A review of clinical trials of anti-VEGF agents for diabetic retinopathy

Review Article

Abstract

Background

Diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population worldwide. Many observational and preclinical studies have implicated vascular endothelial growth factor (VEGF) in the pathogenesis of DR, and recent successes with anti-VEGF therapy for age-related macular degeneration (AMD) have prompted research into the application of anti-VEGF drugs to DR. Here we review the numerous early studies that suggest an important potential role for anti-VEGF agents in the management of diabetic retinopathy.

Conclusions

For diabetic macular edema, phase II trials of intravitreal pegaptanib and intravitreal ranibizumab have shown short-term benefit in visual acuity. Intravitreal bevacizumab also has been shown to have beneficial short-term effects on both visual acuity and retinal thickness. For proliferative diabetic retinopathy (PDR), early studies suggest that intravitreal bevacizumab temporarily decreases leakage from diabetic neovascular lesions, but this treatment may be associated with tractional retinal detachment (TRD). Furthermore, several studies indicate that bevacizumab is likely to prove a helpful adjunct to diabetic pars plana vitrectomy (PPV) for TRD. Finally, three small series suggest a potential beneficial effect of a single dose of bevacizumab to prevent worsening of DME after cataract surgery. Use of anti-VEGF medications for any of these indications is off-label. Despite promising early reports on the safety of these medications, we eagerly await the results of large, controlled trials to substantiate the safety and efficacy of anti-VEGF drugs for diabetic retinopathy.

Keywords

Diabetic retinopathy Pegaptanib Ranibizumab Bevacizumab Vascular endothelial growth factor (VEGF) 

References

  1. 1.
    Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP (2004) Global data on vision impairment in the year 2002. Bull World Health Organ 82:844–851PubMedGoogle Scholar
  2. 2.
    Klein BE (2007) Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 14:179–183CrossRefPubMedGoogle Scholar
  3. 3.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431CrossRefPubMedGoogle Scholar
  4. 4.
    Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S, ANCHOR Study Group (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444CrossRefPubMedGoogle Scholar
  5. 5.
    Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group (1999) Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 117:1329–1345Google Scholar
  6. 6.
    Verteporfin In Photodynamic Therapy Study Group (2001) 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 131:541–560CrossRefGoogle Scholar
  7. 7.
    Diabetes Statistics. http://www.diabetes.org/diabetes-statistics.jsp. Accessed July 20, 2009
  8. 8.
    Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin Epidemiologic Study of Diabetic Retinopathy . II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 102:520–526PubMedGoogle Scholar
  9. 9.
    Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 102:527–532PubMedGoogle Scholar
  10. 10.
    West SK, Munoz B, Klein R, Broman AT, Sanchez R, Rodriguez J, Snyder R (2002) Risk factors for Type II diabetes and diabetic retinopathy in a Mexican-American population: Proyecto VER. Am J Ophthalmol 134:390–398CrossRefPubMedGoogle Scholar
  11. 11.
    Xie XW, Xu L, Jonas JB, Wang YX (2009) Prevalence of diabetic retinopathy among subjects with known diabetes in China: the Beijing Eye Study. Eur J Ophthalmol 19:91–99PubMedGoogle Scholar
  12. 12.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
  13. 13.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  14. 14.
    UK Prospective Diabetes Study (UKPDS) Group (2004) Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus (UKPDS 69). Arch Ophthalmol 122:1631–1640CrossRefGoogle Scholar
  15. 15.
    The Diabetic Retinopathy Study Research Group (1987) Indications for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report no. 14. Int Ophthalmol Clin 27:239–253CrossRefGoogle Scholar
  16. 16.
    Vander JF, Duker JS, Benson WE, Brown GC, McNamara JA, Rosenstein RB (1991) Long-term stability and visual outcome after favorable initial response of proliferative diabetic retinopathy to panretinal photocoagulation. Ophthalmology 98:1575–1579PubMedGoogle Scholar
  17. 17.
    Gentile RC, Stegman Z, Liebmann JM, Dayan AR, Tello C, Walsh JB, Ritch R (1996) Risk factors for ciliochoroidal effusion after panretinal photocoagulation. Ophthalmology 103:827–832PubMedGoogle Scholar
  18. 18.
    McDonald HR, Schatz H (1985) Macular edema following panretinal photocoagulation. Retina 5:5–10CrossRefPubMedGoogle Scholar
  19. 19.
    Jardeleza MS, Miller JW (2009) Review of anti-VEGF therapy in proliferative diabetic retinopathy. Sem Ophthalmol 24:87–92CrossRefGoogle Scholar
  20. 20.
    Diabetic Retinopathy Clinical Research Network (2008) Randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 115:1447–1459CrossRefGoogle Scholar
  21. 21.
    Schachat AP (2008) A new look at an old treatment for diabetic macular edema. Ophthalmology 115:1445–1446CrossRefPubMedGoogle Scholar
  22. 22.
    Early Treatment Diabetic Retinopathy Study Research Group (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 103:1796–1806Google Scholar
  23. 23.
    Early Treatment Diabetic Retinopathy Study Research Group (1991) Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology 98:766–785Google Scholar
  24. 24.
    Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME (2008) Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 27:331–371CrossRefPubMedGoogle Scholar
  25. 25.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66CrossRefPubMedGoogle Scholar
  26. 26.
    Witte MH, Erickson R, Bernas M, Andrade M, Reiser F, Conlon W, Hoyme HE, Witte CL (1998) Phenotypic and genotypic heterogeneity in familial Milroy lymphedema. Lymphology 31:145–155PubMedGoogle Scholar
  27. 27.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248CrossRefPubMedGoogle Scholar
  28. 28.
    Adamis AP, Shima DT, Yeo KT, Yeo TK, Brown LF, Berse B, D’Amore PA, Folkman J (1993) Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun 193:631–638CrossRefPubMedGoogle Scholar
  29. 29.
    Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15:4738–4747PubMedGoogle Scholar
  30. 30.
    Robbins SG, Conaway JR, Ford BL, Roberto KA, Penn JS (1997) Detection of vascular endothelial growth factor (VEGF) protein in vascular and non-vascular cells of the normal and oxygen-injured rat retina. Growth Factors 14:229–241CrossRefPubMedGoogle Scholar
  31. 31.
    Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544PubMedGoogle Scholar
  32. 32.
    Lutty GA, McLeod DS, Merges C, Diggs A, Plouét J (1996) Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 114:971–977PubMedGoogle Scholar
  33. 33.
    Gilbert RE, Vranes D, Berka JL, Kelly DJ, Cox A, Wu LL, Stacker SA, Cooper ME (1998) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 145:574–584Google Scholar
  34. 34.
    Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108:2369–2379PubMedGoogle Scholar
  35. 35.
    Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2001) VEGF-initiated blood–retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42:2408–2413PubMedGoogle Scholar
  36. 36.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487CrossRefPubMedGoogle Scholar
  37. 37.
    Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE (1996) Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci U S A 93:4851–4856CrossRefPubMedGoogle Scholar
  38. 38.
    Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA (2002) Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 133:373–385CrossRefPubMedGoogle Scholar
  39. 39.
    Lu M, Perez VL, Ma N, Miyamoto K, Peng HB, Liao JK, Adamis AP (1999) VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci 40:1808–1812PubMedGoogle Scholar
  40. 40.
    Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marmé D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343PubMedGoogle Scholar
  41. 41.
    Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, Aiello LP, Ogura Y, Adamis AP (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A 96:10836–10841CrossRefPubMedGoogle Scholar
  42. 42.
    Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, Amano S, Hida T, Oguchi Y, Adamis AP (2003) VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 44:2155–2162CrossRefPubMedGoogle Scholar
  43. 43.
    Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y, Hida T, Oguchi Y, Ambati J, Miller JW, Gragoudas ES, Ng YS, D’Amore PA, Shima DT, Adamis AP (2003) VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198:483–489CrossRefPubMedGoogle Scholar
  44. 44.
    Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2002) Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 160:501–509PubMedGoogle Scholar
  45. 45.
    McLeod DS, Lefer DJ, Merges C, Lutty GA (1995) Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 147:642–653PubMedGoogle Scholar
  46. 46.
    Bell C, Lynam E, Landfair DJ, Janjic N, Wiles ME (1999) Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro. In Vitro Cell Dev Biol Anim 35:533–542CrossRefPubMedGoogle Scholar
  47. 47.
    Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group (2004) Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816CrossRefPubMedGoogle Scholar
  48. 48.
    Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, Arevalo JF, Berrocal MH, Farah ME, Maia M, Roca JA, Rodriguez FJ, for the PanAmerican Collaborative Retina Group (PACORES) (2008) Twelve-month safety of intravitreal injections of bevacizumab (Avastin(R)): Results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 246:81–87CrossRefPubMedGoogle Scholar
  49. 49.
    Mason JO 3rd, White MF, Feist RM, Thomley ML, Albert MA, Persaud TO, Yunker JJ, Vail RS (2008) Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 28:564–567CrossRefPubMedGoogle Scholar
  50. 50.
    Barron H (2004) Important drug warning. Available at: http://www.fda.gov/medwatch/SAFETY/2004/avastin_deardoc_mod.pdf. Accessed October 2004
  51. 51.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti vascular endothelial cell growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434CrossRefPubMedGoogle Scholar
  52. 52.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
  53. 53.
    Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS (2005) Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 112:1035–1047CrossRefPubMedGoogle Scholar
  54. 54.
    Moshfeghi AA, Rosenfeld PJ, Puliafito CA, Michels S, Marcus EN, Lenchus JD, Venkatraman AS (2006) Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 113:1–12CrossRefGoogle Scholar
  55. 55.
    Gunther JB, Altaweel MM (2009) Bevacizumab (Avastin) for the treatment of ocular disease. Surv Ophthalmol 54:372–400CrossRefPubMedGoogle Scholar
  56. 56.
    VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group, D’Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz B (2006) Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 113:992–1001CrossRefPubMedGoogle Scholar
  57. 57.
    Singerman LJ, Masonson H, Patel M, Adamis AP, Buggage R, Cunningham E, Goldbaum M, Katz B, Guyer D (2008) Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol 92:1606–1611CrossRefPubMedGoogle Scholar
  58. 58.
    Lucentis (Ranibizumab injection) Package Insert, Genentech CorporationGoogle Scholar
  59. 59.
    Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, Goldbaum M, Guyer DR, Katz B, Patel M, Schwartz SD, Macugen Diabetic Retinopathy Study Group (2005) A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 112:1747–1757CrossRefPubMedGoogle Scholar
  60. 60.
    Diabetic Retinopathy Clinical Research Network (2007) A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 114:1860–1867CrossRefGoogle Scholar
  61. 61.
    Lam DS, Lai TY, Lee VY, Chan CK, Liu DT, Mohamed S, Li CL (2009) Efficacy of 1.25 mg versus 2.5 mg intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial. Retina 29:292–299CrossRefPubMedGoogle Scholar
  62. 62.
    Fang X, Sakaguchi H, Gomi F, Oshima Y, Sawa M, Tsujikawa M, Ikuno Y, Kamei M, Kusaka S, Tano Y (2008) Efficacy and safety of one intravitreal injection of bevacizumab in diabetic macular oedema. Acta Ophthalmol 86:800–805PubMedGoogle Scholar
  63. 63.
    Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, Abraham P, Campochiaro PA, READ-2 Study Group (2009) Primary end point (six months) results of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. doi:10.1016/jophtha.2009.04.023 Google Scholar
  64. 64.
    Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA (2006) Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 142:961–969CrossRefPubMedGoogle Scholar
  65. 65.
    Ahmadieh H, Ramezani A, Shoeibi N, Bijanzadeh B, Tabatabaei A, Azarmina M, Soheilian M, Keshavarzi G, Mohebbi MR (2008) Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 246:483–489CrossRefPubMedGoogle Scholar
  66. 66.
    Faghihi H, Roohipoor R, Mohammadi SF, Hojat-Jalali K, Mirshahi A, Lashay A, Piri N, Faghihi Sh (2008) Intravitreal bevacizumab versus combined bevacizumab–triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol 18:941–948PubMedGoogle Scholar
  67. 67.
    Soheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, Azarmina M, Moradian S, Tabatabaei H, Peyman GA (2007) Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 27:1187–1195CrossRefPubMedGoogle Scholar
  68. 68.
    Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, Ahmadieh H, Dehghan MH, Azarmina M, Moradian S, Peyman GA (2009) Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 116:1142–1150CrossRefPubMedGoogle Scholar
  69. 69.
    Diabetic Retinopathy Clinical Research Network (2009) Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 127:245–251CrossRefGoogle Scholar
  70. 70.
    Paccola L, Costa RA, Folgosa MS, Barbosa JC, Scott IU, Jorge R (2008) Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study). Br J Ophthalmol 92:76–80CrossRefPubMedGoogle Scholar
  71. 71.
    Shimura M, Nakazawa T, Yasuda K, Shiono T, Iida T, Sakamoto T, Nishida K (2008) Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol 145:854–861CrossRefPubMedGoogle Scholar
  72. 72.
    Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, Gandorfer A, Ulbig M, Kampik A (2006) Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 26:999–1005CrossRefPubMedGoogle Scholar
  73. 73.
    Kook D, Wolf A, Kreutzer T, Neubauer A, Strauss R, Ulbig M, Kampik A, Haritoglou C (2008) Long-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema. Retina 28:1053–1060CrossRefPubMedGoogle Scholar
  74. 74.
    Kumar A, Sinha S (2007) Intravitreal bevacizumab (Avastin) treatment of diffuse diabetic macular edema in an Indian population. Indian J Ophthalmol 55:451–455CrossRefPubMedGoogle Scholar
  75. 75.
    Velez-Montoya R, Fromow-Guerra J, Burgos O, Landers MB 3rd, Morales-Catón V, Quiroz-Mercado H (2009) The effect of unilateral intravitreal bevacizumab (avastin), in the treatment of diffuse bilateral diabetic macular edema: a pilot study. Retina 29:20–26CrossRefPubMedGoogle Scholar
  76. 76.
    Early Treatment Diabetic Retinopathy Study Research Group (1995) Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol 113:1144–1155Google Scholar
  77. 77.
    Bonini-Filho M, Costa RA, Calucci D, Jorge R, Melo LA Jr, Scott IU (2009) Intravitreal bevacizumab for diabetic macular edema associated with severe capillary loss: one-year results of a pilot study. Am J Ophthalmol 147:1022–1030CrossRefPubMedGoogle Scholar
  78. 78.
    Mirshahi A, Roohipoor R, Lashay A, Mohammadi SF, Abdoallahi A, Faghihi H (2008) Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol 18:263–269PubMedGoogle Scholar
  79. 79.
    Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG (2008) Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 92:213–216CrossRefPubMedGoogle Scholar
  80. 80.
    Moradian S, Ahmadieh H, Malihi M, Soheilian M, Dehghan MH, Azarmina M (2008) Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 246:1699–1705CrossRefPubMedGoogle Scholar
  81. 81.
    Cho WB, Oh SB, Moon JW, Kim HC (2009) Panretinal photocoagulation combined with intravitreal bevacizumab in high-risk proliferative diabetic retinopathy. Retina 29:516–522CrossRefPubMedGoogle Scholar
  82. 82.
    Tonello M, Costa RA, Almeida FP, Barbosa JC, Scott IU, Jorge R (2008) Panretinal photocoagulation versus PRP plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy (IBeHi study). Acta Ophthalmol 86:385–389CrossRefPubMedGoogle Scholar
  83. 83.
    Jorge R, Costa RA, Calucci D, Cintra LP, Scott IU (2006) Intravitreal bevacizumab (Avastin) for persistent new vessels in diabetic retinopathy (IBEPE study). Retina 26:1006–1013CrossRefPubMedGoogle Scholar
  84. 84.
    Yang CM, Yeh PT, Yang CH, Chen MS (2008) Bevacizumab pretreatment and long-acting gas infusion on vitreous clear-up after diabetic vitrectomy. Am J Ophthalmol 146:211–217CrossRefPubMedGoogle Scholar
  85. 85.
    Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ, Wendel R, Patel A (2006) Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 113:1695–1705CrossRefPubMedGoogle Scholar
  86. 86.
    Ahmadieh H, Shoeibi N, Entezari M, Monshizadeh R (2009) Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients a randomized clinical trial. Ophthalmology. doi:10.1016/j.ophtha.2009.07.001 Google Scholar
  87. 87.
    Rizzo S, Genovesi-Ebert F, Di Bartolo E, Vento A, Miniaci S, Williams G (2008) Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol 246:837–842CrossRefPubMedGoogle Scholar
  88. 88.
    Yeh PT, Yang CM, Lin YC, Chen MS, Yang CH (2009) Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina 29:768–774CrossRefPubMedGoogle Scholar
  89. 89.
    Da R Lucena D, Ribeiro JA, Costa RA (2009) Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study). Br J Ophthalmol 93:688–691CrossRefPubMedGoogle Scholar
  90. 90.
    Romano MR, Gibran SK, Marticorena J, Wong D, Heimann H (2008) Can a preoperative bevacizumab injection prevent recurrent postvitrectomy diabetic vitreous haemorrhage? Eye 23:1698–1701CrossRefPubMedGoogle Scholar
  91. 91.
    Cheema RA, Al-Mubarak MM, Amin YM, Cheema MA (2009) Role of combined cataract surgery and intravitreal bevacizumab injection in preventing progression of diabetic retinopathy: prospective randomized study. J Cataract Refract Surg 35:18–25CrossRefPubMedGoogle Scholar
  92. 92.
    Takamura Y, Kubo E, Akagi Y (2009) Analysis of the effect of intravitreal bevacizumab injection on diabetic macular edema after cataract surgery. Ophthalmology 116:1151–1157CrossRefPubMedGoogle Scholar
  93. 93.
    Lanzagorta-Aresti A, Palacios-Pozo E, Menezo Rozalen JL, Navea-Tejerina A (2009) Prevention of vision loss after cataract surgery in diabetic macular edema with intravitreal bevacizumab: a pilot study. Retina 29:530–535CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Cole Eye InstituteCleveland ClinicClevelandUSA

Personalised recommendations