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Reviews on Recent Clinical Trials

Editor-in-Chief

ISSN (Print): 1574-8871
ISSN (Online): 1876-1038

Review Article

Review on Recent Trials Evaluating the Effect of Intravitreal Injections of Anti-VEGF Agents on the Macular Perfusion of Diabetic Patients with Diabetic Macular Edema

Author(s): Ayman G. Elnahry*, Ahmed A. Abdel-Kader, Ahmed E. Habib, Gehad A. Elnahry, Karim A. Raafat and Khaled Elrakhawy

Volume 15, Issue 3, 2020

Page: [188 - 198] Pages: 11

DOI: 10.2174/1574887115666200519073704

Abstract

Background: Diabetic macular edema (DME) is a major cause of vision loss in diabetics worldwide. Anti-vascular endothelial growth factor (anti-VEGF) agents have become the mainstay of treatment of vision loss due to DME. Long-term effects of these agents on the macular perfusion (MP) are a current concern.

Objective: To review recently published studies that evaluated the effect of intravitreal injection of anti-VEGF agents on the MP of diabetics with DME.

Methods: Different databases were searched including PubMed, Medline, Ovid, Science Direct, and Google Scholar for relevant studies published between 2010 and 2019. All studies found were compared regarding methodology and results and included in this review. Some studies relating to retinal perfusion in general and not strictly MP were also included for comprehensiveness.

Results: Several studies utilizing different anti-VEGF agents were identified. All the large randomized controlled clinical trials identified utilized primarily fluorescein angiography (FA) and human graders and found generally no worsening of MP associated with anti-VEGF agents use in diabetic patients with DME. Some of these studies, however, depended on post-hoc analysis. Several more recent, but smaller case series, have utilized the relatively new and non-invasive optical coherence tomography angiography (OCTA) in this evaluation and found more conflicting results.

Conclusion: The large clinical trials recently performed depended mainly on FA in the analysis of MP changes following injections and generally found no worsening of MP. More recently, smaller case series have utilized OCTA in this analysis, yielding more conflicting results. Large randomized controlled trials using OCTA are thus needed.

Keywords: Anti-VEGF agents, diabetic macular edema, fluorescein angiography, macular perfusion, optical coherence tomography angiography, clinical trials.

Graphical Abstract
[1]
Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014; 121(11): 2247-54. [http://dx.doi.org/10.1016/j.ophtha.2014.05.006 ]. [PMID: 25012934].
[2]
Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010; 304(6): 649-56. [http://dx.doi.org/10.1001/jama.2010.1111 ]. [PMID: 20699456].
[3]
Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol 2007; 14(4): 179-83. [http://dx.doi.org/10.1080/09286580701396720 ]. [PMID: 17896294].
[4]
Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998; 105(6): 998-1003. [http://dx.doi.org/10.1016/S0161-6420(98)96025-0 ]. [PMID: 9627648].
[5]
Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3): 556-64. [http://dx.doi.org/10.2337/dc11-1909 ]. [PMID: 22301125].
[6]
Bahrami B, Zhu M, Hong T, Chang A. Diabetic macular oedema: Pathophysiology, management challenges and treatment resistance. Diabetologia 2016; 59(8): 1594-608. [http://dx.doi.org/10.1007/s00125-016-3974-8 ]. [PMID: 27179659].
[7]
Elnahry AG, Hassan FK, Abdel-Kader AA. Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina. Ophthalmic Genet 2018; 39(6): 759-62. [http://dx.doi.org/10.1080/13816810.2018.1536220 ]. [PMID: 30335551].
[8]
Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial. Ophthalmology 2017; 124(9): 1296-304. [http://dx.doi.org/10.1016/j.ophtha.2017.03.057 ]. [PMID: 28551167].
[9]
Elnahry AG, Sallam EM, Guirguis KJ, Talbet JH, Abdel-Kader AA. Vitrectomy for a secondary epiretinal membrane following treatment of adult-onset Coats’ disease. Am J Ophthalmol Case Rep 2019; 15100508 [http://dx.doi.org/10.1016/j.ajoc.2019.100508 ]. [PMID: 31334386].
[10]
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9(6): 669-76. [http://dx.doi.org/10.1038/nm0603-669 ]. [PMID: 12778165].
[11]
Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1(10): 1024-8. [http://dx.doi.org/10.1038/nm1095-1024 ]. [PMID: 7489357].
[12]
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438(7070): 967-74. [http://dx.doi.org/10.1038/nature04483 ]. [PMID: 16355214].
[13]
Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M. Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 2012; 122(11): 4213-7. [http://dx.doi.org/10.1172/JCI65157 ]. [PMID: 23093773].
[14]
Sun FY, Guo X. Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor. J Neurosci Res 2005; 79(1-2): 180-4. [http://dx.doi.org/10.1002/jnr.20321 ]. [PMID: 15573409].
[15]
Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of the effect of repeated intravitreal bevacizumab injections on the macular microvasculature of a diabetic patient using optical coherence tomography angiography. Case Rep Ophthalmol Med 2019; 20193936168 [http://dx.doi.org/10.1155/2019/3936168 ]. [PMID: 31139483].
[16]
Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? Br J Ophthalmol 2012; 96(2): 179-84. [http://dx.doi.org/10.1136/bjophthalmol-2011-301087 ]. [PMID: 22250209].
[17]
Dorrell MI, Aguilar E, Scheppke L, Barnett FH, Friedlander M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci USA 2007; 104(3): 967-72. [http://dx.doi.org/10.1073/pnas.0607542104 ]. [PMID: 17210921].
[18]
Baffert F, Le T, Sennino B, et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 2006; 290(2): H547-59. [http://dx.doi.org/10.1152/ajpheart.00616.2005 ]. [PMID: 16172161].
[19]
Classification of diabetic retinopathy from fluorescein angiograms. ETDRS report number 11. Ophthalmology 1991; 98(5)(Suppl.): 807-22. [http://dx.doi.org/10.1016/S0161-6420(13)38013-0 ]. [PMID: 2062514].
[20]
Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol 2012; 130(8): 972-9. [http://dx.doi.org/10.1001/archophthalmol.2012.393 ]. [PMID: 22491395].
[21]
Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010; 117(6): 1078-1086.e2. [http://dx.doi.org/10.1016/j.ophtha.2010.03.045 ]. [PMID: 20416952].
[22]
Michaelides M, Fraser-Bell S, Hamilton R, et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study): Report 1. Retina 2010; 30(5): 781-6. [http://dx.doi.org/10.1097/IAE.0b013e3181d2f145 ]. [PMID: 20464787].
[23]
Chung EJ, Roh MI, Kwon OW, Koh HJ. Effects of macular ischemia on the outcome of intravitreal bevacizumab therapy for diabetic macular edema. Retina 2008; 28(7): 957-63. [http://dx.doi.org/10.1097/IAE.0b013e3181754209 ]. [PMID: 18698297].
[24]
Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology 2014; 121(9): 1783-9. [http://dx.doi.org/10.1016/j.ophtha.2014.03.021 ]. [PMID: 24768239].
[25]
Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996; 103(11): 1820-8. [http://dx.doi.org/10.1016/S0161-6420(96)30420-X ]. [PMID: 8942877].
[26]
Wykoff CC, Shah C, Dhoot D, et al. Longitudinal retinal perfusion status in eyes with diabetic macular edema receiving intravitreal aflibercept or laser in VISTA study. Ophthalmology 2019; 126(8): 1171-80. [http://dx.doi.org/10.1016/j.ophtha.2019.03.040 ]. [PMID: 30946887].
[27]
Feucht N, Schönbach EM, Lanzl I, Kotliar K, Lohmann CP, Maier M. Changes in the foveal microstructure after intravitreal bevacizumab application in patients with retinal vascular disease. Clin Ophthalmol 2013; 7: 173-8. [http://dx.doi.org/10.2147/OPTH.S37544 ]. [PMID: 23355773].
[28]
Erol N, Gursoy H, Kimyon S, Topbas S, Colak E. Vision, retinal thickness, and foveal avascular zone size after intravitreal bevacizumab for diabetic macular edema. Adv Ther 2012; 29(4): 359-69. [http://dx.doi.org/10.1007/s12325-012-0009-9 ]. [PMID: 22402896].
[29]
Wykoff CC, Nittala MG, Zhou B, et al. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy study group. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: Outcomes from the Randomized RECOVERY Trial. Ophthalmol Retina 2019; 3(12): 1076-86. [http://dx.doi.org/10.1016/j.oret.2019.07.011 ]. [PMID: 31542339].
[30]
Bonnin S, Dupas B, Lavia C, et al. Anti–vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina 2019; 39(3): 426-34. [http://dx.doi.org/10.1097/IAE.0000000000002422 ]. [PMID: 30664126].
[31]
Couturier A, Rey PA, Erginay A, et al. Widefield OCT-Angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor. Ophthalmology 2019; 126(12): 1685-94. [http://dx.doi.org/10.1016/j.ophtha.2019.06.022 ]. [PMID: 31383483].
[32]
Figueiredo N, Srivastava SK, Singh RP, et al. Longitudinal panretinal leakage and ischemic indices in retinal vascular disease after aflibercept therapy: The PERMEATE Study. Ophthalmol Retina 2020; 4(2): 154-63. [http://dx.doi.org/10.1016/j.oret.2019.09.001 ]. [PMID: 31757691].
[33]
Hwang TS, Gao SS, Liu L, et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmol 2016; 134(4): 367-73. [http://dx.doi.org/10.1001/jamaophthalmol.2015.5658 ]. [PMID: 26795548].
[34]
Gill A, Cole ED, Novais EA, et al. Visualization of changes in the foveal avascular zone in both observed and treated diabetic macular edema using optical coherence tomography angiography. Int J Retina Vitreous 2017; 3: 19. [http://dx.doi.org/10.1186/s40942-017-0074-y ]. [PMID: 28642823].
[35]
Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 2015; 133(1): 45-50. [http://dx.doi.org/10.1001/jamaophthalmol.2014.3616 ]. [PMID: 25317632].
[36]
Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence tomography angiography in diabetic retinopathy: a prospective pilot study. Am J Ophthalmol 2015; 160(1): 35-44.e1. [http://dx.doi.org/10.1016/j.ajo.2015.04.021 ]. [PMID: 25896459].
[37]
Garcia JM, Lima TT, Louzada RN, Rassi AT, Isaac DL, Avila M. Diabetic macular ischemia diagnosis: Comparison between optical coherence tomography angiography and fluorescein angiography. J Ophthalmol 2016; 20163989310 [http://dx.doi.org/10.1155/2016/3989310 ]. [PMID: 27891250].
[38]
Bradley PD, Sim DA, Keane PA, et al. The evaluation of diabetic macular ischemia using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016; 57(2): 626-31. [http://dx.doi.org/10.1167/iovs.15-18034 ]. [PMID: 26903223].
[39]
Rabiolo A, Gelormini F, Sacconi R, et al. Comparison of methods to quantify macular and peripapillary vessel density in optical coherence tomography angiography. PLoS One 2018; 13(10)e0205773 [http://dx.doi.org/10.1371/journal.pone.0205773 ]. [PMID: 30335815].
[40]
Lei J, Durbin MK, Shi Y, et al. Repeatability and reproducibility of superficial macular retinal vessel density measurements using optical coherence tomography angiography en face images. JAMA Ophthalmol 2017; 135(10): 1092-8. [http://dx.doi.org/10.1001/jamaophthalmol.2017.3431 ]. [PMID: 28910435].
[41]
Al-Sheikh M, Tepelus TC, Nazikyan T, Sadda SR. Repeatability of automated vessel density measurements using optical coherence tomography angiography. Br J Ophthalmol 2017; 101(4): 449-52. [http://dx.doi.org/10.1136/bjophthalmol-2016-308764 ]. [PMID: 27450146].
[42]
Eladawi N, Elmogy M, Helmy O, et al. Automatic blood vessels segmentation based on different retinal maps from OCTA scans. Comput Biol Med 2017; 89: 150-61. [http://dx.doi.org/10.1016/j.compbiomed.2017.08.008 ]. [PMID: 28806613].
[43]
Kim AY, Chu Z, Shahidzadeh A, Wang RK, Puliafito CA, Kashani AH. Quantifying microvascular density and morphology in diabetic retinopathy using spectral-domain optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016; 57(9): 362-70. [http://dx.doi.org/10.1167/iovs.15-18904 ]. [PMID: 27409494].
[44]
Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986; 93(5): 611-7. [http://dx.doi.org/10.1016/S0161-6420(86)33697-2 ]. [PMID: 3523356].
[45]
Reddy RK, Pieramici DJ, Gune S, et al. Efficacy of Ranibizumab in Eyes with Diabetic Macular Edema and Macular Nonperfusion in RIDE and RISE. Ophthalmology 2018; 125(10): 1568-74. [http://dx.doi.org/10.1016/j.ophtha.2018.04.002 ]. [PMID: 29752001].
[46]
Ghasemi Falavarjani K, Iafe NA, Hubschman JP, Tsui I, Sadda SR, Sarraf D. Optical coherence tomography angiography analysis of the foveal avascular zone and macular vessel density after anti-VEGF therapy in eyes with diabetic macular edema and retinal vein occlusion. Invest Ophthalmol Vis Sci 2017; 58(1): 30-4. [http://dx.doi.org/10.1167/iovs.16-20579 ]. [PMID: 28114569].
[47]
Sorour OA, Sabrosa AS, Yasin Alibhai A, et al. Optical coherence tomography angiography analysis of macular vessel density before and after anti-VEGF therapy in eyes with diabetic retinopathy. Int Ophthalmol 2019; 39(10): 2361-71. [http://dx.doi.org/10.1007/s10792-019-01076-x ]. [PMID: 31119505].
[48]
Busch C, Wakabayashi T, Sato T, et al. Retinal microvasculature and visual acuity after intravitreal aflibercept in diabetic macular edema: An optical coherence tomography angiography study. Sci Rep 2019; 9(1): 1561. [http://dx.doi.org/10.1038/s41598-018-38248-1 ]. [PMID: 30733512].
[49]
Hsieh YT, Alam MN, Le D, et al. OCT angiography biomarkers for predicting visual outcomes after ranibizumab treatment for diabetic macular edema. Ophthalmol Retina 2019; 3(10): 826-34. [http://dx.doi.org/10.1016/j.oret.2019.04.027 ]. [PMID: 31227330].
[50]
Dastiridou A, Karathanou K, Riga P, et al. OCT angiography study of the macula in patients with diabetic macular edema treated with intravitreal aflibercept. Ocul Immunol Inflamm 2020; •••: 1-6. [http://dx.doi.org/10.1080/09273948.2019.1704028 ]. [PMID: 31951761].
[51]
Pereira F, Godoy BR, Maia M, Regatieri CV. Microperimetry and OCT angiography evaluation of patients with ischemic diabetic macular edema treated with monthly intravitreal bevacizumab: a pilot study. Int J Retina Vitreous 2019; 5(1): 24. [http://dx.doi.org/10.1186/s40942-019-0176-9 ]. [PMID: 31508244].
[52]
Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of changes in macular perfusion detected by optical coherence tomography angiography following 3 intravitreal monthly bevacizumab injections for diabetic macular edema in the IMPACT Study. J Ophthalmol 2020; •••20205814165 [http://dx.doi.org/10.1155/2020/5814165].
[53]
Michalska-Małecka K, Heinke Knudsen A. Optical coherence tomography angiography in patients with diabetic retinopathy treated with anti-VEGF intravitreal injections: Case report. Medicine (Baltimore) 2017; 96(45)e8379 [http://dx.doi.org/10.1097/MD.0000000000008379 ]. [PMID: 29137019].
[54]
Barash A, Chui TYP, Garcia P, Rosen RB. Acute macular and peripapillary angiographic changes with intravitreal injections. Retina 2020; 40(4): 648-56. [PMID: 30762649].
[55]
Mastropasqua L, Toto L, Borrelli E, Carpineto P, Di Antonio L, Mastropasqua R. Optical coherence tomography angiography assessment of vascular effects occurring after aflibercept intravitreal injections in treatment-naïve patients with wet age-related macular degeneration. Retina 2017; 37(2): 247-56. [http://dx.doi.org/10.1097/IAE.0000000000001145 ]. [PMID: 27628926].
[56]
Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res 2018; 64: 1-55. [http://dx.doi.org/10.1016/j.preteyeres.2017.11.003 ]. [PMID: 29229445].
[57]
Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence tomography angiography. Retina 2015; 35(11): 2163-80. [http://dx.doi.org/10.1097/IAE.0000000000000765 ]. [PMID: 26428607].
[58]
Ramsey DJ, Elnahry AG. Automated image alignment for comparing vascular changes in fundus fluorescein angiography and optical coherence tomography angiography in the macula of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci 2019; 60(9): 3035.
[59]
Elnahry AG, Ramsey DJ. Spatial correlation of microaneurysms detected by fluorescein angiography aligned with microdomains of macular ischemia delineated by optical coherence tomography angiography in patients with diabetic retinopathy. Invest Ophthalmol Vis Sci 2019; 60(11): PB061.
[60]
Rosen R, Romo JSA, Toral MVC, et al. Reference-Based OCT angiography perfusion density mapping for identifying acute and chronic changes in eyes with retinopathy over time 2019.
[61]
Hofman P, van Blijswijk BC, Gaillard PJ, Vrensen GF, Schlingemann RO. Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Arch Ophthalmol 2001; 119(6): 861-6. [http://dx.doi.org/10.1001/archopht.119.6.861 ]. [PMID: 11405837].
[62]
Kurt MM, Çekiç O, Akpolat Ç, Elçioglu M. Effects of intravitreal ranibizumab and bevacizumab on the retinal vessel size in diabetic macular edema. Retina 2018; 38(6): 1120-6. [http://dx.doi.org/10.1097/IAE.0000000000001682 ]. [PMID: 28520638].
[63]
Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 2007; 49(2): 186-93. [http://dx.doi.org/10.1053/j.ajkd.2006.11.039 ]. [PMID: 17261421].
[64]
Bonnin P, Pournaras JA, Lazrak Z, et al. Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin(®)) in neovascular age-related macular degeneration. Acta Ophthalmol 2010; 88(6): 641-5. [http://dx.doi.org/10.1111/j.1755-3768.2009.01526.x ]. [PMID: 19563370].
[65]
Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998; 125(9): 1591-8. [PMID: 9521897].
[66]
Lindahl P, Johansson BR, Levéen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277(5323): 242-5. [http://dx.doi.org/10.1126/science.277.5323.242 ]. [PMID: 9211853].
[67]
Stitt AW, Gardiner TA, Archer DB. Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br J Ophthalmol 1995; 79(4): 362-7. [http://dx.doi.org/10.1136/bjo.79.4.362 ]. [PMID: 7742285].
[68]
Markham A. Brolucizumab: First Approval. Drugs 2019; 79(18): 1997-2000. [http://dx.doi.org/10.1007/s40265-019-01231-9 ]. [PMID: 31768932].
[69]
Sahni J, Patel SS, Dugel PU, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with Faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology 2019; 126(8): 1155-70. [http://dx.doi.org/10.1016/j.ophtha.2019.03.023 ]. [PMID: 30905643].

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