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      Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study

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          Abstract

          Purpose

          To identify the strongest variable(s) linked with the number of ranibizumab injections and outcomes in AURA, and to identify ways to improve outcomes using this association.

          Methods

          AURA was a large observational study that monitored visual acuity over a 2-year period in patients with neovascular age-related macular degeneration (AMD) who received ranibizumab injections. Baseline characteristics, resource use, and outcomes were analyzed using an instrumental variable approach and regression analysis.

          Results

          Data were analyzed from 2227 patients enrolled in AURA. Optical coherence tomography (OCT) and ophthalmoscopy were the most common diagnostic tests used, and this combination was the strongest instrumental variable. Use of OCT and ophthalmoscopy affected the number of injections given and resulted in an increase in visual acuity gains from baseline of 17.6 letters in year 1 and 2.5 letters in year 2. Regression models using the instrumental variable (OCT and ophthalmoscopy combined) showed that ≥5.1 (95% CI: 3.3–11.4) ranibizumab injections were needed to maintain visual acuity from baseline to year 1 and ≥8.3 (95% CI: 5.3–18.8) injections were needed to maintain visual acuity from year 1 to year 2. To gain ≥15 letters, ≥7.9 (95% CI: 5.1–17.5) ranibizumab injections would be needed in year 1 and ≥16.1 (95% CI: 10.3–36.4) injections would be needed over 2 years.

          Conclusions

          These findings highlight the role that regular monitoring plays in guiding neovascular AMD therapy and they showed that the number of ranibizumab injections needed to maintain visual acuity is higher than that administered in AURA.

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          Most cited references16

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          Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.

          To evaluate the efficacy and safety of ranibizumab administered monthly for three months and then quarterly in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic CNV lesions. Patients were randomized 1:1:1 to 0.3 mg ranibizumab (n = 60), 0.5 mg ranibizumab (n = 61), or sham (n = 63) treatment groups. The primary efficacy endpoint was mean change from baseline visual acuity (VA) at month 12. Mean changes from baseline VA at 12 months were -16.3, -1.6, and -0.2 letters for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or = .0001, each ranibizumab dose vs sham). Ranibizumab arrested CNV growth and reduced leakage from CNV. However, the treatment effect declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA had been gains of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Few serious ocular or nonocular adverse events occurred in any group. Ranibizumab administered monthly for three months and then quarterly provided significant VA benefit to patients with AMD-related subfoveal CNV and was well tolerated. The incidence of serious ocular or nonocular adverse events was low.
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            Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

            Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. Trial registration number NCT01318941.
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              Causal effects in clinical and epidemiological studies via potential outcomes: concepts and analytical approaches.

              A central problem in public health studies is how to make inferences about the causal effects of treatments or agents. In this article we review an approach to making such inferences via potential outcomes. In this approach, the causal effect is defined as a comparison of results from two or more alternative treatments, with only one of the results actually observed. We discuss the application of this approach to a number of data collection designs and associated problems commonly encountered in clinical research and epidemiology. Topics considered include the fundamental role of the assignment mechanism, in particular the importance of randomization as an unconfounded method of assignment; randomization-based and model-based methods of statistical inference for causal effects; methods for handling noncompliance and missing data; and methods for limiting bias in the analysis of observational data, including propensity score matching and sensitivity analysis.
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                Author and article information

                Journal
                Eye (Lond)
                Eye (Lond)
                Eye
                Nature Publishing Group
                0950-222X
                1476-5454
                August 2016
                20 May 2016
                1 August 2016
                : 30
                : 8
                : 1063-1071
                Affiliations
                [1 ]Department of Ophthalmology, University of Bonn , Bonn, Germany
                [2 ]Department of Ophthalmology, Hôpital Lariboisière , Paris, France
                [3 ]Department of Ophthalmology, Institute of Eye Surgery , Waterford, Ireland
                [4 ]Department of Ophthalmology and Vision Sciences, University of Toronto, and St Michael's Hospital , Toronto, Ontario, Canada
                [5 ]Department of Biomedical and Clinical Science Luigi Sacco, Luigi Sacco Hospital, University of Milan , Milan, Italy
                [6 ]NIHR Biomedical Centre for Research in Ophthalmology, Moorfields Eye Hospital , London, UK
                [7 ]Bayer Pharmaceuticals , Berlin, Germany
                [8 ]Mapi Group, Real World Strategy and Analysis , Stockholm, Sweden
                [9 ]Health Economics, AstraZeneca Nordic-Baltic , Södertälje, Sweden
                [10 ]Department of Ophthalmology, King's College Hospital , London, UK
                Author notes
                [* ]Department of Ophthalmology, King's College Hospital, Denmark Hill , London SE5 9RS, UK Tel: +44 (0)20 3299 4548; Fax: +44 (0)20 3299 3738. E-mail: senswathi@ 123456aol.com
                Article
                eye201690
                10.1038/eye.2016.90
                4985685
                27197868
                9691ef5e-7be1-435f-a2b0-66504fe0d8ff
                Copyright © 2016 Royal College of Ophthalmologists

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 January 2016
                : 23 March 2016
                Categories
                Clinical Study

                Vision sciences
                Vision sciences

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