Progression to Advanced Age-related Macular Degeneration in Drusen-driven and Pachychoroid-driven Disease: The Korean Age-Related Maculopathy Study (KARMS)

Purpose To estimate 5-year progression to advanced age-related macular degeneration (AMD), exudative AMD or any geographic atrophy (GA), and to identify phenotype-specific risk factors in two pre-advanced macular phenotypes, drusen-driven non-advanced AMD and pachychoroid-driven disease. Participants 868 Korean participants with pre-advanced macular disease at risk of advanced AMD in the Korean Age-Related Maculopathy Study: 551 with drusen-driven non-advanced AMD (Arm 1) and 317 with pachychoroid-driven disease (Arm 2); 335 (196 Arm 1, 139 Arm 2) completed 5-year follow-up. Methods Phenotypes were classified by multimodal imaging, and incident exudative AMD and GA were adjudicated by retinal specialists. Two prespecified analyses were performed: a complete-case analysis of 5-year incidence and risk factors using logistic generalized estimating equations (Analysis 1) and a full-cohort time-to-event analysis using inverse-probability-of-censoring-weighted Cox models with a competing-risk extension (Analysis 2). Main Outcome Measures Five-year incidence of, and risk factors for, exudative AMD and any GA. Results In the complete-case cohort (Analysis 1), 5-year incidence in Arm 1 was 20.4% (95% CI, 14.8–26.0) for exudative AMD and 12.2% (7.6–16.9) for GA, versus 5.0% (1.4–8.7) and 2.2% (0.5–6.2) in Arm 2. In Arm 1, large soft drusen (odds ratio [OR], 5.12; 95% CI, 1.85–14.19) and reticular pseudodrusen (RPD; OR, 2.21; 95% CI, 1.02–4.81) were independently associated with exudative AMD, and RPD (OR, 10.21; 95% CI, 3.02–34.49) with GA; large soft drusen and RPD acted additively on exudative conversion, whereas GA was driven by RPD. The full-cohort time-to-event analysis (Analysis 2) gave consistent estimates, additionally quantified a strong calcified drusen–GA association (hazard ratio [HR], 7.67; 95% CI, 2.93–20.07), and showed a lower hazard of both outcomes in Arm 2 (exudative AMD HR, 0.47; 95% CI, 0.22–1.00; GA HR, 0.13; 95% CI, 0.03–0.48). In Arm 2, pachydrusen was not associated with progression, whereas exudative conversion was confined to eyes with both pigmentary abnormality and the double-layer sign. Conclusions Five-year progression to advanced AMD differs by phenotype, with substantially higher risk in drusen-driven disease. Distinct biomarker profiles support drusen-driven and pachychoroid-driven disease as distinct phenotypic groups, which may inform risk stratification.