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

Key Points Question Are fluctuations in retinal thickness associated with visual and anatomic outcomes in eyes with neovascular age-related macular degeneration treated with anti–vascular endothelial growth factor drugs? Findings In this study of 1731 participants from 2 randomized clinical trials, increasing variation in retinal thickness was associated with worse outcomes in post hoc analyses of protocol-directed treatment regimens. Meaning These findings suggest that fluctuating activity may be a marker for poor prognosis in eyes with neovascular age-related macular degeneration treated with anti–vascular endothelial growth factor drugs.


Grading methods1-additional information
In IVAN, grading for fibrosis and GA, used color images and fluorescein angiograms (FA) at baseline, 12 and 24 months. Fibrosis was graded as present when creamy white or yellow material was observed within the boundaries of the nAMD lesion on color images. On FA, fibrosis was deemed to be present if there was an area of blocked fluorescence in the early phase with hyperfluorescence in the mid-phase which faded in late frames. GA was defined as any area of atrophy, present either in regions previously occupied by the nAMD complex or elsewhere. In color images GA is seen as a region of pallor with or without sharp edges leading to visibility of underlying choroidal large vessels. On FA, this corresponds to an area of early hyperfluorescence with welldefined borders which does not change during the angiographic run.
In CATT, fibrotic scars were defined as obvious white or yellow mounds of fibrous-appearing tissue that were well defined in shape and appeared solid on color stereo images. Hyperfluorescence due to tissue staining or blocked fluorescence of the underlying choroid was present on FA. Both CFP and FA were used in assessing and characterizing GA. The diagnosis of GA required the presence within the macular vascular arcades of ≥1 patches ≥250 μ in longest linear dimension of partial or complete depigmentation in the CFP that had ≥1 of these additional characteristics: sharply demarcated borders seen in CFP and/or FA, visibility of underlying choroidal vessels, excavated or punched out appearance on stereoscopy of CFP or FA, or uniform hyperfluorescence bounded by sharp borders on late-phase angiography.

Statistical methods1-additional information
All analyses were restricted to eyes for which data for all model covariates were available and included trial as a fixed effect. An interaction term between FCPTSD quartile and trial was included to investigate whether the association differed between the studies. If the interaction was not statistically significant at the 10% level, we report an overall effect. If the interaction was statistically significant, we report the effect sizes for the two studies separately. Assumptions underpinning the statistical models were checked using standard methods (e.g. residual plots). If the assumptions were not satisfied, transformations or alternative methods were explored.
Three sensitivity analyses (SA) were carried out to test the robustness of the estimates from the model. SA1. Restricting the model to participants who had ≥9 FCPT measurements during time on study, to minimize the variation in precision of FCPTSD across participants in the analysis. SA2. Adjusting the model additionally for age, lesion size, choroidal neovascularization (CNV) type (classic/occult), FCPT and intraretinal fluid (IRF) at baseline, because these covariates are prognostic for BCVA and might confound the association. SA3. Restricting the analyses to the groups allocated to treatment-when-required, because in the monthly groups (a) the distribution of treatment frequency was highly skewed and (b) non-adherence to monthly treatment was likely to have arisen due to missed visits. SA4. Censoring FCPT measurements at one year in the calculation of FCPTSD in eyes which develop fibrosis during the first year, to limit the inclusion of FCPT fluctuations that occurred after the development of fibrosis.
To explore whether the association between FCPTSD quartile and outcome differed between study eyes with a high FPCT compared to those with a low FCPT, for each individual average FCPT measurements during follow-up was calculated (within-person mean). Study eyes were dichotomized to low or high average FCPT and an interaction between average FCPT group and FCPTSD quartile was included in the model.