Abstract
Purpose
To evaluate the efficacy of intravitreal aflibercept monotherapy for submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).
Methods
This prospective, phase 4 clinical trial included 29 patients diagnosed with fovea-involving submacular hemorrhage secondary to neovascular AMD (7 patients) or PCV (22 patients). Patients were initially administered 3 monthly aflibercept injections, followed by 1 injection every 2 months. The primary outcome measure was changes in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) during the 56-week study period. Other key outcome measures were the proportion of patients who exhibited changes in BCVA of ≥ 15 ETDRS letters from baseline and changes in central retinal thickness (CRT).
Results
The mean size of hemorrhage was 6.2 ± 4.8-disc-diameter area. The mean BCVA significantly improved from 52.9 ± 17.8 ETDRS letters at week 0 (baseline) to 71.8 ± 16.1 letters at week 56 (P < 0.001). At week 56, improvement in BCVA of ≥ 15 letters was noted in 16 patients (55.2%), whereas none of the patients experienced a loss of ≥ 15 letters. The mean CRT significantly decreased from 498.9 ± 194.2 μm at week 0 to 248.3 ± 45.0 μm at week 56 (P < 0.001). During the study period, retinal break developed in one patient.
Conclusions
Intravitreal aflibercept administered every 2 months after the 3 initial monthly doses was found to be an effective and safe treatment method for submacular hemorrhage secondary to neovascular AMD.
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References
Buch H, Vinding T, La Cour M, Appleyard M, Jensen GB, Nielsen NV (2004) Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology 111:53–61
Congdon N, O’Colmain B, Klaver CC, Klein R, Munoz B, Friedman DS, Kempen J, Taylor HR, Mitchell P (2004) Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 122:477–485
Avery RL, Fekrat S, Hawkins BS, Bressler NM (1996) Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina 16:183–189
Bennett SR, Folk JC, Blodi CF, Klugman M (1990) Factors prognostic of visual outcome in patients with subretinal hemorrhage. Am J Ophthalmol 109:33–37
Glatt H, Machemer R (1982) Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol 94:762–773
Toth CA, Morse LS, Hjelmeland LM, Landers MB 3rd (1991) Fibrin directs early retinal damage after experimental subretinal hemorrhage. Arch Ophthalmol 109:723–729
Bhisitkul RB, Winn BJ, Lee OT, Wong J, Pereira Dde S, Porco TC, He X, Hahn P, Dunaief JL (2008) Neuroprotective effect of intravitreal triamcinolone acetonide against photoreceptor apoptosis in a rabbit model of subretinal hemorrhage. Invest Ophthalmol Vis Sci 49:4071–4077
Kim JH, Chang YS, Lee DW, Kim CG, Kim JW (2018) Quantification of retinal changes after resolution of submacular hemorrhage secondary to polypoidal choroidal vasculopathy. Jpn J Ophthalmol 62:54–62
Kim JH, Chang YS, Kim CG, Lee DW, Han JI (2018) Hyperpigmented spots after treatment for submacular hemorrhage secondary to polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 256:469–477
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364:1897–1908
Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, Toth CA, Ferris FL 3rd, Fine SL (2016) 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 123:1751–1761
Adrean SD, Chaili S, Ramkumar H, Pirouz A, Grant S (2018) Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol. Ophthalmology 125:1047–1053
Shienbaum G, Garcia Filho CA, Flynn HW Jr, Nunes RP, Smiddy WE, Rosenfeld PJ (2013) Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. Am J Ophthalmol 155:1009–1013
Kim JH, Chang YS, Kim JW, Kim CG, Yoo SJ, Cho HJ (2014) Intravitreal anti-vascular endothelial growth factor for submacular hemorrhage from choroidal neovascularization. Ophthalmology 121:926–935
Altaweel MM, Daniel E, Martin DF, Mittra RA, Grunwald JE, Lai MM, Melamud A, Morse LS, Huang J, Ferris FL 3rd, Fine SL, Maguire MG (2015) Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology 122:391–398 e395
Chang MA, Do DV, Bressler SB, Cassard SD, Gower EW, Bressler NM (2010) Prospective one-year study of ranibizumab for predominantly hemorrhagic choroidal neovascular lesions in age-related macular degeneration. Retina 30:1171–1176
Rao P, Lum F, Wood K, Salman C, Burugapalli B, Hall R, Singh S, Parke DW 2nd, Williams GA (2018) Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry. Ophthalmology 125:522–528
Niwa Y, Kakinoki M, Sawada T, Wang X, Ohji M (2015) Ranibizumab and aflibercept: intraocular pharmacokinetics and their effects on aqueous VEGF level in vitrectomized and nonvitrectomized macaque eyes. Invest Ophthalmol Vis Sci 56:6501–6505
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119:2537–2548
Kherani S, Scott AW, Wenick AS, Zimmer-Galler I, Brady CJ, Sodhi A, Meyerle C, Solomon SD, Shaukat R, Channa R, Adeyemo O, Handa JT, Wang J, Campochiaro PA (2018) Shortest distance from fovea to subfoveal hemorrhage border is important in patients with neovascular age-related macular degeneration. Am J Ophthalmol 189:86–95
Stanescu-Segall D, Balta F, Jackson TL (2016) Submacular hemorrhage in neovascular age-related macular degeneration: a synthesis of the literature. Surv Ophthalmol 61:18–32
Fleissig E, Barak A, Goldstein M, Loewenstein A, Schwartz S (2017) Massive subretinal and subretinal pigment epithelial hemorrhage displacement with perfluorocarbon liquid using a two-step vitrectomy technique. Graefes Arch Clin Exp Ophthalmol 255:1341–1347
Bardak H, Bardak Y, Ercalik Y, Erdem B, Arslan G, Timlioglu S (2018) Sequential tissue plasminogen activator, pneumatic displacement, and anti-VEGF treatment for submacular hemorrhage. Eur J Ophthalmol 28:306–310
Sharma S, Kumar JB, Kim JE, Thordsen J, Dayani P, Ober M, Mahmoud TH (2018) Pneumatic displacement of submacular hemorrhage with subretinal air and tissue plasminogen activator: initial United States experience. Ophthalmol Retina 2:180–186
Kim JH, Chang YS, Kim JW, Kim CG (2017) Characteristics of submacular hemorrhages in age-related macular degeneration. Optom Vis Sci 94:556–563
Muether PS, Hoerster R, Hermann MM, Kirchhof B, Fauser S (2013) Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 251:453–458
Inoue M, Arakawa A, Yamane S, Kadonosono K (2014) Short-term efficacy of intravitreal aflibercept in treatment-naive patients with polypoidal choroidal vasculopathy. Retina 34:2178–2184
Cho HJ, Kim KM, Kim HS, Han JI, Kim CG, Lee TG, Kim JW (2016) Intravitreal aflibercept and ranibizumab injections for polypoidal choroidal vasculopathy. Am J Ophthalmol 165:1–6
Fassnacht-Riederle H, Becker M, Graf N, Michels S (2014) Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 252:1705–1709
Hata M, Oishi A, Tsujikawa A, Yamashiro K, Miyake M, Ooto S, Tamura H, Nakanishi H, Takahashi A, Yoshikawa M, Yoshimura N (2014) Efficacy of intravitreal injection of aflibercept in neovascular age-related macular degeneration with or without choroidal vascular hyperpermeability. Invest Ophthalmol Vis Sci 55:7874–7880
Shin YI, Sung JY, Sagong M, Lee YH, Jo YJ, Kim JY (2018) Risk factors for breakthrough vitreous hemorrhage after intravitreal anti-VEGF injection in age-related macular degeneration with submacular hemorrhage. Sci Rep 8:10560
Jung JH, Lee JK, Lee JE, Oum BS (2010) Results of vitrectomy for breakthrough vitreous hemorrhage associated with age-related macular degeneration and polypoidal choroidal vasculopathy. Retina 30:865–873
Freund KB, Korobelnik JF, Devenyi R, Framme C, Galic J, Herbert E, Hoerauf H, Lanzetta P, Michels S, Mitchell P, Mones J, Regillo C, Tadayoni R, Talks J, Wolf S (2015) Treat-and-extend regimens with anti-VEGF agents in retinal diseases: a literature review and consensus recommendations. Retina 35:1489–1506
Kim JH, Chang YS, Kim JW, Kim CG, Lee DW (2017) Submacular hemorrhage and grape-like polyp clusters: factors associated with reactivation of the lesion in polypoidal choroidal vasculopathy. Eye (Lond) 31:1678–1684
Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr, Esquiabro M (2007) An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 143:566–583
Funding
Bayer Korea (Seoul, South Korea) provided financial support and investigational drugs for the study.
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Jae Hui Kim: advisory board of Bayer and Novartis. The following authors have no financial disclosure: Chul Gu Kim, Dong Won Lee, Su Jin Yoo, Young Ju Lew, Han Joo Cho, Joo Yeon Kim, Seok Hyun Lee, Jong Woo Kim.
Ethical approval
The study was approved by the institutional review board of Kim’s Eye Hospital (Seoul, South Korea). This study was conducted in accordance with the tenets of the Declaration of Helsinki.
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Informed consent was obtained for all the patients before study enrollment. Identifying information about participants is not presented in this study.
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Kim, J.H., Kim, C.G., Lee, D.W. et al. Intravitreal aflibercept for submacular hemorrhage secondary to neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 258, 107–116 (2020). https://doi.org/10.1007/s00417-019-04474-0
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DOI: https://doi.org/10.1007/s00417-019-04474-0