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

Abstract

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. To determine the incidence and progression of non-GA (NGA) and associated risk factors. 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. 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. Incidence of nAMD-associated NGA (hypopigmentation and hyperpigmentation in color images) and progression; adjusted risk ratios (aRR) for baseline characteristics. 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). 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. ClinicalTrials.gov Identifier: NCT00593450.