Association of Early Anatomic Response with Visual Function in Neovascular Age-Related Macular Degeneration
Authors: Michael Singer, Rishi P. Singh, Andrea Gibson, Hadi Moini, Kimberly Reed, Robert Vitti, Weiming Du, David Eichenbaum
Journal: Ophthalmology (2021)

Patients with neovascular age-related macular degeneration (nAMD) experience impaired visual acuity (VA), with some also reporting a loss of vision-related functions affecting activities such as reading, writing, and driving.1Williams R.A. Brody B.L. Thomas R.G. et al.The psychosocial impact of macular degeneration.Arch Ophthalmol. 1998; 116: 514-520Crossref PubMed Scopus (352) Google Scholar Clinical treatment of nAMD is commonly guided by OCT, which gives information on retinal thickness and fluid location, typically in combination with vision measurement. However, there is often no or poor correlation between retinal thickness and vision,2Ou W.C. Brown D.M. Payne J.F. Wykoff C.C. Relationship between visual acuity and retinal thickness during anti-vascular endothelial growth factor therapy for retinal diseases.Am J Ophthalmol. 2017; 180: 8-17Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and neither of the assessments incorporate vision-related function changes into the criteria used for retreatment. Furthermore, the relationship between vision-related functions and fluid location has been less characterized than the relationship between vision and fluid location, and the impact of a less than complete dryness response to anti-vascular endothelial growth factor (VEGF) therapy on subsequent vision and vision-related function outcomes is unknown. In this integrated analysis of the Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials,3Heier J.S. Brown D.M. Chong V. et al.Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.Ophthalmology. 2012; 119: 2537-2548Abstract Full Text Full Text PDF PubMed Scopus (1578) Google Scholar we assessed whether early persistent retinal dryness in response to anti-VEGF therapy translates into vision-related function and/or VA benefit.Each clinical site’s respective institutional review board or ethics committee approved the study protocol. All patients provided written informed consent. The VIEW trials adhered to the ethical guidelines of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act.Of the 2412 eyes in the full analysis set of the VIEW trials, this analysis included 1815 eyes with known retinal fluid status from baseline through week 12 that were treated with 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4; n = 595), 2 mg intravitreal aflibercept injection (IAI) every 4 weeks (2q4; n = 613), or 2 mg IAI every 8 weeks after 3 initial monthly doses (2q8; n = 607). Eyes were categorized into 2 subgroups based on qualitative status of retinal fluid at the first 3 visits (weeks 4, 8, and 12) after initiation of treatment: eyes with no retinal fluid (persistently dry [PD]) and eyes with retinal fluid at 1 or more visit (not persistently dry [NPD]). Changes from baseline through week 24 in vision-related function (combined treatment groups) and best-corrected VA (BCVA; both combined and individual treatment groups) were evaluated by anatomic location of fluid: intraretinal fluid (IRF), subretinal fluid (SRF), and overall retinal fluid (ORF). Vision-related function was assessed using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) at baseline and weeks 12 and 24. A difference of 5 points or more in the NEI-VFQ-25 score was considered a clinically significant change.4Suñer I.J. Kokame G.T. Yu E. et al.Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials.Invest Ophthalmol Vis Sci. 2009; 50: 3629-3635Crossref PubMed Scopus (112) Google Scholar Best-corrected VA was measured by an Early Treatment Diabetic Retinopathy Study chart every 4 weeks through week 24.At week 12, 28.2% of eyes were PD in the combined treatment group, with 23.7%, 30.7%, and 30.0% in the Rq4, IAI 2q4, and IAI 2q8 groups, respectively. Compared with Rq4, a greater proportion of eyes were PD with IAI 2q4 (adjusted difference, 6.8%; 95% CI, 1.8–11.7) and IAI 2q8 (adjusted difference, 6.1%; 95% CI, 1.1–11.0). Baseline characteristics of PD and NPD eyes were generally similar, except for NPD eyes having relatively greater baseline central retinal thickness across treatment groups compared with PD eyes (Table S1, available at www.aaojournal.org).In the combined treatment groups, PD eyes showed greater odds of improving on the role difficulties and driving subscales of the NEI-VFQ-25 by 5 points or more over NPD eyes with IRF at week 24 (Fig 1). Similar magnitude of improvements in PD eyes were observed over NPD eyes with SRF for the composite score, distance activities subscale, and social functioning subscale and over NPD eyes with ORF for the composite score and near activities subscale at week 24 (Fig 1). No differences were noted between PD and NPD eyes for other NEI-VFQ-25 subscales.Mean BCVA gain from baseline through week 24 in the combined treatment group was marginally greater in PD eyes compared with NPD eyes with IRF (difference, 1.7 letters; 95% CI, 0.61–2.82 letters), whereas it was similar in PD and NPD eyes with SRF or with ORF (Fig 1). When broken down by the treatment groups, mean BCVA gains in PD eyes compared with NPD eyes with IRF were greater with Rq4 (difference, 3.4 letters; 95% CI, 1.58–5.16 letters), marginally greater with IAI 2q8 (difference, 2.2 letters; 95% CI, 0.12–4.32 letters), and similar with IAI 2q4 (difference, –0.3 letters; 95% CI, –2.14 to 1.52 letters). Mean BCVA gain within each treatment group was similar in PD and NPD eyes with SRF or ORF (Fig S1, available at www.aaojournal.org).These findings suggest that patients with nAMD experience early visual function changes based on the extent of anatomic improvement after anti-VEGF treatment. At week 12, a significantly greater proportion of eyes treated with IAI achieved persistent dryness after the first 3 initial doses than those treated with Rq4. Eyes that achieved persistent dryness through week 12 demonstrated clinically relevant4Suñer I.J. Kokame G.T. Yu E. et al.Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials.Invest Ophthalmol Vis Sci. 2009; 50: 3629-3635Crossref PubMed Scopus (112) Google Scholar greater improvements than NPD eyes in several vision-related functions, varying by the location of fluid, which included role difficulties, driving, distance activities, social functioning, and near activities. Early persistent dryness was associated with a greater VA gain only when compared with NPD eyes that had IRF, primarily in eyes treated with Rq4. These findings are consistent with reports from the Comparison of Age-Related Macular Degeneration Treatments Trials5Sharma S. Toth C.A. Daniel E. et al.Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials.Ophthalmology. 2016; 123: 865-875Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar and HARBOR,6Holekamp N.M. Ghanekar A. Hill L. et al.What do the HARBOR data reveal about the relationship between the drying of subretinal and intraretinal fluid and associated vision outcomes? 2019. 37th Annual Meeting of the American Society of Retina Specialists, July 26–30. Chicago, Illinois, 2019Google Scholar indicating detrimental effects of IRF on VA, and a report from VIEW suggesting additional visual benefit of IAI 2q4 over Rq4 and IAI 2q8 in eyes with early persistent fluid.7Jaffe G.J. Kaiser P.K. Thompson D. et al.Differential response to anti-VEGF regimens in age-related macular degeneration patients with early persistent retinal fluid.Ophthalmology. 2016; 123: 1856-1864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Of note in our study is the observation that SRF affected vision-related functions, but not VA; potential implications of this finding for tolerating residual SRF during management of nAMD remain to be elucidated.Limitations of this study include the exploratory post hoc nature of the analysis based on relatively short-term data, use of time-domain rather than spectral-domain OCT, the qualitative and not quantitative assessment of retinal fluid, potential differences in baseline characteristics of NPD and PD eyes, and potential impact on NEI-VFQ-25 scores given that the study eyes were the worse-seeing eyes. Strengths included the large sample size with fixed dosing schedules from 2 large randomized trials and independent, masked evaluation of BCVA and OCT according to a standardized protocol.In conclusion, this exploratory analysis provides important insights into the impact of an early persistent retinal dryness response and the location of fluid on vision-related functions and visual acuity in patients with nAMD. Using effective anti-VEGF agents and dosing strategies initially during management of nAMD are important considerations for achieving early persistent retinal dryness to maximize improvements in visual function outcomes. Patients with neovascular age-related macular degeneration (nAMD) experience impaired visual acuity (VA), with some also reporting a loss of vision-related functions affecting activities such as reading, writing, and driving.1Williams R.A. Brody B.L. Thomas R.G. et al.The psychosocial impact of macular degeneration.Arch Ophthalmol. 1998; 116: 514-520Crossref PubMed Scopus (352) Google Scholar Clinical treatment of nAMD is commonly guided by OCT, which gives information on retinal thickness and fluid location, typically in combination with vision measurement. However, there is often no or poor correlation between retinal thickness and vision,2Ou W.C. Brown D.M. Payne J.F. Wykoff C.C. Relationship between visual acuity and retinal thickness during anti-vascular endothelial growth factor therapy for retinal diseases.Am J Ophthalmol. 2017; 180: 8-17Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and neither of the assessments incorporate vision-related function changes into the criteria used for retreatment. Furthermore, the relationship between vision-related functions and fluid location has been less characterized than the relationship between vision and fluid location, and the impact of a less than complete dryness response to anti-vascular endothelial growth factor (VEGF) therapy on subsequent vision and vision-related function outcomes is unknown. In this integrated analysis of the Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials,3Heier J.S. Brown D.M. Chong V. et al.Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.Ophthalmology. 2012; 119: 2537-2548Abstract Full Text Full Text PDF PubMed Scopus (1578) Google Scholar we assessed whether early persistent retinal dryness in response to anti-VEGF therapy translates into vision-related function and/or VA benefit. Each clinical site’s respective institutional review board or ethics committee approved the study protocol. All patients provided written informed consent. The VIEW trials adhered to the ethical guidelines of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. Of the 2412 eyes in the full analysis set of the VIEW trials, this analysis included 1815 eyes with known retinal fluid status from baseline through week 12 that were treated with 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4; n = 595), 2 mg intravitreal aflibercept injection (IAI) every 4 weeks (2q4; n = 613), or 2 mg IAI every 8 weeks after 3 initial monthly doses (2q8; n = 607). Eyes were categorized into 2 subgroups based on qualitative status of retinal fluid at the first 3 visits (weeks 4, 8, and 12) after initiation of treatment: eyes with no retinal fluid (persistently dry [PD]) and eyes with retinal fluid at 1 or more visit (not persistently dry [NPD]). Changes from baseline through week 24 in vision-related function (combined treatment groups) and best-corrected VA (BCVA; both combined and individual treatment groups) were evaluated by anatomic location of fluid: intraretinal fluid (IRF), subretinal fluid (SRF), and overall retinal fluid (ORF). Vision-related function was assessed using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) at baseline and weeks 12 and 24. A difference of 5 points or more in the NEI-VFQ-25 score was considered a clinically significant change.4Suñer I.J. Kokame G.T. Yu E. et al.Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials.Invest Ophthalmol Vis Sci. 2009; 50: 3629-3635Crossref PubMed Scopus (112) Google Scholar Best-corrected VA was measured by an Early Treatment Diabetic Retinopathy Study chart every 4 weeks through week 24. At week 12, 28.2% of eyes were PD in the combined treatment group, with 23.7%, 30.7%, and 30.0% in the Rq4, IAI 2q4, and IAI 2q8 groups, respectively. Compared with Rq4, a greater proportion of eyes were PD with IAI 2q4 (adjusted difference, 6.8%; 95% CI, 1.8–11.7) and IAI 2q8 (adjusted difference, 6.1%; 95% CI, 1.1–11.0). Baseline characteristics of PD and NPD eyes were generally similar, except for NPD eyes having relatively greater baseline central retinal thickness across treatment groups compared with PD eyes (Table S1, available at www.aaojournal.org). In the combined treatment groups, PD eyes showed greater odds of improving on the role difficulties and driving subscales of the NEI-VFQ-25 by 5 points or more over NPD eyes with IRF at week 24 (Fig 1). Similar magnitude of improvements in PD eyes were observed over NPD eyes with SRF for the composite score, distance activities subscale, and social functioning subscale and over NPD eyes with ORF for the composite score and near activities subscale at week 24 (Fig 1). No differences were noted between PD and NPD eyes for other NEI-VFQ-25 subscales. Mean BCVA gain from baseline through week 24 in the combined treatment group was marginally greater in PD eyes compared with NPD eyes with IRF (difference, 1.7 letters; 95% CI, 0.61–2.82 letters), whereas it was similar in PD and NPD eyes with SRF or with ORF (Fig 1). When broken down by the treatment groups, mean BCVA gains in PD eyes compared with NPD eyes with IRF were greater with Rq4 (difference, 3.4 letters; 95% CI, 1.58–5.16 letters), marginally greater with IAI 2q8 (difference, 2.2 letters; 95% CI, 0.12–4.32 letters), and similar with IAI 2q4 (difference, –0.3 letters; 95% CI, –2.14 to 1.52 letters). Mean BCVA gain within each treatment group was similar in PD and NPD eyes with SRF or ORF (Fig S1, available at www.aaojournal.org). These findings suggest that patients with nAMD experience early visual function changes based on the extent of anatomic improvement after anti-VEGF treatment. At week 12, a significantly greater proportion of eyes treated with IAI achieved persistent dryness after the first 3 initial doses than those treated with Rq4. Eyes that achieved persistent dryness through week 12 demonstrated clinically relevant4Suñer I.J. Kokame G.T. Yu E. et al.Responsiveness of NEI VFQ-25 to changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials.Invest Ophthalmol Vis Sci. 2009; 50: 3629-3635Crossref PubMed Scopus (112) Google Scholar greater improvements than NPD eyes in several vision-related functions, varying by the location of fluid, which included role difficulties, driving, distance activities, social functioning, and near activities. Early persistent dryness was associated with a greater VA gain only when compared with NPD eyes that had IRF, primarily in eyes treated with Rq4. These findings are consistent with reports from the Comparison of Age-Related Macular Degeneration Treatments Trials5Sharma S. Toth C.A. Daniel E. et al.Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials.Ophthalmology. 2016; 123: 865-875Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar and HARBOR,6Holekamp N.M. Ghanekar A. Hill L. et al.What do the HARBOR data reveal about the relationship between the drying of subretinal and intraretinal fluid and associated vision outcomes? 2019. 37th Annual Meeting of the American Society of Retina Specialists, July 26–30. Chicago, Illinois, 2019Google Scholar indicating detrimental effects of IRF on VA, and a report from VIEW suggesting additional visual benefit of IAI 2q4 over Rq4 and IAI 2q8 in eyes with early persistent fluid.7Jaffe G.J. Kaiser P.K. Thompson D. et al.Differential response to anti-VEGF regimens in age-related macular degeneration patients with early persistent retinal fluid.Ophthalmology. 2016; 123: 1856-1864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Of note in our study is the observation that SRF affected vision-related functions, but not VA; potential implications of this finding for tolerating residual SRF during management of nAMD remain to be elucidated. Limitations of this study include the exploratory post hoc nature of the analysis based on relatively short-term data, use of time-domain rather than spectral-domain OCT, the qualitative and not quantitative assessment of retinal fluid, potential differences in baseline characteristics of NPD and PD eyes, and potential impact on NEI-VFQ-25 scores given that the study eyes were the worse-seeing eyes. Strengths included the large sample size with fixed dosing schedules from 2 large randomized trials and independent, masked evaluation of BCVA and OCT according to a standardized protocol. In conclusion, this exploratory analysis provides important insights into the impact of an early persistent retinal dryness response and the location of fluid on vision-related functions and visual acuity in patients with nAMD. Using effective anti-VEGF agents and dosing strategies initially during management of nAMD are important considerations for achieving early persistent retinal dryness to maximize improvements in visual function outcomes. The authors thank the patients for their participation in this study. Supplementary Data Download .pdf (.24 MB) Help with pdf files Supplementary Materials Download .pdf (.24 MB) Help with pdf files Supplementary Materials