Natural History of Predominantly Classic, Minimally Classic, and Occult Subgroups in Exudative Age-related Macular Degeneration Ankoor R. Shah, BS, Lucian V. Del Priore, MD, PhD Objectives: We previously showed that the pattern of vision loss in eyes with subfoveal neovascularization in age-related macular degeneration (AMD) is uniform across a wide range of clinical trials, with apparent differences arising from differences in the time of entry of patients into clinical trials. In the current study, we used a similar analysis to compare the visual loss of untreated control eyes classified as predominantly classic (PC), minimally classic (MC), and occult with no classic (occult) based on fluorescein angiography. Design: Meta-analysis of prior clinical trials. Participants: Data from patients enrolled in the Macular Photocoagulation Study (MPS), Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study, Verteporfin in Photodynamic Therapy (VIP) Study, Anecortave Acetate (AA) Trial, VEGF Inhibition Study in Ocular Neovascularization (VISION), and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) Trials. Methods: Visual acuity (VA) data of untreated control eyes for each study from appropriate subgroups were plotted on a double reciprocal (Lineweaver-Burke) plot of 1/[letters lost] versus 1/[months]. To correct for differences in time of entry into clinical trials, we introduced a horizontal translation factor to shift each data subset. Main Outcome Measures: We determined the coefficient of determination before and after adjustments for visual acuity at the time of enrollment. Results: On a Lineweaver-Burke plot, the cumulative subgroups had an overall coefficient of determi- nation of only r 2 0.01 for the raw data but improved to a remarkably high r 2  0.90 when data were corrected for time of entry into clinical trials. For each subgroup there was excellent correlation between 1/[letters lost] versus 1/[months of exudative disease] for PC (r 2  0.91), MC (r 2  0.95), and occult (r 2  0.98) choroidal neovascularization. Conclusions: We were able to demonstrate a strong correlation for visual acuity as a function of time that is independent of the fluorescein angiography classification of a lesion, suggesting that initial protocol visual acuity, rather than angiographic classification, is the major determinant of the behavior of visual acuity as a function of time in exudative AMD. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2009;116:1901–1907 © 2009 by the American Academy of Ophthalmology. In the United States and Western Europe, age-related mac- ular degeneration (AMD) is the leading cause of visual loss in patients older than 50 years, and a shift in patient demo- graphics to older populations will increase the prevalence of this disease in the future. 1,2 Visual loss in AMD occurs by 2 distinct mechanisms. In nonexudative AMD, visual loss develops as the result of geographic atrophy involving the foveal center. 1,2 In exudative AMD, visual loss develops secondary to ingrowth of choroidal neovascularization within Bruch’s membrane and between Bruch’s membrane and the retinal pigment epithelium (RPE), leading to bleed- ing, exudation, and eventual scar formation in the untreated eye. 3 In the course of developing therapy for exudative AMD the observed lesions have been divided into various sub- groups based on the characteristics of fluorescein angiogra- phy. Early studies focused on whether the lesion was ill defined or well defined based on fluorescein angiography giving rise to the categories of occult and classic lesions, respectively. Subsequently, classic lesions were further di- vided to predominantly classic (PC) or minimally classic (MC) depending on whether the lesion showed 50% clas- sic component or not. 4 During the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study, the subgroup distinctions were used because treat- ments such as photodynamic therapy with verteporfin (PDT) were only found to be effective in certain sub- groups. 4 Since then, subgroup classification has been im- plemented in numerous trials, and prior authors have em- phasized the importance of fluorescein angiographic classification on natural history of visual loss and the effi- cacy of some treatments. 5–7 We previously showed that the pattern of vision loss experienced in AMD eyes with subfoveal neovasculariza- 1901 © 2009 by the American Academy of Ophthalmology ISSN 0161-6420/09/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2009.03.055