Incidence and Progression of Nongeographic Atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Clinical Trial

This post hoc analysis of a cohort study within the Comparison of Age-Related Treatments Trials (CATT) clinical trial seeks to determine incidence and progression of and risk factors for nongeographic atrophy in eyes treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Importance Retinal hypopigmentation and hyperpigmentation are precursors of geographic atrophy (GA). Incidence and progression to GA in eyes treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration (nAMD) have not been investigated. Objective To determine the incidence and progression of non-GA (NGA) and associated risk factors. Design, Setting, and Participants This study is a post hoc analysis of a cohort study within the Comparison of Age-Related Treatments Trials (CATT) clinical trial. Participants were recruited February 20, 2008, through December 9, 2009; released from protocol follow-up and treatment after 2 years; and recalled from March 14, 2014, through March 31, 2015. Data analyses were conducted from January 11, 2019, through November 27, 2019. Interventions Participants were randomized to ranibizumab or bevacizumab for (1) 2 years of monthly or as-needed injections or (2) monthly injections for 1 year and as-needed injections the following year. Participants were treated according to best medical judgement thereafter. Main Outcomes and Measures Incidence of nAMD-associated NGA (hypopigmentation and hyperpigmentation in color images) and progression; adjusted risk ratios (aRR) for baseline characteristics. Results Among 1107 participants, risk of NGA was 35% (391 eyes), 59% (246 eyes), and 81% (122 eyes) at 1, 2, and 5 years, respectively. Risk factors for NGA included worse visual acuity (20/200-20/320: aRR, 1.74 [95% CI, 1.24-2.43], compared with <= 20/40; P = .006), larger neovascularization area (>4 disc areas: aRR, 1.31 [95% CI, 1.01-1.71], compared with <= 1 disc areas; P = .007), switched drug regimen (aRR, 1.28 [95% CI, 1.06-1.54], compared with as-needed injections; P = .02), and single-nucleotide variants Age-Related Maculopathy Susceptibility 2 (ARMS2) (TT variant: relative risk [RR], 1.53 [95% CI, 1.22-1.93]; P = .001) and HtrA Serine Peptidase 1 (HTRA1) (AG variant: RR, 1.23 [95% CI, 1.01-1.48]; AA variant: RR, 1.51 [95% CI, 1.20-1.91]; P = .002). Sub-retinal pigment epithelium thickness was protective (>275 mu m: aRR, 0.59 [95% CI, 0.46-0.75], compared with <= 75 mu m; P < .001). Among 389 eyes with NGA by 2 years and subsequent color images, risk of progression to GA was 29%, 43%, and 50% at 1, 3, and 4 years, respectively. Risk factors for progression to GA included worse visual acuity (20/200-20/320: aRR, 2.75 [95% CI, 1.54-4.93], compared with <= 20/40; P < .001), worse fellow-eye visual acuity (<20/40: aRR, 1.77 [95% CI, 1.12-2.79], compared with >= 20/40; P = .01), fellow-eye GA (aRR, 1.71 [95% CI, 1.06-2.75]; P = .03), and pseudodrusen in either eye (aRR, 1.65 [95% CI, 1.17-2.34]; P = .005). Subretinal fluid was associated with a decreased risk of progression (aRR, 0.42 [95% CI, 0.28-0.63]; P < .001). Conclusions and Relevance In this study, after 2 years of protocol-guided anti-vascular endothelial growth factor treatment for nAMD, more than half of the eyes in the study developed NGA in the location of nAMD. After 3 additional years of regular care, half of them progressed to GA. Question What is the incidence of nongeographic atrophy (NGA) in eyes treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration, and how often does it progress to geographic atrophy (GA)? Findings In this longitudinal study, the cumulative risk of NGA was 35%, 59%, and 81% at 1-year, 2-year, and 5-year follow-ups, respectively. The cumulative risk of progression from incident NGA in years 1 and 2 to GA was 29%, 43%, and 50% at 1, 3, and 4 years, respectively. Meaning Nongeographic atrophy, as defined in CATT, is common and progresses to GA in about 50% of participants by 4 years after onset.