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

Abstract

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 μm: aRR, 0.59 [95% CI, 0.46-0.75], compared with ≤75 μm; 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.

Trial registration: ClinicalTrials.gov Identifier: NCT00593450.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Daniel reported grants from the National Eye Institue during the conduct of the study. Dr Maguire reported grants from the National Eye Institute during the conduct of the study and personal fees from Genentech/Roche outside the submitted work. Dr Toth reported grants from the National Institutes of Health during the conduct of the study and royalties from Alcon (through Duke University) and other support from Hemosonics outside the submitted work. Dr Jaffe reported personal fees from Heidelberg Engineering, Genentech/Roche, Neurotech, Alcon/Novartis, Graybug, and EyePoint outside the submitted work. Dr Ying reported grants from the National Eye Institute during the conduct of the study and personal fees from Chengdu Kanghong Biotech Ltd, Ziemer Ophthalmic Systems AG, and Synergy Research Inc outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Examples of Nongeographic Atrophy (NGA) Evolution in Color Fundus Photographs in the Area of Baseline Choroidal Neovascularization

A and B, NGA present at year 1 remained present at year 5 without progressing to geographic atrophy (GA). C and D, NGA present at year 1 (C; white arrowhead) progressed to GA at year 5 (D; black arrowhead).

Figure 2.. Kaplan-Meier Curves for the Incidence of Nongeographic Atrophy and Probability of Progression From Nongeographic Atrophy (NGA) to Geographic Atrophy (GA)

A, Kaplan-Meier curve for the cumulative incidence of NGA. B, Kaplan-Meier curve for the cumulative probability of progression from to geographic atrophy.