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

Abstract

Objective: To describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).

Design: Prospective cohort study within a randomized clinical trial.

Participants: Patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).

Methods: Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation.

Main outcome measures: Scar formation.

Results: Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars.

Conclusions: Approximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar.

Trial registration: ClinicalTrials.gov NCT00593450.

Figure 1

Development of fibrotic scar from classic choroidal neovascularization (CNV). A, Choroidal neovascularization at baseline developing into a fibrotic scar at 2 years. B, Classic CNV seen on color fundus photography and fluorescein angiography (FA) at baseline does not extend into the foveal center (white X), whereas baseline optical coherence tomography shows subretinal hyperreflective material under the fovea (B4, white arrows). Color fundus photographs and FA at 2 years show a fibrotic scar extending into the foveal center and beyond the baseline CNV. C, Baseline early FA (C2) shows leakage (black arrow) that characterizes classic CNV within a large occult CNV lesion (C2, white arrow). Optical coherence tomography shows retinal pigment epithelium (RPE) elevation with a hyperreflective “onion peel” appearance in the sub-RPE space that corresponds to the occult lesion (C4, black arrow). At 2 years, there is a small yellow fibrotic scar (C5 , black arrow) at the site of the baseline classic CNV. There is no fibrous scarring in the area of occult CNV. Optical coherence tomography shows flattening of the RPE elevation (C8, white arrow) and a persisting “onion-peel” appearance in the subretinal space.

Figure 2

Development of nonfibrotic scars. A, Classic choroidal neovascularization (CNV) (A2) at baseline. At 2 years, color fundus photography (CFP) (A3, A4) shows a circumscribed small area of hypopigmentation surrounded by a ring of dark pigmentation. B, Classic CNV at baseline (B1–4). Dark pigmentation in the area of the baseline CNV (B5 and B6, white arrow) at 1 year. Optical coherence tomography shows retinal pigment epithelium (RPE) elevation with hyperreflective material in the sub-RPE space. At 2 years, an area of hypopigmentation is seen within the darkly pigmented area. C, Baseline CFP shows several areas of geographic atrophy around the foveal center. Fluorescein angiogram shows classic CNV (complement component 3) and optical coherence tomography shows subretinal fluid overlying an area of subretinal hyperreflective material (C4, white arrow). There is increased signal penetration into the choroid. At 2 years, the CFP shows a small, yellow, flat scar in the area of baseline CNV, closely resembling the geographic atrophy (within the black square on C5). However, unlike the adjacent areas of geographic atrophy, in this region, the choroidal vessels are not visible. Optical coherence tomography shows thickened hyperreflective material (C8). The first 2 examples (A1-A4 and B1-B12) demonstrate the typical appearance of a nonfibrotic scar with signet-shaped hyperpigmentation surrounding an area of hypopigmentation. The last example (C1-C8) shows a flat scar without pigmentation that seems to be an uncommon presentation of nonfibrotic scar.