Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management.

Objective: To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened.

Design, setting, and participants: This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019.

Interventions: Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened.

Main outcomes and measures: Whether individuals received aflibercept.

Results: Among 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range, 53-67 years]) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 μm (Zeiss-Stratus equivalent) vs less than 300 μm (45% vs 26%; hazard ratio [HR], 1.98 [95% CI, 1.26-3.13], continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 [95% CI, 1.42-3.47], ordinal P < .001), and among participants whose nonstudy eye received DME treatment within 4 months of randomization vs not (52% vs 25%; HR, 2.55 [95% CI, 1.64-3.99], P < .001).

Conclusions and relevance: Most eyes managed with initial observation plus aflibercept only if VA worsened maintained good vision at 2 years and did not require aflibercept for VA loss. However, the eyes in the trial were approximately twice as likely to receive aflibercept for VA loss if they had greater baseline central subfield thickness, worse diabetic retinopathy severity level, or a nonstudy eye receiving treatment for DME.

Trial registration: ClinicalTrials.gov Identifier: NCT01909791.

Conflict of interest statement

Conflict of Interest Disclosures: Mr Glassman reported receiving grants from the National Institutes of Health (NIH) and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Baker reported receiving grants for clinical research from Allergan, F. Hoffman-LaRoche Ltd, Novartis AG, and Regeneron Pharmaceuticals Inc outside the submitted work. Dr Beaulieu reported receiving grants from the NIH and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Bressler reported receiving grants from Jaeb Center for Health Research during the conduct of the study and receiving grants from Bayer AG, F. Hoffman-LaRoche Ltd, Novartis AG, and Samsung Bioepis outside the submitted work. Dr Punjabi reported receiving clinical and epidemiological research support from F. Hoffman-LaRoche Ltd. Ms Stockdale reported receiving grants from the NIH and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Wykoff reported receiving grants and personal fees from Adverum Biotechnologies, Aerpio Pharmaceuticals Inc, Allergan, Apellis Pharmaceuticals, Chengdu Kanghong, Clearside Biomedical, F. Hoffman-LaRoche Ltd, Iveric Bio (formerly Ophthotech), Kodiak, Novartis AG, Recens Medical, Regeneron Pharmaceuticals Inc, Regenxbio Inc, and Santen Pharmaceutical Co Inc; receiving grants from Neurotech, Opthea, Outlook Therapeutics, and Samsung; and receiving personal fees from Alimera Sciences, Allegro, Bayer, DORC, EyePoint, Fosun, ONL Therapeutics, PolyPhotonix, and Takeda outside the submitted work. Dr Jampol reported receiving grants from the NIH, National Eye Institute during the conduct of the study and receiving personal fees from Sanofi and Appelis Pharmaceuticals outside of the submitted work. Dr Sun reported receiving grants from the Jaeb Center during the conduct of the study; receiving nonfinancial support from Adaptive Sensory Technologies, Boston Micromachines, Novo Nordisk, and Optovue; receiving grants and nonfinancial support from Boehringer Ingelheim International, F. Hoffman-LaRoche Ltd, and Kalvista; receiving grants from JDRF; receiving personal fees from Current Diabetes Reports and JAMA Ophthalmology; and receiving personal fees and nonfinancial support from Merck and Novartis AG outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. DRCR Retina Network Initial Observation Treatment Algorithm

anti-VEGF indicates anti–vascular endothelial growth factor. aVisual acuity was considered worse if it was 5 to 9 letters (1 line) worse from baseline at 2 consecutive visits every 4 weeks (±2 weeks) apart or at least 10 letters (2 lines or more) worse at any visit. Of note, increasing central subfield thickness or change in any other parameter did not initiate injections if the visual acuity was not worse. bOnce injections were initiated, the DRCR Retina Network anti-VEGF for diabetic macular edema regimen was followed. cIf central subfield thickness worsened by at least 10% from the last visit or became greater than 400 μm (Zeiss-Stratus equivalent) without vision loss, the follow-up interval was halved with a minimum interval of 4 weeks. If central subfield thickness subsequently stabilized at 2 consecutive visits without vision loss, follow-up could be extended to 8 weeks and then to 16 weeks.

Figure 2.. Eyes Completing the 104-Week Visit in the Initial Observation Group

Injections for “other” category were given for 1 case of proliferative diabetic retinopathy and 1 case of vision loss of 7 letters accompanied by a 150-μm increase in central subfield thickness. Group included 208 of 236 randomized; excluding 4 participants who died during follow-up, 90% of participants completed the 4-year visit.