Compartmental Exudative Dynamics in Neovascular AMD: Volumetric Outcomes and Impact of Volatility in a Phase III Clinical Trial

Purpose To examine retinal feature dynamics in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (anti-VEGF) therapy and the relationship of these features with visual acuity. Design Post hoc analysis of the phase 3, randomized, HAWK nAMD clinical trial. Participants Participants randomized to the brolucizumab 6 mg or aflibercept 2 mg arms of the trial. Methods Spectral domain optical coherence tomography (OCT) scans collected at 4-week intervals were analyzed using an automated machine learning-enhanced segmentation and feature-extraction platform with manual verification. Quantitative volumetric measures of retinal and exudative features were exported at multiple timepoints over 48 weeks. Volatility of exudative features was calculated as the standard deviation of each feature value during the maintenance phase (week 12–48) of treatment. These features were examined for their associations with anatomic and functional outcomes. Main Outcome Measures Longitudinal intraretinal fluid (IRF) and subretinal fluid (SRF) volume, subretinal hyperreflective material (SHRM) volume, ellipsoid zone (EZ) integrity (EZ-retinal pigment epithelium [RPE] volume/thickness), and correlation with best corrected visual acuity (BCVA). Results IRF, SRF, and SHRM demonstrated significant volumetric reduction from baseline with anti-VEGF therapy (P<0.001 at each timepoint). EZ integrity measures demonstrated significant improvement from baseline (P<0.001 at each timepoint). Both EZ integrity and SHRM measures significantly correlated with BCVA at all timepoints (EZ-RPE volume: 0.38≤ r ≤0.47; EZ-RPE central subfield thickness: 0.22≤ r ≤0.41; SHRM volume: -0.33≤ r ≤-0.44). Following treatment initiation, correlations of IRF and SRF volume with BCVA were weak or nonsignificant. Eyes with lower volatility of IRF, SRF, and SHRM volumes during the maintenance phase showed greater improvements in EZ integrity (all P<0.01) and greater gains in BCVA (all P<0.01) at week 48 compared to eyes with higher volatility in those exudative parameters. Conclusions Quantitative measures of SHRM volume and EZ integrity correlated more strongly with BCVA than retinal fluid volumes during treatment. High volatility of exudative parameters, including SRF, during the maintenance phase of treatment was associated with loss of EZ integrity and BCVA.