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.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Surgical, Medical and Molecular Pathology and of Critical Area. Operative Unit of "University Ophthalmology", University of Pisa, Pisa, Italy.|Bietti Foundation, IRCCS, Rome, Italy.
Stefano
S
Lazzeri
Bietti Foundation, IRCCS, Rome, Italy.
Guido
G
Ripandelli
Department of Surgical, Medical and Molecular Pathology and of Critical Area. Operative Unit of "University Ophthalmology", University of Pisa, Pisa, Italy.
Maria Sole
MS
Sartini
Bietti Foundation, IRCCS, Rome, Italy.
Mariacristina
M
Parravano
Bietti Foundation, IRCCS, Rome, Italy.
Monica
M
Varano
Department of Surgical, Medical and Molecular Pathology and of Critical Area. Operative Unit of "University Ophthalmology", University of Pisa, Pisa, Italy.
Marco
M
Nardi
Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Scuola Medica - Via Roma 55, 56126, Pisa, Italy.
Teresa
T
Di Desidero
Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Scuola Medica - Via Roma 55, 56126, Pisa, Italy.
Paola
P
Orlandi
Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Scuola Medica - Via Roma 55, 56126, Pisa, Italy. guido.bocci@med.unipi.it.
Guido
G
Bocci
D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance / Q000187:drug effects*; D006801:Humans; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor
Aflibercept; Anti-VEGF drug; Intravitreal injections; Recurrent exudative AMD; Resistant wet AMD