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

Abstract

Importance: Prevalence of persistent central-involved diabetic macular edema (DME) through 24 weeks of anti-vascular endothelial growth factor therapy and its longer-term outcomes may be relevant to treatment.

Objective: To assess outcomes of DME persisting at least 24 weeks after randomization to treatment with 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab.

Design, setting, and participants: Post hoc analyses of a clinical trial, the DRCR.net Protocol T among 546 of 660 participants (82.7%) meeting inclusion criteria for this investigation.

Interventions: Six monthly intravitreous anti-vascular endothelial growth factor injections (unless success after 3 to 5 injections); subsequent injections or focal/grid laser as needed per protocol to achieve stability.

Main outcomes and measures: Persistent DME through 24 weeks, probability of chronic persistent DME through 2 years, and at least 10-letter (≥ 2-line) gain or loss of visual acuity.

Results: The mean age of participants was 60 years, 363 (66.5%) were white, and 251 (46.0%) were women. Persistent DME through 24 weeks was more frequent with bevacizumab (118 of 180 [65.6%]) than aflibercept (60 of 190 [31.6%]) or ranibizumab (73 of 176 [41.5%]) (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; and aflibercept vs ranibizumab, P = .05). Among eyes with persistent DME through 24 weeks (n = 251), rates of chronic persistent DME through 2 years were 44.2% with aflibercept, 68.2% with bevacizumab (aflibercept vs bevacizumab, P = .03), and 54.5% with ranibizumab (aflibercept vs ranibizumab, P = .41; bevacizumab vs ranibizumab, P = .16). Among eyes with persistent DME through 24 weeks, proportions with vs without chronic persistent DME through 2 years gaining at least 10 letters from baseline were 62% of 29 eyes vs 63% of 30 eyes (P = .88) with aflibercept, 51% of 70 vs 55% of 31 (P = .96) with bevacizumab, and 45% of 38 vs 66% of 29 (P = .10) with ranibizumab. Only 3 eyes with chronic persistent DME lost at least 10 letters.

Conclusions and relevance: Persistent DME was more likely with bevacizumab than with aflibercept or ranibizumab. Among eyes with persistent DME, eyes assigned to bevacizumab were more likely to have chronic persistent DME than eyes assigned to aflibercept. These results suggest meaningful gains in vision with little risk of vision loss, regardless of anti-vascular endothelial growth factor agent given or persistence of DME through 2 years. Caution is warranted when considering switching therapies for persistent DME following 3 or more injections; improvements could be owing to continued treatment rather than switching therapies.

Trial registration: clinicaltrials.gov Identifier: NCT01627249.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Beaulieu reports other support from the National Eye Institute and National Institute of Diabetes and Digestive and Kidney Diseases and nonfinancial support Genentech and Regeneron during the conduct of the study. Dr Blinder reports personal fees from Regeneron Pharmaceuticals, Bausch and Lomb, and Allergan outside the submitted work. Dr Neil M. Bressler reports grants from Bayer, Genentech/Roche, Novartis, and Samsung Bioepis outside the submitted work. Dr Susan B. Bressler reports grants from Jaeb Center during the conduct of the study and grants from Bayer HealthCare Pharmacueticals Inc, Boehringer Ingelheim Pharm, Notal Vision, Novartis, Genentech, Jaeb Center, and Merck outside the submitted work; .Dr Glassman reports grants from National Institutes of Health during the conduct of the study and grants from Regeneron and Genentech outside the submitted work. Dr Jampol reports a grant from the National Eye Institute. Ms Melia reports grant support from the National Eye Institute and provision of study drug from Regeneron and Genentech during the conduct of the study. Dr Wells reports consultancy for Genentech, Iconic Pharmaceuticals, Alimera, and Alcon and grants for Genentech, Regeneron, Ophthotech, Emmes, Iconic Pharmaceuticals, Neurotech, KalVista Pharmaceuticals, Opthea, LPath, and Bayer. No other disclosures were reported.

Figures

Figure 1.. Persistent Diabetic Macular Edema (DME) Through 24 Weeks

At 24 weeks, P < .001 for aflibercept vs bevacizumab,P = .05 for aflibercept vs ranibizumab, and P < .001 for ranibizumab vs bevacizumab.

Figure 2.. Probability of Chronic Persistent Diabetic Macular Edema (DME) Through 2 Years by Treatment Group

Eyes in which chronic persistent diabetic macular edema (DME) did not resolve by 104 weeks were censored at their last visit (n = 145), on the date of the first nonprotocol DME treatment (n = 3), or on the date of the 52-week visit if there were fewer than 4 visits in year 2 (n = 10). Two-year life-table survival estimates are shown for each group. Dark blue indicates aflibercept, bright blue indicates bevacizumab, and orange indicates ranibizumab. An event was defined as central subfield thickness less than 250 μm (Stratus equivalent) and at least 10% reduction relative to the 24-week study visit at 2 consecutive visits subsequent to the 24-week visit.