyphylaxis. Clin Ophthalmol 7:1591–1595
Yonekawa Y (2013) Aflibercept for the treatment of refractory polypoidal choroidal vasculopathy. Can J Ophthalmol 48:e59–e60
Yamashita M, Nishi T, Hasegawa T et al (2014) Response of serous retinal pigment epithelial detachments to intravitreal aflibercept in polypoidal choroidal vasculopathy refractory to ranibizumab. Clin Ophthalmol 2:343–346
Saito M, Kano M, Itagaki K et al (2014) Switching to intravitreal aflibercept injection for polypoidal choroidal vasculopathy refractory to ranibizumab. Retina 34:2192–2201
Imamura Y, Engelbert M, Iida T et al (2010) Polypoidal choroidal vasculopathy: a review. Surv Ophthalmol 55:501–505
Okubo A, Ito M, Sameshima M et al (2005) Pulsatile blood flow in the polypoidal choroidal vasculopathy. Ophthalmology 112:1436–1441
Maruko I, Iida T, Saito M et al (2007) Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 144:15–22
Sasahara M, Tsujikawa A, Musashi K et al (2006) Polypoidal choroidal vasculopathy with choroidal vascular hyperpermeability. Am J Ophthalmol 142:601–607
Okubo A, Hirakawa M, Ito M et al (2008) Clinical features of early and late stage polypoidal choroidal vasculopathy characterized by lesion size and disease duration. Graefes Arch Clin Exp Ophthalmol 246:491–499
Laude A, Cackett PD, Vithana EN et al (2010) Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: same or different disease? Prog Retina Eye Res 29:19–29
Matsumiya W, Honda S, Bessho H, et al (2011). Early responses to intravitreal ranibizumab in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. J Ophthalmic 742020
Ruamviboonsuk P, Tadarati M, Vanichvaranont S et al (2010) Photodynamic therapy combined with ranibizumab for polypoidal choroidal vasculopathy: results of a 1-year preliminary study. Br J Ophthalmol 94:1045–1051
Sonoda S, Sakamoto T, Otsuka H et al (2013) Responsiveness of eyes with polypoidal choroidal vasculopathy with choroidal hyperpermeability to intravitreal ranibizumab. BMC Ophthalmol 13:43
Ho VY, Yeh S, Olsen TW et al (2013) Short-term outcomes of aflibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors. Am J Ophthalmol 156:23–28
Kumar N, Marsiglia M, Mrejen S et al (2013) Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 33:1605–1612
Grewal DS, Gill MK, Sarezky D et al (2014) Visual and anatomical outcomes following intravitreal aflibercept in eyes with recalcitrant neovascular age-related macular degeneration: 12-month results. Eye 28:895–899
Yonekawa Y, Andreoli C, Miller JB et al (2013) Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 156:29–35
Kawashima Y, Oishi A, Tsujikawa A, et (2014). Effects of aflibercept for ranibizumab-resistant neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol. 2014 [Epud ahead of print]
Fujii A, Imai H, Kanai M et al (2014) Effect of intravitreal aflibercept injection for age-related macular degeneration with retinal pigment epithelial tear refractory to intravitreal ranibizumab injection. Clin Ophthalmol 24:1199–1202
Hanh P (2014) Successful treatment of neovascular age-related macular degeneration following single bevacizumab failure using aflibercept in a vitrectomized eye. Clin Ophthalmol 17:2129–2131
Rusu IM, Deobhakta A, Yoon D et al (2014) Intraocular pressure in patients with neovascular age-related macular degeneration switched to aflibercept injection after previous anti-vascular endothelial growth factor treatments. Retina 34:2161–2166
Broadhead GK, Hong T, Zhu M, et al (2015). Response of pigment epithelial detachments to intravitreal aflibercept among patients with treatment-resistant neovascular age-related macular degeneration. Retina [Epud ahead of print]
de Oliveira Dias JR, Xavier CO, Maia A et al (2015) Intravitreal injection of ziv-aflibercept in patient with refractory age-related macular degeneration. Ophthalmic Surg Lasers Imaging. Retina. 46:91–94
Patel KH, Chow CC, Rathod R et al (2013) Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab. Eye 27:663–667
Bakall B, Folk JC, Boldt HC et al (2013) Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 156:15–22
Heussen FM, Shao Q, Ouyang Y, et al (2013). Clinical outcomes after switching treatment from intravitreal ranibizumab to aflibercept in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol [Epub ahead of print]
Cho H, Shah CP, Weber M et al (2013) Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 97:1032–1035
Fassnacht-Riederle H, Becker M, Graf N, et al (2014). Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp. Ophthalmol [Epub ahead of print]
Hall LB, Zebardast N, Huang JJ, et al (2014). Aflibercept in the Treatment of Neovascular Age-Related Macular Degeneration in Previously Treated Patients. J Ocul Pharmacol Ther [Epub ahead of print]
Messenger WB, Campbell JP, Faridi A et al (2014) Injection frequency and anatomic outcomes 1 year following conversion to aflibercept in patients with neovascular age-related macular degeneration. Br J Ophthalmol 98:1205–1207
Gharbiya M, Iannetti L, Parisi F et al (2014) Visual and anatomical outcomes of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Biomed Res Int 2014:273754
Arcinue CA, Ma F, Barteselli G, Sharpsten L et al (2015) One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 159:426–436
Griffin DR, Richmond PP, Olson JC (2014) Intravitreal aflibercept outcomes in patients with persistent macular exudate previously treated with bevacizumab and/or ranibizumab for neovascular age-related macular degeneration. J Ophthalmol 2014:497178
Thorell MR, Nunes RP, Chen GW et al (2014) Response to aflibercept after frequent re-treatment with bevacizumab or ranibizumab in eyes with neovascular AMD. Ophthalmic Surg Lasers Imaging Retina 45:526–533
Eadie JA, Gottlieb JL, Ip MS et al (2014) Response to aflibercept in patients with persistent exudation despite prior treatment with bevacizumab or ranibizumab for age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina 45:394–397
Michalewski J, Nawrocki J, Trębińska M et al (2014) Switch to a single dose of aflibercept in bevacizumab nonresponders with AMD. Can J Ophthalmol 49:431–435
Wykoff CC, Brown DM, Maldonado ME, et al (2014). Aflibercept treatment for patients with exudative age-related macular degeneration who were incomplete responders to multiple ranibizumab injections (TURF trial). Br J Ophthalmol [Epub ahead of print]
Chang AA, Li H, Broadhead GK et al (2014) Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology 121:188–192
Singh RP, Srivastava S, Ehlers JP et al (2014) A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 98(Suppl 1):i22–i27
Lazzeri S, Nardi M, Bocci G (2013) Pharmacogenetic labyrinth of neovascular age-related macular degeneration therapy: how to escape and move forward? Pharmacogenomics 14:1239–1242
Chong V (2012) Biological, preclinical and clinical characteristics of inhibi-tors of vascular endothelial growth factors. Ophthalmologica 227(Suppl 1):2–10
Browning DJ, Kaiser PK, Rosenfeld PJ et al (2012) Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol 154:222–226
Schmidt-Erfurth U, Eldem B, Guymer R, EXCITE Study Group et al (2011) Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 118:831–839
Funk M, Karl D, Georgopoulos M et al (2009) Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology 116:2393–2399
Lai TY, Liu DT, Chan KP et al (2009) Visual outcomes and growth factor changes of two dosages of intravitreal bevacizumab for neovascular age-related macular degeneration: a randomized, controlled trial. Retina 29:1218–1226
Meier CH, Krohne TU, Holz FG (2011) Intraocular pharmacokinetics after a single intravitreal injection of 1.5 mg versus 3.0 mg of bevacizumab in humans. Retina 31:1877–1884
Busbee BG, Ho AC, Brown DM et al (2013) Twelve-month efficacy and safety of 0.5 or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 120:1046–1056
Stewart MW, Rosenfeld PJ, Penha FM et al (2012) Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab and aflibercept (vascular endothelial growth factor Trap-eye). Retina 32:434–457
Forooghian F, Chew EY, Meyerle CB et al (2011) Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis. Acta Ophthalmol 89:e206–e207
Zhang F, Tang Z, Hou X et al (2009) VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 106:6152–6157
Rakic JM, Lambert V, Devy L et al (2003) Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3186–3193
Grossniklaus HE, Ling JX, Wallace TM et al (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8:119–126
Espinosa-Heidmann DG, Suner IJ, Hernandez P et al (2003) Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3586–3592
Sakurai E, Anand A, Ambati BK et al (2003) Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3578–3585
Leveziel N, Pelat T, Watier H et al (2013). Detection of anti-ranibizumab antibodies among exudative AMD patients. Association for Research in Vision and Ophthalmology (ARVO) Meeting. Seattle, WA, USA, 5–9 May 2013 (Abstract 3170)
Bressler NM (2004) Age-related macular degeneration is the leading cause of blindness. JAMA 291:1900–1901
Wickremasinghe SS, Michalova K, Gilhotra J et al (2008) Acute intraocular inflammation after intravitreous injections of bevacizumab for treatment of neovascular age-related macular degeneration. Ophthalmology 115:1911–1915
Lazzeri S, Figus M, Orlandi P et al (2013) VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration. Pharmacogenomics 14:623–630
Agosta E, Lazzeri S, Orlandi P et al (2012) Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration. Pharmacogenomics 13:1037–1053
Kitchens JW, Kassem N, Wood W et al (2013) A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration. Clin Ophthalmol 7:1987–1993
Park UC, Shin JY, Kim SJ et al (2014) Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration. Retina 34:288–297
Park UC, Shin JY, McCarthy LC et al (2014) Pharmacogenetic associations with long-term response to anti-vascular endothelial growth factor treatment in neovascular AMD patients. Mol Vis 20:1680–1694
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Financial disclosure
None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.
Rights and permissions
About this article
Cite this article
Lazzeri, S., Ripandelli, G., Sartini, M.S. et al. Aflibercept administration in neovascular age-related macular degeneration refractory to previous anti-vascular endothelial growth factor drugs: a critical review and new possible approaches to move forward. Angiogenesis 18, 397–432 (2015). https://doi.org/10.1007/s10456-015-9483-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-015-9483-4