Avoid Persistent Macular Edema During Anti-VEGF Therapy

Macular degeneration treatment. 75-year-old female patient receiving an intra-ocular bevacizumab (Avastin) injection to treat macular degeneration and retinal vein thrombosis. Bevacizumab is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is usually used in chemotherapy to treat a number of cancers but here is being used to treat age-related eye conditions. Macular degeneration caused damage to the macula, the central area of the retina in the eye, which leads to a loss of vision in the central field of vision. Retinal vein thrombosis, or central retinal vein occlusion, is a blockage of the central retinal vein. As one of only two sources of blood supply to the eye, occlusion of the central retinal vein can lead to blindness.
Persistent leakage can compromise visual acuity in patients with CRVO who are undergoing treatment with intravitreal injections.

Anti-vascular endothelial growth factor (Anti-VEGF) injections are largely effective to reduce macular edema (ME), and most often letters will be gained, with more than half of patients typically achieving at least 10 letters; however, less than a third will add 15 or more.1 Studies have explored these diverse responses by comparing medications, levels of intraocular inflammatory mediators, and impact of macular fluid on visual outcomes.

An investigation published in JAMA Ophthalmology examines the resolution patterns of persistently dry macula, continuing wet macula, and intermittently recurrent ME during treatment for central retinal vein occlusion (CRVO), and relationships to final best corrected visual acuity (BCVA). The 2019 analysis explores data from Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) clinical trial conducted at 44 UK National Health Service ophthalmology departments between December 2014 and December 2016. The post hoc study included 425 eyes of 425 participants, mean age 69.2±12.7 years, with CRVO-related ME onset within the prior 12 months.1

After 100 weeks of anti-VEGF therapy, 28.5% of eyes achieved persistently dry macula, 10.7% continued to be wet with ME, and 60.8% experienced recurrent ME. Compared with dry macula, those persistently wet finished at -10.98 ETDRS letters, and patients with recurrent ME at -5.58 letters. Further, those with persistent ME at 52 weeks also had worse 100-week BCVA than individuals with persistently dry macula (P <.001) or recurrent ME (P =.06).

Levels of intraocular VEGF can vary widely in eyes with CRVO. The research explains that “although the VEGF drive in eyes with recurrent ME is intermittently suppressible, these eyes may have entered a self-perpetuating cycle of VEGF-induced retinal vascular permeability, probably from retinal ischemia.”1 Further, VEGF may not be the principal cytokine in nonresponding eyes.

LEAVO participants were randomized 1:1:1 between the intravitreal injections. At 100 weeks, fewer individuals receiving aflibercept had persistently wet macula compared with bevacizumab (P <.001), and those in the ranibizumab group experienced less continuing ME than patients undergoing bevacizumab treatment (P =.01). Although the aflibercept group displayed the least percentage of recurrent ME, 28% still faced repeated events. Investigators speculate these eyes may exhibit “continual production” of VEGF. The research group previously wrote that baseline CST or intraretinal fluid do not predict visual results — now adding that continued fluid presence may prompt “secondary effects on the neuronal cells.”1

After a 4-injection loading phase, LEAVO’s design employed pro re nata retreatment based on changes in CST and visual acuity. The investigation noted that its data demonstrates CST and VA are not adequate indicators of high VEGF in all patients with CRVO. A treat-and-extend regimen may prove better for some individuals, and merits further study. 

The current analysis underlines “early and ongoing aggressive treatment of persistent or recurrent fluid” and significance to reduce ME, according to an invited commentary posted on JAMA Ophthalmology.2 For patients with CRVO who are incomplete responders to anti-VEGF therapy, “it is unknown whether VEGF or other cytokines are upregulated or downregulated in this population relative to responders,” according to the researchers.2

Limitations of this study included possible bias involved with a post hoc design, limited wet group sample size, and no assessment of capillary nonperfusion. Conversely, mandated clinic visits at weeks 0, 12, 24, 52, 76, and 100 produced appreciable data for refracted BCVA.

Disclosure: Multiple study authors also declared affiliations with the biotech, pharmaceutical, and/or medical device industries. Please see the original reference for a full list of authors’ disclosures. 


1. Gurudas S, Patrao N, Nicholson L, et al. Visual outcomes associated with patterns of macular edema resolution in central retinal vein occlusion treated with anti-vascular endothelial growth factor therapy: a post hoc analysis of the Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) trial. JAMA Ophthalmol. Published online January 6, 2022. doi:10.1001/jamaophthalmol.2021.5619

2. Popovic MM, Kertes PJ. Central retinal vein occlusion — what is the potential importance of persistent and recurrent macular edema? JAMA Ophthalmol. Published online January 6, 2022. doi:10.1001/jamaophthalmol.2021.5620