Impact of Vitreomacular Adhesion on Ranibizumab Mono- and Combination Therapy for Neovascular Age-Related Macular Degeneration


      To investigate the influence of vitreomacular adhesion on the efficacy of pro re nata (PRN) ranibizumab monotherapy and verteporfin photodynamic therapy (PDT) combination therapy for neovascular age-related macular degeneration.


      Post hoc analysis of prospective randomized 12-month multicenter clinical trial data.


      patient population: Total of 255 treatment-naïve patients with subfoveal choroidal neovascularization. observation procedure: Assessment of the vitreomacular interface on monthly optical coherence tomography with division of patients into the following categories according to continuous 1-year grading: posterior vitreous detachment (n = 154), dynamic release of vitreomacular adhesion (n = 32), stable vitreomacular adhesion (n = 51). main outcome measures: Mean best-corrected visual acuity (BCVA) letter and central retinal thickness changes at month 12 in the vitreomacular interface groups.


      Mean BCVA changes at month 12 were +3.5 (posterior vitreous detachment), +4.3 (release of vitreomacular adhesion), and +6.3 (vitreomacular adhesion) in patients receiving monotherapy (P = .767), and +0.1 (posterior vitreous detachment), +6.6 (release of vitreomacular adhesion), and +9.2 (vitreomacular adhesion) in patients receiving combination therapy (P = .009). Mean central retinal thickness changes were −113 μm (posterior vitreous detachment), −89 μm (release of vitreomacular adhesion), and −122 μm (vitreomacular adhesion) in monotherapy (P = .725) and −121 μm (posterior vitreous detachment), −113 μm (release of vitreomacular adhesion), and −113 μm (vitreomacular adhesion) in combination therapy (P = .924). Mean ranibizumab retreatments during 12 months were 4.9 (posterior vitreous detachment), 6.6 (release of vitreomacular adhesion), and 5.3 (vitreomacular adhesion) in monotherapy (P = .018) and 4.7 (posterior vitreous detachment), 5.2 (release of vitreomacular adhesion), and 5.8 (vitreomacular adhesion) in combination therapy (P = .942).


      This study adds evidence that the vitreomacular interface status impacts functional outcomes and retreatment requirements. Patients with posterior vitreous detachment achieve acceptable results with fewer injections in PRN monotherapy, but lose potential vision gain with PDT. Patients with other vitreomacular interface configurations may potentially achieve optimized vision outcomes by combination of antiangiogenic treatment and vaso-occlusive PDT.
      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


        • Lim L.S.
        • Mitchell P.
        • Seddon J.M.
        • Holz F.G.
        • Wong T.Y.
        Age-related macular degeneration.
        Lancet. 2012; 379: 1728-1738
        • Ferrara N.
        • Damico L.
        • Shams N.
        • Lowman H.
        • Kim R.
        Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.
        Retina. 2006; 26: 859-870
        • 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
        • Brown D.M.
        • Kaiser P.K.
        • Michels M.
        • et al.
        Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
        N Engl J Med. 2006; 355: 1432-1444
        • Fung A.E.
        • Lalwani G.A.
        • Rosenfeld P.J.
        • et al.
        An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
        Am J Ophthalmol. 2007; 143: 566-583
        • Martin D.F.
        • Maguire M.G.
        • Ying G.S.
        • Grunwald J.E.
        • Fine S.L.
        • Jaffe G.J.
        Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
        N Engl J Med. 2011; 364: 1897-1908
        • Martin D.F.
        • Maguire M.G.
        • Fine S.L.
        • et al.
        Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
        Ophthalmology. 2012; 119: 1388-1398
        • Chakravarthy U.
        • Harding S.P.
        • Rogers C.A.
        • et al.
        Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.
        Ophthalmology. 2012; 119: 1399-1411
        • Chakravarthy U.
        • Harding S.P.
        • Rogers C.A.
        • et al.
        Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.
        Lancet. 2013; 382: 1258-1267
        • Cohen S.Y.
        • Mimoun G.
        • Oubraham H.
        • et al.
        Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.
        Retina. 2013; 33: 474-481
        • Simader C.
        • Ritter M.
        • Bolz M.
        • et al.
        Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related macular degeneration.
        Ophthalmology. 2014;
        • Jackson T.L.
        • Nicod E.
        • Angelis A.
        • et al.
        Vitreous attachment in age-related macular degeneration, diabetic macular edema, and retinal vein occlusion: a systematic review and metaanalysis.
        Retina. 2013; 33: 1099-1108
        • Lee S.J.
        • Koh H.J.
        Effects of vitreomacular adhesion on anti-vascular endothelial growth factor treatment for exudative age-related macular degeneration.
        Ophthalmology. 2011; 118: 101-110
        • Uney G.O.
        • Unlu N.
        • Acar M.A.
        • et al.
        Role of posterior vitreous detachment on outcome of anti-vascular endothelial growth factor treatment in age-related macular degeneration.
        Retina. 2014; 34: 32-37
        • Duker J.S.
        • Kaiser P.K.
        • Binder S.
        • et al.
        The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole.
        Ophthalmology. 2013; 120: 2611-2619
        • Schaal K.B.
        • Pang C.E.
        • Pozzoni M.C.
        • Engelbert M.
        The premacular bursa's shape revealed in vivo by swept-source optical coherence tomography.
        Ophthalmology. 2014; 121: 1020-1028
        • Kakehashi A.
        • Schepens C.L.
        • Trempe C.L.
        Vitreomacular observations. I. Vitreomacular adhesion and hole in the premacular hyaloid.
        Ophthalmology. 1994; 101: 1515-1521
        • Geck U.
        • Pustolla N.
        • Baraki H.
        • Atili A.
        • Feltgen N.
        • Hoerauf H.
        Posterior vitreous detachment following intravitreal drug injection.
        Graefes Arch Clin Exp Ophthalmol. 2013; : 1-5
        • Stalmans P.
        • Benz M.S.
        • Gandorfer A.
        • et al.
        Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes.
        N Engl J Med. 2012; 367: 606-615
        • Green-Simms A.E.
        • Fechtel B.M.
        • Agarwal Z.
        • Bakri S.J.
        Visual and anatomical outcomes of anti-vascular endothelial growth factor therapy in exudative age-related macular degeneration and vitreomacular interface disease: vitreomacular adhesion and epiretinal membrane.
        Retina. 2013; 33: 1359-1364
        • Mayr-Sponer U.
        • Waldstein S.M.
        • Kundi M.
        • et al.
        Influence of the vitreomacular interface on outcomes of ranibizumab therapy in neovascular age-related macular degeneration.
        Ophthalmology. 2013; 120: 2620-2629
        • VIP Study Group
        Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy Report 2.
        Am J Ophthalmol. 2001; 131: 541-560
        • TAP Study Group
        Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials—TAP Report 2.
        Arch Ophthalmol. 2001; 119: 198-207
        • Schmidt-Erfurth U.
        • Niemeyer M.
        • Geitzenauer W.
        • Michels S.
        Time course and morphology of vascular effects associated with photodynamic therapy.
        Ophthalmology. 2005; 112: 2061-2069
        • Schmidt-Erfurth U.
        • Schlötzer-Schrehard U.
        • Cursiefen C.
        • Michels S.
        • Beckendorf A.
        • Naumann G.O.H.
        Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium–derived factor.
        Invest Ophthalmol Vis Sci. 2003; 44: 4473-4480
        • Chan W.
        • Lim T.-H.
        • Pece A.
        • Silva R.
        • Yoshimura N.
        Verteporfin PDT for non-standard indications—a review of current literature.
        Graefes Arch Clin Exp Ophthalmol. 2010; 248: 613-626
        • Larsen M.
        • Schmidt-Erfurth U.
        • Lanzetta P.
        • et al.
        Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results.
        Ophthalmology. 2012; 119: 992-1000
        • Kaiser P.K.
        • Boyer D.S.
        • Cruess A.F.
        • Slakter J.S.
        • Pilz S.
        • Weisberger A.
        Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI Study.
        Ophthalmology. 2012; 119: 1001-1010
        • Koh A.
        • Lee W.K.
        • Chen L.-J.
        • et al.
        EVEREST Study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy.
        Retina. 2012; 32: 1453-1464
        • Tozer K.
        • Roller A.B.
        • Chong L.P.
        • et al.
        Combination therapy for neovascular age-related macular degeneration refractory to anti–vascular endothelial growth factor agents.
        Ophthalmology. 2013; 120: 2029-2034
        • Krebs I.
        • Brannath W.
        • Glittenberg C.
        • Zeiler F.
        • Sebag J.
        • Binder S.
        Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration?.
        Am J Ophthalmol. 2007; 144: 741-746
        • Robison C.D.
        • Krebs I.
        • Binder S.
        • et al.
        Vitreomacular adhesion in active and end-stage age-related macular degeneration.
        Am J Ophthalmol. 2009; 148: 79-82
        • Mojana F.
        • Cheng L.
        • Bartsch D.U.
        • et al.
        The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results.
        Am J Ophthalmol. 2008; 146: 218-227
        • Lee S.J.
        • Lee C.S.
        • Koh H.J.
        Posterior vitreomacular adhesion and risk of exudative age-related macular degeneration: paired eye study.
        Am J Ophthalmol. 2009; 147: 621-626
        • Waldstein S.M.
        • Sponer U.
        • Simader C.
        • Sacu S.
        • Schmidt-Erfurth U.
        Influence of vitreomacular adhesion on the development of exudative age-related macular degeneration: 4-year results of a longitudinal study.
        Retina. 2012; 32: 424-433
        • Schmidt-Erfurth U.M.
        • Michels S.
        Changes in confocal indocyanine green angiography through two years after photodynamic therapy with verteporfin.
        Ophthalmology. 2003; 110: 1306-1314
        • Itakura H.
        • Kishi S.
        Evolution of vitreomacular detachment in healthy subjects.
        JAMA Ophthalmol. 2013; 131: 1348-1352


      Sebastian M. Waldstein is a supervisor at the Vienna Reading Center (VRC) and a resident at the Department of Ophthalmology, Medical University Vienna, Austria. He coordinates the Christian-Doppler-Laboratory for Ophthalmic Image Analysis, a multidisciplinary research endeavor aiming at the personalization of antiangiogenic treatment strategies for macular diseases by automated analysis and interpretation of large-scale optical coherence tomography data. His primary research interests are neovascular age-related macular degeneration and innovative retinal imaging.