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State-of-the art pharmacotherapy for non-neovascular age-related macular degeneration.
Veritti, D, Sarao, V, Samassa, F, Danese, C, Löwenstein, A, Schmidt-Erfurth, U, Lanzetta, P
Expert opinion on pharmacotherapy. 2020;(7):773-784
Abstract
INTRODUCTION Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the industrialized world. While effective treatment is available for neovascular AMD, no therapy is successful for the non-neovascular form. Herein, the authors report the current knowledge on non-neovascular AMD pathogenesis and the promising research on treatments. AREAS COVERED In the present review, the authors summarize the most recent advances in the treatment of non-neovascular AMD and provide an update on current treatment strategies. Evidence available from preclinical and clinical studies and from a selective literature search is reported. EXPERT OPINION When investigating AMD, numerous pathological cascades and alterations of physiological processes have been investigated. It is well-known that AMD is a multifactorial disease, with environmental causes and genetics playing a role. Perturbations in multiple pathogenic pathways have been identified and this led to the development of several molecules directed at specific therapeutic targets. However, despite the huge research effort, the only proven approach so far is oral antioxidant supplementation. We believe that, in addition to successful advancement of promising drugs, further research should be directed at tailoring therapy to specific patient groups, eventually employing a combinational therapy strategy.
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Association of Visit Adherence and Visual Acuity in Patients With Neovascular Age-Related Macular Degeneration: Secondary Analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial.
Ramakrishnan, MS, Yu, Y, VanderBeek, BL
JAMA ophthalmology. 2020;(3):237-242
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IMPORTANCE Visit adherence has been shown to play a significant role in patient health outcomes. The effect of missing visits on visual acuity (VA) in individuals with neovascular age-related macular degeneration has yet to be characterized. OBJECTIVE To quantify the association between patients' adherence to randomized clinical trial visits and VA in individuals with neovascular age-related macular degeneration based on 4 visit adherence metrics. DESIGN, SETTING, AND PARTICIPANTS This is a secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial randomized clinical trial. Individuals with age-related macular degeneration were recruited from 44 clinical centers in the United States between February 2008 and December 2009. The 2-year study protocol required 1 visit every 4 weeks (every 21-35 days for a total of 26 visits) for monthly vs pro re nata treatments of bevacizumab vs ranibizumab. Analysis took place from November 2018 through May 2019. EXPOSURES Visit adherence was measured in 4 ways: total number of missed visits, average number of days (avg days) between each visit, longest duration in days (max days) between visits, and visit constancy (the tally of 3-month periods with at least 1 visit attended). Average and max days were also categorized as on time (28-35 days), late (36-60 days), and very late (>60 days). MAIN OUTCOMES AND MEASURES Change in Early Treatment Diabetic Retinopathy Study VA between the baseline and the last visit. Linear multivariate regression models were applied to analyze the association between visit adherence and change in VA, controlling for age, sex, baseline VA, anti-vascular endothelial growth factor drug, number of injections, and dosing regimen. RESULTS Of 1178 patients, the mean (SD) age was 79.1 (7.3) years, and 727 (61.7%) were women. The mean (SD) number of missed visits was 2.4 (3.1). Overall, 1091 patients (92.6%) had complete visit constancy during the entire study period. Average days were categorized with 1060 patients (90.0%) classified as on time, 108 (9.2%) were late, and 10 (0.8%) were very late. For max days between visits, 197 patients (16.7%) were on time, 773 (65.6%) were late, and 208 (17.7%) were very late. After controlling for covariates, the late (avg days = -6.1; max days = -2.0) and very late (avg days = -12.5; max days = -5.9) groups saw fewer letters in both the avg and max days categories than patients in the on-time group (P < .001). CONCLUSIONS AND RELEVANCE These results provide evidence to support the concept that visit adherence contributes to VA outcomes in neovascular age-related macular degeneration. The magnitude of the association of visit adherence with VA outcomes in this clinical scenario suggests that substantial effort should be expended to strive for visit adherence or therapeutic strategies that reduce the visit burden without compromising VA outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00593450.
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Long-term Effect of Intraocular Lens vs Contact Lens Correction on Visual Acuity After Cataract Surgery During Infancy: A Randomized Clinical Trial.
Lambert, SR, Cotsonis, G, DuBois, L, Nizam Ms, A, Kruger, SJ, Hartmann, EE, Weakley, DR, Drews-Botsch, C, ,
JAMA ophthalmology. 2020;(4):365-372
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IMPORTANCE Although intraocular lenses (IOLs) are often implanted in children, little is known whether primary IOL implantation or aphakia and contact lens correction results in better long-term visual outcomes after unilateral cataract surgery during infancy. OBJECTIVE To compare long-term visual outcomes with contact lens vs IOL correction following unilateral cataract surgery during infancy. DESIGN, SETTING, AND PARTICIPANTS This multicenter randomized clinical trial enrolled 114 infants with a unilateral congenital cataract who underwent cataract surgery with or without primary IOL implantation between 1 and 6 months of age. Data on long-term visual outcomes were collected when the children were age 10.5 years (July 14, 2015, to July 12, 2019) and analyzed from March 30 through August 6, 2019. INTERVENTIONS Intraocular lens implantation at the time of cataract surgery. MAIN OUTCOMES AND MEASURES Best-corrected visual acuity using the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) testing protocol. Analysis was performed on an intention-to-treat basis. RESULTS Best-corrected visual acuity was measured at age 10.5 years for 110 of the 114 patients (96%) enrolled as infants. The participants included 58 girls (53%) and 52 boys (47%). Overall, 27 of the children (25%) had good (logMAR 0.30 [Snellen equivalent, 20/40] or better) visual acuity in the treated eye (12 [22%] in the IOL group and 15 [27%] in the aphakia group), but 50 children (44%) had a visual acuity of logMAR 1.00 (Snellen equivalent, 20/200) or worse (25 [44%] in the IOL group and 25 [44%] in the aphakia group). The median logMAR acuity in the treated eye was similar in children randomized to receive an IOL at the time of cataract extraction (0.89; interquartile range [IQR], 0.33-1.43 [Snellen equivalent, 20/159]) and those who remained aphakic (0.86; IQR, 0.30-1.46 [Snellen equivalent, 20/145]) (IQR, 0.30-1.46; P = .82). Although the overall difference in median visual acuity between the 2 groups was small, the estimate was imprecise (99% CI for the difference in medians was -0.54 to 0.47). CONCLUSIONS AND RELEVANCE As in previous phases of the study, visual acuity outcomes were highly variable with only 27 children (25%) achieving excellent visual acuity in their treated eye and 50 children (44%) having poor vision in the treated eye. Implanting an IOL at the time of cataract extraction was neither beneficial nor detrimental to the visual outcome. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00212134.
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Efficacy and Treatment Burden of Intravitreal Aflibercept Versus Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison.
Ohji, M, Lanzetta, P, Korobelnik, JF, Wojciechowski, P, Taieb, V, Deschaseaux, C, Janer, D, Tuckmantel, C
Advances in therapy. 2020;(5):2184-2198
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PURPOSE To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.
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Associations of Variation in Retinal Thickness With Visual Acuity and Anatomic Outcomes in Eyes With Neovascular Age-Related Macular Degeneration Lesions Treated With Anti-Vascular Endothelial Growth Factor Agents.
Evans, RN, Reeves, BC, Maguire, MG, Martin, DF, Muldrew, A, Peto, T, Rogers, C, Chakravarthy, U
JAMA ophthalmology. 2020;(10):1043-1051
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IMPORTANCE When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation. OBJECTIVE To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness. DESIGN, SETTING, AND PARTICIPANTS In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020. MAIN OUTCOMES AND MEASURES Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy. RESULTS Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy. CONCLUSIONS AND RELEVANCE Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.
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Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial.
Campochiaro, PA, Iftikhar, M, Hafiz, G, Akhlaq, A, Tsai, G, Wehling, D, Lu, L, Wall, GM, Singh, MS, Kong, X
The Journal of clinical investigation. 2020;(3):1527-1541
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BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.
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Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial.
Glassman, AR, Baker, CW, Beaulieu, WT, Bressler, NM, Punjabi, OS, Stockdale, CR, Wykoff, CC, Jampol, LM, Sun, JK, ,
JAMA ophthalmology. 2020;(4):341-349
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IMPORTANCE Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management. OBJECTIVE To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened. DESIGN, SETTING, AND PARTICIPANTS This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019. INTERVENTIONS Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened. MAIN OUTCOMES AND MEASURES Whether individuals received aflibercept. RESULTS Among 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range, 53-67 years]) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 μm (Zeiss-Stratus equivalent) vs less than 300 μm (45% vs 26%; hazard ratio [HR], 1.98 [95% CI, 1.26-3.13], continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 [95% CI, 1.42-3.47], ordinal P < .001), and among participants whose nonstudy eye received DME treatment within 4 months of randomization vs not (52% vs 25%; HR, 2.55 [95% CI, 1.64-3.99], P < .001). CONCLUSIONS AND RELEVANCE Most eyes managed with initial observation plus aflibercept only if VA worsened maintained good vision at 2 years and did not require aflibercept for VA loss. However, the eyes in the trial were approximately twice as likely to receive aflibercept for VA loss if they had greater baseline central subfield thickness, worse diabetic retinopathy severity level, or a nonstudy eye receiving treatment for DME. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01909791.
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Idebenone increases chance of stabilization/recovery of visual acuity in OPA1-dominant optic atrophy.
Romagnoli, M, La Morgia, C, Carbonelli, M, Di Vito, L, Amore, G, Zenesini, C, Cascavilla, ML, Barboni, P, Carelli, V
Annals of clinical and translational neurology. 2020;(4):590-594
Abstract
We previously documented that idebenone treatment in OPA1-Dominant Optic Atrophy (OPA1-DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off-label idebenone administration in a larger OPA1-DOA group compared with untreated patients. Inclusion criteria were: OPA1-DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone-treated as compared to untreated patients. This effect was retained after controlling for confounders.
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Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.
Khurana, RN, Chang, L, Day, BM, Ghanekar, A, Stoilov, I
Ophthalmology. Retina. 2020;(8):760-766
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PURPOSE To investigate whether time to peak best-corrected visual acuity (BCVA) was predictive of magnitude of BCVA changes at study end in patients with neovascular age-related macular degeneration (nAMD) who received ranibizumab and assess whether patient baseline characteristics and on-study events were predictive of time to peak BCVA. DESIGN Exploratory analysis of data from HARBOR (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS Treatment-naïve patients 50 years of age or older with subfoveal nAMD. METHODS Data by ranibizumab dose were pooled; data by dosing schedule (pro re nata [PRN] and monthly) were evaluated separately. Time to peak BCVA was the monthly evaluation at which the patient's greatest gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline was achieved. Early peakers achieved peak BCVA between day 7 and month 6; late peakers achieved peak BCVA between months 7 and 12, months 13 and 18, and months 19 and 24. Variables evaluated for effect of time to peak BCVA included baseline demographic and clinical characteristics, presence of persistent subretinal fluid (SRF) or intraretinal fluid (IRF), and on-study events (atrophy status, fibrosis, retinal pigment epithelium tears). MAIN OUTCOME MEASURES Time to peak BCVA and its predictive value for magnitude of BCVA changes and BCVA at month 24 (study end). RESULTS Most patients reached peak BCVA after more than 6 months of treatment: 64% in the PRN group (301/474) and 70% in the monthly groups (327/469). Thirty-six percent and 30% of patients, respectively, peaked early, and 64% and 70%, respectively, peaked late. At month 24, early peakers on average lost vision (PRN, -1.6 ETDRS letters; monthly, -1.9 ETDRS letters). By contrast, late peakers achieved significantly better vision gains from baseline (PRN, 8.5-17.7 ETDRS letters; monthly, 10.1-18.7 ETDRS letters). No differences were found in patient characteristics, persistent SRF or IRF, or on-study events to account for the observed different outcomes between early and late peakers. CONCLUSIONS In most treatment-naïve patients with nAMD, vision gains were achieved at a slower rate (>6 months), and a slower response was associated with better vision outcomes after 24 months of ranibizumab. These findings suggest that continued treatment may result in greater vision improvements when consistent anti-vascular endothelial growth factor therapy is maintained over a longer period.
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FOVEAL SPARING INTERNAL LIMITING MEMBRANE PEELING FOR IDIOPATHIC MACULAR HOLES: EFFECTS ON ANATOMICAL RESTORATION OF THE FOVEA AND VISUAL FUNCTION.
Murphy, DC, Fostier, W, Rees, J, Steel, DH
Retina (Philadelphia, Pa.). 2020;(11):2127-2133
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PURPOSE Muller cells seem to be important in maintaining foveal morphology through connections between their foot processes and the internal limiting membrane (ILM). Internal limiting membrane peeling causes Muller cell trauma. We hypothesized that leaving a rim of unpeeled ILM around idiopathic macular holes undergoing vitrectomy surgery would improve postoperative foveal morphology and vision. METHODS Prospective pilot study of fovea-sparing ILM peeling in a consecutive cohort of patients with macular holes over a 12-month period. Spectral-domain optical coherence tomography and Early Treatment Diabetic Retinopathy Study letters best-corrected visual acuity were assessed preoperatively and postoperatively, and foveal morphology and metamorphopsia postoperatively. The foveal sparing group was compared with a second consecutive cohort who received standard ILM peeling (control group). RESULTS Thirty-four eyes of 34 patients were included in each group. Groups showed no significant preoperative differences. 34/34 holes were successfully closed with surgery in the foveal sparing group and 32/34 in the control group. The foveal sparing group showed better postoperative best-corrected visual acuity (67.7 vs. 63.8, P = 0.003) and best-corrected visual acuity improvement (25.1 vs. 20.2, P = 0.03). The foveal sparing group demonstrated thicker minimum foveal thickness (211 vs. 173 μm, P = 0.002) and less steep foveal depression (158 vs. 149, P = 0.002). CONCLUSION Preserving nonpeeled ILM around macular holes resulted in a high closure rate, improved foveal morphology, and better postoperative best-corrected visual acuity. An appropriately powered randomized controlled study is warranted.