Materials and Methods
The design and protocol of the READ-2 study have been described in detail elsewhere and are summarized here. After the primary end point at M6, patients and investigators had the option to switch to RBZ only treatment. Consequently, during the 18-month follow-up period, patients in all three groups were mostly treated with RBZ alone. Patients were divided based upon visual outcome at M24 into poor visual outcome (≤20/100) vs better visual outcome (>20/100). Patients in the poor visual outcome group were further divided into two groups based on presence (poor vision/edema) or absence (poor vision/no edema) of edema contributing to poor BCVA. Edema was judged to be contributing to poor vision if there was foveal thickening at M24, and during months 12–24 there was a correlation between reduced FTH and improved BCVA. Patients were included in the analysis if they had completed 20–24 months of the READ-2 study, and M24 data were used when available. If a patient did not have the M24 study visit, but had a study visit at M20 or beyond, the last observation was carried forward. If fundus photography and fluorescein angiography (FA) images from M24 were not available, images from M12 were used for analysis as long as no laser treatment was administered between months 12 and 24. Data regarding demographics, baseline characteristics, BCVA, presence of edema, FTH, treatment received during the study, and grading of fundus photographs and FA images were analyzed and compared among groups. Fundus photography and FAs were analyzed at the Wilmer Retinal Imaging Research and Reading Center (RIRRC) for the presence of the following characteristics: evidence of extensive laser treatment, foveal atrophy, laser within 1 mm of the fovea, pigment changes within 1 mm of the fovea, and severe macular ischemia. Information regarding duration of macular edema was obtained from patient charts in which macular edema was first documented as a finding on exam or ophthalmic imaging. FTH of the central 1 mm of the macula was measured using Stratus Optical Coherence Tomography, scans were reviewed at the RIRRC and the thickness values were used for analysis. Images were received electronically from all sites via a central database. Images acquired from different cameras were resized to have uniform dimensions across images, an ETDRS grid was overlaid, the area of the macula covered by laser scars was measured using the software Image J (National Institutes of Health, Bethesda, MD, USA; available at http://rsbweb.nih.gov) and expressed as a percentage of the total area covered by the ETDRS grid. Patients were considered to have evidence of extensive laser treatment if more than 20% of the macula had laser scars or if patients had a history of having received laser treatment with more than 200 burns before being enrolled in the study. Laser scars were further assessed to look for presence in the central 1 mm of the ETDRS grid to determine whether laser treatment closer to the fovea was associated with poor visual outcomes. Severe macular ischemia was considered to be present if there was closure of perifoveal capillaries for 360° extending at least 1 mm from the fovea. Foveal atrophy was judged from the presence of window defect on FA and retinal thinning on OCT images. If hyper- or hypopigmentary changes were identified on color FP in the central 1 mm of the macula, the patient was judged to have pigmentary changes.
Statistical Package for the Social Sciences version 19 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. For the purposes of analysis, fundus photo and FA characteristics that could not be graded were considered as missing values. The independent samples t-test was used for parametric variables, and the Wilcoxon Signed-Rank test was used for non-parametric variables. Differences in proportion among categorical variables were determined using Pearson's χ and Fisher's exact test. Variables that had a P-value of <0.05 upon univariate analysis were selected for the multivariate model. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.