Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial

Abstract

Importance: Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown.

Objective: To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation.

Design, setting, and participants: Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018.

Interventions: Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits.

Main outcomes and measures: The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported.

Results: Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups.

Conclusions and relevance: Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME.

Trial registration: ClinicalTrials.gov Identifier: NCT01909791.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Baker reports receipt of grants for clinical research from Regeneron, Genentech, Allergan, and Novartis. Mr Glassman reports receipt of grants from the National Eye Institute, Regeneron, and Genentech. Dr Beaulieu reports receipt of grants to his institution from the National Eye Institute and Regeneron. Dr Antoszyk reports receipt of grants from Roche Genentech and Clearside and personal/consultant fees from Jaeb Center for Health Research, Opthea, Clearside, and Roche Genentech. Dr Jampol reports receipt of grants from the National Eye Institute and personal fees from Sanofi and Appelis. Dr Jhaveri reports receipt of personal fees from Novartis and Allergan. Ms Melia reports receipt of grants from the National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Juvenile Diabetes Research Foundation, and Regeneron as well as nonfinancial support from Regeneron in the form of study drug to her institution to distribute to clinical sites for conduct of clinical trials. Ms Stockdale reports receipt of grants from the National Eye Institute and Regeneron as well as nonfinancial support from Regeneron in the form of study drug to her institution to distribute to clinical sites for conduct of clinical trials. Dr Martin reports receipt of grants from the National Institutes of Health. Dr Sun reports receipt of grants from Roche Genentech, Juvenile Diabetes Research Foundation, and Kalvista; personal fees from Current Diabetes Reports, JAMA Ophthalmology, and Merck; and nonfinancial support from Optovue (equipment loaned for research), Roche Genentech (food/beverage), and KalVista (travel support). No other disclosures were reported.

Figures

Figure 1.. Participant Flow From Screening to Final 2-Year Visit

Participants were not formally screened before obtaining informed consent. Reasons for participant ineligibility were not collected. Visit completion at 2 years was prespecified as completion of any study visit from 92 to 116 weeks. Deaths exclude 1 participant from each group who completed a visit in this window but died before completing the designated 2-year study visit. For eyes not completing the 2-year visit, multiple imputation was used to impute missing data in the primary analysis. There were 77 eyes that had values imputed: 21 in the aflibercept group; 28 in the laser photocoagulation group; and 28 in the observation group.

Figure 2.. Time to First Aflibercept Injection in the Laser Photocoagulation and Observation Groups

Post hoc analysis of prespecified within-group outcomes. Hazard ratio and P value are from Cox proportional hazards regression with robust variance estimation and adjustment for recent or planned diabetic macular edema treatment in the nonstudy eye. The median follow-up time was 719 (interquartile range, 703-736) days and 721 (interquartile range, 707-735) days in the laser photocoagulation and observation groups, respectively.

Figure 3.. Mean Visual Acuity and Central Subfield Thickness Change From Baseline to 2 Years

For each box-and-whisker plot, the horizontal bar within the box represents median; top and bottom of box, interquartile range; white square, mean. Upper whisker extends from the upper quartile to the closest observed data point below the upper quartile plus 1.5 times the interquartile range; lower whisker extends from the lower quartile to the closest observed data point above the lower quartile minus 1.5 times the interquartile range. Outlying values are plotted as circles. Values in panel A at or above the horizontal dashed line (84 letters) represent visual acuity of 20/20 or better. Numbers of participant eyes shown are observed data only.