Associations of Variation in Retinal Thickness With Visual Acuity and Anatomic Outcomes in Eyes With Neovascular Age-Related Macular Degeneration Lesions Treated With Anti-Vascular Endothelial Growth Factor Agents

Abstract

Importance: When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation.

Objective: To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness.

Design, setting, and participants: In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020.

Main outcomes and measures: Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy.

Results: Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy.

Conclusions and relevance: Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.

Figure 1.. Estimates of Associations of Foveal Center Point Thickness (FCPT) SD Quartile With Final Best-Corrected Visual Acuity (BCVA)

A, The primary analysis model adjusted for baseline BCVA, trial, and randomized allocations to drug and treatment regimen and included 1720 participants. B, Sensitivity analysis 1, which restricted the primary model to participants with 9 or more FCPT measurements, included 1169 participants. C, Sensitivity analysis 2, which additionally adjusted the primary model for age, baseline legion size, choroidal neovascularization type, FCPT, and intraretinal fluid, included 1577 participants with complete data. D, Sensitivity analysis 3, which restricted the primary model to participants in the pro re nata groups only, included 870 participants. Quartile 1 was defined as an FCPT SD less than 34.01 μm; quartile 2, 34.01 μm to less than 51.49 μm; quartile 3, 51.49 μm to less than 80.59 μm; and quartile 4, greater than 80.59 μm. ETDRS indicates Early Treatment Diabetic Retinopathy Study.

Figure 2.. Estimates of Associations of Foveal Center Point Thickness (FCPT) SD Quartile With Development of Fibrosis

Models were restricted to participants with fibrosis absent at baseline and data available at final visit (n = 1443). A, The primary analysis model adjusted for baseline trial and randomized allocations to drug and treatment regimen and included 1443 participants, of which 789 developed fibrosis. B, Sensitivity analysis 1, which restricted the primary model to participants with 9 or more FCPT measurements, included 1007 participants. C, Sensitivity analysis 2, which additionally adjusted the primary model for age, baseline legion size, choroidal neovascularization type, FCPT, and intraretinal fluid, included 1335 participants with complete data. D, Sensitivity analysis 3, which restricted the primary model to participants in the pro re nata groups only, included 718 participants. Effect estimates by trial for sensitivity analysis 3 are described in eFigure 9 in the Supplement, as the interaction with trial was statistically significant. Quartile 1 was defined as an FCPT SD less than 34.01 μm; quartile 2, 34.01 μm to less than 51.49 μm; quartile 3, 51.49 μm to less than 80.59 μm; and quartile 4, greater than 80.59 μm. OR indicates odds ratio.

Figure 3.. Estimates of Association of Foveal Center Point Thickness (FCPT) SD Quartile With Development of Geographic Atrophy (GA)

Models were restricted to participants with GA absent at baseline and data available at final visit (n = 1463). A, The primary analysis model adjusted for baseline trial and randomized allocations to drug and treatment regimen and included 1463 participants, of which 310 developed GA. B, Sensitivity analysis 1, which restricted the primary model to participants with 9 or more FCPT measurements, included 1001 participants. C, Sensitivity analysis 2, which additionally adjusted the primary model for age, baseline legion size, choroidal neovascularization type, FCPT, and intraretinal fluid, included 1354 participants with complete data. D, Sensitivity analysis 3, which restricted the primary model to participants in the pro re nata groups only, included 734 participants. Quartile 1 was defined as an FCPT SD less than 34.01 μm; quartile 2, 34.01 μm to less than 51.49 μm; quartile 3, 51.49 μm to less than 80.59 μm; and quartile 4, greater than 80.59 μm. OR indicates odds ratio.