Anti-VEGF Effective in Persistent Diabetic Macular Edema

Saumya M. Shah; Sophie J. Bakri, MD


September 12, 2018

Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema With Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial

Bressler NM, Beaulieu WT, Glassman AR, et al; Diabetic Retinopathy Clinical Research Network
JAMA Ophthalmol. 2018;136:257-269

Study Summary

The Diabetic Retinopathy Clinical Research Network ( conducted a comparative effectiveness trial evaluating the prevalence of persistent diabetic macular edema (DME) and its effect on visual acuity in eyes treated with aflibercept, ranibizumab, or bevacizumab injections. performed this as a post hoc analysis of their Protocol T randomized clinical trial[1] of eyes with chronic persistent DME.

Patients were randomly assigned to receive one of the three anti-vascular endothelial growth factor (VEGF) injections every 4 weeks for the first 20 weeks, unless the visual acuity letter score was 84 or better (Snellen equivalent 20/20), or the central subfield thickness (CST) was less than 250 ?m at any visit during this period. Reinjection was conducted at 24 weeks or restarted at a later time if there was worsening of visual acuity (five or more letters) or CST (change ≥ 10%). Patients were included if they had persistent DME through 24 weeks (defined as centrally involved DME on clinical examination), a best corrected visual acuity score of 78 through 24 (Snellen equivalent 20/32 to 20/320), and a CST of at least 250 ?m; these criteria were met by 546 patients.

Prevalence of eyes with persistent DME continued to decrease through 24 weeks in all three treatment groups. Persistent DME at 24 weeks was more prevalent in the bevacizumab group (65.6%) than in the aflibercept (31.6%) and ranibizumab (41.5%) cohorts (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; aflibercept vs ranibizumab, P = .05). At 24 weeks, the mean change in visual acuity was significantly greater among eyes without persistent DME than in those with DME in the aflibercept and ranibizumab groups, but not in the bevacizumab group.

The majority of improvement in vision in eyes with persistent DME occurred within the first 24 weeks of injection administration; however, small improvement, ranging from 1.1-3.4 letters, continued to occur from 24 weeks to 104 weeks. At 2 years of follow-up after the initial 24 weeks, the prevalence of persistent DME eyes that developed chronic persistent DME was 68.2% with bevacizumab, 44.2% with aflibercept, and 54.5% with ranibizumab.


This study is important in helping us understand the response of DME to anti-VEGF treatment. Continued resolution of DME was evident in eyes treated with anti-VEGF therapy through 24 weeks and later, indicating that changing therapies owing to a limited response after three initial anti-VEGF injections should be reconsidered. Furthermore, the loss in visual acuity was no more than 3.3% in any of the treatment groups with chronic persistent DME at 2 years, suggesting low risk for vision loss on intravitreal anti-VEGF agents. However, it is unclear what effect anti-VEGF agents would have for patients beyond 2 years. Also, given that this was a post hoc analysis, it is important to note that the primary outcomes of the study were assessed on the basis of groups created by treatment response rather than in a randomized fashion.

The study found that patients treated with aflibercept to have the lowest prevalence of DME at 24 weeks and at 2 years. Bevacizumab was reported as being the least effective at preventing and achieving resolution of persistent DME. Of note, there was a large imbalance in the number of eyes with persistent DME through 24 weeks within each treatment group (bevacizumab, n = 118; ranibizumab, n = 73; aflibercept, n = 60), which could have affected these results.

Although the authors discuss the value of continuing anti-VEGF injections in patients with a limited initial response, investigating when it may be appropriate to switch to alternative therapies if the preliminary therapy is ineffective could be beneficial.

Regardless, all three anti-VEGF agents were found to help in persistent DME resolution to some degree, with worthwhile gains in vision and minimal risk for vision loss. This study highlights the importance of continuous treatment for persistent DME after three or more injections rather than switching therapies, owing to the gradual resolution of DME and improvement in visual acuity.


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