A Review of Efficacy and Safety of Anti-Vascular Endothelial Growth Factor (Anti-VEGF) Therapies Compared to Conventional Treatment in Patients with Retinal Vein Occlusion (RVO)

Phalguni Deswal

Department of Applied Medicine, University of Chester, Chester, United Kingdom. 

Abstract

Anti-VEGF therapies, which are mainly used in cancer treatment, are now being used for the treatment of retinal vein occlusion (RVO). With diabetes being the major risk factor for developing RVO, which can cause permanent blindness. This systematic review was undertaken to assess the efficacy and safety of newer Anti-VEGF therapy compared to conventional laser photocoagulation and intra-vitreal steroid therapy for RVO, from the data reported in randomized controlled clinical trials (RCTs). A search for relevant studies was conducted in the Cochrane Library, ClinicalTrials.gov, MEDLINE, PubMed, and Web of Science using the search term. “Retinal vein occlusion AND (anti VEGF OR ranibizumab OR bevacizumab OR aflibercept OR Lucentis OR Avastin OR VEGF trap OR eylea) AND (laser OR corticosteroid* OR dexamethasone OR triamcinolone)”. Out of the initial 2,236 trials, 12 were chosen to be reviewed according to inclusion and exclusion criteria. Anti-VEGF reports better visual acuity outcomes compared to intra-vitreal corticosteroids and laser photocoagulation. It also showed a greater reduction in CRT than other therapeutic options. Anti-VEGF’s safety profile was comparable to other therapies. Anti-VEGF drugs show better efficacy in patients with RVO as compared to conventional treatments. Nevertheless, the long-term safety and treatment cost need to be considered while prescribing the treatment.  

Keywords: Diabetes mellitus; Intra-vitreal corticosteroids; Laser photocoagulation; BRVO; CRVO

References

1. Klein, R., Moss, S.E., Meuer, S.M. & Klein, B.E.K. (2008) ‘The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam eye study’, Archives of Ophthalmology, 126, pp. 513–518.
2. Cho, B.J., Bae, S.H., Park, S.M., Shin, M.C., Park, I.W., Kim, H.K. et al. (2019) ‘Comparison of systemic conditions at diagnosis between central retinal vein occlusion and branch retinal vein occlusion’, PLoS One, 14(8), p. e0220880.
3. WHO (2018) Priority eye diseases. World Health Organization Available at: http://www.who.int/blindness/causes/priority/en/ (Accessed: 21 September 2020).
4. Zhou, J.Q., Xu, L., Wang, S., Wang, Y.X., You, Q.S., Tu, Y. et al. (2013) ‘The 10-year incidence and risk factors of retinal vein occlusion: the Beijing eye study’, Ophthalmology, 120, pp. 803–808. doi:10.1016/j.ophtha.2012.09.033.
5. Kolar, P. (2014) ‘Risk factors for central and branch retinal vein occlusion: a meta-analysis of published clinical data’, Journal of Ophthalmology, 2014, p. 724780.
6. Hayreh, S.S. (2014) ‘Ocular vascular occlusive disorders: natural history of visual outcome’, Progress in Retinal and Eye Research, 41, pp. 1–25. doi:10.1016/j.preteyeres.2014.04.001.
7. Qian, T., Zhao, M., Wan, Y., Li, M. & Xu, X. (2018) ‘Comparison of the efficacy and safety of drug therapies for macular edema secondary to central retinal vein occlusion’, BMJ Open, 8(12), p. e022700.
8. Braithwaite, T., Nanji, A.A., Lindsley, K. & Greenberg, P.B. (2014) ‘Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion’, Cochrane Database of Systematic Reviews, 2014(5), CD007325. doi:10.1002/14651858.CD007325.pub3.
9. Rehak, J. & Rehak, M. (2008) ‘Branch retinal vein occlusion: Pathogenesis, visual prognosis, and treatment modalities’, Current Eye Research, 33, pp. 111–131. doi:10.1080/02713680701851902.
10. Holz, F.G., Roider, J., Ogura, Y., Korobelnik, J.F., Simader, C., Groetzbach, G. et al. (2013) ‘VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-Month results of the phase III GALILEO study’, British Journal of Ophthalmology, 97, pp. 278–284. doi:10.1136/bjophthalmol-2012-301504.
11. Schmucker, C., Ehlken, C., Agostini, H.T., Antes, G., Ruecker, G., Lelgemann, M. et al. (2012) ‘A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus gold-standard’, PLoS ONE, 7(8), p. e42701.
12. Pielen, A., Feltgen, N., Isserstedt, C., Callizo, J., Junker, B. and Schmucker, C. (2013) ‘Efficacy and safety of intravitreal therapy in macular edema due to branch and central retinal vein occlusion: a systematic review’, PLoS ONE, 8(10), p. e78538.
13. Brown, D.M., Campochiaro, P.A., Bhisitkul, R.B., Ho, A.C., Gray, S., Saroj, N. et al. (2011) ‘Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study’, Ophthalmology, 118, pp. 1594–1602. doi:10.1016/j.ophtha.2011.02.022.
14. Schmucker, C., Loke, Y.K., Ehlken, C., Agostini, H.T., Hansen, L.L., Antes, G. et al. (2011) ‘Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a safety review’, British Journal of Ophthalmology, 95, pp. 308–317. doi:10.1136/bjo.2009.178574.
15. Jadad, A.R., Moore, R.A., Carroll, D., Jenkinson, C., Reynolds, D.J.M., Gavaghan, D.J. et al. (1996) ‘Assessing the quality of reports of randomized clinical trials: is blinding necessary?’, Controlled Clinical Trials, 17, pp. 1–12. doi:10.1016/0197-2456(95)00134-4.
16. Mylonas, G., Schranz, M., Scholda, C., Karst, S., Reiter, G., Baumann, L. et al. (2020) ‘Response of retinal sensitivity to intravitreal anti-angiogenic bevacizumab and triamcinolone acetonide for patients with diabetic macular edema over one year’, Current Eye Research, 45, pp. 1107–1113.
17. Russo, V., Barone, A., Conte, E., Prascina, F., Stella, A. and Noci, N.D. (2009) ‘Bevacizumab compared with macular laser grid photocoagulation for cystoid macular edema in branch retinal vein occlusion’, Retina, 29, pp. 511–515.
18. Campochiaro, P.A., Bhisitkul, R.B., Shapiro, H. and Rubio, R.G. (2013) ‘Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion’, Ophthalmology, 120, pp. 795–802. doi:10.1016/j.ophtha.2012.09.032.
19. Cao, W., Cui, H. and Biskup, E. (2019) ‘Combination of grid laser photocoagulation and a single intravitreal ranibizumab as an efficient and cost-effective treatment option for macular edema secondary to branch retinal vein occlusion’, Rejuvenation Research, 22, pp. 335–341. doi:10.1089/rej.2018.2141.
20. Guignier, B., Subilia-Guignier, A., Fournier, I., Ballonzoli, L., Speeg-Schatz, C. and Gaucher, D. (2013) ‘Prospective pilot study: efficacy of intravitreal dexamethasone and bevacizumab injections in the treatment of macular oedema associated with branch retinal vein occlusion’, Ophthalmologica, 230, pp. 43–49.
21. Yumusak, E., Buyuktortop, N. and Ornek, K. (2015) ‘Early results of dexamethasone implant, ranibizumab, and triamcinolone in macular edema due to branch retinal vein occlusion’, European Journal of Ophthalmology, 26, pp. 54–59.
22. Kaldırım, H.E. and Yazgan, S. (2018) ‘A comparison of three different intravitreal treatment modalities of macular edema due to branch retinal vein occlusion’, International Ophthalmology, 38, pp. 1549–1558.
23. Chatziralli, I., Theodossiadis, G., Kabanarou, S.A., Parikakis, E., Xirou, T., Mitropoulos, P. et al. (2017) ‘Ranibizumab versus dexamethasone implant for central retinal vein occlusion: the RANIDEX study’, Graefe’s Archive for Clinical and Experimental Ophthalmology, 255, pp. 1899–1905.
24. Hattenbach, L.O., Feltgen, N., Bertelmann, T., Schmitz-Valckenberg, S., Berk, H., Eter, N. et al. (2018) ‘Head-to-head comparison of ranibizumab PRN versus single-dose dexamethasone for branch retinal vein occlusion (COMRADE-B)’, Acta Ophthalmologica, 96, pp. e10–e18. doi:10.1111/aos.13381.
25. Brown, D.M., Schmidt-Erfurth, U., Do, D.V., Holz, F.G., Boyer, D.S., Midena, E. et al. (2015) ‘Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies’, Ophthalmology, 122, pp. 2044–2052.
26. Lucatto, L.F.A., Magalhães-Junior, O., Prazeres, J.M.B., Ferreira, A.M., Oliveira, R.A., Moraes, N.S. et al. (2017) ‘Incidence of anterior segment neovascularization during intravitreal treatment for macular edema secondary to central retinal vein occlusion’, Arquivos Brasileiros de Oftalmologia, 80, pp. 97–103. doi:10.5935/0004-2749.20170024.
27. Higashiyama, T., Sawada, O., Kakinoki, M., Sawada, T., Kawamura, H. and Ohji, M. (2013) ‘Prospective comparisons of intravitreal injections of triamcinolone acetonide and bevacizumab for macular oedema due to branch retinal vein occlusion’, Acta Ophthalmologica, 91, pp. 318–324.
28. Regeneron Pharmaceuticals (2011) Study of intravitreal aflibercept injection (IAI; Eylea®; BAY86-5321) in patients with diabetic macular edema. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01363440 (Accessed: 21 September 2020).
29. Ramezani, A., Esfandiari, H., Entezari, M., Moradian, S., Soheilian, M., Dehsarvi, B. et al. (2012) ‘Three intravitreal bevacizumab versus two intravitreal triamcinolone injections in recent-onset branch retinal vein occlusion’, Graefe’s Archive for Clinical and Experimental Ophthalmology, 250, pp. 1149–1160. doi:10.1007/s00417-012-1941-8.
30. Pielen, A., Mirshahi, A., Feltgen, N., Lorenz, K., Korb, C., Junker, B. et al. (2015) ‘Ranibizumab for branch retinal vein occlusion associated macular edema study (RABAMES): Six-month results of a prospective randomized clinical trial’, Acta Ophthalmologica, 93, pp. e29–e37. doi:10.1111/aos.12488.
31. NCT01396083 (2011) Efficacy and safety of ranibizumab intravitreal injections versus dexamethasone intravitreal implant in patients with central retinal vein occlusion (CRVO). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01396083 (Accessed: 21 September 2020).
32. Bandello, F., Augustin, A., Tufail, A. and Leaback, R. (2018) ‘A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion’, European Journal of Ophthalmology, 28, pp. 697–705.
33. NCT01521559 (2014) Study to assess the clinical efficacy and safety of intravitreal aflibercept injection (IAI; EYLEA®; BAY86-5321) in patients with branch retinal vein occlusion (BRVO) (VIBRANT). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01521559 (Accessed: 21 September 2020).
34. Tadayoni, R., Waldstein, S.M., Boscia, F., Gerding, H., Gekkieva, M., Barnes, E. et al. (2017) ‘Sustained benefits of ranibizumab with or without laser in branch retinal vein occlusion: 24-month results of the BRIGHTER study’, Ophthalmology, Elsevier Inc., pp. 1778–1787.
35. Chang-Lin, J.E., Attar, M., Acheampong, A.A., Robinson, M.R., Whitcup, S.M., Kuppermann, B.D. et al. (2011) ‘Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant’, Investigative Ophthalmology & Visual Science, 52, pp. 80–86. doi:10.1167/iovs.10-5285.
36. Ji, K., Zhang, Q., Tian, M. and Xing, Y. (2019) ‘Comparison of dexamethasone intravitreal implant with intravitreal anti-VEGF injections for the treatment of macular edema secondary to branch retinal vein occlusion: a meta-analysis’, Medicine (Baltimore), 98, p. e15798. doi:10.1097/MD.0000000000015798.
37. Yong, M., Zhou, M. and Deng, G. (2015) ‘Photodynamic therapy versus anti-vascular endothelial growth factor agents for polypoidal choroidal vasculopathy: a meta-analysis’, BMC Ophthalmology, 15, p. 82. doi:10.1186/s12886-015-0064-5.
38. Eter, N., Mohr, A., Wachtlin, J., Feltgen, N., Shirlaw, A., Leaback, R. et al. (2017) ‘Dexamethasone intravitreal implant in retinal vein occlusion: real-life data from a prospective, multicenter clinical trial’, Graefe’s Archive for Clinical and Experimental Ophthalmology, 255, pp. 77–87. doi:10.1007/s00417-016-3431-x.
39. Fogli, S., Del Re, M., Rofi, E., Posarelli, C., Figus, M. and Danesi, R. (2018) ‘Clinical pharmacology of intravitreal anti-VEGF drugs’, Eye (Basingstoke), 32, pp. 1010–1020. doi:10.1038/s41433-018-0021-7.
40. Chen, Z. and Ai, D. (2016) ‘Cardiotoxicity associated with targeted cancer therapies’, Molecular and Clinical Oncology, 4, pp. 675–681.
41. Gu, X., Yu, X., Song, S. and Dai, H. (2017) ‘Intravitreal dexamethasone implant versus intravitreal ranibizumab for the treatment of macular edema secondary to retinal vein occlusion in a Chinese population’, Ophthalmic Research, 58, pp. 8–14. doi:10.1159/000458534.
42. Hirami, Y., Tsujikawa, A., Otani, A., Yodoi, Y., Aikawa, H., Mandai, M. et al. (2007) ‘Hemorrhagic complications after photodynamic therapy for polypoidal choroidal vasculopathy’, Retina, 27, pp. 335–341. doi:10.1097/01.iae.0000233647.78726.46.
43. Li, X., Wang, N., Liang, X., Xu, G., Li, X.Y., Jiao, J. et al. (2018) ‘Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study’, Graefe’s Archive for Clinical and Experimental Ophthalmology, 256, pp. 59–69. doi:10.1007/s00417-017-3831-6.