Purpose: To assess the longitudinal change in panretinal leakage index on ultrawidefield fluorescein angiography (UWFA) in eyes with proliferative diabetic retinopathy (PDR) following intravitreal aflibercept injections (IAI).

Methods: The RECOVERY Study (NCT02863354) randomized 40 subjects (1: 1 ratio) with PDR without vitreous hemorrhage (VH) or prior panretinal photocoagulation into 2 treatment groups. The 2q4 group received 2 mg IAI every 4 weeks or the 2q12 group received 2 mg IAI every 12 weeks. All eyes underwent UWFA imaging at baseline, 24 weeks, and 48 weeks. Following image dewarping using the Optos dewarping system, quantitative UWFA was performed using a novel semi-automated image analysis platform developed at the Cleveland Clinic. Panretinal leakage index was defined as the percentage of leaking retinal area defined as the areas of leakage divided by the analyzable retinal area. Two independent masked expert readers reviewed all images and manually corrected any segmentation errors. Longitudinal change within each group and comparative assessment between groups was evaluated.

Results: Forty eyes of 40 subjects were included with a mean age of 48±12.1 years. Nineteen (47.5%) subjects were female and 21 (52.5%) were male. The mean number of injections in the 2q4 arm was 11±1.7 and 4±0.4 in the 2q12 arm. The median baseline panretinal leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (p= 0.22). At week 24 and week 48, the 2q4 group had significantly improved to 1.1%(-79%, p< 0.0001). At week 24, the 2q12 group improved but not significantly to 3.4%(-21%, p= 0.47), but at week 48 the leakage index had improved significantly to 1.4%(-68%, p= 0.02). The 2q4 group resulted in lower leakage indices compared to the 2q12 group at 24 weeks (1.1% vs 3.4%, respectively; p= 0.008), but by week 48 the leakage indices were similar between the 2q4 and 2q12 groups (1.1% vs 1.4%, respectively; p=. 34).

Conclusions: IAI resulted in dramatic reductions in panretinal leakage index in eyes with PDR. 2q4 dosing provided more rapid reduction in leakage index compared to 2q12 dosing. Future research will focus on the impact of leakage index dynamics on outcomes and its potential as a quantitative biomarker for treatment indication.