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      Effects of Aflibercept for Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis of Observational Comparative Studies

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          Abstract

          Purposes

          To compare the effects of aflibercept and other anti-vascular endothelial growth factor (anti-VEGF) medications on both functional and anatomical outcomes for treatment-naïve neovascular age-related macular degeneration (nAMD) in the real world.

          Methods

          A systematic review and meta-analysis of observational comparative studies.

          Results

          A total of 18 studies remained after literature selection and quality assessment of 1697 studies. The most common aflibercept treatment regimen was three monthly injections followed by pro re nata (PRN). Aflibercept and ranibizumab had similar effects in 2-year treatment. At 3, 6, 12, and 24 months, the differences in the logarithm of minimum angle of resolution (logMAR) decrease in aflibercept and ranibizumab groups were 0.00 (95% confidence interval [CI]: −0.03 to 0.02); 0.01 (95% CI: −0.02 to 0.05); −0.03 (95% CI: −0.07 to 0.01); and –0.06 (95% CI: −0.30 to 0.17), respectively; the differences in decrease of central retinal thickness (CRT) were 3.25 μm (95% CI: −15.03 to 21.53); 7.89 μm (95% CI: −31.91 to 47.69); 2.89 μm (95% CI: −18.33 to 24.11); and −2.42 μm (95% CI: −77.87 to 73.03), respectively. However, aflibercept was significantly more effective in patients with initial reduced visual acuity (logMAR >0.6 or <55 letters; P = 0.001). In the first year, treatment frequency was not significantly different for aflibercept and ranibizumab, but aflibercept required fewer injections than ranibizumab with PRN regimen (mean −0.90; 95% CI: −1.80 to 0.00).

          Conclusions

          Aflibercept has comparable effects with ranibizumab for treatment-naïve nAMD in the real world, and may be more effective for patients with initial lower visual acuity.

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          Most cited references36

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          Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.

          Angiogenesis is a key aspect of the wet form of age-related neovascular (AMD), the leading cause of blindness in the elderly population. Substantial evidence indicated that vascular endothelial growth factor (VEGF)-A is a major mediator of angiogenesis and vascular leakage in wet AMD. VEGF-A is the prototype member of a gene family that includes also PlGF, VEGF-B, VEGF-C, VEGF-D and the orf virus-encoded VEGF-E. Several isoforms of VEGF-A can be generated due to alternative mRNA splicing. Various VEGF inhibitors have been clinically developed. Among these, ranibizumab is a high affinity recombinant Fab that neutralizes all isoforms of VEGF-A. The article briefly reviews the biology of VEGF and then focuses on the path that led to clinical development of ranibizumab. The safety and efficacy of ranibizumab in the treatment of neovascular AMD have been evaluated in two large phase III, multicenter, randomized, double-masked, controlled pivotal trials in different neovascular AMD patient populations. Combined, the trial results indicate that ranibizumab results not only in a slowing down of vision loss but also in a significant proportion of patients experiencing a clinically meaningful vision gain. The visual acuity benefit over control was observed regardless of CNV lesion type. Furthermore, the benefit was associated with a low rate of serious adverse events. Ranibizumab represents a novel therapy that, for the first time, appears to have the potential to enable many AMD patients to obtain a meaningful and sustained gain of vision. On June 30 2006, ranibizumab was approved by the US Food and Drug Administration for the treatment of wet AMD.
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            Novel method for analyzing snellen visual acuity measurements.

            Most retrospective reviews convert Snellen visual acuity measurements obtained during routine clinic visits to logarithm of the minimum angle of resolution (logMAR) units so that statistical manipulations can be performed. However, visual acuity measurements expressed as logMAR units are not intuitively interpretable by clinicians. A more intuitive approach is presented here which uses the conversion of Snellen visual acuity fractions to Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical manipulations. Snellen visual acuity measurements were converted to approximate ETDRS (approxETDRS) letter scores for statistical manipulations and then converted back to Snellen equivalent fractions. The formula to convert Snellen visual acuity measurements to approxETDRS letter scores is 85 + 50 x log (Snellen fraction), which may be rounded to the nearest letter. A linear relationship exists between true ETDRS letter scores, approxETDRS letter scores, and logMAR units. The interconversion between Snellen visual acuity measurements, logMAR units, and approxETDRS letter scores was prepared in a tabular form for easy reference. The same outcomes (in Snellen fractions) were obtained with statistical manipulation of either approxETDRS letter scores or logMAR conversions. Conversion of Snellen visual acuity fractions to approxETDRS letter scores for the purpose of performing statistical manipulations provides more readily interpretable outcomes compared with the current strategy of converting Snellen visual acuity fractions to logMAR units.
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              A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact.

              To evaluate the visual outcome, number of injections, and direct medical cost of a "treat and extend" regimen (TER) in managing neovascular age-related macular degeneration (nAMD) with intravitreal ranibizumab. Retrospective, interventional, consecutive case series. Ninety-two eyes of 92 patients met the entry criteria from May 2006 to May 2008. All patients with treatment-naïve nAMD were treated monthly until no intraretinal or subretinal fluid was observed on optical coherence tomography (OCT). The treatment intervals were then sequentially lengthened by 2 weeks until signs of exudation recurred. The interval was individualized for each patient in an attempt to maintain an exudation-free macula. Change from baseline visual acuity, proportion of eyes losing < 3 lines and gaining ≥ 3 lines at 1 year of follow-up, annual mean number of injections, change from baseline OCT central retinal thickness (CRT), maximum period of extension, and adverse ocular and systemic events. The mean follow-up was 1.52 years. Mean Snellen visual acuity improved from 20/135 at baseline to 20/77 at 1 year follow-up (P < 0.001) and 20/83 at 2 years follow-up (P = 0.002). The proportion of eyes that lost < 3 Snellen visual acuity lines at final follow-up was 96% and the proportion that gained ≥ 3 Snellen visual acuity lines was 32%. The mean OCT CRT decreased from 303 μm at baseline to 238 μm at 1 year follow-up (P < 0.001). The mean number of injections over the first year and between years 1 and 2 was 8.36 and 7.45, respectively. The mean maximum period of extension was 79.9 days. No adverse ocular or systemic events were reported during the follow-up period. The direct annual medical cost per patient was $16,114.52 for the TER. The direct annual medical cost per patient ranged from $15,880.07 to $28,314.16 based on previous clinical trial protocols. Eyes with nAMD experienced significant visual improvement when managed with intravitreal ranibizumab using a TER. This treatment approach also was associated with significantly fewer patient visits, injections, and direct annual medical cost compared with monthly injections such as in the phase III clinical trials. Proprietary or commercial disclosure may be found after the references. Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                Invest Ophthalmol Vis Sci
                IOVS
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                November 2017
                : 58
                : 13
                : 5616-5627
                Affiliations
                [1 ]Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, United States
                [2 ]Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States
                [3 ]Stephen A. Wynn Institute for Vision Research, The University of Iowa, Iowa City, Iowa, United States
                [4 ]Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States
                [5 ]Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, Iowa, United States
                [6 ]Iowa City VA Health Care System, Iowa City, Iowa, United States
                [7 ]Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa, United States
                [8 ]VA Center for Diagnosis and Treatment of Visual Loss, Iowa City, Iowa, United States
                Author notes
                Correspondence: Michael D. Abràmoff, The University of Iowa, 11205 Pomerantz Family Pavilion, Iowa City, IA 52242, USA; michael-abramoff@ 123456uiowa.edu .
                Article
                iovs-58-11-75 IOVS-17-22471
                10.1167/iovs.17-22471
                5667400
                29094167
                18162f14-79a4-4179-a4f1-e89ac2947be0
                Copyright 2017 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 20 June 2017
                : 10 September 2017
                Categories
                Review

                aflibercept,age-related macular degeneration,comparative effectiveness

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