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      Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD

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          Abstract

          Purpose

          Evaluation of three aflibercept injections at 4-week intervals in patients with neovascular AMD showing an “insufficient anatomic response” to prior anti-VEGF therapy with ranibizumab or bevacizumab.

          Methods

          The retrospective analysis included 96 eyes that had received at least three intravitreal 0.5 mg ranibizumab or 1.25 mg bevacizumab injections over a period of no more than 4 months prior to switching to aflibercept. In addition, the selected eyes had to have evidence of persisting or increasing sub- or intraretinal fluid, observed in optical coherence tomography (OCT). All patients received a loading dose of three intravitreal 2 mg aflibercept injections at 4-week intervals. Evaluation included central retinal thickness (CRT) and maximum pigment epithelium (PED) height measured by spectral domain OCT and best-corrected visual acuity (BCVA) prior to the switch of therapy and 4 weeks after the third aflibercept injection.

          Results

          A significant reduction of mean CRT (−39 μm; p < 0.001) and maximum PED height (−46 μm; p < 0.001) as found 4 weeks after the third aflibercept injection. Eighty-two out of 96 eyes (85 %) had a PED just prior to switching to aflibercept. There was an improvement in BCVA of 1.9 letters 4 weeks after the last aflibercept injection; the vision gain, however, did not reach statistical significance ( p = 0.061). The further analysis did not show any correlation of the change in CRT, maximum PED, and BCVA with the number of prior anti-VEGF treatments.

          Conclusion

          Retinal edema and PEDs regressed significantly after switching to aflibercept in patients insufficiently responding to prior therapy with ranibizumab or bevacizumab. No correlation could be found with regard to the number of prior treatments.

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          Most cited references13

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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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            Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab.

            To evaluate the outcome of intravitreal injection of aflibercept in cases with exudative age-related macular degeneration, (AMD) resistant to injections of bevacizumab or ranibizumab.
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              Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration?

              To determine whether repetitive injections of intravitreal bevacizumab and/or triamcinolone acetate in patients with exudative age-related macular degeneration (AMD) results in a decrease in biological response. Retrospective comparative case series. Forty-three eyes of 43 patients with exudative AMD. Pre- and postinjection optical coherence tomography (OCT) sections of 43 patients with AMD were analyzed to determine the change in the biologic response after each subsequent injection of intravitreal bevacizumab (2.5 mg/100 microL), preservative-free triamcinolone acetonide (pfTA) (4.0 mg/100 microL), or a combination of bevacizumab (1.25 mg/50 microL) and pfTA (2.0 mg/50 microL). The retinal thickness of each OCT sector was determined and expressed as volume. Standardized volumetric change index (SVCI) was determined to identify a statistically significant change. Pre- and postinjection (6 weeks) SVCI differences were plotted as a function of time to determine the biological response after each intravitreal treatment. Change in SVCI after intravitreal injections and the number of injections required to decrease the biological response by 50% (INJ(50)). There was no difference in the age, gender, and preinjection thickness of the retina in each of the 3 groups. The SVCI after intravitreal bevacizumab injections decreased, indicating a possible tachyphylactic response to bevacizumab. This decrease in biological response was partially alleviated with the addition of pfTA. Combination of pfTA and bevacizumab increased the INJ(50) from 2.9 with bevacizumab alone to 5.1 injections. A biphasic biologic response was observed with pfTA characterized by a rapid increase in efficacy with the second injection, peaking at the third injection and gradually decreasing afterward. Repeated intravitreal injections of bevacizumab in exudative AMD seemed to be associated with decreased bioefficacy. However, combined pharmacotherapy with triamcinolone acetate lessened this effect. Thus, multitargeted pharmacotherapy in exudative AMD may have a therapeutic benefit. Proprietary or commercial disclosure may be found after the references.
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                Author and article information

                Contributors
                +41-(0)44-4663200 , +41-(0)44-4662888 , stephan.michels@triemli.zuerich.ch
                Journal
                Graefes Arch Clin Exp Ophthalmol
                Graefes Arch. Clin. Exp. Ophthalmol
                Graefe's Archive for Clinical and Experimental Ophthalmology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0721-832X
                1435-702X
                11 March 2014
                11 March 2014
                2014
                : 252
                : 11
                : 1705-1709
                Affiliations
                [ ]Department of Ophthalmology, City Hospital Triemli, Birmensdorferstrasse 497, 8063 Zurich, Switzerland
                [ ]Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany
                [ ]Graf Biostatistics, Winterthur, Switzerland
                [ ]University of Zurich, Zurich, Switzerland
                Article
                2589
                10.1007/s00417-014-2589-3
                4218980
                24614949
                7f8c6e47-48b5-4cdc-874a-0f530f9174a7
                © The Author(s) 2014

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 8 January 2014
                : 31 January 2014
                : 4 February 2014
                Categories
                Retinal Disorders
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2014

                Ophthalmology & Optometry
                age-related macular degeneration,aflibercept,ranibizumab,bevacizumab,tolerance,tachyphylaxis

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