Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy

  • Raffaello di Lauro
  • Pio De Ruggiero
  • Raffaella di Lauro
  • Maria Teresa di Lauro
  • Mario Rosario Romano
Retinal Disorders

Abstract

Background

The purpose of this study is to evaluate the role, the safety and the effectiveness of intravitreal bevacizumab (IVB) injections as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy (PDR).

Design

Case-Control Study

Methods

Randomized controlled trial performed on 72 eyes of 68 patients affected by vitreous haemorrhage (VH) and tractional retinal detachment (TRD), which occurred as a consequence of active proliferative diabetic retinopathy (PDR). We randomly assigned eligible patients in a 1: 1: 1 ratio to receive a sham injection or an intravitreal injection of 1.25 mg of bevacizumab, either 7 or 20 days before the vitrectomy. In order to obtain three homogeneous groups of surgical complexity, we assigned to the following preoperative parameters a score from 0 to 3: a) vitreous haemorrhage, b) prior retinal laser-photocoagulation, c) morphological types of retinal detachment such as focal, hammock, central diffuse, table-top. Complete ophthalmic examinations and color fundus photography were performed at baseline and 1, 6, 12, and 24 weeks after the surgery.

Main outcome measures

Intraoperative management, safety, efficacy of IVB at different time injection as an adjunct to vitrectomy in the management of severe PDR

Results

Group A (sham injection): intraoperative bleeding occurred in 19 cases (79.1%), the use of endodiathermy was necessary in 13 patients (54.1%), relaxing retinotomy was performed on one patient (4.1%), and in four cases (16.6%) iatrogenic retinal breaks occurred. The surgical mean time was 84 minutes (SD 12 minutes). Group B (bevacizumab administered 7 days before vitrectomy): intraoperative bleeding occurred in two cases (8.3%) and the use of endodiathermy was necessary in two patients (8.3%). No iatrogenic breaks occurred during the surgery. The surgical mean time was 65 minutes (SD 18 minutes). Group C (bevacizumab administered 20 days before vitrectomy): intraoperative bleeding occurred in three cases (12.5%), the use of endodiathermy was necessary in three patients (1.5%), and an iatrogenic break occurred in one patient (4.1%) while the delamination of fibrovascular tissue was being performed. The surgical mean time was 69 minutes (SD 21 minutes). The average difference in the surgical time was statistically significant between group A and group B (p = 0.025), and between group A and group C (p = 0.031). At the end of the surgery, the retina was completely attached in all eyes. At the 6-month follow-up, we observed the development of tractional retinal detachment (TRD) in one out of 24 patients from group C (4%).

Conclusions

A preoperative intravitreal injection of bevacizumab may represent a new strategy for the surgical treatment of severe PDR by reducing retinal and iris neovascularization: this would make surgery much easier and safer, thus improving the anatomical and functional prognosis. According to our study, the best surgical results are achieved performing the IVB 7 days preoperatively.

Keywords

Intravitreal bevacizumab Proliferative diabetic retinopathy Tractional retinal detachment 

References

  1. 1.
    Avanta A, Algvere PV, Berglin L, Seregard S (1996) Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 37:1929–1934Google Scholar
  2. 2.
    Kliffen M, Sharma HS, Mooy CM, Kerkvliet S, de Jong PT (1997) Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 81:154–162CrossRefPubMedGoogle Scholar
  3. 3.
    Otani A, Taxagi H, Oh H, Koyama S, Ogura Y, Matumura M, Honda Y (2002) Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes. Microvasc Res 64:162–169CrossRefPubMedGoogle Scholar
  4. 4.
    Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450PubMedGoogle Scholar
  5. 5.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (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
  6. 6.
    Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP (1996) Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in non humane primate. Arch Ophthalmol 114:964–970PubMedGoogle Scholar
  7. 7.
    Tripathi RC, Li J, Tripathi BJ, Chalam KV, Adamis AP (1998) Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 105:232–237CrossRefPubMedGoogle Scholar
  8. 8.
    Lashkari K, Hirose T, Yazdany J, McMeel JW, Kazlauskas A, Rahimi N (2000) Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Am J Pathol 156:1337–1334PubMedGoogle Scholar
  9. 9.
    Adamis AP, Shima DT (2005) The role of vascular endothelial growth factor in ocular health and disease. Retina 25:111–118CrossRefPubMedGoogle Scholar
  10. 10.
    Ferrara N (2002) Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 29:10–14PubMedGoogle Scholar
  11. 11.
    Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF- receptor chimeric proteins. Proc Natl Acad Sci USA 92:10457–10461CrossRefPubMedGoogle Scholar
  12. 12.
    Eyetech Study Group (2003) Antivascular endothelial growth factor therapy for subfoveal choroideal neovascularization secondary to age-related macular degeneration. Phase II study results. Am J Ophthalmol 110:979–986Google Scholar
  13. 13.
    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
  14. 14.
    Ng EW, Svima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP (2006) Pegaptanib, a targeted anti-VEGF optamer for ocular vascular disease. Nat Rev Drug Discov 5:123–132CrossRefPubMedGoogle Scholar
  15. 15.
    VEGF inhibition study in ocular neovascularization (V.I.S.I.O.N.) clinical trial group (2006) Pegaptanib sodium for neovascular age-related macular degeneration. two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophtalmology 113:992–1001CrossRefGoogle Scholar
  16. 16.
    VEGF inhibition study in ocular neovascularization (V.I.S.I.O.N.) clinical trial group (2006) Two-year efficacy results of the two randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 113:1508–1525Google Scholar
  17. 17.
    Rosenfeld PJ, Schwartz SD, Blumenkranz MS, Miller JW, Haller JA, Reimann JD, Greene WL, Shams N (2005) Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 112:1048–1053CrossRefPubMedGoogle Scholar
  18. 18.
    Rosenfeld PJ, Hein JS, Hantsbarger G, Shams N (2006) Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology 113:631–632CrossRefGoogle Scholar
  19. 19.
    Ferrara N, D’amico L, Shams N, Lowman M, Kim R (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26:859–870CrossRefPubMedGoogle Scholar
  20. 20.
    Heier JS, Antoszyk AN, Pavak PR, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N (2006) Ranibizumab for treatment of neovascular age-related macular degeneration. Ophthalmology 113:633–642CrossRefPubMedGoogle Scholar
  21. 21.
    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 335:1419–1431CrossRefGoogle Scholar
  22. 22.
    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 335:1432–1444CrossRefGoogle Scholar
  23. 23.
    Ferrara N, Millan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature 3:391–400CrossRefGoogle Scholar
  24. 24.
    Marshall J (2005) The role of bevacizumab as first-line therapy for colon cancer. Semin Oncol 32:543–547CrossRefGoogle Scholar
  25. 25.
    Beer PM, Wong SJ, Hammad AM, Falk NS, O’Malley MR, Khan S (2006) Vitreous level of unbound bevacizumab and unbound vascular endothelial growth factor in two patients. Retina 26:871–876CrossRefPubMedGoogle Scholar
  26. 26.
    Shahar JS, Avery RL, Heilweil G, Barak A, Zemel E, Lewis GP, Johnson PT, Fisher SK, Perlman I, Loewenstein A (2006) Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab. Retina 26:262–269CrossRefPubMedGoogle Scholar
  27. 27.
    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
  28. 28.
    Laud K, Spaide RF, Freund KB, Slakter J, Klancnik JM Jr (2006) Treatment of choroidal neovascularization in pathologic myopia with intravitreal bevacizumab. Retina 26:960–963CrossRefPubMedGoogle Scholar
  29. 29.
    Tewari A, Dhalla MS, Apte RS (2006) Intravitreal bevacizumab for treatment of choroidal neovascularization in pathologic myopia. Retina 26:1093–1094CrossRefPubMedGoogle Scholar
  30. 30.
    Nguyen SD, Sham S, Tatlipinar S, Do DV, Anden EV, Campochiaro PA (2005) Bevacizumab suppresses choroidal neovascularization caused by pathological myopia. Br J Ophthalmol 89:1368–1370CrossRefPubMedGoogle Scholar
  31. 31.
    Spaide RF, Fisher YL (2006) Intravitreal bevacizumab (Avastin) treatment of proliferative retinopathy complicated by vitreous hemorrhage. Retina 26:275–278CrossRefPubMedGoogle Scholar
  32. 32.
    Jorge R, Costa RA, Calioli D, Cintra LP, Scott IU (2006) Intravitreal bevacizumab (avastin) for persistent new vessels in diabetic retinopathy (IBEPE study). Retina 26:1006–1013CrossRefPubMedGoogle Scholar
  33. 33.
    Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, Berrocal MH, Solis-Vivanco A, Farah ME, Pan-American Collaborative Retina Study Group (2007) Primary intravitreal bevacizumab (avastin) for diabetic macular oedema. results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 114:743–750CrossRefPubMedGoogle Scholar
  34. 34.
    di Lauro R, di Lauro R, de Ruggiero P, di Lauro MT, D’Aloia A (2007) Bevacizumab (Avastin) preoperatorio nel trattamento chirurgico della retinopatia diabetica proliferante. Notiziario Soc Oftalmol It 38:39–45Google Scholar
  35. 35.
    Iturralde D, Spaide RF, Meyerle CB, Klancnik JM, Yannuzzi LA, Fisher YL, Sorenson J, Slakter JS, Freund KB, Cooney M, Fine HF (2006) Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 26:279–284CrossRefPubMedGoogle Scholar
  36. 36.
    Pai SA, Shetty R, Vijayan PB, Venkatasubramaniam G, Yadav NK, Shetty BK, Babu RB, Narayana KM (2007) Clinical, anatomic and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion. Am J Ophthalmol 143:601–606CrossRefPubMedGoogle Scholar
  37. 37.
    Rabena MD, Pieramici DJ, Castellarin AA, Nasir MA, Avery RL (2007) Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 27:419–425CrossRefPubMedGoogle Scholar
  38. 38.
    Davidorf FM, Mouser JG, Derick RJ (2006) Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina 26:354–356CrossRefPubMedGoogle Scholar
  39. 39.
    Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf-Schnurrbursch U, Wolf S, Sarra GM (2006) Bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 142:1054–1056CrossRefPubMedGoogle Scholar
  40. 40.
    Costagliola C, Cipollone U, Rinaldi M, della Corte M, Semeraro F, Romano MR (2008) Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 cases throughout 12-month follow-up. Br J Clin Pharmacol 66:667–673PubMedGoogle Scholar
  41. 41.
    Mason JO, Albert MA Jr, Vail R (2006) Intravitreal bevacizumab (Avastin) for refractory pseudophakic cystoid macular edema. Retina 26:356–360CrossRefPubMedGoogle Scholar
  42. 42.
    Quiroz-Mercado H, Ustariz-Gonzales O, Martinez-Castellanos MA, Covarrubias P, Dominguez F, Sanchez-Huerta V (2007) Our experience after 1765 intravitreal injections of bevacizumab: the importance of being part of a developing story. Sem Ophthalmol 22:109–125CrossRefGoogle Scholar
  43. 43.
    Travassos A, Teixeira S, Ferreira P, Regadas I, Travassos AS, Esperancinha FE, Prieto I, Pires G, van Velze R, Valido A, Machado Mdo C (2007) Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers 38:233–237Google Scholar
  44. 44.
    Yeoh J, Williams C, Allen P, Buttery R, Chiu D, Clark B, Essex R, McCombe M, Qureshi S, Campbell WG (2008) Avastin as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series. Clin Experiment Ophthalmol 36:449–454PubMedGoogle Scholar
  45. 45.
    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
  46. 46.
    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
  47. 47.
    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 113:1695CrossRefPubMedGoogle Scholar
  48. 48.
    Krohne TU, Eter N, Holz FG, Meyer CH (2008) Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 146:508–512CrossRefPubMedGoogle Scholar
  49. 49.
    Warner T (1999) Relationships between the endothelin and nitric oxide pathways. Clin Exp Pharmacol Physiol 26:247–252CrossRefPubMedGoogle Scholar
  50. 50.
    Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331–335PubMedGoogle Scholar
  51. 51.
    Avery RL, Pieramici DJ, Rabena MD, Rabena MD, Castellarin AA, Nasir MA, Giust MJ, Wendel R, Patel A (2006) Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 113:363–372CrossRefPubMedGoogle Scholar
  52. 52.
    Spaide RF, Laud K, Fine MF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, Sorenson J, Slakter J, Fisher YL, Cooney MJ (2006) Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 26:383–390CrossRefPubMedGoogle Scholar
  53. 53.
    Chen E, Park CH (2006) Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 26:699–700CrossRefPubMedGoogle Scholar
  54. 54.
    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

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Raffaello di Lauro
    • 1
  • Pio De Ruggiero
    • 1
  • Raffaella di Lauro
    • 1
  • Maria Teresa di Lauro
    • 1
  • Mario Rosario Romano
    • 2
    • 3
  1. 1.Department of Ophthalmology, Hospital C.T.O. of NaplesNaplesItaly
  2. 2.Department of Ophthalmology, Istituto Clinico HumanitasMilanItaly
  3. 3.Department of OphthalmologyUniversity of MoliseCampobassoItaly

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