Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials

Abstract

Purpose: To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).

Design: Cohort within a randomized clinical trial.

Participants: We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment.

Methods: Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs).

Main outcome measures: Development of GA.

Results: By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.

Conclusions: Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.

Figure 1

Development of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (AMD) after 2 years of anti-vascular endothelial growth factor therapy. A1, Choroidal neovascularization (CNV) at baseline on color fundus photography (CFP). A2, Classic CNV (white arrow) at baseline on fluorescein angiography (FA). A3, Optical coherence tomography (OCT) showing at baseline the CNV lesion with prominent intraretinal fluid (white arrow). A4, At 2 years of follow-up, CFP depicts a large GA lesion in the area of the previously active CNV (black arrow) and an additional small area of GA superior to the baseline CNV (white arrow). A5, At 2 years of follow-up, FA shows areas of hyperfluorescence with well-demarcated margins corresponding with the areas of GA in A4. A6, An OCT scan showing at 2-year follow-up increased choroidal signal penetration (white arrows) corresponding with the GA in A4. B1, Baseline CFP of active CNV. B2, Baseline FA shows active CNV with leakage. B3, Baseline OCT shows CNV with subretinal fluid (white arrow). B4, At 2 years, CFP shows a large area of central GA. B5, At 2 years, FA image shows a well-demarcated area of hyperfluorescence corresponding to the GA lesion in B4. B6, At 2 years, OCT shows attenuated retina overlying a well-demarcated area of increased choroidal signal penetration in the central macula (white arrows) corresponding with the GA lesion. C1, Baseline CFP shows a peripapillary active CNV lesion surrounded by hemorrhage (white arrow). C2, Baseline FA shows hyperfluorescence and leakage in the area of active CNV (white arrow) seen in C1. C3, Baseline OCT shows subretinal hyperreflective material in the area of CNV (black arrow) and subretinal fluid under the fovea (white arrow). C4, At 2 years, CFP shows a well-defined area of GA adjacent to the area of CNV present in C1. C5, At 2 years FA shows hyperfluorescence corresponding to the area of GA seen in C1. C6, At 2 years, OCT shows outer retinal layer loss and areas of increased choroidal signal penetration (white arrows) corresponding with the GA seen in C4.

Figure 2

Typical case of contiguous blocked fluorescence surrounding choroidal neovascularization. A, Color fundus photography shows active choroidal neovascularization. B, Fluorescein angiography depicts an area of blocked fluorescence contiguous with the choroidal neovascularization (white arrows).

Figure 3

Flow chart describing the patients of the study. GA = geographic atrophy.