Aflibercept Linked With Improvement in DRSS Levels

Patients with diabetic retinopathy experienced significant increases in retinal nonperfusion whether they were treated or not. But treated patients had reduced severity, a study shows.

The final 2-year outcomes of the RECOVERY trial found that nearly all proliferative diabetic retinopathy (PDR) patients divided into 2 treatment arms had significant increases in retinal nonperfusion (RNP), but 82% also experienced improvement in the Diabetic Retinopathy Severity Scale (DRSS) levels from baseline — and no patient had worsening in the scale, according to a study published in Ophthalmology Retina.

The prospective randomized open-label pilot RECOVERY (Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy) trial looked at intravitreal aflibercept (Eylea, Regeneron, Tarrytown, NY) injections in 40 treatment-naïve eyes of 40 patients with PDR, who also had substantial nonperfusion (>20 disc areas) but did not have center-involved diabetic macular edema. 

Patients in the study’s 2 arms received 2 mg aflibercept injections at different dosing times at baseline, with treatment randomized at intervals ranging from 1:1 to monthly (arm 1) or quarterly (arm 2). Treatment crossover was in year 2 of the trial, with those who were dosed monthly switching to quarterly dosing, and those who received quarterly dosing then receiving monthly dosing.

The main outcome measures were change in total RNP area through year 2, and the secondary outcomes included DRSS scores, best-corrected visual acuity, central subfield thickness, more measures of RNP such as ischemic index (ISI), and adverse events incidence. Other measures calculated included means and 95% confidence intervals.

Researchers found that from baseline to the second year in all patients, mean RNP increased from 235 mm2 to 402 mm2 (P<0.0001). ISI increased from 25.8% to 50.4% (P <.0001). From year 1 to year 2, they found increases in mean RNP (P <.0001) and ISI (P <.0001). 

“Mean total RNP increased from 264 mm2 at baseline to 386 mm2 (P <.0001) at year 2 in arm 1 and from 207 mm2 at baseline to 421 mm2 (P <.0001) at year 2 in arm 2 (P =.023, arm 1 vs arm 2),” investigators report. “Increases in mean RNP for both treatment arms (P <.0001) were also observed specifically within year 2 (P =.32, arms 1 vs 2).” 

By the end of the second year, DRSS scores had improved in 82% (n=27) of patients compared with baseline, remained stable in 18% (n=6) of patients, and no patient worsened. DRSS scores also improved by 2 or more steps in 65% (n=11) and 81% (n=13) in arms 1 and 2, respectively.

The study’s limitations include its relatively small sample size, meaningful discontinuation rate, and that its patients were actively treated. “Additionally, there are inherent challenges to accurately and precisely measure RNP using UWF FA images, though the reproducibility of the methods employed has been reported,” according to the investigators. 

“[Optical coherence tomography angiography] may be able to more consistently visualize and quantify areas of RNP at a more granular level including discernment between vascular pathologies within the superficial compared to the deep capillary networks and ideally, studies focused on RNP will incorporate both modalities moving forward.”

More comprehensive natural history studies that look at diabetic retinopathy-associated RNP longitudinally without intravitreal pharmacotherapy are needed, they report.


Wykoff CC, Nittala MG, Boone CV, Yu HJ, Fan W, for the RECOVERY Study Group. Final outcomes from the randomized RECOVERY trial of aflibercept for retinal nonperfusion in proliferative diabetic retinopathy. Ophthalmol Retina. March 5, 2022. doi:10.1016/j.oret.2022.02.013