Meticulous multimodal analysis of aflibercept therapy for submacular vascularized pigment epithelial detachment associated with neovascular AMD in a prospective case series, the EVEN study

PURPOSE: This prospective case series investigates the visual and anatomical outcomes including detailed volumetrics of eyes with vascularized pigment epithelial detachments (PED) treated with aflibercept in eyes with neovascular age-related macular degeneration (nAMD) through meticulous analysis in a reading center setting. METHODS: We conducted a single-arm multicenter, prospective, open-labeled, interventional case series, comparing visual and anatomic outcomes at 12 months with baseline for intense aflibercept therapy. Eyes with submacular vascularized PED due to AMD received 2.0 mG of intravitreal aflibercept at baseline and then monthly for 6 months. During the subsequent 6 months, mandatory aflibercept therapy was given for every other month, while additional aflibercept injections were allowed between mandatory injections if necessary, at 4 weeks after last injection, contingent on pre-defined visual and anatomic re-treatment criteria. Standardized ETDRS vision measurement, anterior and posterior segment examination, and high-density spectral-domain optical coherence tomography scans were obtained at baseline and monthly, while fundus photography and fluorescein angiography were obtained at baseline, 3,6, and 12 months. Indocyanine-green angiography was obtained at baseline and 3 months. Meticulous multidimensional assessment of the scanned multimodal serial images was then performed by Doheny Image Reading Center. RESULTS: Of 36 eyes and patients with mean age of 80, mean baseline and 12-month-ETDRS BCVA was 59 ± 8.9 letters (20/66), and 65 ± 27 letters (20/50), respectively; (6.5 letters improvement, p = 0.02). Significant reductions from baseline to month-12 were noted for multiple anatomic measures, including PED maximum height, entire lesion and central 1-mm subfield of PED mean thickness and volume, and mean subretinal hyperreflective material (SHRM) thickness and volume, also entire lesion of retinal thickness, retinal volume, and mean subretinal fluid (SRF) thickness (mean reductions in magnitude ranging from 37.5 to 91.7%, all p < 0.001). FA measurements also showed significant decrease from baseline to month-12, including area and greatest linear diameter (GLD) of fibrovascular PED, area and GLD of NV area and leakage (mean reductions in magnitude from 41.9 to 87.7%, p value from 0.002 to <0.001). This case series shows that while majority of reductions in SRF volume occurred during first month from baseline, majority of reduction in retinal, PED, and SHRM volumes occurred during first 2 months after onset of anti-VEGF injections. RPE tears developed in 5 eyes (13.9%) correlating with eyes with large PED height and volume at baseline (mean height >800 μm, mean volume >4 mm(3)). Geographic atrophy (GA) was noted in only 1 eye at baseline, but in 16 eyes (44.4%) by 12 months. CONCLUSIONS AND IMPORTANCE: Significant improvement in vision and anatomic measures including volumetrics of vPED were noted at 12 months after aflibercept therapy. Besides substantial PED height, large PED volume at baseline also correlated with RPE tears in 13.9% of eyes with vPED after anti-VEGF therapy. Reduction in SHRM correlated directly with decrease in PED, and more than 40% of study eyes developed GA by 12 months following intense anti-VEGF therapy.