Association of 2-Year Progression Along the AREDS AMD Scale and Development of Late Age-Related Macular Degeneration or Loss of Visual Acuity: AREDS Report 41 | Geriatrics | JAMA Ophthalmology | JAMA Network
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Figure 1.  Five-Year (Years 2-7) Crude Risk of Each Outcome Stratified by Baseline Age-Related Macular Degeneration (AMD) Score and Presence or Absence of at Least 2-Step or at Least 3-Step 2-Year Progression of AMD Score in the First 2 Years After Randomization
Five-Year (Years 2-7) Crude Risk of Each Outcome Stratified by Baseline Age-Related Macular Degeneration (AMD) Score and Presence or Absence of at Least 2-Step or at Least 3-Step 2-Year Progression of AMD Score in the First 2 Years After Randomization

All eyes were from participants who were free of late AMD in both eyes at baseline. The number of events (cumulative) at 5 years was divided by the number at risk at baseline. BCVA indicates best-corrected visual acuity; CGA, central geographic atrophy; GA, geographic atrophy; and NV, neurovascular.

Figure 2.  Adjusted Hazard Ratios (HRs) and 99% CIs Associated With at Least 2-Step or at Least 3-Step 2-Year Progression of Age-Related Macular Degeneration (AMD) Score in the First 2 Years After Randomization for Each Outcome Stratified by Baseline AMD Score
Adjusted Hazard Ratios (HRs) and 99% CIs Associated With at Least 2-Step or at Least 3-Step 2-Year Progression of Age-Related Macular Degeneration (AMD) Score in the First 2 Years After Randomization for Each Outcome Stratified by Baseline AMD Score

All eyes were from participants with a baseline AMD score ranging from 1 to 8 in both eyes. Data were adjusted for age, race, educational level, diabetes, smoking, and use of anti-inflammatory medications. In A and C, the arrowhead followed by a number indicates the upper confidence limit when that limit is so large that it is beyond the range of the x-axis. BCVA indicates best-corrected visual acuity; CGA, central geographic atrophy; GA, geographic atrophy; and NV, neurovascular.

Figure 3.  Adjusted Hazard Ratios (HRs) and 99% CIs Associated With at Least 2-Step or at Least 3-Step 2-Year Progression in the First 2 Years After Randomization for Each Outcome Separately for the Age-Related Eye Disease Study (AREDS) and AREDS2 Cohorts
Adjusted Hazard Ratios (HRs) and 99% CIs Associated With at Least 2-Step or at Least 3-Step 2-Year Progression in the First 2 Years After Randomization for Each Outcome Separately for the Age-Related Eye Disease Study (AREDS) and AREDS2 Cohorts

All eyes were from participants with a baseline age-related macular degeneration (AMD) score ranging from 1 to 8 in both eyes. Data were adjusted for age, sex, race, educational level, and baseline AMD score. The first 2 lines show in each category represent the 2-step 2-year progression, and the last 2 lines represent 3-step 2-year progression. BCVA indicates best-corrected visual acuity; CGA, central geographic atrophy; GA, geographic atrophy; NE, not estimable; and NV, neurovascular.

Table 1.  Hazard Ratios (HRs) for 2-Year Progression of Age-Related Macular Degeneration (AMD) Score in the First 2 Years After Randomization Associated With Each Outcomea
Hazard Ratios (HRs) for 2-Year Progression of Age-Related Macular Degeneration (AMD) Score in the First 2 Years After Randomization Associated With Each Outcomea
Table 2.  Estimated Difference in Final Best-Corrected Visual Acuity (BCVA) at 5-Year Follow-up (Years 2-7) Stratified by Baseline Age-Related Macular Degeneration (AMD) Scorea
Estimated Difference in Final Best-Corrected Visual Acuity (BCVA) at 5-Year Follow-up (Years 2-7) Stratified by Baseline Age-Related Macular Degeneration (AMD) Scorea
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    Original Investigation
    April 9, 2020

    Association of 2-Year Progression Along the AREDS AMD Scale and Development of Late Age-Related Macular Degeneration or Loss of Visual Acuity: AREDS Report 41

    Author Affiliations
    • 1Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland
    • 2The Emmes Company, LLC, Rockville, Maryland
    • 3Fundus Photograph Reading Center, University of Wisconsin–Madison
    • 4Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison
    JAMA Ophthalmol. 2020;138(6):610-617. doi:10.1001/jamaophthalmol.2020.0824
    Key Points

    Question  Could 2-year progression along the Age-Related Eye Disease Study age-related macular degeneration (AREDS AMD) scale be used to estimate the risk of late age-related macular degeneration or loss of visual acuity?

    Findings  Among 3868 participants in the AREDS, this cohort study found statistically significant associations between at least 2-step and at least 3-step 2-year progression of AMD score (occurring between baseline and the 2-year study visit) and subsequent 5-year development of neovascular AMD, central geographic atrophy, any geographic atrophy, or best-corrected visual acuity loss.

    Meaning  Two-year progression of AMD score may be a useful measure in estimating the risk of late AMD outcomes and loss of visual acuity; this finding demonstrates the viability of the AREDS AMD scale in describing AMD progression.

    Abstract

    Importance  The Age-Related Eye Disease Study age-related macular degeneration (AREDS AMD) scale is designed to classify AMD severity. The present cohort study explored whether 2-year progression along this scale was useful for estimating the risk of future progression to late AMD or best-corrected visual acuity (BCVA) loss.

    Objective  To assess whether 2-year progression along the AREDS AMD scale can be used to estimate the probability of long-term clinically meaningful outcome measures for clinical trials or epidemiologic studies.

    Design, Setting, and Participants  Age-Related Eye Disease Study participants enrolled in a clinical trial of oral micronutrient supplements had annual color fundus photographs graded centrally using the AREDS AMD scale. Two-year progression (≥2-step and ≥3-step increases in AMD score between baseline and the 2-year study visit) was evaluated as a method of estimating the risk of long-term progression to late AMD or BCVA loss. The AREDS (1992-2001) was a randomized, placebo-controlled clinical trial based at 11 retinal specialty clinics in the United States. The dates of analysis in the present cohort study were November 1992 through November 2005.

    Main Outcomes and Measures  Development of neovascular (NV) AMD, central geographic atrophy (CGA), any geographic atrophy (GA), or BCVA loss of at least 2 lines or at least 3 lines.

    Results  Among 3868 participants in the AREDS free of late AMD at baseline, the mean (SD) age was 68.3 (5.0) years, and 2180 of 3868 (56.4%) were women. In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression. In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss. After adjusting for demographic and clinical confounders and stratifying by baseline AMD score, statistically significant associations were observed between at least 2-step and at least 3-step 2-year progression of AMD score and subsequent 5-year development of NV AMD: hazard ratios (HRs) ranged from 3.6 (99% CI, 2.4-5.2) to 19.4 (99% CI, 7.7-48.9). For CGA, HRs ranged from 2.6 (99% CI, 1.7-4.0) to 4.7 (99% CI, 2.5-8.9); the results were similar for any GA. For at least 2-line and at least 3-line BCVA loss, HRs ranged from 1.3 (99% CI, 1.0-1.7) to 2.8 (99% CI, 1.8-4.3). For all outcomes, at least 3-step 2-year progression had stronger associations than at least 2-step 2-year progression. These findings were also validated in the AREDS2 cohort.

    Conclusions and Relevance  Two-year progression of AMD score was associated with progression to clinically meaningful anatomic (late AMD) and vision (≥2-line or ≥3-line loss) outcomes, suggesting that this scale may be useful for future clinical trials designed to slow the progression of AMD.

    Introduction

    Age-related macular degeneration (AMD) is the most common cause of loss of visual acuity among older individuals in high-income countries.1-3 Therapies for AMD have focused on the late forms of AMD, neovascular (NV) AMD and geographic atrophy (GA). Although in the past decade anti–vascular endothelial growth factor agents have markedly improved the visual outcome of those with NV AMD,4-6 there is still no effective therapy for GA associated with AMD. Therapies, including complement inhibitors, visual cycle modulators, anti-inflammatory and immunosuppressive agents, and others, have been evaluated for the treatment of established GA. Laser photocoagulation of drusen in eyes with intermediate AMD also proved to be ineffective in reducing the progression to late AMD.7 A recent randomized clinical trial8 of subthreshold nanosecond laser treatment also found no overall beneficial treatment effect on AMD, although a post hoc subgroup analysis demonstrated a possible beneficial effect in eyes with large drusen and without atrophy or reticular pseudodrusen.

    Data from the Age-Related Eye Disease Study (AREDS) were used to develop the AREDS AMD scale9; higher AMD scores at baseline were associated with an increased risk of late AMD over a 5-year period, and risk of late AMD was similar between AREDS and AREDS2 participants with the same AMD scores at baseline.10 Other researchers examined the value of AMD scores in estimating development of late AMD over a 5-year period.11 However, a 5-year follow-up period may be costly (in terms of resources and ongoing relevance) to achieve in clinical trials for new AMD treatments.

    Because best-corrected visual acuity (BCVA) is not greatly affected at the early stages of AMD,12 BCVA may be a less useful surrogate end point in studies of AMD progression at earlier AMD stages. In addition, slow progression rates to late AMD, with resultant requirements for large sample sizes or long follow-up times needed for trials, may discourage efforts to develop earlier-stage therapies to slow AMD progression. Therefore, this cohort study sought to identify a surrogate measure that could be assessed in a shorter time frame and at earlier stages of AMD to estimate the risk of late AMD or loss of visual acuity.

    A 2-step or greater progression in the Early Treatment Diabetic Retinopathy Study (ETDRS) scale13,14 has been used as a primary outcome measure in numerous treatment trials for diabetic retinopathy. Similarly, we assessed whether step changes along the AREDS AMD scale might be useful as a surrogate outcome measure or to estimate the risk for progression to late AMD or loss of visual acuity, which could be useful for future clinical trials of AMD treatments, particularly those targeted at earlier levels of AMD severity. Hence, this report analyzes the association of 2-year progression (≥2-step and ≥3-step increases in AMD score between baseline and the 2-year study visit) with the risk of long-term progression to late AMD or BCVA loss 5 years later (between year 2 and year 7 of the study).

    Methods
    Study Design

    The AREDS (1992-2001) was a randomized, placebo-controlled clinical trial based at 11 retinal specialty clinics in the United States that enrolled 4757 participants. The dates of analysis in the present cohort study were November 1992 through November 2005. Eligible participants for the AREDS were aged 55 to 80 years and could have no AMD in either eye, early or intermediate AMD in one or both eyes, or late AMD in one eye only. Institutional review board approval was obtained at each clinical site (the National Institutes of Health Combined Neuroscience Institutional Review Board was the lead center for the study), and written informed consent for the research was obtained from all study participants.15 The research complied with the tenets of the Declaration of Helsinki16 and the Health Insurance Portability and Accountability Act of 1996; however, this study was conducted before the effective adherence date (April 14, 2003) of the Privacy Rule of the Health Insurance Portability and Accountability Act. Study participants were not compensated or given financial incentive to participate in the study.

    The participants in the AREDS underwent color fundus photography at baseline and annual visits and at visits every 6 months if progression to late AMD was suspected. At each of these visits, updated information on any history of treatment for late AMD was collected. Annual color fundus photographs were graded at the University of Wisconsin Fundus Photograph Reading Center by masked graders with a standardized protocol using the AREDS AMD scale.17 The AREDS AMD scale9 provides an eye-specific, detailed AMD score ranging from 1 to 9 (1 indicates low risk, and 9 indicates high risk) that has been shown to have value for estimating the risk of progression to late AMD. Late AMD was defined as a color fundus photographic grading of NV AMD or central GA (CGA) or a history of treatment for NV AMD. Development of any GA as an outcome was also evaluated.

    For each eye, 2-year progression of AMD score was calculated as the number of step changes in AMD score from baseline through the 2-year study visit. For example, an eye with AMD score of 2 at baseline and AMD score of 5 at the 2-year study visit would have at least a 3-step 2-year progression of AMD score.

    The BCVA was measured with a standardized method at each study visit by examiners using an ETDRS logMAR chart. The BCVA was recorded as the number of letters correctly read (range, 0-100).

    To provide an external validation for the findings herein regarding associations of outcomes with 2-year progression of AMD score, the AREDS2 cohort was used. The AREDS2 (2006-2012)18 demonstrated that lutein and zeaxanthin were a safe, effective substitute for beta carotene in the original AREDS oral micronutrient supplement formulation. The study protocols used to measure study outcomes, particularly color fundus photographic assessment of AMD status, were the same for AREDS and AREDS2, and all image grading was performed at the same reading center.

    Statistical Analysis

    This study included only eyes from participants free of late AMD and any GA in both eyes at the baseline study visit; therefore, only participants with an AMD score of 1 through 8 for both eyes at the baseline study visit were eligible. Outcomes considered were development of NV AMD, CGA, any GA, and at least a 2-line or 3-line BCVA loss. Baseline risk factors were defined at the baseline study visit or, for 2-year progression of AMD score variables, over the 2-year period from baseline to the 2-year study visit. The study included outcomes that occurred between the 2-year visit and the 7-year visit to obtain 5-year follow-up information (outcomes occurring before 2 years were censored for purposes of analysis). Cox proportional hazards regression models (SAS, version 9.4; SAS Institute Inc) were used to estimate the hazard ratio (HR) associated with having 2-year progression of AMD score after controlling for potential confounders (age, sex, race, educational level, body mass index, diabetes, smoking, use of anti-inflammatory or antacid medications, and baseline AMD score) and adjusting for the correlation of eyes within a person.19

    For NV AMD, CGA, and any GA outcomes, statistically significant interactions were found between baseline AMD score and at least 2-step and at least 3-step 2-year progression (ie, the association of 2-year progression differed depending on the eye’s baseline AMD score). Because the interactions did not allow a simple overall assessment of the main association of 2-year progression, all multivariable analyses were performed stratifying by baseline AMD score. For consistency, multivariable analyses were also stratified for the BCVA outcomes. Because the number of events was small for some strata, with consequent instability of HR estimates, baseline AMD score was combined into the following 3 categories: 1 to 3, 4 to 6, and 7 to 8.

    Similar analyses were performed of the associations of 2-year progression of AMD score with NV AMD, GA, and BCVA outcomes in the AREDS2 cohort. Because AREDS2 had less follow-up time available, the 3-year risk of NV AMD, GA, and BCVA outcomes was compared in the AREDS and AREDS2 cohorts. Although AREDS2 recruited patients with a more severe level of AMD, this issue was addressed by stratifying by baseline AMD score. Definitions of 2-year progression and outcome measures were the same for AREDS and AREDS2 for these comparisons.

    Results
    Overall Study Findings

    A total of 3868 participants in the AREDS (mean [SD] age, 68.3 [5.0] years; 2180 [56.4%] women) were free of late AMD in both eyes at baseline (eTable 1 in the Supplement). Almost all (3676 of 3868) participants self-identified as being white individuals. One-quarter (950 of 3865) of participants were obese, 311 (8.0%) had diabetes, and approximately one-third (1460 of 3868) had smoked at least 10 pack-years. A total of 7736 eyes were included in this analysis: 3469 (44.8%) had baseline AMD score of 1, and 210 (2.7%) had baseline AMD score of 8 (the highest level before reaching the level of any GA). The mean (SD) BCVA at baseline was 84.5 (7.3) letters (mean of 20/20). In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression.

    In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss. These results are summarized in eTable 2 in the Supplement.

    After adjusting for demographic and clinical confounders and stratifying by baseline AMD score, statistically significant associations were observed between at least 2-step and at least 3-step 2-year progression of AMD score and subsequent 5-year development of NV AMD: HRs ranged from 3.6 (99% CI, 2.4-5.2) to 19.4 (99% CI, 7.7-48.9) (Table 1). For CGA, HRs ranged from 2.6 (99% CI, 1.7-4.0) to 4.7 (99% CI, 2.5-8.9); the results were similar for any GA. For at least 2-line and at least 3-line BCVA loss, HRs ranged from 1.3 (99% CI, 1.0-1.7) to 2.8 (99% CI, 1.8-4.3). For all outcomes, at least 3-step 2-year progression had stronger associations than at least 2-step 2-year progression.

    Progression to Late AMD and BCVA Loss Based on 2-Year Progression of AMD Score

    The probability of each outcome (late AMD and BCVA loss) was higher for at least 3-step 2-year progression than for at least 2-step 2-year progression (Figure 1 and eTable 2 in the Supplement). The crude risk of NV AMD was 24.0% for those with at least 2-step 2-year progression and 40.7% for those with at least 3-step 2-year progression; for CGA, the respective risks were 15.0% and 21.1%; for any GA, the respective risks were 29.0% and 36.9%. For at least 2-line BCVA loss, the risks were 52.0% for those with at least 2-step 2-year progression and 59.8% for those with at least 3-step 2-year progression; and for at least 3-line BCVA loss, the risks were 38.5% and 48.3%, respectively. eTable 3 and eTable 4 in the Supplement summarize these results stratified by baseline AMD score.

    The univariable risks (HRs) of each outcome associated with baseline status and demographic variables were estimated (eTable 5 in the Supplement). Risks of NV AMD, CGA, any GA, and at least 2-line BCVA loss and at least 3-line BCVA loss were higher for those with than those without 2-year progression of AMD score for all baseline AMD score categories (Figure 1 and eTable 4 in the Supplement).

    Sex, body mass index, and use of antacid medications were not statistically significantly or consistently associated with either of the outcomes and were not included in multivariable analyses. The HRs associated with at least 2-step and at least 3-step 2-year progression variables stratified by baseline AMD score and adjusted for age, race, educational level, diabetes, smoking, and use of anti-inflammatory medications are summarized in Table 1 and Figure 2. The HRs for NV AMD, CGA, and any GA associated with 2-year progression variables were all statistically significant and ranged from 1.6 to 19.4. The risk associated with 2-year progression was greater for eyes with lower baseline AMD scores, particularly for late AMD (NV and any GA) (Table 1): for baseline AMD score of 1 to 3, the HR for NV AMD was 11.8 (99% CI, 5.0-28.0), whereas for baseline AMD score of 7 to 8, the HR for NV AMD was 3.9 (99% CI, 2.6-6.1); for any GA, the HRs were 14.9 (99% CI, 6.0-36.9) and 2.3 (99% CI, 1.6-3.3) for baseline AMD scores of 1 to 3 and 7 to 8, respectively. The HRs were lower for the outcomes of at least 2-line and at least 3-line BCVA loss (range, 1.3-2.8); all were statistically significant except for at least 2-line BCVA loss (for baseline AMD score of 1-3 and ≥3-step 2-year progression of AMD score) (Figure 2 and Table 1).

    Association of 2-Year Progression of AMD Score With Final BCVA

    At least 2-step and at least 3-step 2-year progression of AMD score were both statistically significantly associated with final BCVA after adjusting for baseline confounders (Table 2). After adjustment, at least 2-step 2-year progression of AMD score was associated with a mean of −5.39 (99% CI, −7.34 to −3.44) fewer letters of final BCVA; at least 3-step 2-year progression of AMD score was associated with a mean of −8.45 (99% CI, −12.19 to −4.70) fewer letters of final BCVA. For baseline AMD score of 1 to 3, the association of 2-year progression was smaller (only −1.44 [99% CI, −3.14 to −0.25] to −0.97 [99% CI, −3.89 to 1.94] letters), and the association was not statistically significant for at least 3-step 2-year progression.

    As an external validation of the findings herein, 2-year progression analyses in the AREDS2 cohort were performed. Because follow-up in AREDS2 was shorter (at the time of these analyses), this analysis was limited to risk of 3-year rather than 5-year outcomes. The associations of 2-year progression with outcome variables were similar in the AREDS and AREDS2 cohorts (Figure 3), particularly for the BCVA outcomes. For AREDS and AREDS2, respectively, HRs for the association of at least 2-step 2-year progression with development of NV AMD were strong and of similar magnitude (Figure 3): 5.11 (99% CI, 3.81-6.85) vs 6.56 (99% CI, 5.41-9.34); for CGA, the risks were 3.67 (99% CI, 2.45-5.49) vs 4.75 (99% CI, 3.71-7.50); for any GA, the risks were 3.49 (99% CI, 2.65-4.59) vs 3.37 (99% CI, 2.76-4.85); and for at least 3-line loss of BCVA, the risks were 2.12 (99% CI, 1.72-2.61) vs 2.20 (99% CI, 1.82-3.09). The HRs associated with at least 3-step 2-year progressions in AREDS and AREDS2, respectively, were similarly strong and consistent: for NV AMD, 9.15 (99% CI, 6.39-13.10) vs 15.10 (99% CI, 12.14-22.56); for CGA, 4.55 (99% CI, 2.69-7.69) vs 2.57 (99% CI, 1.83-4.84); for any GA, 3.30 (99% CI, 2.26-4.81) vs 1.57 (99% CI, 1.16-2.73); and for at least 3-line loss of BCVA, the risks were 2.86 (99% CI, 2.12-3.85) vs 2.98 (99% CI, 2.42-4.37).

    Discussion

    Eyes that had 2-year progression of AMD score of at least 2 steps or at least 3 steps had a statistically significantly increased risk of late AMD and loss of visual acuity outcomes 5 years later compared with eyes that did not have 2-year progression of AMD score; this finding held true even after adjustment for demographic variables, a number of clinical risk factors, and baseline AMD score. The risk of late AMD and loss of visual acuity was greater for larger step sizes, suggesting that eyes with more rapid worsening of AMD even in the early stages of the disease are at greater risk. Indeed, the risk associated with 2-year progression was greater for eyes with lower baseline AMD scores, particularly for late AMD (NV and any GA) (Table 1).

    This study sought to evaluate the performance of the AREDS AMD scale in estimating the risk of progression to late AMD or BCVA loss. This type of assessment has been carried out for other scales and other ocular diseases. For example, the ETDRS has a detailed scale for diabetic retinopathy that was used as an end point in major clinical trials.20,21 One advantage of a detailed grading scale is that it has the potential to be used to define surrogate measures for end points that occur infrequently or only after years of follow-up. Clinical trials based on the surrogate end points might require fewer participants or shorter follow-up time to achieve adequate power for detecting clinically meaningful differences between treatments. The ETDRS scale has been used to develop a surrogate end point based on steps of progression along the scale over a 4-year period22; this surrogate measure was demonstrated to be useful for estimating the risk of developing late-stage diabetic retinopathy.

    Indaram et al23 used AREDS data to conduct a study similar to the present report of the association of changes on a cataract grading scale over a 2-year period with 5-year outcomes (progression to cataract surgery and loss of visual acuity). They reported that 2-year changes in nuclear (≥1.0-unit increase), cortical (≥5% increase), and posterior subcapsular cataract (≥5% increase) scores were statistically significantly associated with progression to cataract surgery and at least 2-line decrease in BCVA.

    We are unaware of other studies that have examined the value of short-term changes in AMD status in estimating the risk of late AMD outcomes. Few long-term follow-up studies have such levels of phenotyping and outcome reporting. For comparison purposes, analyses were also performed to assess the value of 2-year progression of AMD score in estimating the risk of progression in the AREDS2 cohort,18 the only available study with comparable annual color fundus photographic grading of AMD. The associations of 2-year progression with outcome variables were similar in the 2 studies, although they were not as consistent for NV AMD and GA outcomes as for the BCVA outcomes.

    Strengths and Limitations

    This study has several strengths. These strengths include the standardized assessment of AMD status by masked reading center grading and standardized measurement of BCVA, regularly spaced study visits, long-term follow-up (5 years) with limited loss to follow-up of the study cohort, and large sample size.

    This study also has some limitations. They include the potential consequences of cataract formation on the results herein. The main outcome measures of interest were late AMD outcomes (progression to NV AMD, CGA, or GA). Included were at least 2-line BCVA loss and at least 3-line BCVA loss mainly as secondary outcomes. Ascertainment of late AMD outcomes was not substantially altered by cataract progression or cataract surgery during follow-up: color fundus photographs were gradable in most cases, suggesting that progression to dense cataract was uncommon. Furthermore, because refracted BCVA was used, ascertainment of BCVA outcomes was not likely altered by lesser degrees of cataract. Nevertheless, a small number of study eyes might have met the 2-line to 3-line BCVA loss outcome through cataract progression in addition to or instead of progression to late AMD. Unfortunately, distinguishing the relative contributions of cataract progression vs AMD progression to BCVA loss is not straightforward; therefore, we opted not to increase the complexity of the analyses by accounting for cataract grading.

    In addition, clinical trials of potential therapies to slow AMD progression require large samples sizes and long follow-up time, often limited to eyes at high risk of progression, to obtain a sufficient number of late AMD events. The ability to study progression earlier along the AREDS AMD scale as a surrogate outcome would improve the capability to perform clinical trials with fewer numbers of participants and shorter follow-up time and to include eyes with lower baseline severity. The aim herein was to evaluate 2-year progression of AMD score as a research tool, not as an application for day-to-day clinical settings; we believe the impracticality of using the 9-step AREDS AMD scale in a clinical setting does not alter the interpretation of the results herein (the AREDS simplified severity scale24 is a better clinical tool for clinicians).

    An additional limitation is that the AMD grading herein is based on color fundus photographs, which were the primary method for assessing AMD during the study. Optical coherence tomography imaging is used to more precisely document pathological changes associated with AMD; it is possible that different associations might have been found if optical coherence tomography imaging had been available. A further limitation is that the definition of 2-year progression of AMD score used herein was based on the study baseline through the 2-year study visit; therefore, it is unknown whether progression may have occurred before baseline. In addition, because participants with GA at study baseline were excluded (because GA constituted a study outcome), it is unknown whether the findings of the present study might be applicable to GA studies specifically. Finally, many factors were tested in these analyses, so some of the statistically significant findings may be due to chance; however, the consistency of the results, particularly with the AREDS2 comparisons, bolsters the validity of the findings. It is anticipated that future studies may provide additional validation for the AREDS AMD scale and for 2-year progression as risk factors for late AMD or loss of visual acuity outcomes.

    Conclusions

    Eyes that had 2-year progression of AMD score were at increased risk of late AMD or BCVA loss. The risk associated with 2-year progression was greater for eyes with lower baseline AMD scores and was increased in terms of progression to NV AMD vs GA. Because NV AMD is an eminently treatable form of late AMD but requires rapid detection for optimal visual outcomes, it is recommended that eyes with 2-year progression be monitored closely. We believe that these findings further demonstrate the viability of the AREDS AMD scale to describe progression of AMD. Others should replicate these analyses in independent studies to further assess the value of 2-year progression of AMD score in estimating the risk for development of late AMD or loss of visual acuity.

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    Article Information

    Accepted for Publication: February 23, 2020.

    Published Online: April 9, 2020. doi:10.1001/jamaophthalmol.2020.0824

    Correction: This article was corrected on May 21, 2020 to fix the subtitle.

    Corresponding Author: Susan Vitale, PhD, MHS, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, 10 Center Dr, Room 10D45, Bethesda, MD 20892 (sev@nei.nih.gov).

    Author Contributions: Dr Vitale had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Vitale, Chew.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Vitale, Chew.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Vitale, Agrón, Clemons.

    Obtained funding: Chew.

    Administrative, technical, or material support: Domalpally, Danis.

    Supervision: Chew.

    Conflict of Interest Disclosures: Dr Clemons reported receiving a contract from the National Eye Institute (NEI) as principal investigator of the Data Coordinating Center for the AREDS/AREDS2 studies. Dr Keenan reported receiving grants from Bayer and being the 2015 Bayer Global Ophthalmology Award Program Awardee. Dr Domalpally reported receiving grants from the University of Wisconsin, Madison. Dr Danis reported receiving grants from the NEI and receiving personal fees from EyeKor, Inc. No other disclosures were reported.

    Funding/Support: This study was supported by intramural program funds and contract NOI-EY-0-2127 from the NEI. It was supported in part by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison (Drs Domalpally and Danis).

    Role of the Funder/Sponsor: The NEI participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Research to Prevent Blindness participated in the collection, management, analysis, and interpretation of the data.

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