Longitudinal analysis of structural biomarkers for disease progression in intermediate age-related macular degeneration: a MACUSTAR study report.

PURPOSE: To investigate the prognostic impact of qualitative and quantitative structural biomarkers including their topographic distribution for progression to geographic atrophy (GA) or neovascular age-related macular degeneration (nAMD) in eyes with intermediate AMD (iAMD) within the longitudinal part of the MACUSTAR study (NCT03349801). DESIGN: Longitudinal, prospective low-interventional European multicenter cohort study. SUBJECTS: 577 eyes of 577 study patients with iAMD. METHODS: Study eyes with iAMD underwent multimodal retinal imaging at each study visit followed by a standardized grading of structural biomarkers, including presence of subretinal drusenoid deposits (SDDs), vitelliform lesion, pigmentary abnormalities (PAs), refractile deposits, pigment epithelium detachment (PED), non-exudative choroidal neovascularization (nCNV), incomplete (i) retinal pigment epithelium and outer retinal atrophy (RORA), complete (c) RORA, and hyperreflective foci presence (HRF). Automated assessment of the retinal pigment epithelium drusen complex (RPEDC) volume and HRF area including their topographic distribution based on spectral-domain optical coherence tomography (OCT) imaging was conducted using a deep-learning based algorithm. Disease progression (GA/nAMD) was assessed at each study visit up to a follow-up time of 4 years. Multivariable time-discrete hazard models were used to evaluate the biomarkers' relevance for disease progression in the entire OCT volume, the central 3 mm disk, and the central subfield of the Early Treatment Diabetes Retinopathy Study (ETDRS) Grid. MAIN OUTCOME MEASURES: Disease progression to GA/nAMD, hazard ratios of structural biomarkers for disease progression RESULTS: A total of 577 study eyes of 577 iAMD study patients (mean age 72.01 ± 7.01 years, 66.1 % female, median follow-up 3 years) were included. Disease progression was detected in 82 eyes (9.01 %), 37 (6.4 %) progressed to GA, and 45 (7.7 %) to nAMD. Inside the central 3 mm presence of SDDs, PED, nCNV and cRORA conferred overall risk for progression, whereas PAs, RPEDC volume, iRORA, cRORA were associated with risk for progression to GA. Only nCNV volume increased risk for nAMD. CONCLUSIONS: Structural biomarkers indicate risk for iAMD progression and may differentiate eyes progressing to GA from eyes progressing to nAMD. Biomarker topography impacts their prognostic relevance and needs to be considered in clinical trial design.