Prophylactic Aflibercept For Diabetic Retinopathy Halts Disease, But Not Acuity Loss

Patients with nonproliferative diabetic retinopathy (NPDR), without center-involving diabetic macular edema (CI-DME) treated prophylactically with intravitreal aflibercept injections experience anatomic benefits — but no significant improvements in visual acuity (VA), when compared with sham injections, according to the 4-year report of Protocol W randomized trial, published in JAMA Ophthalmology. The results of this study do not support prophylactic aflibercept injections for diabetic retinopathy, investigators explain.

This randomized, double-masked study was conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018. The investigators included 399 eyes of 328 participants (mean age, 56 years; 42.4% women) with type 1 or type 2 diabetes, who had at least 1 eye with severe NPDR, best-corrected VA of at least 79 letters (Snellen equivalent 20/25 or better), and no signs of CI-DME or neovascularization within the 7 modified early treatment diabetic retinopathy study, were included in the study. Patients with prior panretinal photocoagulation or a history of DME or diabetic retinopathy treatment within 12 months prior to enrollment were ineligible.

Study eyes were randomly assigned 1:1 to receive 2 mg intravitreal aflibercept or sham injections, given at baseline, 1, 2, and 4 months and then every 4 months through 2 years. In years 3 and 4, preventative injections could be deferred if the clinical assessment of the eye indicated mild NPDR or better. If PDR or CI-DME with vision loss (10 or more letters at 1 visit or 5 or more at 2 consecutive visits) developed, then aflibercept treatment was initiated, and re-treatment for PDR or CI-DME was determined by DRCR Retina Network algorithms. A total of 200 eyes were randomly assigned to aflibercept and 199 to sham.

Both groups showed a minor decrease in VA from baseline to 4 years, a mean (SD) of 2.7 (6.5) letters for eyes in the aflibercept group vs 2.4 (5.8) letters for eyes in the sham group (adjusted mean difference, −0.5 [97.5% CI, −2.3 to 1.3]; P =.52). The team did not find any meaningful difference between VA of treatment and sham groups in any of the preplanned subgroups analysis (baseline diabetic retinopathy severity scale [DRSS], baseline noncentral DME, race and ethnicity, or sex).

The investigators report a statistically significant difference between the 4-year cumulative incidence of PDR or CI-DME in the aflibercept eyes compared with the sham eyes (33.9% vs. 56.9%, respectively, adjusted HR, 0.40 [97.5% CI, 0.28 to 0.57]; P <.001). A larger number of eyes in the aflibercept group improved by 2 or more steps in DRSS when compared with sham eyes (54.3% vs. 28.5%, adjusted OR 2.97[97.5% CI, 1.70 to 5.19]; P <.001). 

Aflibercept eyes received a mean of 13 injections (8.7 and 4.3 during years 1-2 and 3-4, respectively), whereas sham eyes received a mean of 8.7 aflibercept injections (3.1 and 5.6 during years 1-2 and 3-4, respectively). 

The team did not find significant differences in change activity impairment or in work productivity loss from baseline to 2 and 4 years between unilateral participants of patients who did and did not receive prophylactic aflibercept injections for diabetic retinopathy.

“While DRSS improvement may seem desirable, this alone may not confer clinically relevant benefit from prophylaxis as there is evidence that underlying nonperfusion is not substantially affected by anti-VEGF treatment and progression of the disease can still occur,” the investigators explain. 

The limitations of the study include participant retention of 75% at 4 years (excluding deaths) and lack of tests that evaluate measures of visual function other than BCVA.