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Global Burden of Dry Age-Related Macular Degeneration: A Targeted Literature Review

Open AccessPublished:September 18, 2021DOI:https://doi.org/10.1016/j.clinthera.2021.08.011

      Abstract

      Purpose

      Age-related macular degeneration (AMD) is a leading cause of blindness, particularly in higher-income countries. Although dry AMD accounts for 85% to 90% of AMD cases, a comprehensive understanding of the global dry AMD burden is needed.

      Methods

      A targeted literature review was conducted in PubMed, MEDLINE, Embase, and the Cochrane Database of Systematic Reviews (1995-2019) to identify data on the epidemiology, management, and humanistic and economic burden of dry AMD in adults. A landscape analysis of patient-reported outcome (PRO) instruments in AMD was also conducted via searches in PubMed (1995-2019), ClinicalTrials.gov, PROQOLID, PROLABELS, and health technology assessment reports (2008-2018).

      Findings

      Thirty-seven of 4205 identified publications were included in the review. Dry AMD prevalence was 0.44% globally, varied across ethnic groups, and increased with age. Patients with dry AMD had higher risks of all-cause mortality (hazard ratio [HR] = 1.46; 95% CI, 0.99–2.16) and tobacco-related (HR = 2.86; 95% CI, 1.15–7.09) or cancer deaths (HR = 3.37; 95% CI, 1.56–7.29; P = 0.002) than those without dry AMD. Smoking, increasing age or cholesterol levels, and obesity are key risk factors for developing dry AMD. No treatment guidelines were identified for dry AMD specifically; management focuses on risk factor reduction and use of dietary supplements. In the United States and Italy, direct medical costs and health care resource utilization were lower in patients with dry versus wet AMD. Patients with dry AMD, particularly advanced disease, experienced significant visual function impairment. Dry AMD symptoms included reduced central vision, decreased ability to see at night, increased visual blurriness, distortion of straight lines and text, and faded color vision. Most PRO instruments used in AMD evaluations covered few, if any, of the identified symptoms reported by patients with dry AMD. Although the Quality of Life and Vision Function Questionnaire, 25-item National Eye Institute Vision Function Questionnaire, Low Vision Quality of Life, Impact of Vision Impairment–Very Low Vision, and Functional Reading Independence Index had strong content validity and psychometric properties in patients with dry AMD, they retained limited coverage of salient concepts.

      Implications

      Despite dry AMD accounting for most AMD cases, there are substantial gaps in the published literature, particularly the humanistic and economic burden of disease and the lack of differentiation among dry, wet, or unspecified dry AMD. The significant burden of illness alludes to a high unmet need for tolerable and effective treatment options, as well as PRO instruments with more coverage of dry AMD symptoms and salient concepts.

      Key words

      Introduction

      Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, particularly in higher-income countries, and was projected to affect 196 million people globally in the year 2020.
      • Bourne RRA
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      Causes of vision loss worldwide, 1990-2010: a systematic analysis.
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      • Wong WL
      • Su X
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      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      AMD is a progressive condition characterized by degeneration of the macula; although several classification systems exist, there is no standardized clinical definition for AMD and corresponding disease stages.
      AMD includes the dry or atrophic form, characterized by retinal pigmented epithelium (RPE) dysfunction, photoreceptor loss, and retinal degeneration, and the wet form, characterized by choroidal neovascularization with intraretinal or subretinal leakage, hemorrhage, and RPE detachments.
      • Hernández-Zimbrón LF
      • Zamora-Alvarado R
      • Ochoa-De la Paz L
      • et al.
      Age-related macular degeneration: new paradigms for treatment and management of AMD.
      Dry AMD accounts for 85% to 90% and wet AMD for 10% to 15% of cases.
      • Ambati J
      • Fowler BJ.
      Mechanisms of age-related macular degeneration.
      ,
      • Ferris III, FL
      • Fine SL
      • Hyman L
      Age-related macular degeneration and blindness due to neovascular maculopathy.
      Dry and wet AMD are not mutually exclusive conditions, such that wet AMD can develop independently in patients with dry AMD.
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.
      ,
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      The late stage of dry AMD is known as geographic atrophy (GA), which typically begins in the parafoveal region (noncentral GA) and, over time, involves the central fovea (central GA).
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Although several pharmacologic therapies exist for wet AMD,
      • Macugen
      Prescribing information.
      • Lucentis
      Prescribing information.
      • Eylea
      Prescribing information.
      • Martin DF
      • Maguire MG
      • Fine SL
      • et al.
      Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
      as of 2020, no therapies have been approved for dry AMD.
      • Flaxel CJ
      • Adelman RA
      • Bailey ST
      • et al.
      Age-related macular degeneration preferred practice pattern.
      The objective of this targeted literature review was to gain a detailed understanding of the epidemiology, clinical management, and humanistic and economic burden of dry AMD. Furthermore, a landscape analysis for patient-reported outcome (PRO) instruments used in AMD was conducted to identify the PRO instruments developed and used in AMD and assess the instruments’ coverage of salient sign, symptom, and impact concepts in a recently published conceptual model of dry AMD.
      • Schultz NM
      • Braunack-Mayer L
      • Schwartz J
      • Gaspar L.
      The patient experience: symptoms and impact of dry age-related macular degeneration.

      Methods

       Targeted Literature Review

       Search Strategy

      We conducted targeted literature searches to assess the epidemiology, management, and economic and humanistic burdens of dry AMD. The searches were conducted using predefined search terms (Supplemental Table I) and included studies of adult patients (≥18 years of age) with dry AMD with no limits on intervention, comparator, or study design and no restrictions on specific dry AMD histologic features, disease stage, or biomarker. Given the limited literature on dry AMD, we included, where applicable, findings on AMD in general, wet AMD, and/or late AMD (dry and wet forms) for context. However, wet AMD was not included as a proxy for cost-effectiveness and budget impact analyses given the difference in disease progression and treatment options for dry and wet AMD.
      The searches were conducted in multiple databases to identify studies published from 1995 to 2019 (Table I). There was no language restriction for the searches, but only articles with the abstract and body text written in English were eligible for inclusion. There were no geographic restrictions for the epidemiologic, economic, or humanistic burden searches; the management search was restricted to the United States and 5 countries of the European Union (ie, France, Germany, Italy, Spain, and the United Kingdom).
      Table IDatabases used for each targeted review.
      DatabaseTargeted Review Type
      EpidemiologyManagementHumanisticEconomic
      PubMed
      CDSR in the Cochrane Library
      MEDLINE and MEDLINE in process
      EMBASE
      EconLIT
      NHS EED, HEED, and HTA in the Cochrane Library
      CEA Registry
      Relevant websites
      Including https://www.clinicaltrials.gov, https://www.rpfightingblindness.org.uk, and https://nei.nih.gov/health/pigmentosa/pigmentosa_facts.
      Abbreviations: CDSR, Cochrane Database of Systematic Reviews; CEA, cost-effectiveness analysis; EED, Economic Evaluation Database; HEED, Health Economic Evaluation Database; HTA, health technology assessment; NHS, National Health Service.
      Websites of the following conferences and societies were also searched to identify relevant abstracts published from 2017 through 2019: American Academy of Ophthalmology, American Ophthalmological Society, Pan-American Association of Ophthalmology, European Society of Ophthalmology, European Society of Retina Specialists (EURETINA), Royal College of Ophthalmologists (to identify clinical guidelines), International Society for Pharmacoeconomics and Outcomes Research, European Ophthalmology Conference, International Congress on Vision Science and Eye, and International Conference on Glaucoma and Retinal Diseases.

       Study Selection and Data Extraction

      Articles were screened to select those that met the review eligibility criteria. Quality assessment and data extraction were performed by a first reviewer (LG) with quality checking undertaken on a sample (10%) of records by a second reviewer (SB) and discrepancies resolved by a third reviewer (CB).
      The epidemiologic outcomes of interest were dry AMD prevalence, incidence, mortality, morbidity, epidemiology trends, risk factors, and subgroups. Management outcomes of interest were treatment pathways, clinical guidelines, and treatment patterns. Humanistic burden outcomes were symptoms, health-related quality of life (HRQoL) (patient and caregiver), vision-related quality of life (VRQoL), and PROs. Economic burden outcomes were total, direct, and indirect costs and health care resource utilization (HCRU).

       Assessment of Study Quality

      The quality and risk of bias of each included study were assessed by a first reviewer (LG) with quality assessment undertaken on a sample of records by a second reviewer (SB). Any discrepancies were resolved through discussion or by consulting a third reviewer (CB).
      The quality and level of evidence of review studies were assessed using an abridged checklist based on the Appraisal of Guidelines for Research and Evaluation (AGREE) II standards

      M Brouwers, ME Kho, GP Browman, et al. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. 2013. http://www.agreetrust.org/wp-content/uploads/2013/10/AGREE-II-Users-Manual-and-23-item-Instrument_2009_UPDATE_2013.pdf. Accessed November 3, 2020.

      and the latest Scottish Intercollegiate Guidelines Network (SIGN) criteria,

      Scottish Intercollegiate Guidelines Network. Methodology: Checklists. https://www.sign.ac.uk/what-we-do/methodology/checklists/. Accessed February 12, 2021.

      respectively. The quality of economic studies was assessed using adapted Drummond and Jefferson criteria as recommended by the UK National Institute for Health and Care Excellence (NICE).

      National Institute for Health and Care Excellence. Single technology appraisal: User guide for company evidence submission template [PMG24]. 2015. https://www.nice.org.uk/process/pmg24/chapter/instructions-for-companies. Accessed November 3, 2020.

       PRO Landscape Analysis

      PRO instruments were recorded during the targeted literature searches to identify the signs and symptoms of AMD and the associated immediate and long-term impacts important to patients. The population of interest was adults (≥18 years of age) with dry AMD; all study designs except expert opinion were included and no limits on comparators or interventions applied. The literature search was conducted in PubMed for publications in the last 15 years (Supplemental Table II).
      In addition, we searched ClinicalTrials.gov (search terms disease: dry AMD or equivalent term and Phase: Phase III) to identify PRO instruments from end points in AMD clinical trials. The PROQOLID database and product labels for macular degeneration in PROLABELS were also searched, as were health technology assessment (HTA) reports from 2008 to 2018. All instruments mentioned in HTA reports were considered.
      A set of instruments was further analyzed based on frequency of mention in HTA reports and/or impact on HTA decisions, frequency of use in AMD clinical trials, instrument development targeted at patients with AMD or low vision, and online availability and author traceability. Instrument prioritization was based on concept mapping. Each instrument was reviewed in full, and each item within an instrument was evaluated against the 35 sign, symptom, and impact concepts present in the conceptual model of dry AMD.
      • Schultz NM
      • Braunack-Mayer L
      • Schwartz J
      • Gaspar L.
      The patient experience: symptoms and impact of dry age-related macular degeneration.
      The content validity and psychometric properties of the priority instruments were evaluated according to the US Food and Drug Administration's 2009 PRO Guidance for Industry.
      Food and Drug Administration
      Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.
      Psychometrics evaluation was considered for dry AMD; psychometric properties in other populations were captured but not considered for scoring.

      Results

       Epidemiology

       Study Selection and Characteristics

      Of 1255 epidemiology-related records identified, 13 studies were included in this review (Figure 1). Citations included registry or cohort studies (n = 10), systematic literature reviews (SLRs, n = 2), and a pooled meta-analysis of prevalence data (n = 1).
      Figure 1
      Figure 1PRISMA Flow Diagrams for A. Epidemiology Studies, B. Management-Related Studies, C. Economic Burden Studies, and D. Humanistic Burden Studies.
      *Of the 1255 epidemiology records, 505 were retrieved from PubMed, 111 from Cochrane, and 639 from Embase.
      Of the 2140 management-related records, 950 were retrieved from PubMed, 294 from Cochrane, and 896 from Embase.
      Of the 4 management-related records, 2 were retrieved from congresses and 2 from websites.
      §Of the 229 economic burden records, 60 were retrieved from PubMed, 15 from Cochrane, 142 from Embase, and 12 from EconLit.
      ||Of the 577 humanistic burden records, 152 were retrieved from PubMed, 64 from Cochrane, and 360 from Embase.
      Ten studies assessed the epidemiology of dry AMD,
      • Wong WL
      • Su X
      • Li X
      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      ,
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.
      ,
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      ,
      • Cho B-J
      • Heo JW
      • Kim TW
      • Ahn J
      • Chung H.
      Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010–2011.
      • Clemons TE
      • Milton RC
      • Klein R
      • et al.
      Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.
      • Korb CA
      • Kottler UB
      • Wolfram C
      • et al.
      Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study.
      • McGuinness MB
      • Finger RP
      • Karahalios A
      • et al.
      Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study.
      • Papudesu C
      • Clemons TE
      • Agrón E
      • Chew EY.
      Association of mortality with ocular diseases and visual impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      • Varma R
      • Choudhury F
      • Chen S
      • et al.
      Prevalence of age-related macular degeneration in Chinese American adults: the Chinese American Eye Study.
      whereas 3 studies provided reports on late AMD without dry AMD distinctions.
      • Colijn JM
      • Buitendijk GHS
      • Prokofyeva E
      • et al.
      Prevalence of age-related macular degeneration in Europe: the past and the future.
      • McGuinness MB
      • Karahalios A
      • Finger RP
      • Guymer RH
      • Simpson JA.
      Age-related macular degeneration and mortality: a systematic review and meta-analysis.
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      Most studies provided an overall view of AMD, with subsections on late AMD. Studies that focused on dry AMD concentrated on patients with GA.
      Topics covered by the included studies were prevalence (n = 7 studies), incidence (n = 4 studies), mortality (n = 3 studies), morbidity (n = 2 studies), and AMD/dry AMD risk factors (n = 5 studies). The SIGN level of evidence was B for most identified studies (ie, well-conducted meta-analyses, systematic reviews, or randomized controlled trials [RCTs] with a low risk of bias) (Supplemental Table III). Three studies
      • Wong WL
      • Su X
      • Li X
      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      ,
      • Colijn JM
      • Buitendijk GHS
      • Prokofyeva E
      • et al.
      Prevalence of age-related macular degeneration in Europe: the past and the future.
      ,
      • McGuinness MB
      • Karahalios A
      • Finger RP
      • Guymer RH
      • Simpson JA.
      Age-related macular degeneration and mortality: a systematic review and meta-analysis.
      met all risk of bias criteria (Supplemental Table IV). The limitations of the reviewed studies were not expected to significantly impact major outcomes.

       Prevalence

      Dry AMD prevalence was reported as 0.44% globally,
      • Wong WL
      • Su X
      • Li X
      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      with similar or slightly higher values reported for wet AMD (Table II). Dry AMD prevalence varied across ethnic groups (1.11% European, 0.21% Asian, 0.16% Hispanic, and 0.14% African).
      • Wong WL
      • Su X
      • Li X
      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      Table IIPrevalence of dry, wet, and late AMD.
      Region/CountryStudy TypeAge Group, yDry AMD %Wet AMD, %Late AMD, %
      Late AMD can include both wet and dry AMD because the 2 are not mutually exclusive (ie, patients may present with both forms).
      Global
      • Wong WL
      • Su X
      • Li X
      • et al.
      Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
      Literature review45–850.440.460.37
      United States
      Keenan et al8 reported a prevalence of 9.8% for dry AMD at baseline; however, this publication reported results of a separate cohort study conducted within a controlled clinical trial for dry AMD treatment (Age-Related Eye Disease Study), which could potentially introduce a skew in the data.
      8
      Cohort studyNA9.8NANA
      United States
      The study population in the study by Varma et al25 included self-identified Chinese Americans only and was conducted in California.
      25
      Cohort study50–59NANA0.3
      Europe
      • Colijn JM
      • Buitendijk GHS
      • Prokofyeva E
      • et al.
      Prevalence of age-related macular degeneration in Europe: the past and the future.
      Literature review45–85NANA0.2–5.6
      Germany
      • Korb CA
      • Kottler UB
      • Wolfram C
      • et al.
      Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study.
      Cohort study35–740.10.10.2
      Japan
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      Cohort study≥50NANA0.58
      South Korea
      • Cho B-J
      • Heo JW
      • Kim TW
      • Ahn J
      • Chung H.
      Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010–2011.
      Cohort study40–97

      (mean, 55.2)
      0.20.50.7
      Abbreviations: AMD, age-related macular degeneration; NA, not applicable.
      low asterisk Late AMD can include both wet and dry AMD because the 2 are not mutually exclusive (ie, patients may present with both forms).
      Keenan et al8 reported a prevalence of 9.8% for dry AMD at baseline; however, this publication reported results of a separate cohort study conducted within a controlled clinical trial for dry AMD treatment (Age-Related Eye Disease Study), which could potentially introduce a skew in the data.
      The study population in the study by Varma et al25 included self-identified Chinese Americans only and was conducted in California.
      Dry AMD prevalence was found to increase with age (Table III). Although there was insufficient granularity on prevalence segmented by age in Europe, late AMD was reported to increase from 0% to 3.0% at 70 years of age and up to 9.8% at >85 years of age (Supplemental Figure 1).
      • Korb CA
      • Kottler UB
      • Wolfram C
      • et al.
      Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study.
      ,
      • Colijn JM
      • Buitendijk GHS
      • Prokofyeva E
      • et al.
      Prevalence of age-related macular degeneration in Europe: the past and the future.
      Table IIIAge-related prevalence of dry and late AMD.
      Country/RegionAge-Related Prevalence, %
      40–49 y50–59 y60–69 y70–79 y≥80 y
      Dry AMD
      South Korea
      • Cho B-J
      • Heo JW
      • Kim TW
      • Ahn J
      • Chung H.
      Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010–2011.
      0.00.10.30.61.8
      Late AMD
      Japan
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.390.530.99
      Age-related prevalence for ages 70 to 74 years.
      NA
      Singapore
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.210.392.49NA
      United States (Monterey Park, California)
      Study population was limited to self-identified Chinese Americans only.
      25
      NA0.20.31.01.0
      United States (Los Angeles, California)
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.220.261.50NA
      United States (Beaver Dam, Wisconsin)
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.20.83.7NA
      United States (Baltimore, Maryland)
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.30.420.0NA
      Australia (Blue Mountains)
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.00.52.6NA
      Barbados
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      NA0.70.41.0NA
      Abbreviations: AMD, age-related macular degeneration; NA, not applicable.
      low asterisk Age-related prevalence for ages 70 to 74 years.
      Study population was limited to self-identified Chinese Americans only.

       Incidence

      In a population-based cohort study that pooled data from 3 population-based cohort studies (mean age, 60.1–65.7 years), age-adjusted dry AMD incidence ranged from 0.3% to 0.4%, with follow-up times ranging from 4.8 to 6.5 years
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      ; increased incidence was linked to late-stage AMD disease at baseline. Dry AMD incidence was also linked to baseline drusen status in a North American study (N = 3549), with the 10-year incidence risk of dry AMD diagnosis increasing from 9.9% in patients with bilateral large drusen at baseline (n = 241) to 44.3% in patients with bilateral large drusen and RPE changes at baseline (n = 636) and 53.9% in patients with late AMD (dry or wet) in 1 eye at baseline (n = 390).
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.

       Morbidity

      Dry AMD was associated with poor visual acuity (VA). Both central and noncentral GA reduced visual function, leading to difficulties with reading and facial recognition.
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Central GA was associated with worse baseline best-corrected VA (BCVA, measured using the electronic Early Treatment Diabetic Retinopathy Study VA charts) at first appearance compared with noncentral dry AMD (mean, 58 vs 75 letters).
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Mean BCVA in patients with GA decreased from 70 letters (20/40, noncentral) at first appearance to 58 letters (20/80, central) by 5 years.
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Progression rates from noncentral to central GA were 32% at 2 years and 57% at 4 years.
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Two studies reported that patients with dry AMD can subsequently develop wet AMD. The 2-year rate of development of new wet AMD in eyes with incident dry AMD was 14%, and the 4-year rate of wet AMD development in patients who did not have wet AMD at any time prior was 54%. Among patients with a diagnosis of wet AMD in the fellow eye, the 4-year rate of wet AMD development was 76%.
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      Chew et al
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.
      reported the wet AMD incidence rate in a 10-year follow-up of the Age-Related Eye Disease Study (AREDS), which assessed the effect of the AREDS formulation (vitamin C, vitamin E, beta-carotene, zinc, and copper) on AMD progression and VA. In eyes that developed any dry AMD, the presence of wet AMD in the fellow eye at baseline markedly increased the risk of subsequently developing wet AMD in that eye. At 5 years, the rate of wet AMD development in eyes that developed dry AMD was 36.4% when the fellow eye had wet AMD at baseline compared with 16.0% when it did not.
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.

       Mortality

      In a large Australian cohort study (N = 21,129), the presence of dry AMD was associated with increased risk of all-cause mortality (hazard ratio [HR] = 1.46; 95% CI, 0.99–2.16) compared with no dry AMD.
      • McGuinness MB
      • Finger RP
      • Karahalios A
      • et al.
      Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study.
      Patients with dry AMD also had an increased risk of tobacco- (HR = 2.86; 95% CI, 1.15–7.09)
      • McGuinness MB
      • Finger RP
      • Karahalios A
      • et al.
      Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study.
      and cancer-related deaths (HR = 3.37; 95% CI, 1.56–7.29; P = 0.002).
      • Papudesu C
      • Clemons TE
      • Agrón E
      • Chew EY.
      Association of mortality with ocular diseases and visual impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.
      Inflammation is believed to play a prominent role in the development of AMD, cancer, and cardiovascular disease, although the link between AMD and cancer is not known.
      Late AMD (wet and dry) was associated with a 20% increased rate of all-cause mortality (HR = 1.20; 95% CI, 1.02–1.41).
      • McGuinness MB
      • Karahalios A
      • Finger RP
      • Guymer RH
      • Simpson JA.
      Age-related macular degeneration and mortality: a systematic review and meta-analysis.
      Data on cardiovascular mortality risk were available only for late AMD and wet AMD. Late AMD was associated with a 46% increased rate of cardiovascular mortality (HR = 1.46; 95% CI, 1.13–1.89),
      • McGuinness MB
      • Karahalios A
      • Finger RP
      • Guymer RH
      • Simpson JA.
      Age-related macular degeneration and mortality: a systematic review and meta-analysis.
      and wet AMD was associated with a higher risk of cardiovascular death (HR = 3.16; 95% CI, 1.62–6.15) in the Australian cohort study.
      • McGuinness MB
      • Finger RP
      • Karahalios A
      • et al.
      Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study.
      The relationship among mortality, VA, and AMD was evaluated using data from the AREDS2 trial,
      • Papudesu C
      • Clemons TE
      • Agrón E
      • Chew EY.
      Association of mortality with ocular diseases and visual impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.
      which evaluated the natural history and risk factors of AMD and the effect of the AREDS2 formulation (vitamin C, vitamin E, zinc, copper, lutein, zeaxanthin, and ω3 fatty acids) on disease progression. Age- and sex-adjusted results from this US analysis found that mortality rates nearly doubled per decade of life for those ≥65 years of age compared with younger patients (65–74 years of age: HR = 2.25; 95% CI, 1.32–3.85; 75–79 years of age: HR = 4.64; 95% CI, 2.75–7.81; ≥80 years of age: HR = 7.79; 95% CI, 4.65–13.06).
      • Papudesu C
      • Clemons TE
      • Agrón E
      • Chew EY.
      Association of mortality with ocular diseases and visual impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.
      Mortality rates were higher for current smokers and patients with diabetes, high blood pressure, or a history of cardiovascular disease. Age- and sex-adjusted all-cause mortality in patients with AMD also increased with decreasing VA (BCVA ≤20/40 in one eye: HR = 1.32; 95% CI, 1.05–1.66).
      • Papudesu C
      • Clemons TE
      • Agrón E
      • Chew EY.
      Association of mortality with ocular diseases and visual impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.

       Risk Factors

      Smoking, increasing age, increasing total serum cholesterol levels, and obesity were identified as key risk factors for dry AMD. Current smokers were 5.32 to 6.65 times more likely to develop dry AMD versus nonsmokers.
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      Increasing age was consistently identified as a risk factor for dry or late AMD across geographic areas.
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.
      ,
      • Cho B-J
      • Heo JW
      • Kim TW
      • Ahn J
      • Chung H.
      Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010–2011.
      ,
      • Korb CA
      • Kottler UB
      • Wolfram C
      • et al.
      Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study.
      ,
      • Varma R
      • Choudhury F
      • Chen S
      • et al.
      Prevalence of age-related macular degeneration in Chinese American adults: the Chinese American Eye Study.
      ,
      • Colijn JM
      • Buitendijk GHS
      • Prokofyeva E
      • et al.
      Prevalence of age-related macular degeneration in Europe: the past and the future.
      ,
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      For total serum cholesterol, the odds ratio (OR) for dry AMD risk was 1.08 per 10-mg/dL increase (95% CI, 1.00–1.15; P = 0.04) based on pooled data from 3 population-based cohort studies; in the Blue Mountain Eye study specifically, the odds of developing dry AMD increased by 16% for every 10-mg/dL increase in total cholesterol.
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      One study reported that the incidence of dry AMD in patients with baseline bilateral drusen was associated with fewer years of formal education (OR for high school graduate or less vs college graduate = 1.75; 95% CI, 1.10–2.78) and not using antacids (OR for antacid use vs no antacid use = 0.29; 95% CI, 0.09–0.91).
      • Clemons TE
      • Milton RC
      • Klein R
      • et al.
      Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.

       Management

       Study Selection and Characteristics

      Of 2144 records identified in the management search, 10 publications were included (Figure 1B).
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      • Danis RP
      • Lavine JA
      • Domalpally A.
      Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      National Institute for Health and Care Excellence
      Miniature lens system implantation for advanced age-related macular degeneration.
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      • Le Mer Y
      Subretinal implantations of PRIMA wireless photovoltaic chip, a new surgical technique for atrophic dry agerelated macular degeneration: technical feasibility and early results.
      • Monés J.
      Complement C5 inhibition as a potential treatment for geographic atrophy secondary to dry agerelated macular degeneration.
      • Wei Y
      • Liao H
      • Ye J.
      Therapeutic effects of various therapeutic strategies on non-exudative age-related macular degeneration: A PRISMA-compliant network meta-analysis of randomized controlled trials.
      Two publications were from the United Kingdom,
      National Institute for Health and Care Excellence
      Miniature lens system implantation for advanced age-related macular degeneration.
      ,
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      2 from other European countries,
      • Le Mer Y
      Subretinal implantations of PRIMA wireless photovoltaic chip, a new surgical technique for atrophic dry agerelated macular degeneration: technical feasibility and early results.
      ,
      • Monés J.
      Complement C5 inhibition as a potential treatment for geographic atrophy secondary to dry agerelated macular degeneration.
      and 6 from unspecified countries or regions.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      • Danis RP
      • Lavine JA
      • Domalpally A.
      Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      ,
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.
      ,
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      ,
      • Wei Y
      • Liao H
      • Ye J.
      Therapeutic effects of various therapeutic strategies on non-exudative age-related macular degeneration: A PRISMA-compliant network meta-analysis of randomized controlled trials.
      One AMD treatment guideline, 1 guidance on an implant system, 6 literature reviews that provided an overview of AMD/dry AMD management, and 2 dry AMD abstracts from the 2018 EURETINA conference were included. Eight publications assessed dry AMD management.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      • Danis RP
      • Lavine JA
      • Domalpally A.
      Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      ,
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      • Le Mer Y
      Subretinal implantations of PRIMA wireless photovoltaic chip, a new surgical technique for atrophic dry agerelated macular degeneration: technical feasibility and early results.
      • Monés J.
      Complement C5 inhibition as a potential treatment for geographic atrophy secondary to dry agerelated macular degeneration.
      • Wei Y
      • Liao H
      • Ye J.
      Therapeutic effects of various therapeutic strategies on non-exudative age-related macular degeneration: A PRISMA-compliant network meta-analysis of randomized controlled trials.
      One publication each assessed late AMD management
      National Institute for Health and Care Excellence
      Miniature lens system implantation for advanced age-related macular degeneration.
      and AMD management with specific guidance for dry AMD.
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      The included publications covered current management (n = 6 studies), future treatments (n = 7 studies), and diagnosis (n = 4 studies).
      A SIGN level of evidence of B was assigned to all studies (Supplemental Table III). Two studies
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      ,
      • Wei Y
      • Liao H
      • Ye J.
      Therapeutic effects of various therapeutic strategies on non-exudative age-related macular degeneration: A PRISMA-compliant network meta-analysis of randomized controlled trials.
      met all risk of bias criteria (Supplemental Table IV). The only criterion met by all studies was whether the search for evidence was reasonably comprehensive. Most reviewed studies did not pool data. The limitations of the reviewed studies were not expected to significantly impact major outcomes.

       Diagnosis

      Numerous techniques were used in diagnosing dry AMD, including fundus photography, fundus autofluorescence, and optical coherence tomography. Dry AMD was initially diagnosed through fundus examination and photography.
      • Clemons TE
      • Milton RC
      • Klein R
      • et al.
      Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.
      ,
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      Fundus autofluorescence was identified as the gold standard for monitoring dry AMD progression because it allowed a reproducible measure of atrophic areas and better lesion boundary discrimination. Fundus photography was described as having limited value in assessing and monitoring the progression of atrophic areas.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      ,
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.

       Treatment Guidelines

      No treatment guidelines were identified for dry AMD specifically. One NICE guideline for AMD was included because it referred to the diagnosis and management of dry AMD.
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      However, the focus of the management recommendations was centered on wet AMD, with no pharmacologic treatments recommended for dry AMD.

       Management

      No pharmacologic treatments are approved for dry AMD because no treatment can currently restore damaged RPE or photoreceptors.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      ,
      • Danis RP
      • Lavine JA
      • Domalpally A.
      Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.
      ,
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.
      ,
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      Thus, current approaches to dry AMD treatment aim to prevent and slow progression of existing atrophy.
      Dry AMD management primarily focuses on risk factor reduction and use of dietary supplements. NICE guidelines recommend dietary modifications and smoking cessation.
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      Dietary modifications and exercise are recommended because obesity and a high-fat diet are also linked to AMD risk.
      • Clemons TE
      • Milton RC
      • Klein R
      • et al.
      Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.
      ,
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      ,
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      ,
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      Smoking cessation is recommended given the significantly higher risk of AMD for smokers versus nonsmokers.
      • Keenan TD
      • Agrón E
      • Domalpally A
      • et al.
      Progression of geographic atrophy in age-related macular degeneration: AREDS2 Report Number 16.
      ,
      • Clemons TE
      • Milton RC
      • Klein R
      • et al.
      Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.
      .
      • Tomany SC
      • Wang JJ
      • van Leeuwen R
      • et al.
      Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents.
      ,
      • Nakata I
      • Yamashiro K
      • Nakanishi H
      • et al.
      Prevalence and characteristics of age-related macular degeneration in the Japanese population: the Nagahama study.
      ,
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      ,
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      ,
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      Old age and family history are also linked to AMD and monitoring is recommended.
      • Chew EY
      • Clemons TE
      • Agrón E
      • et al.
      Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.
      ,
      • Cho B-J
      • Heo JW
      • Kim TW
      • Ahn J
      • Chung H.
      Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010–2011.
      ,
      National Institute for Health and Care Excellence
      Age-related macular degeneration: NICE guideline [NG82].
      Numerous dietary supplements have been investigated for dry AMD. There is consensus that the AREDS and AREDS2 formulations have a positive impact on slowing dry AMD progression.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      In the AREDS trial, there was an estimated 20% to 25% overall risk reduction in AMD disease progression and VA loss with long-term AREDS supplementation; patients taking AREDS2 were less likely to lose ≥15 letters of VA (adjusted OR = 0.77; 95% CI, 0.62–0.96).
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      However, these results were derived from 1 large US trial in a relatively well-nourished population; consequently, the findings may not be generalizable to other populations. Vitamin E, zinc, and vitamin B1, B6, and B12* were investigated for AMD treatment or management, but results were inconclusive because most studies had small trial populations and short treatment durations.
      • Evans JR
      • Lawrenson JG
      Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.
      Ginkgo biloba extract may protect against AMD by modulating choroidal blood flow and scavenging free radicals, but there is no clinical trial evidence.
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      *Trademark: OcuGuard® (Gaco Pharmaceuticals Ltd, Dhaka, Bangladesh).

       Treatments in Development

      Therapies in development for dry AMD treatment include anti-inflammatory agents, neuroprotective agents, vasodilators, complement inhibitors, and devices. However, many of these therapies have failed to meet primary clinical trial end points (eg, changes in GA area and growth, drusen area, or VA and BCVA), many therapies have not provided updated trial results in many years, or the trials were terminated.
      • Bandello F
      • Sacconi R
      • Querques L
      • et al.
      Recent advances in the management of dry age-related macular degeneration: a review.
      ,
      • Danis RP
      • Lavine JA
      • Domalpally A.
      Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.
      ,
      • Sacconi R
      • Corbelli E
      • Querques L
      • Bandello F
      • Querques G.
      A review of current and future management of geographic atrophy.
      ,
      • Wright CB
      • Ambati J.
      Dry age-related macular degeneration pharmacology.
      Some treatments have shown promising results in clinical trials. For example, preliminary Phase II results for brimonidine, a neuroprotective agent, indicated significant GA growth reduction, and further Phase III trials are planned.
      • Freeman WR.
      Brimonidine DDS safety and efficacy in patients with geographic atrophy secondary to age-related macular degeneration.
      A miniature lens system for advanced AMD found promising results for late AMD, but NICE deemed its long-term efficacy and safety evidence insufficient and recommended use only with special arrangements for clinical governance or research.
      National Institute for Health and Care Excellence
      Miniature lens system implantation for advanced age-related macular degeneration.
      Four cell therapies and 1 gene therapy are also in development for dry AMD, but clinical trial results are not yet available.

       Economic Burden

       Study Selection and Characteristics

      Of 229 records identified in the search, 6 studies were included (Figure 1C).
      • Bonastre J
      • Le Pen C
      • Anderson P
      • et al.
      The epidemiology, economics and quality of life burden of age-related macular degeneration in France, Germany, Italy and the United Kingdom.
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      • Garattini L
      • Castelnuovo E
      • Lanzetta P
      • et al.
      Direct medical costs of age-related macular degeneration in Italian hospital ophthalmology departments. A multicenter, prospective 1-year study.
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      • Schmier JK
      • Covert DW
      • Lau EC.
      Patterns and costs associated with progression of age-related macular degeneration.
      • Schmier JK
      • Jones ML
      • Halpern MT.
      The burden of age-related macular degeneration.
      No studies were available on the economic burden of dry AMD specifically. Three studies examined direct medical costs for dry compared with wet and/or no AMD. One study reported indirect medical costs for AMD, and 1 study evaluated work loss and productivity loss for AMD. No cost-effectiveness models or budget impact analyses were identified for dry AMD therapies specifically. One study described a budget impact analysis for AMD management in the European Union in 2001, broadly considering the late AMD population (ie, no dry vs wet distinction), but the costs applied were more relevant to wet AMD (eg, photodynamic therapy and photocoagulation).
      • Bonastre J
      • Le Pen C
      • Anderson P
      • et al.
      The epidemiology, economics and quality of life burden of age-related macular degeneration in France, Germany, Italy and the United Kingdom.
      The SIGN level of evidence was B (n = 3) or C (n = 3; ie, well-conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal) (Supplemental Table III). For risk of bias, only 1 study complied with ≥30% of criteria
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      ; none of the studies assessed the economic impact of treatment, so some questions were not applicable (Supplemental Table V). The limitations of the reviewed studies were not expected to significantly affect major outcomes.

       HCRU

      Results from the included studies in Italy and the United States reported that patients with dry AMD have lower HCRU compared with patients with wet AMD (Table IV); however, both analyses were conducted before the introduction of anti–vascular endothelial growth factor therapies in 2006. The 2006 literature review by Halpern et al
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      also discussed a previous analysis of the 1991 Medicare 5% sample data that reported that 4.9% of ophthalmologist visits and 4.8% of optometrist visits were under the macular degeneration diagnosis code, with no distinction for dry AMD. The 1991 analysis results also indicated a linear increase in total eye care visits from those 65 to 69 years of age to 80 to 84 years of age but no differences between men and women.
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      Table IVMean (95% CI) HCRU per patient per year for patients with AMD.
      Italy
      • Garattini L
      • Castelnuovo E
      • Lanzetta P
      • et al.
      Direct medical costs of age-related macular degeneration in Italian hospital ophthalmology departments. A multicenter, prospective 1-year study.
      United States
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      Dry AMDWet AMDDry AMDWet AMD
      Physician interaction
      Internal specialist consultations0.8 (0.6–1.0)2.8 (2.5–3.0)NANA
      External specialist consultations0.8 (0.7–1.0)0.7 (0.6–0.8)NANA
      Private outpatient consultations0.3 (0.2–0.4)0.3 (0.2–0.4)NANA
      Ophthalmologist visitsNANA1.311.38
      Generalist visitsNANA0.891.32
      ConsultationsNANA0.170.36
      Diagnostic procedures
      Fundus photography0.1 (0–0.2)0.3 (0.2–0.4)0.240.91
      Fluorescein angiography0.7 (0.5–0.8)1.9 (1.7–2.1)0.21.08
      Indocyanine green angiography0.1 (0.04–0.2)0.8 (0.7–1.0)0.00160.065
      Other0.02 (0–0.06)0.03 (0–0.05)NANA
      OphthalmoscopyNANA0.410.82
      Retinal ultrasoundNANA0.0690.051
      Visual field examNANA0.10.1
      Visual refractionNANA0.460.25
      Therapy
      Photocoagulation0.01 (0–0.04)0.5 (0.3–0.6)0.00840.1
      Photodynamic therapyNANA00.12
      Hospitalizations
      Admissions0.03 (0–0.08)0.2 (0.1–0.2)NANA
      Day hospital0.01 (0–0.04)0.05 (0.02–0.09)NANA
      Abbreviations: AMD, age-related macular degeneration; HCRU, health care resource use; NA, not applicable.

       Direct Medical Costs

      Direct medical costs were lower in the United States and Italy for patients with dry compared with wet AMD.
      • Garattini L
      • Castelnuovo E
      • Lanzetta P
      • et al.
      Direct medical costs of age-related macular degeneration in Italian hospital ophthalmology departments. A multicenter, prospective 1-year study.
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      • Schmier JK
      • Covert DW
      • Lau EC.
      Patterns and costs associated with progression of age-related macular degeneration.
      Anti–vascular endothelial growth factor therapies are likely responsible for the difference in treatment costs between the 2 related conditions since 2006.
      Results from a US Medicare analysis (1998–2009) indicated an increase in annual Medicare expenditures for patients with AMD from 1998 to 2009 for both the dry and wet forms.
      • Schmier JK
      • Covert DW
      • Lau EC.
      Patterns and costs associated with progression of age-related macular degeneration.
      Annual direct medical costs for patients with dry AMD increased from $10,555 in 1998 to $24,494 in 2009. Patients with dry AMD had lower annual ophthalmic expenditures (range, $287–$682 in 2011 US dollars) compared with wet AMD (range, $1737–$2899); the authors noted that this difference may be attributable to a paucity of treatment options and because patients with dry AMD may be using AREDS-recommended supplements, which are not covered by insurance or Medicare.
      • Schmier JK
      • Covert DW
      • Lau EC.
      Patterns and costs associated with progression of age-related macular degeneration.
      Another study of Medicare data (1999–2001) found that dry AMD costs ($206) were 2.5 times lower than wet AMD costs ($513) in 1999, increasing to 3.4 times lower in 2001.
      • Halpern MT
      • Schmier JK
      • Covert D
      • Venkataraman K.
      Resource utilization and costs of age-related macular degeneration.
      In Italy, mean total costs for the Italian National Health Services per patient per year for dry AMD were significantly lower (2–3 times) compared with wet AMD (P = 0.0002).
      • Garattini L
      • Castelnuovo E
      • Lanzetta P
      • et al.
      Direct medical costs of age-related macular degeneration in Italian hospital ophthalmology departments. A multicenter, prospective 1-year study.
      Hospital stays accounted for 53.3% of total dry AMD expenditures (vs 58.6% for wet AMD) and absolute hospital treatment costs for dry AMD were 4 times lower than for wet AMD because patients with dry AMD had fewer laser treatments, which are primarily performed in hospitals. Diagnostic procedures were the second-largest cost for dry AMD (27.9% vs 24.9% for wet AMD). Private consultations and over-the-counter products accounted for 46.5% of dry AMD costs paid directly by patients (vs 8.6% of Italian National Health Services costs for patients with wet AMD). Over-the-counter product expenditure (eg, dietary supplements and vitamins) was likely higher for dry AMD because of the lack of alternative therapies; however, this analysis was conducted before 2006.

       Indirect Costs

      There was limited literature on the indirect costs of AMD and none for dry AMD specifically. Results from a previous study indicated that formal and informal caregiving were key contributors to indirect costs in AMD generally. The use of support services (eg, counseling, job training, recreational activities, rehabilitation, transportation, and support groups) was found to increase with decreasing VA.
      • Schmier JK
      • Jones ML
      • Halpern MT.
      The burden of age-related macular degeneration.
      In the United States, caregiver costs were found to increase with decreasing VA, ranging from $225 for VA ≥20/32 to $47,086 for VA ≤20/250.
      • Schmier JK
      • Jones ML
      • Halpern MT.
      The burden of age-related macular degeneration.
      For persons with AMD, caregiving assistance was provided, on average, for 4.7 days per week 3.7 hours per day.
      In France, annual nonmedical costs were 3.7 times greater for patients with VA ≤20/64 than those with VA >20/64 (P < 0.001), with the difference most prominent in terms of caregiving costs.
      • Schmier JK
      • Jones ML
      • Halpern MT.
      The burden of age-related macular degeneration.
      Sixty percent of patients with wet AMD in France with VA in the best eye ≤20/40 required home help, more than half of the time from someone other than family.
      Limited information was available on the impact of dry AMD on work loss and productivity. The total annual loss in gross domestic product from dry and early AMD was estimated at approximately $24 billion in the United States in 2003, including an estimated salary loss of approximately $17 billion attributable to dry AMD and mild visual loss.
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      The estimated annual gross domestic product loss for all AMD was approximately $30 billion in the United States and $2.6 billion in Canada, driven by lower employment rates and lower mean wages for those with AMD.
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      Although AMD is typically viewed as a disease of older individuals, Brown et al
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      examined employment rates for individuals with severe visual limitation and late AMD, defined as wet AMD, GA, or both. Using this definition, a cohort of patients 21 to 64 years of age was identified. Despite the inclusion of younger patients (a limitation of the study), employment rates for individuals with late AMD were less than half the rate for individuals without AMD (30.6% vs 78.2%). Mean wage was 38% lower for patients with severe visual loss (such as that associated with advanced AMD) compared with those without vision loss ($19,326 vs $31,182).
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.

       Humanistic Burden

       Study Selection and Characteristics

      Of the 577 records identified in the search, 8 publications were included (Figure 1D). Two publications examined general quality of life, 4 reported on VRQoL (including 1 abstract), 1 reported on utility values, and 1 reported on depression and anxiety prevalence. Two abstracts reported on the knowledge gaps for humanistic burden in dry AMD. Four studies assessed the humanistic burden of dry AMD,
      • Schmier JK
      • Rajput Y
      • Patel SS
      • Singh RP
      • Nielsen JS
      Geographic atrophy disease burden: Need for better characterization.
      • Schmier JK
      • Rajput Y
      • Singh RP
      • Patel SS
      • Nielsen JS
      Engaging patients, caregivers, and physicians to understand the burden of illness of geographic atrophy.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      • Wang F
      • Fries M
      • Wurzelmann JI
      • et al.
      Patient-reported visual function in patients with geographic atrophy secondary to age-related macular degeneration (AMD): baseline characteristics of the BAM114341 cohort.
      and 4 studies assessed the humanistic burden of late AMD.
      • Butt T
      • Dunbar H
      • Morris S
      • Orr S
      • Rubin G
      Patient and public preferences for health states associated with AMD.
      • Choudhury F
      • Varma R
      • Klein R
      • et al.
      Age-related macular degeneration and quality of life in Latinos: the Los Angeles Latino Eye Study.
      • Dawson SR
      • Mallen CD
      • Gouldstone MB
      • Yarham R
      • Mansell G
      The prevalence of anxiety and depression in people with age-related macular degeneration: a systematic review of observational study data.
      • Mangione CM
      • Gutierrez PR
      • Lowe G
      • Orav EJ
      • Seddon JM
      Influence of age-related maculopathy on visual functioning and health-related quality of life.
      The only humanistic outcome reported for dry AMD specifically was VRQoL; no dry AMD–specific studies were available for HRQoL or depression and anxiety. None of the publications focused on caregiver impact.
      The SIGN level of evidence for all identified studies was either A (ie, high quality meta-analysis, systematic reviews of RCTs, or RCTs with a very low risk of bias, n = 2) or B (n = 6; Supplemental Table III).
      Few studies focused on the humanistic burden of dry AMD. One identified study was conducted to understand humanistic burden knowledge gaps in dry AMD.
      • Schmier JK
      • Rajput Y
      • Patel SS
      • Singh RP
      • Nielsen JS
      Geographic atrophy disease burden: Need for better characterization.
      ,
      • Schmier JK
      • Rajput Y
      • Singh RP
      • Patel SS
      • Nielsen JS
      Engaging patients, caregivers, and physicians to understand the burden of illness of geographic atrophy.
      Phase I of this 3-phase study was a literature review to identify the impact of dry AMD on HRQoL, functioning, and economic burden and to catalog instruments used to assess burden in patients with dry AMD. Phase I findings outlined that only 1 publication (of 318 identified) focused on dry AMD, whereas others were on late AMD (no dry vs wet distinction). No studies were identified on the mental health burden of dry AMD, and the authors found a lack of consensus on dimensions of functioning relevant to patients with dry AMD or instruments that should be used to assess them.
      • Schmier JK
      • Rajput Y
      • Patel SS
      • Singh RP
      • Nielsen JS
      Geographic atrophy disease burden: Need for better characterization.
      In Phase II, the authors conducted semistructured interviews with patients (n = 8), caregivers (n = 6), and health care professionals (n = 5) to explore the importance of concepts in existing questionnaires (eg, patient and caregiver quality of life, mental and social health, and out-of-pocket costs) and identify additional topics for future studies. For patients, dry AMD affected household chores, socializing, sports and outdoor hobbies, participation in religious activities, and long-distance travel and contributed to direct out-of-pocket expenses for low-vision aids. For caregivers, dry AMD led to modifying schedules, providing transportation, and other assistance to the affected individual. For health care professionals, key concerns included mental health issues and variable adherence with low-vision aids among patients with dry AMD.
      • Schmier JK
      • Rajput Y
      • Singh RP
      • Patel SS
      • Nielsen JS
      Engaging patients, caregivers, and physicians to understand the burden of illness of geographic atrophy.
      Phase III outcomes were not reported at the time of our review.

       Symptoms

      Reported dry AMD symptoms included reduced central vision, decreased night vision, increased visual blurriness, distortion of straight lines and text, and faded color vision.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      Although none of the included studies assessed the impact of dry AMD symptoms specifically, the results of the SLR conducted by Taylor et al
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      indicated that AMD symptoms affect daily living in patients with AMD. PRO instrument and performance-based analyses found that AMD negatively affects quality of life, including many activities of daily living, such as mobility, driving, face recognition, scene perception, and computer use. Patients with AMD are less likely to drive and more likely to fall and require assistance with daily tasks (39%–45% require assistance with ≥1 daily living activity).
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      Furthermore, individuals with AMD are perceived to be at increased risk of reduced psychological well-being compared with those with other causes of visual impairment.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.

       Quality of Life

      Patients with dry AMD experience significant impairment in multiple aspects of visual function. The 25-item National Eye Institute Vision Function Questionnaire (NEI-VFQ-25) was the most commonly used measure of VRQoL in AMD.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      ,
      • Wang F
      • Fries M
      • Wurzelmann JI
      • et al.
      Patient-reported visual function in patients with geographic atrophy secondary to age-related macular degeneration (AMD): baseline characteristics of the BAM114341 cohort.
      ,
      • Choudhury F
      • Varma R
      • Klein R
      • et al.
      Age-related macular degeneration and quality of life in Latinos: the Los Angeles Latino Eye Study.
      In patients with dry AMD, mean NEI-VFQ-25 scores correlated with decreasing BCVA (>20/40 and 20/40-20/80 subgroups) and enlarged GA area.
      • Wang F
      • Fries M
      • Wurzelmann JI
      • et al.
      Patient-reported visual function in patients with geographic atrophy secondary to age-related macular degeneration (AMD): baseline characteristics of the BAM114341 cohort.
      Patients with late AMD (dry and wet) have significantly lower mean NEI-VFQ scores than those with early AMD or no AMD (59.5 vs 79.4 vs 80.7; P < 0.001), indicating that disease progression affects VRQoL.
      • Choudhury F
      • Varma R
      • Klein R
      • et al.
      Age-related macular degeneration and quality of life in Latinos: the Los Angeles Latino Eye Study.
      Similarly, age-, sex-, and comorbidity-adjusted pairwise comparison scores for individuals with mild versus severe age-related maculopathy were statistically significant for the overall, near vision, daytime driving, and disability glare subscales of the Activities of Daily Vision Scale, suggesting that age-related maculopathy severity is a unique and significant correlate of VRQoL (overall R2 = 0.14 [model 1] and 0.4 [model 2]).
      • Mangione CM
      • Gutierrez PR
      • Lowe G
      • Orav EJ
      • Seddon JM
      Influence of age-related maculopathy on visual functioning and health-related quality of life.
      No significant differences were found for HRQoL (measured by the 36-Item Short Form Survey [SF-36]) between patients with and without AMD,
      • Choudhury F
      • Varma R
      • Klein R
      • et al.
      Age-related macular degeneration and quality of life in Latinos: the Los Angeles Latino Eye Study.
      and no relationship was identified between early or late AMD and SF-36 score.
      • Mangione CM
      • Gutierrez PR
      • Lowe G
      • Orav EJ
      • Seddon JM
      Influence of age-related maculopathy on visual functioning and health-related quality of life.

       Depression and Anxiety

      The SLR by Taylor et al
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      identified 14 studies (n = 1880 participants) investigating the effect of AMD on depression. Estimated depression prevalence rates ranged from 15.7% to 44% in patients with AMD (no dry vs wet distinction).
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      Depression in AMD was strongly correlated with increasing VA loss and could be predicted by neurotic personality. Patients with AMD (n = 144) who reported poor adaptation to vision loss, especially with respect to acceptance of and compensation for vision loss, reported more depressive symptoms than those who adapted better. The risk of suicide because of AMD-related vision loss was identified in 1 case report, suggesting the need to train eye care practitioners to identify patients with suicide risk.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      In another SLR that included 16 studies, Dawson et al
      • Dawson SR
      • Mallen CD
      • Gouldstone MB
      • Yarham R
      • Mansell G
      The prevalence of anxiety and depression in people with age-related macular degeneration: a systematic review of observational study data.
      reported that the prevalence of depressive symptoms in adults with AMD (no dry vs wet distinction) was higher than in those without. The depression prevalence estimates ranged from 15.7% to 44% in the cross-sectional and cohort studies, whereas case–control studies reported a significantly (P < 0.05) higher prevalence of depression in participants with AMD versus non-AMD. Dawson et al
      • Dawson SR
      • Mallen CD
      • Gouldstone MB
      • Yarham R
      • Mansell G
      The prevalence of anxiety and depression in people with age-related macular degeneration: a systematic review of observational study data.
      also investigated anxiety in patients with AMD, and the estimated anxiety prevalence ranged from 9.6% to 30.1%. In a cross-sectional study that compared AMD with severe visual impairment versus minimal impairment, no statistically significant difference (P = 0.13) in anxiety levels was found between the 2 groups. Furthermore, this study did not find a relationship between an increase in anxiety symptoms and AMD severity.
      • Dawson SR
      • Mallen CD
      • Gouldstone MB
      • Yarham R
      • Mansell G
      The prevalence of anxiety and depression in people with age-related macular degeneration: a systematic review of observational study data.

       Utility Values

      In the SLR by Taylor et al,
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      mean utility values for AMD (no dry vs wet distinction) ranged from 0.60 to 0.81 across 8 studies (n = 1768 participants), with lower values noted for worse vision loss. The AMD utility values were comparable with values for asymptomatic HIV (0.69), mild hip osteoarthritis (0.69), mild and moderate angina (0.88 and 0.83), mild and moderate myocardial infarction (0.91 and 0.80), and diabetes mellitus (0.88). Utility values for other eye diseases ranged from 0.64 to 1.0 for glaucoma and 0.59 to 0.94 for diabetic retinopathy.
      Brown et al
      • Brown MM
      • Brown GC
      • Stein JD
      • et al.
      Age-related macular degeneration: economic burden and value-based medicine analysis.
      reported utility values for patients with AMD (no dry vs wet distinction) from a patient versus an ophthalmologist perspective. In both groups, ophthalmic utility values decreased as AMD severity increased, but mean utility values were significantly lower (P < 0.0001) in the patient group versus the treating ophthalmologists. For severe AMD (VA ≤20/200 in better-seeing eye), the patient-perceived utility value (0.47) was 96% worse than the ophthalmologist estimate (0.73). For very severe AMD (VA ≤20/800), the mean patient utility value (0.37) was 103% worse than the ophthalmologist estimate (0.69).

       PRO Landscape Analysis

      The NEI-VFQ-25 was the most commonly identified PRO instrument in the literature, clinical trials, and HTA reports. Among the other instruments, only the generic EuroQol 5-dimension and Health Utilities Index 3 instruments were identified in HTA reports, and use of the remaining instruments in the literature and past clinical trials was fragmented. Most of the identified instruments covered few, if any, of the symptoms identified in the targeted literature review.
      The most frequently used AMD-specific instruments were reviewed for concept coverage (Table V). The conceptual model concepts for immediate effects of dry AMD were widely covered by the identified PRO instruments; for example, the NEI-VFQ-25 covered all 7 immediate-impact higher prevalence concepts (ie, concepts mentioned by ≥50% of articles in the targeted literature review). In contrast, few instruments covered the general effects of dry AMD identified in the conceptual model
      • Schultz NM
      • Braunack-Mayer L
      • Schwartz J
      • Gaspar L.
      The patient experience: symptoms and impact of dry age-related macular degeneration.
      ; for example, depression and financial difficulties appeared in only 2 PRO instruments.
      Table VDry AMD conceptual model concepts covered by PRO instruments used to evaluate quality of life in patients with AMD.
      Bold text indicates instruments selected for detained content validity and psychometrics evaluation. The ALQ, AMD-SEQ, AMD-HIQ, and Eye-Tem Bank instruments were considered for analysis, but because of unavailability of a sample copy item mapping was not possible.
      No. of Concepts Covered Per Instrument
      Symptoms (n = 14)Immediate Impacts (n = 17)General Impacts (n = 4)Total Concepts (n = 35)Total Higher Prevalence Concepts (n = 11)
      Higher prevalence concepts included blurred vision, restricted visual fields, dependency on other people, poor spatial perception and mobility, difficulty reading, difficulty completing activities of daily living, difficulty driving, worry about disease and future, frustration, inability or limitation in participation of social and leisure activities, and financial difficulties.
      ADVS24175
      AVL06283
      DAF11020
      DLTV44195
      EQ-5D13152
      FRI Index15174
      FRQ02132
      FVSQ24175
      HADS01231
      IVI-VLV181106
      LLQ562137
      LVQOL
      Instruments identified via additional unstructured literature reviews.
      25298
      MacDQol06396
      MDSQ641112
      NEI-VFQ-254102169
      NVQ22042
      OPS00000
      PHQ03251
      QOL-VFQc4721311
      RBI01011
      SF-3614383
      VCM105274
      VF-1405165
      Abbreviations: ADVS, Activities of Daily Vision Scale; ALQ, Activity Limitation Questionnaire; AMD-HIQ, Age-related Macular Degeneration Health Impact Questionnaire; AMD-SEQ, Age-Related Macular Degeneration Self-Efficacy Questionnaire; AVL, Adaptation to Age-related Vision Loss; DAF, Discomfort Anxiety Fear Questionnaire; DLTV, Daily Living Tasks Dependent on Vision; EQ-5D, EuroQol 5-dimension; FRI Index, Functional Reading Independence Index; FRQ, Face Recognition Questionnaire; FVSQ, Functional Vision Screening Questionnaire; HADS, Hospital Anxiety and Depression Scale; IVI-VLV, Impact of Vision Impairment-Very Low Vision; LLQ, Low Luminance Questionnaire; LVQOL, Low Vision Quality of Life; MacDQoL, Macular Disease Quality of Life; MDSQ, Macular Disease Society Questionnaire; NEI-VFQ-25, National Eye Institute Vision Function Questionnaire; NVQ, Night Vision Questionnaire; OPS, Optimization in Primary and Secondary Control Scale; PHQ, Patient Health Questionnaire; PRO, patient-reported outcome; QOL-VFQ, Quality of Life and Vision Function Questionnaire; RBI, Reading Behavior Inventory; SF-36, 36-item Short Form Survey; VCM1, Vision Core Measure 1; VF-14, Visual Function Index.
      low asterisk Bold text indicates instruments selected for detained content validity and psychometrics evaluation.The ALQ, AMD-SEQ, AMD-HIQ, and Eye-Tem Bank instruments were considered for analysis, but because of unavailability of a sample copy item mapping was not possible.
      Higher prevalence concepts included blurred vision, restricted visual fields, dependency on other people, poor spatial perception and mobility, difficulty reading, difficulty completing activities of daily living, difficulty driving, worry about disease and future, frustration, inability or limitation in participation of social and leisure activities, and financial difficulties.
      Instruments identified via additional unstructured literature reviews.
      The following 13 instruments were selected for detailed content validity and psychometric evaluation based on individual concept and domain coverage and prevalence in literature: Activities of Daily Vision Scale, Eye-Tem Bank, Functional Reading Independence (FRI) Index, Hospital Anxiety and Depression Scale, Impact of Vision Impairment–Very Low Vision (IVI-VLV), Low Luminance Questionnaire, Low Vision Quality of Life (LVQOL), Macular Disease Quality of Life, Macular Disease Society Questionnaire, NEI-VFQ-25, Quality of Life and Vision Function Questionnaire (QOL-VFQ), SF-36, and Vision Core Measure 1.
      The NEI-VFQ-25 covered most of the 11 salient impacts (ie, impact concepts mentioned by ≥50% of patients during concept elicitation interviews with mean disturbance rating ≥5) identified in the dry AMD conceptual model and had strong content validity and psychometric properties. Although the QoL-VFQ, NEI-VFQ-25, LVQOL, IVI-VLV, and FRI Index had strong content validity and psychometric properties in patients with dry AMD, they had limited coverage of salient concepts. The remaining shortlisted instruments lacked coverage, content validity, and/or psychometric properties in patients with dry AMD (Supplemental Table VI).

      Discussion

      Results from this targeted literature review report that dry AMD negatively affects patients’ lives. The identified evidence reports that patients with dry AMD have increased risks of all-cause mortality and tobacco-related or cancer deaths; they also experience significant impairment in multiple aspects of visual function. We identified limited research on the humanistic and economic burden of dry AMD, which may adversely affect advances in treatment and understanding of patient burden.
      No treatment guidelines were identified for dry AMD specifically. Because of the lack of approved treatment options for dry AMD, management approaches focused on risk factor reduction and use of dietary supplements. Therefore, an unmet need exists for tolerable and effective treatments in this population, as evidenced by the sense of profound loss experienced among patients with dry AMD, particularly advanced forms of dry AMD, attributable to lack of treatment.
      • Taylor DJ
      • Hobby AE
      • Binns AM
      • Crabb DP
      How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review.
      The results of our PRO landscape analysis illustrate that the PRO instruments developed and used in AMD had limited coverage of the salient concepts cross-referenced in a recently published conceptual model of dry AMD.
      • Schultz NM
      • Braunack-Mayer L
      • Schwartz J
      • Gaspar L.
      The patient experience: symptoms and impact of dry age-related macular degeneration.
      There is an unmet need for PRO instruments with more coverage of dry AMD symptoms and salient concepts because research that identifies the key effects of dry AMD on the patient experience can enhance regulatory decision making and serve as a resource for regulators, payers, clinicians, and patients.
      Food and Drug Administration
      Patient-Focused Drug Development: Collecting Comprehensive and Representative Input. Draft Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders.
      Several additional clinical, economic, and humanistic evidence gaps were identified through this analysis. Specifically, despite dry AMD accounting for most diagnosed AMD cases, most published AMD research was specific to wet AMD or nonspecified AMD, perhaps because of the lack of approved treatment options for dry AMD. There is a need for studies to differentiate between dry and wet AMD because they have different manifestations and treatments and a need for more consistent, large studies to provide evidence for dry AMD specifically. Limited country-level and large-scale analyses were available for dry AMD epidemiology, with many studies focusing on late AMD. Few data were available regarding dry AMD disease or functional vision severity; thus, only overall dry AMD prevalence data were available. Limited economic data specific to dry AMD were available. Data on HCRU and direct medical costs in dry AMD were available only from the United States and Italy, illustrating a need for more geographically diverse research on economic burden. In addition, those 2 studies did not explain the specific reasons why HCRU was lower in patients with dry AMD versus wet AMD, indicating a need for more evidence on this topic. Finally, there were limited humanistic data available specific to dry AMD. VRQoL was the only humanistic outcome reported for dry AMD, indicating a need for further research on HRQoL, psychological well-being, utility values, and caregiver impact of dry AMD.
      This report is the first literature review to comprehensively evaluate the epidemiology, management, economic burden, and humanistic burden of dry AMD distinct from wet AMD. It is also the first to analyze HTA reports and/or decisions with regard to AMD treatments and the PRO development landscape. Overall, our results reveal gaps in the foundational knowledge base that, when filled, may enable a more extensive evaluation and contextualization of new therapies for dry AMD.
      However, the analysis has some limitations. The search terms selected may have inadvertently narrowed the number of citations retrieved, and the focus on dry AMD may have limited some of the articles on the different types of AMD. However, limited data and evidence were specifically available for dry AMD, so many results may not have been exclusive to the condition. Although only articles published in English were included in the analysis, a broad range of countries were represented in the included articles. Finally, the analysis was limited by geographic scope for some study outcomes; for example, most of the economic burden research was focused on the United States and therefore may not be generalizable to other populations.

      Conclusions

      Despite the high global prevalence of dry AMD, there are substantial gaps in published information, most notably with respect to the humanistic and economic burden of the disease. More importantly, the significant burden of illness alludes to a high unmet need for tolerable and effective treatment options, as well as validated instruments to characterize the patient experience.

      Disclosure

      Neil M. Schultz and Jason Schwartz are employees of Astellas Pharma Inc. Shweta Bhardwaj and Luis Gaspar are employees of IQVIA. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

      Acknowledgments

      Medical writing and editorial support was provided by Catherine Mirvis, BA, and Beth Lesher, PharmD, BCPS (Pharmerit, an OPEN Health Company, Bethesda, Maryland), and Mark Pfeiffer and Elizabeth Hermans, PhD (Peloton Advantage, LLC, an OPEN Health Company, Parsippany, New Jersey), and funded by the study sponsor. Neil M. Schultz, Shweta Bhardwaj, and Claudia Barclay were responsible for the design of the study and the acquisition, analysis, and interpretation of the study data. Luis Gaspar and Jason Schwartz were responsible for the analysis and interpretation of study data. All authors contributed to the writing of the manuscript or critically revised the manuscript for important intellectual content, and all authors read and approved the final manuscript.

      Funding Sources

      This study was funded by Astellas Pharma Inc. The study sponsor provided input on the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication.

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