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      Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

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          Abstract

          Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.

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          Most cited references175

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          Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

          Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).
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            Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group.

            (1985)
            Data from the Early Treatment Diabetic Retinopathy Study (ETDRS) show that focal photocoagulation of "clinically significant" diabetic macular edema substantially reduces the risk of visual loss. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. In this randomized clinical trial, which was supported by the National Eye Institute, 754 eyes that had macular edema and mild to moderate diabetic retinopathy were randomly assigned to focal argon laser photocoagulation, while 1,490 such eyes were randomly assigned to deferral of photocoagulation. The beneficial effects of treatment demonstrated in this trial suggest that all eyes with clinically significant diabetic macular edema should be considered for focal photocoagulation. Clinically significant macular edema is defined as retinal thickening that involves or threatens the center of the macula (even if visual acuity is not yet reduced) and is assessed by stereo contact lens biomicroscopy or stereo photography. Follow-up of all ETDRS patients continues without other modifications in the study protocol.
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              Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.

              Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab. Double-masked, multicenter, parallel-group, active-controlled, randomized trials. Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4). The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures. All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. Proprietary or commercial disclosure may be found after the references. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                29 April 2021
                May 2021
                : 10
                : 5
                : 1049
                Affiliations
                [1 ]Department of Ophthalmology, Albany Medical College, Albany, NY 12208, USA; jwallsh@ 123456hotmail.com
                [2 ]Retina Macula Institute, Torrance, CA 90503, USA
                Author notes
                Article
                cells-10-01049
                10.3390/cells10051049
                8145407
                33946803
                549c52bf-b88f-4c0e-bec6-62b74909f39f
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 03 April 2021
                : 28 April 2021
                Categories
                Review

                anti-vegf,macular degeneration,diabetic retinopathy,resistant,retinal vein occlusion

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