Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema

Published:December 31, 2015DOI:


      To evaluate the short-term functional and anatomic outcomes of patients with persistent diabetic macular edema (DME) who were converted from bevacizumab and/or ranibizumab to aflibercept.


      Retrospective, interventional, noncomparative, consecutive case series.


      Only eyes treated with at least 4 consecutive injections of ranibizumab/bevacizumab spaced 4–6 weeks apart prior to conversion and with at least 2 aflibercept injections afterward were considered for inclusion. Pertinent patient demographic, examination, and treatment data were extracted from clinical charts and tabulated for analysis.


      Fifty eyes of 37 patients were included. Eyes received a mean of 13.7 bevacizumab/ranibizumab injections prior to conversion, followed by 4.1 aflibercept injections over 4.6 months of subsequent follow-up. The mean logMAR visual acuity at the pre-switch visit was 0.60 ± 0.43 (Snellen equivalent, 20/80). This improved to 0.55 ± 0.48 (Snellen equivalent, 20/70) by the second visit after conversion, corresponding to a mean logMAR change of −0.05 ± 0.22 (P = .12). The average central macular thickness from the pre-switch spectral-domain optical coherence tomography scan was 459.2 ± 139.2 μm. This significantly improved to 348.7 ± 107.8 μm by the second visit following conversion, reflecting a mean decrease of 112 ± 141 μm (P < .0001). The mean intraocular pressure (IOP) recorded at the pre-switch visit was 15.1 ± 3.3 mm Hg. At the second follow-up after converting to aflibercept, the IOP averaged 14.9 ± 3.2 mm Hg, with a mean decrease of 0.2 ± 3.0 mm Hg (P = .63).


      Conversion to aflibercept for persistent DME resulted in significant anatomic improvements. While trends towards improved visual acuity and reduction in IOP were observed, these were not statistically significant.
      To read this article in full you will need to make a payment


      Subscribe to American Journal of Ophthalmology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Romero-Aroca P.
        Managing diabetic macular edema: The leading cause of diabetes blindness.
        World J Diabetes. 2011; 2: 98-104
        • Yau J.W.
        • Rogers S.L.
        • Kawasaki R.
        • et al.
        Global prevalence and major risk factors of diabetic retinopathy.
        Diabetes Care. 2012; 35: 556-564
        • Wild S.
        • Roglic G.
        • Green A.
        • Sicree R.
        • King H.
        Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
      1. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group.
        Arch Ophthalmol. 1985; 103: 1796-1806
        • Nguyen Q.D.
        • Brown D.M.
        • Marcus D.M.
        • et al.
        Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.
        Ophthalmology. 2012; 119: 789-801
        • Rajendram R.
        • Fraser-Bell S.
        • Kaines A.
        • et al.
        A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3.
        Arch Ophthalmol. 2012; 130: 972-979
        • Korobelnik J.F.
        • Do D.V.
        • Schmidt-Erfurth U.
        • et al.
        Intravitreal aflibercept for diabetic macular edema.
        Ophthalmology. 2014; 121: 2247-2254
        • Brown D.M.
        • Schmidt-Erfurth U.
        • Do D.V.
        • et al.
        Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies.
        Ophthalmology. 2015; 122: 2044-2052
        • Wells J.A.
        • Glassman A.R.
        • Ayala A.R.
        • et al.
        Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
        N Engl J Med. 2015; 372: 1193-1203
        • Liang K.Y.
        • Zeger S.L.
        Longitudinal data analysis using generalized linear models.
        Biometrika. 1986; 73: 13-22
        • Yonekawa Y.
        • Andreoli C.
        • Miller J.B.
        • et al.
        Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration.
        Am J Ophthalmol. 2013; 156: 29-35.e2
        • Bakall B.
        • Folk J.C.
        • Boldt H.C.
        • et al.
        Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab.
        Am J Ophthalmol. 2013; 156: 15-22.e1
        • Ho V.Y.
        • Yeh S.
        • Olsen T.W.
        • et al.
        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. 2013; 156: 23-28.e2
        • Wood E.H.
        • Karth P.A.
        • Moshfeghi D.M.
        • Leng T.
        Short-term outcomes of aflibercept therapy for diabetic macular edema in patients with incomplete response to ranibizumab and/or bevacizumab.
        Ophthalmic Surg Lasers Imaging Retina. 2015; 46: 950-954
        • Papadopoulos N.
        • Martin J.
        • Ruan Q.
        • et al.
        Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab.
        Angiogenesis. 2012; 15: 171-185
        • Stewart M.W.
        • Rosenfeld P.J.
        • Penha F.M.
        • et al.
        Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye).
        Retina. 2012; 32: 434-457
        • Miller J.W.
        • Le Couter J.
        • Strauss E.C.
        • Ferrara N.
        Vascular endothelial growth factor A in intraocular vascular disease.
        Ophthalmology. 2013; 120: 106-114
        • Adamis A.P.
        • Miller J.W.
        • Bernal M.T.
        • et al.
        Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy.
        Am J Ophthalmol. 1994; 118: 445-450
        • Aiello L.P.
        • Avery R.L.
        • Arrigg P.G.
        • et al.
        Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.
        N Engl J Med. 1994; 331: 1480-1487
        • Browning D.J.
        • Kaiser P.K.
        • Rosenfeld P.J.
        • Stewart M.W.
        Aflibercept for age-related macular degeneration: a game-changer or quiet addition?.
        Am J Ophthalmol. 2012; 154: 222-226
        • Stewart M.W.
        • Rosenfeld P.J.
        Predicted biological activity of intravitreal VEGF Trap.
        Br J Ophthalmol. 2008; 92: 667-668
        • Mitamura Y.
        • Tashimo A.
        • Nakamura Y.
        • et al.
        Vitreous levels of placenta growth factor and vascular endothelial growth factor in patients with proliferative diabetic retinopathy.
        Diabetes Care. 2002; 25: 2352
        • Miyamoto N.
        • de Kozak Y.
        • Normand N.
        • et al.
        PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema.
        Ophthalmic Res. 2008; 40: 203-207
        • Miyamoto N.
        • de Kozak Y.
        • Jeanny J.C.
        • et al.
        Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy.
        Diabetologia. 2007; 50: 461-470
        • Khaliq A.
        • Foreman D.
        • Ahmed A.
        • et al.
        Increased expression of placenta growth factor in proliferative diabetic retinopathy.
        Lab Invest. 1998; 78: 109-116
        • Roa Vandekerckhove K.
        Aflibercept versus ranibizumab for treating persistent diabetic macular oedema.
        Int Ophthalmol. 2015; 35: 603-609
        • De Falco S.
        The discovery of placenta growth factor and its biological activity.
        Exp Mol Med. 2012; 44: 1-9
        • Forooghian F.
        • Cukras C.
        • Meyerle C.B.
        • Chew E.Y.
        • Wong W.T.
        Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration.
        Retina. 2009; 29: 723-731
        • Schaal S.
        • Kaplan H.J.
        • Tezel T.H.
        Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?.
        Ophthalmology. 2008; 115: 2199-2205
        • Rosenfeld P.J.
        • Brown D.M.
        • Heier J.S.
        • et al.
        Ranibizumab for neovascular age-related macular degeneration.
        N Engl J Med. 2006; 355: 1419-1431
        • Lazic R.
        • Lukic M.
        • Boras I.
        • et al.
        Treatment of anti-vascular endothelial growth factor-resistant diabetic macular edema with dexamethasone intravitreal implant.
        Retina. 2014; 34: 719-724
        • Terasaki H.
        • Kojima T.
        • Niwa H.
        • et al.
        Changes in focal macular electroretinograms and foveal thickness after vitrectomy for diabetic macular edema.
        Invest Ophthalmol Vis Sci. 2003; 44: 4465-4472
        • Kim J.E.
        • Mantravadi A.V.
        • Hur E.Y.
        • Covert D.J.
        Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents.
        Am J Ophthalmol. 2008; 146: 930-934.e1
        • Tseng J.J.
        • Vance S.K.
        • Della Torre K.E.
        • et al.
        Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration.
        J Glaucoma. 2012; 21: 241-247
        • Freund K.B.
        • Hoang Q.V.
        • Saroj N.
        • Thompson D.
        Intraocular pressure in patients with neovascular age-related macular degeneration receiving intravitreal aflibercept or ranibizumab.
        Ophthalmology. 2015; 122: 1802-1810
        • Rusu I.M.
        • Deobhakta A.
        • Yoon D.
        • et al.
        Intraocular pressure in patients with neovascular age-related macular degeneration switched to aflibercept injection after previous anti-vascular endothelial growth factor treatments.
        Retina. 2014; 34: 2161-2166
        • Wells J.A.
        • Glassman A.R.
        • Jampol L.M.
        • et al.
        Association of baseline visual acuity and retinal thickness with 1-year efficacy of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema.
        JAMA Ophthalmol. 2015; 25: 1-8
        • Browning D.J.
        • Glassman A.R.
        • Aiello L.P.
        • et al.
        Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema.
        Ophthalmology. 2007; 114: 525-536
        • Otani T.
        • Yamaguchi Y.
        • Kishi S.
        Correlation between visual acuity and foveal microstructural changes in diabetic macular edema.
        Retina. 2010; 30: 774-780
        • Sun J.K.
        • Lin M.M.
        • Lammer J.
        • et al.
        Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema.
        JAMA Ophthalmol. 2014; 132: 1309-1316


      Ehsan Rahimy is currently a vitreoretinal specialist at the Palo Alto Medical Foundation. He recently completed his vitreoretinal fellowship at Wills Eye Hospital. Prior to that he received his undergraduate degree in Cellular & Molecular Biology from the University of Michigan, followed by medical school at Baylor College of Medicine, and then residency at the Jules Stein Eye Institute, UCLA. He was acknowledged as a 2014–15 Heed Ophthalmic Foundation Fellow and a Ronald G. Michels Fellow.


      Abtin Shahlaee is a post-doctoral research fellow at Wills Eye Hospital in Philadelphia, PA. He received his medical degree from Tehran University of Medical Sciences and was was a former research assistant at the Department of Ophthalmology at the Medical University of Vienna. His current research projects focus on diseases of the retina and applications of novel imaging techniques.

      Linked Article

      • Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema
        American Journal of OphthalmologyVol. 168
        • Preview
          The study by Rahimy and associates1 assessed the short-term visual and anatomic outcomes of patients with persistent diabetic macular edema (DME) who were converted from bevacizumab (Avastin; Genentech, Inc, South San Francisco, California, USA) and/or ranibizumab (Lucentis; Genentech, Inc) to aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA). The article has several shortcomings that prevent the validation and extrapolation of their results and that can be specifically summarized as follows.
        • Full-Text
        • PDF