Efficacy of different anti-VEGF drugs in the treatment of macular edema secondary to retinal vein occlusion: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

XIONG Xin , LEI Yingqing , TIAN Min , WANG Yong , TANG Min ,  LV Hongbin

Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou 620302, P.R.China;

Corresponding author：

LV Hongbin, Email: oculistlvhongbin@163.com

Keywords：

Anti-VEGF; Bevacizumab; Ranibizumab; Aflibercept; Retinal vein occlusion; Macular edema; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202106037

Video：

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Objective To systematically review the efficacy of intravitreal injection of anti-vascular endothelial growth factors (anti-VEGF) on macular edema (ME) secondary to retinal vein occlusion (RVO). Methods Databases including PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data and VIP were electronically searched to identify randomized controlled trials on different anti-VEGF drugs in the treatment of RVO-ME from inception to September 17^th 2021. Two reviewers independently screened literature, extracted data, and assessed the risk bias of the included studies. Meta-analysis was then performed using RevMan 5.3 software. Results A total of 11 RCTs were included. Data from these studies included 2 436 eyes, of which 1 682 involved central retinal vein occlusion and 754 involved branch retinal vein occlusion. The results of meta-analysis showed that at 6 months of follow-up, anti-VEGF drug treatment of RVO-ME improved corrected visual acuity (MD=14.97, 95%CI 10.09 to 19.86, P<0.000 01) and reduced central retinal thickness (MD= −218.21, 95%CI −295.56 to −140.86, P<0.000 01) compared with control groups. At 12 months, anti-VEGF treatment of RVO-ME showed better improvement in corrected visual acuity compared with control group (MD=5.70, 95%CI 3.90 to 7.50, P<0.000 01). No statistically differences were observed in the improvements corrected visual acuity with different anti-VEGF drugs. However, for central retinal vein occlusion, different anti-VEGF drugs improved the central retinal thickness including aflibercept vs. bevacizumab (MD=−46.79, 95%CI −83.12 to −10.46, P=0.01), and bevacizumab vs. ranibizumab (MD=76.03, 95%CI 30.76 to 121.30, P=0.001) had significant differences. Conclusions The current evidence shows that anti-VEGF drugs can improve vision and reduce macular edema in the treatment of RVO-ME. Bevacizumab may be an effective alternative to ranibizumab or aflibercept. Existing evidence cannot determine differences between the improvement of best-corrected vision and the reduction of central retinal thickness during the long-term treatment of RVO, which requires to be verified by further research.

Citation： XIONG Xin, LEI Yingqing, TIAN Min, WANG Yong, TANG Min, LV Hongbin. Efficacy of different anti-VEGF drugs in the treatment of macular edema secondary to retinal vein occlusion: a systematic review. Chinese Journal of Evidence-Based Medicine, 2021, 21(12): 1416-1423. doi: 10.7507/1672-2531.202106037 Copy

1.	Brand CS. Management of retinal vascular diseases: a patient-centric approach. Eye (Lond), 2012, 26(Suppl 2): S1-16.
2.	Tah V, Orlans HO, Hyer J, et al. Anti-VEGF therapy and the retina: an update. J Ophthalmol, 2015, 2015: 627674.
3.	Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion-consensus document. Ophthalmologica, 2011, 226(1): 4-28.
4.	Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology, 2010, 117(2): 313-319.
5.	Aref AA, Scott IU. Management of macular edema secondary to central retinal vein occlusion: an evidence-based. Adv Ther, 2011, 28(1): 40-50.
6.	Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol, 2010, 4: 809-816.
7.	Epstein DL, Algvere PV, von Wendt G, et al. Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study. Ophthalmology, 2012, 119(6): 1184-1189.
8.	Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina, 2006, 26(8): 859-870.
9.	Roth DB, Cukras C, Radhakrishnan R, et al. Intravitreal triamcinolone acetonide injections in the treatment of retinal vein occlusions. Ophthalmic Surg Lasers Imaging, 2008, 39(6): 446-454.
10.	Spooner K, Hong T, Fraser-Bell S, et al. Current outcomes of anti-VEGF therapy in the treatment of macular edema secondary to central retinal vein occlusions: a systematic review and meta-analysis. Asia Pac J Ophthalmol (Phila), 2019, 8(3): 236-246.
11.	Ogura Y, Roider J, Korobelnik JF, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol, 2014, 158(5): 1032-1038.
12.	Edington M, Connolly J, Chong NV. Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes. Expert Opin Drug Metab Toxicol, 2017, 13(12): 1217-1224.
13.	Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology, 2010, 117(6): 1124-1133.
14.	Pai SA, Shetty R, Vijayan PB, et al. Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion. Am J Ophthalmol, 2007, 143(4): 601-606.
15.	Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther, 2008, 16(4): 791-799.
16.	Sassa Y, Hata Y. Antiangiogenic drugs in the management of ocular diseases: focus on antivascular endothelial growth factor. Clin Ophthalmol, 2010, 4: 275-283.
17.	Braithwaite T, Nanji AA, Lindsley K, et al. Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. Cochrane Database Syst Rev, 2014, (5): CD007325.
18.	Ehlers JP, Kim SJ, Yeh S, et al. Therapies for macular edema associated with branch retinal vein occlusion: a report by the American academy of ophthalmology. Ophthalmology, 2017, 124(9): 1412-1423.
19.	Schauwvlieghe AM, Dijkman G, Hooymans JM, et al. Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD Study. PLoS One, 2016, 11(5): 1897-1908.
20.	CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med, 2011, 364(20): 1897-908.
21.	Vader MJC, Schauwvlieghe AME, Verbraak FD, et al. Comparing the efficacy of bevacizumab and ranibizumab in patients with retinal vein occlusion: the bevacizumab to ranibizumab in retinal vein occlusions (BRVO) study, a randomized trial. Ophthalmol Retina, 2020, 4(6): 576-587.
22.	Wei W, Weisberger A, Zhu L, et al. Efficacy and safety of ranibizumab in Asian patients with branch retinal vein occlusion: results from the randomized BLOSSOM study. Ophthalmol Retina, 2020, 4(1): 57-66.
23.	Hykin P, Prevost AT, Vasconcelos JC, et al. Clinical effectiveness of intravitreal therapy with ranibizumab vs aflibercept vs bevacizumab for macular edema secondary to central retinal vein occlusion: a randomized clinical trial. JAMA Ophthalmol, 2019, 137(11): 1256-1264.
24.	Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina, 2010, 30(7): 1046-1050.
25.	Clarke M, Horton R. Bringing it all together: Lancet-Cochrane collaborate on systematic reviews. Lancet, 2001, 357(9270): 1728.
26.	Narayanan R, Panchal B, Das T, et al. A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J Ophthalmol, 2015, 99(7): 954-959.
27.	Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology, 2011, 118(8): 1594-1602.
28.	Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology, 2010, 117(6): 1102-1112.
29.	Scott IU, VanVeldhuisen PC, Ip MS, et al. Baseline factors associated with 6-month visual acuity and retinal thickness outcomes in patients with macular edema secondary to central retinal vein occlusion or hemiretinal vein occlusion: SCORE2 study report 4. JAMA Ophthalmol, 2017, 135(6): 639-649.
30.	Scott IU, VanVeldhuisen PC, Ip MS, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial. JAMA, 2017, 317(20): 2072-2087.
31.	Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology, 2014, 121(1): 202-208.
32.	Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol, 2013, 97(3): 278-284.
33.	Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology, 2014, 121(7): 1414-1420.
34.	Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol, 2013, 155(3): 429-437.
35.	Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology, 2012, 119(5): 1024-1032.
36.	Epstein DL, Algvere PV, von Wendt G, et al. Benefit from bevacizumab for macular edema in central retinal vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology, 2012, 119(12): 2587-2591.
37.	Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology, 2011, 118(10): 2041-2049.
38.	Kinge B, Stordahl PB, Forsaa V, et al. Efficacy of ranibizumab in patients with macular edema secondary to central retinal vein occlusion: results from the sham-controlled ROCC study. Am J Ophthalmol, 2010, 150(3): 310-314.
39.	Strauss O. The retinal pigment epithelium in visual function. Physiol Rev, 2005, 85(3): 845-881.
40.	Lardenoye CW, Probst K, DeLint PJ, et al. Photoreceptor function in eyes with macular edema. Invest Ophthalmol Vis Sci, 2000, 41(12): 4048-4053.
41.	Busch C, Rehak M, Sarvariya C, et al. Long-term visual outcome and its predictors in macular oedema secondary to retinal vein occlusion treated with dexamethasone implant. Br J Ophthalmol, 2019, 103(4): 463-468.
42.	Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol, 2012, 130(9): 1153-1161.
43.	Pichi F, Elbarky AM, Elhamaky TR. Outcome of "treat and monitor" regimen of aflibercept and ranibizumab in macular edema secondary to non-ischemic branch retinal vein occlusion. Int Ophthalmol, 2019, 39(1): 145-153.
44.	Lotfy A, Solaiman KAM, Abdelrahman A, et al. Efficacy and frequency of intarvitreal aflibercept versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina, 2018, 38(9): 1795-1800.
45.	Furukawa TA, Barbui C, Cipriani A, et al. Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol, 2006, 59(1): 7-10.

1. Brand CS. Management of retinal vascular diseases: a patient-centric approach. Eye (Lond), 2012, 26(Suppl 2): S1-16.
2. Tah V, Orlans HO, Hyer J, et al. Anti-VEGF therapy and the retina: an update. J Ophthalmol, 2015, 2015: 627674.
3. Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion-consensus document. Ophthalmologica, 2011, 226(1): 4-28.
4. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology, 2010, 117(2): 313-319.
5. Aref AA, Scott IU. Management of macular edema secondary to central retinal vein occlusion: an evidence-based. Adv Ther, 2011, 28(1): 40-50.
6. Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol, 2010, 4: 809-816.
7. Epstein DL, Algvere PV, von Wendt G, et al. Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study. Ophthalmology, 2012, 119(6): 1184-1189.
8. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina, 2006, 26(8): 859-870.
9. Roth DB, Cukras C, Radhakrishnan R, et al. Intravitreal triamcinolone acetonide injections in the treatment of retinal vein occlusions. Ophthalmic Surg Lasers Imaging, 2008, 39(6): 446-454.
10. Spooner K, Hong T, Fraser-Bell S, et al. Current outcomes of anti-VEGF therapy in the treatment of macular edema secondary to central retinal vein occlusions: a systematic review and meta-analysis. Asia Pac J Ophthalmol (Phila), 2019, 8(3): 236-246.
11. Ogura Y, Roider J, Korobelnik JF, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol, 2014, 158(5): 1032-1038.
12. Edington M, Connolly J, Chong NV. Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes. Expert Opin Drug Metab Toxicol, 2017, 13(12): 1217-1224.
13. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology, 2010, 117(6): 1124-1133.
14. Pai SA, Shetty R, Vijayan PB, et al. Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion. Am J Ophthalmol, 2007, 143(4): 601-606.
15. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther, 2008, 16(4): 791-799.
16. Sassa Y, Hata Y. Antiangiogenic drugs in the management of ocular diseases: focus on antivascular endothelial growth factor. Clin Ophthalmol, 2010, 4: 275-283.
17. Braithwaite T, Nanji AA, Lindsley K, et al. Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. Cochrane Database Syst Rev, 2014, (5): CD007325.
18. Ehlers JP, Kim SJ, Yeh S, et al. Therapies for macular edema associated with branch retinal vein occlusion: a report by the American academy of ophthalmology. Ophthalmology, 2017, 124(9): 1412-1423.
19. Schauwvlieghe AM, Dijkman G, Hooymans JM, et al. Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD Study. PLoS One, 2016, 11(5): 1897-1908.
20. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med, 2011, 364(20): 1897-908.
21. Vader MJC, Schauwvlieghe AME, Verbraak FD, et al. Comparing the efficacy of bevacizumab and ranibizumab in patients with retinal vein occlusion: the bevacizumab to ranibizumab in retinal vein occlusions (BRVO) study, a randomized trial. Ophthalmol Retina, 2020, 4(6): 576-587.
22. Wei W, Weisberger A, Zhu L, et al. Efficacy and safety of ranibizumab in Asian patients with branch retinal vein occlusion: results from the randomized BLOSSOM study. Ophthalmol Retina, 2020, 4(1): 57-66.
23. Hykin P, Prevost AT, Vasconcelos JC, et al. Clinical effectiveness of intravitreal therapy with ranibizumab vs aflibercept vs bevacizumab for macular edema secondary to central retinal vein occlusion: a randomized clinical trial. JAMA Ophthalmol, 2019, 137(11): 1256-1264.
24. Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina, 2010, 30(7): 1046-1050.
25. Clarke M, Horton R. Bringing it all together: Lancet-Cochrane collaborate on systematic reviews. Lancet, 2001, 357(9270): 1728.
26. Narayanan R, Panchal B, Das T, et al. A randomised, double-masked, controlled study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in the treatment of macular oedema due to branch retinal vein occlusion: MARVEL Report No. 1. Br J Ophthalmol, 2015, 99(7): 954-959.
27. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology, 2011, 118(8): 1594-1602.
28. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology, 2010, 117(6): 1102-1112.
29. Scott IU, VanVeldhuisen PC, Ip MS, et al. Baseline factors associated with 6-month visual acuity and retinal thickness outcomes in patients with macular edema secondary to central retinal vein occlusion or hemiretinal vein occlusion: SCORE2 study report 4. JAMA Ophthalmol, 2017, 135(6): 639-649.
30. Scott IU, VanVeldhuisen PC, Ip MS, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial. JAMA, 2017, 317(20): 2072-2087.
31. Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology, 2014, 121(1): 202-208.
32. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol, 2013, 97(3): 278-284.
33. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology, 2014, 121(7): 1414-1420.
34. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol, 2013, 155(3): 429-437.
35. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology, 2012, 119(5): 1024-1032.
36. Epstein DL, Algvere PV, von Wendt G, et al. Benefit from bevacizumab for macular edema in central retinal vein occlusion: twelve-month results of a prospective, randomized study. Ophthalmology, 2012, 119(12): 2587-2591.
37. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology, 2011, 118(10): 2041-2049.
38. Kinge B, Stordahl PB, Forsaa V, et al. Efficacy of ranibizumab in patients with macular edema secondary to central retinal vein occlusion: results from the sham-controlled ROCC study. Am J Ophthalmol, 2010, 150(3): 310-314.
39. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev, 2005, 85(3): 845-881.
40. Lardenoye CW, Probst K, DeLint PJ, et al. Photoreceptor function in eyes with macular edema. Invest Ophthalmol Vis Sci, 2000, 41(12): 4048-4053.
41. Busch C, Rehak M, Sarvariya C, et al. Long-term visual outcome and its predictors in macular oedema secondary to retinal vein occlusion treated with dexamethasone implant. Br J Ophthalmol, 2019, 103(4): 463-468.
42. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol, 2012, 130(9): 1153-1161.
43. Pichi F, Elbarky AM, Elhamaky TR. Outcome of "treat and monitor" regimen of aflibercept and ranibizumab in macular edema secondary to non-ischemic branch retinal vein occlusion. Int Ophthalmol, 2019, 39(1): 145-153.
44. Lotfy A, Solaiman KAM, Abdelrahman A, et al. Efficacy and frequency of intarvitreal aflibercept versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina, 2018, 38(9): 1795-1800.
45. Furukawa TA, Barbui C, Cipriani A, et al. Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol, 2006, 59(1): 7-10.

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