- Email: [email protected]
Long-Term Outcomes of Aflibercept Treatment for Neovascular Age-Related Macular Degeneration in a Clinical Setting
Accepted Manuscript Long-term outcomes of aflibercept treatment for neovascular age-related macular degeneration in a clinical setting Maria Eleftheriadou, MBBS MSc, Clara Vazquez-Alfageme, MBBS, Cristina Maria Citu, BSc, Roxanne Crosby-Nwaobi, PHD, Sobha Sivaprasad, FRCOphth, Philip Hykin, FRCOphth, Robin D. Hamilton, FRCOphth, Praveen J. Patel, FRCOphth MD(Res) PII:
S0002-9394(16)30501-3
DOI:
10.1016/j.ajo.2016.09.038
Reference:
AJOPHT 9920
To appear in:
American Journal of Ophthalmology
Received Date: 23 June 2016 Revised Date:
26 September 2016
Accepted Date: 28 September 2016
Please cite this article as: Eleftheriadou M, Vazquez-Alfageme C, Citu CM, Crosby-Nwaobi R, Sivaprasad S, Hykin P, Hamilton RD, Patel PJ, Long-term outcomes of aflibercept treatment for neovascular age-related macular degeneration in a clinical setting, American Journal of Ophthalmology (2016), doi: 10.1016/j.ajo.2016.09.038. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract:
Purpose: To report 2 year treatment outcomes with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) in routine clinical practice.
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Design: Retrospective, non-randomized, interventional case series.
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Methods: Retrospective analysis of electronic medical record (EMR) notes (OpenEyes), paper case notes and review of spectral-domain optical coherence tomography (SD-OCT) imaging of patients with consecutively treated eyes with previously untreated nAMD. Patients were commenced on aflibercept injections in one or both eyes from 1st October 2013 to 31st December 2013. Data including age, gender, visual acuity (VA) measured on Early Treatment of Diabetic Retinopathy Study charts, injection episodes and complications were recorded. Additionally SDOCT data including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1 and 2, were also recorded.
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Results: Of the 109 eyes of 102 patients treated, data from 94 eyes of 88 patients were available at 2 year follow-up (86% of patients). In the analysis of 2 year outcomes, there were 58 women (60%), the mean (± standard deviation) age was 77.5 ± 8 years. Over the 2 years, these eyes received a median of 12 (mean, 11.4 ± 4) injections at a median of 100 (mean, 99.3 ± 5.3) weeks of follow-up. The mean VA changed from 55.9 ± 15 letters at baseline to 61.3 ± 16.9 letters (VA gain 5.4 letters gain) at 1 year and to 61 ± 17.1 letters (VA gain 5.1 ± 14.9 gain) at 2 years. The reduction in CSMT was 79.5 µm with absence of macular fluid in 70.4% of the 88 eyes with SD-OCT data available at 2 year follow-up.
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Conclusions and relevance: The VA and SD-OCT results compare favourably with outcomes seen in randomized controlled trials. The results suggest that good longterm outcomes can be achieved using aflibercept for nAMD in clinical settings.
ACCEPTED MANUSCRIPT Long-term outcomes of aflibercept treatment for neovascular age-
related macular degeneration in a clinical setting.
Maria Eleftheriadou MBBS MSc1, Clara Vazquez-Alfageme MBBS1, Cristina Maria Citu
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BSc1, Roxanne Crosby-Nwaobi PHD1, Sobha Sivaprasad FRCOphth1, Philip Hykin
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FRCOphth1, Robin D. Hamilton FRCOphth1, Praveen J Patel FRCOphth MD(Res)1
NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and
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1 UCL Institute of Ophthalmology, London, United Kingdom
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Word count: 4521
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Short title : Aflibercept for neovascular age-related macular degeneration (AMD).
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Praveen J. Patel, Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, United Kingdom. Email: [email protected] Tel:
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Abbreviations: AMD – age-related macular degeneration CNV – choroidal neovascularisation
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ETDRS – Early Treatment Diabetic Retinopathy Study nAMD – neovascular age-related macular degeneration
CSMT – central subfield macular thickness
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EMR – electronic medical record
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SD-OCT – spectral-domain optical coherence tomography SD – standard deviation SE – standard error
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VA – visual acuity
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Introduction
The prognosis for patients with neovascular age-related macular degeneration (nAMD) has been transformed by agents which block the action of vascular endothelial
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growth factor (VEGF). The first effective, licensed anti-VEGF agent, ranibizumab (Lucentis; Genentech USA Inc, San Francisco, CA, USA) was introduced into clinical practice on the basis of compelling clinical trial data supporting improvement in vision with this agent for 2
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years post initiation of therapy1-3. However, emerging real world data show that outcomes in clinical practice differ from clinical trials with patients receiving fewer treatments in real world
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clinics and achieving less impressive long-term outcomes4-6. Other data suggest that better outcomes may be achieved using a different treat and extend paradigm7 in which the interval between successive treatments is increased when there are no signs of nAMD disease acitvity.
More recently a new agent, aflibercept (Eylea; Regeneron Pharmaceutical Inc,
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Tarrytown, NY, USA and Bayer Healthcare, Berlin, Germany) has been licensed for the treatment of nAMD. This agent has additional activity in blocking the action of placental growth factor in addition to all isoforms of VEGF. In the VEGF Trap-Eye: Investigation of
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Efficacy and Safety in Wet AMD (VIEW protocol8,9) aflibercept was administrated every 8 weeks, after a loading phase of 3 injections given at 4-weeks intervals for the first year of
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treatment. In the second year of treatment the dosing schedule was changed to a capped pro re nata (PRN) paradigm with monthly examination guided injections where indicated and with mandatory quarterly dosing. . Early short term data from the UK show good outcomes of treatment in clinical
practice10 however at the time of writing there are no data reporting longer term visual acuity(VA) and spectral-domain optical coherence tomography (SD-OCT) based outcomes of aflibercept therapy in eyes without previous treatment.
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ACCEPTED MANUSCRIPT The aim of this retrospective study was to report long-term VA and SD-OCT based outcomes of aflibercept treatment in eyes with no previous treatment for nAMD at a large
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teaching hospital in London, UK (Moorfields Eye Hospital NHS Foundation Trust).
Materials and methods
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This was an electronic case note review using Open Eyes supported by review of SD-OCT data and paper case notes. The study was approved by Moorfields IRB (Research
the Declaration of Helsinki.
Study population
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and Development Department ROAD number 15/059) and adhered to the tenets set forth in
Consecutive patients were identified from the electronic record of Eylea National
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Health Service (NHS) funding approvals for the treatment of nAMD at Moorfields Eye Hospital, London, United Kingdom. Eyes receiving their first aflibercept treatment between 1st October 2013 and 31st December 2013 were included in this analysis. Consecutively
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treated eyes were included in the analysis and any exclusions were recorded using a Consolidated Standards of Reporting Trials - like approach (Figure 1) to minimise bias. NHS
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funding of Eylea is approved when National Institute of Health and Care Excellence (NICE) criteria are met including evidence of subfoveal CNV secondary to nAMD with a VA between 20/40 and 20/400 and no evidence of permanent structural damage at the fovea (atrophy or fibrosis) at the time of the funding application. Visual acuity and OCT based outcomes are reported for 1 and 2 years of follow-up.
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ACCEPTED MANUSCRIPT Treatment paradigm The Moorfields Eylea wet AMD treatment protocol (Figure 2) recommends that clinicians follow the VIEW study in year one and then recommends using a treat and extend approach in year 2 with a maximum extension of treatment interval of 3 months. However
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practice varied as Eylea had only just been introduced into clinical practice at the time of initiation of treatment for this cohort and also partly because of the large number of clinicians (consultants, medical retina service fellows and other health care professionals) involved in assessing patients with nAMD at Moorfields Eye Hospital. Given this variability in treatment
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pattern, a secondary analysis of outcomes for the sub-group of eyes which had received treatment as per the VIEW trial treatment paradigm for year 1 followed by a treat and extend
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approach to treatment in year 2, was also performed. Note that in this analysis, no additional exclusion criteria were applied other than the pattern of the treatment over 2 years. This was to make the results as generalizable as possible to the real-world where a wider range of eyes (for example with poorer vision or different CNV morphology) can be
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treated when compared to clinical trials. We also included eyes in which an intensification of treatment was performed in year 2.
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Outcome measures
VA data were analysed at 0, 1 and 2 years for the eyes included in the analysis. VA
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measurement in clinic is carried out using an Early Treatment of Diabetic Retinopathy (ETDRS) chart at a starting distance of 4 m with the patients habitual correction where available (supplemented with pin-hole correction). In a further analysis we divided the patients into two subgroups using the median baseline VA as a cut-off and compared the two groups. In all patients with loss of 15 letters or more, an analysis of fundus photographs, OCT imaging, fluorescein angiography and review of medical notes or combination was performed. Topcon 3DOCT-2000 (Topcon Inc) SD-OCT imaging data were used to determine macular morphology and central subfield macular thickness (CST). Macular 5
ACCEPTED MANUSCRIPT morphology was assessed by a single observer (M.E.) noting the presence or absence of intra and subretinal fluid on SD-OCT imaging at 0, 1 and 2 years. Macular thickness was extracted from the automated values generated by the Topcon Fast Map automated
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software algorithm.
Statistical analyses
Descriptive statistics were calculated including mean and standard deviation (SD) for VA and SD-OCT macular thickness data using Excel (Microsoft Excel for Mac 2011).
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Waterfall plots and other graphical means were used to show changes at both a per patient and cohort level to best present the data in an informative format. The t-tests, Chi-squared or
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Fisher exact test was used for categorical variables. Subanalyses of VA outcomes based on presenting VA, presence of absence of macular fluid and eyes treated as per the Moorfields nAMD treatment protocol (as per VIEW in year 1 and treat and extend in year 2) were also
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Results
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performed.
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Subject characteristics
In total, 109 eyes of 102 patients were treated with a first Eylea injection between 1st
October 2013 and 31st December 2013 at Moorfields Eye Hospital (including at 4 other satellite sites). In the analysis of 1 year treatment outcomes, 103 eyes of 96 patients were suitable for inclusion in the analysis. The reasons for exclusion are shown in Figure 1 with loss to follow-up being the main reason for exclusion (5 eyes) in this first year of treatment. In year 2, a total of 94 eyes of 88 patients were included in the analysis (data from a further 9 eyes of 8 patients were not available between year 1 and 2 as they were lost to follow-up). 6
ACCEPTED MANUSCRIPT In total, data from 15 eyes of 14 patients were excluded or not available for the 2 year analysis (13.7% of eyes and 13.7% of patients). The eyes for which OCT data were missing were not different in the baseline characteristics from those that were included in the analysis (age, sex, CNV type p>0.05). There were 58 (60%) female patients included in the analysis of 2 year follow-up
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outcomes and the mean (± SD) age of patients was 77.5 (± 8.0) years (range 60-93 years). There were 52 right eyes and 42 left eyes included in the 2 year follow up analysis (of these data from both eyes included from 6 patients). CNV morphology included a classic
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component in 25 (27.4%) of cases and purely occult in 66 (72.5%) eyes.
The mean number of Eylea injections was 11.4 ± 4.0 per eye throughout the 2 years
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follow up period (99.3 (± 5.3) weeks), with a minimum of 3 and a maximum of 20 injections and a median of 12 injections. For the patients completing 2 years of follow-up, in year 1 the mean number of treatments was 7.3 ± 1.8 injections and 4.2 ± 2.7 injections in the second
Visual acuity data
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year of treatment.
VA data were available for 103 eyes of 96 patients who completed the first year follow-
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up and for 94 eyes of 88 patients who completed 2 year follow-up. The pre-treatment, baseline VA ranged from 30 to 84 ETDRS letters (mean ± SD, 55.9 ± 15.0 letters) with
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a range of final VA of 26 to 90 ETDRS letters (mean ± SD, 61.0 ± 17.1 letters). After 2 years, the mean gain in vision was 5.1 letters (SD 14.9 letters) as shown in Figure 3 (p value<0.001). Of the 94 eyes included in the analysis of 2 year treatment outcomes, 9 (9.6%) lost more than 15 letters with 21 (22.3%) gaining 15 letters or more. Baseline VA was 73 ETDRS letters (20/40) or better in 15 (14.6%) eyes, with 30 (29.1%) eyes at 1 year and 28 (29.8%) eyes at 2 years with vision of 73 ETDRS letters or greater (Figure 4). Table 1 compares these results to the VIEW study. In 9 eyes (9.6%) which lost 15 letters or more, an analysis of fundus photographs, OCT imaging, 7
ACCEPTED MANUSCRIPT fluorescein angiography, and review of medical notes or combination thereof enabled us to attribute the visual loss to the presence of foveal atrophy in 5 eyes, subretinal fibrosis in 3 eyes, and a retinal pigment epithelial tear in 1 eye. In our group of patients, the median baseline VA was 58 ETDRS letters. Therefore, using starting VA of 58 ETDRS letters (20/63) as a cutoff, we divided the patients into
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two subgroups. 51 eyes had starting vision of less than 58 ETDRS letters (median ±
SD, 45 ±8.7, range of 30 to 57 ETDRS letters) and 52 eyes had equal or better than 58 EDTRS letters (69 ± 7, range of 58 to 84 ETDRS letters). The largest VA gains
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were observed in eyes that started treatment with the worst vision, as shown in Figure 5 (p value <0.001). The median gain in VA for the first group was 9 and 10.5 letters at
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the end of the 1st and 2nd year of treatment respectively. On the other hand, the median gain in vision in the group with better baseline VA was 2 EDTRS letters at year 1 and 2.5 ETDRS letters median gain at year 2 (p value <0.001). Figure 6 is composite figure with waterfall plots of the change in vision for each treated eye over different
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follow-up intervals.
SD-OCT Data Analysis
Baseline and 2 year SD-OCT data were available for 88 eyes of the 82 patients who
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completed 2 year follow-up (85.44% of the included eyes). The baseline central subfield macular thickness (CSMT) ranged from 152 µm to 605 µm (mean ± SD, 311 ±
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92 µm) with a range of CSMT of 119 µm to 390 µm (mean ± SD, 228 ± 46 µm) after 1 year and a range of 108 µm to 475 µm (mean ± SD, 232 ± 52 µm) after 2 years (Figure 7).Analysis of retinal morphology on SDOCT showed that macular fluid (intraretinal fluid, subretinal fluid or both) was present in 100% of eyes at baseline, 42.9% at year one and 29.6 % at year 2 (Figure 8). Note that the eyes with missing OCT data at 2 years were not significantly different with respect to baseline characteristics to the group with available OCT data (baseline VA, 53.6±18 letters and CSMT 318±90
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ACCEPTED MANUSCRIPT microns, p values p = 0.43 and 0.56 respectively compared to the group with OCT data available).
Sub-group Analyses Table 2 summarises the VA and OCT outcomes for the subgroup of eyes and
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patients who had fixed dosing of Eylea in year 1 as per the VIEW study. There were 66 eyes of 62 patients in this subgroup with a mean (± SD) baseline VA of 54.9 (± 15.6) letters with a mean gain of 7.3 (± 15.7) letters (p value <0.001) at 1 year and 7.1 (± 15.4) letter gain from baseline at 2 years follow-up (p value <0.001). There were a
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mean (± SD) number of Eylea injections over 2 years of 13.5 (± 2.4) with a median of 13 injections over 2 years.
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Sub-analysis of VA and correlation to residual fluid on OCT
Table 3 compares the VA and SD-OCT outcomes between eyes with residual fluid versus no fluid, at the end of 12 and 24 months. The number of eyes with residual macular fluid (n=26) at 24 months was less than in the group with dry macula (n=62).
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The baseline VA and SD-OCT thickness was similar in both groups (p>0.05). The mean gain in VA was 5.9 (±14.9) for eyes with no macular fluid and 5.6 (±15.2) for eyes with residual fluid. None of the comparisons between the two groups were found
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to be statistically significant (p>0.05).
Discussion
The results of this study show that excellent long-term morphological and functional treatment outcomes can be achieved when treating nAMD eyes with intravitreous aflibercept in a clinical setting. We found that in this cohort of patients treated at Moorfields Eye Hospital, 95% of patients achieved maintenance of vision (loss of less than 15 ETDRS
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ACCEPTED MANUSCRIPT letters from baseline) at the end of year 1 and 90% maintained vision at the end of year 2, which is comparable to the outcomes reported in the aflibercept VIEW studies,9. In our study, the mean gain was 5.1 ± 14.9 letters at 2 year follow-up. This compares to 8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies in 56 weeks and 7.6 ETDRS letters in 96 weeks. Talks et al10 analyzing the first year VA outcomes of
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aflibercept in the UK according the VIEW Study Protocol, found that the mean gain of vision at the end of follow up was ± 5.1 ETDRS letters which is in agreement with the outcomes found for the first year in our study as well. Recent reports of long-term clinical outcomes of
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nAMD treatment using ranibizumab and a treat and extend paradigm show good outcomes can be achieved in the real world. Kim et al11 recently published a meta-analysis of real-
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world outcomes of ranibizumab for wet AMD including 26,360 patients. The mean change in VA for patients receiving a treat and extend regimen was +8.8 ETDRS letters at year 1 (n=1539) and +6.7 ETDRS letters at year 2 (n=2521). In the treat and extend arm of the meta-analysis, patients received 6.9 mean injections in year 1 vs 4.7 in the PRN group and 4.9 in year 2 vs 3.7 in PRN group. The 2 years results from this meta-analysis using
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ranibizumab in a treat and extend regimen in real life are similar to ours using aflibercept in a fixed 2 monthly dosing in year 1 and treat and extent in year 2 (Fig 1). The results from our study are also in line with those from Arnold JJ el al12 who published the two-year outcomes
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of treat and extend treatment regimen using three drugs: bevacizumab, ranibizumab and
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aflibercept. Arnold et al12 reported a mean gain of 5.3 ETDRS letters at year 2 in comparison to 5.1 letters gain in our study, with a mean number of 7.5 and 5.5 injections in the first and second year respectively whereas in our study the reported mean number of injections were 7.3 injection in year 1 and slightly less , 4.2 injections in year 2. The CATT3 ( Comparison of Age-related macular degeneration Treatment Trials)
compared ranibizumab and bevacizumab given monthly or PRN with monthly monitoring. Both groups achieved significant VA gains over a 2-year period, 8.8 ETDRS letters and 7.8 ETDRS letters in monthly ranibizumab and bevacizumab respectively but these were 10
ACCEPTED MANUSCRIPT marginally yet statistically significantly less in the PRN group, 6.7 ETDRS letters in ranibizumab and 5 letters in Bevacizumab. The mean number of injections over the first 24 months in the PRN treatment groups were 12.6 and 14.1 for ranibizumab and bevacizumab respectively. However, the 5 year outcomes of CATT13 showed that the vision gains were not maintained. One important underlying reason for the erosion of VA gains after 2 years
schedule after the end of the 2 year study protocol.
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was that very few patients continued to be reviewed or treated as per the CATT dosing
In order to draw meaningful conclusions regarding the mean gain in vision it is important to
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know the starting vision in each study. In the VIEW studies8,9, the mean baseline vision was 53.6 letters giving a gain of 7.6 letters at year 2, whereas in our group the starting vision was
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higher at 55.9 ± 15 letters at baseline improving by 5.4 letters at year 1. This higher average baseline vision in our cohort may partly explain why treated eyes in our study did not gain as much vision as in the pivotal VIEW studies though other factors including the wider-range of lesion subtypes and clinician driven variability in treatment will also have contributed to this difference
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Anatomically, the mean reduction of CMT was 82.9 µm at 12 months and 79.5 µm at 2 years, compared to a mean reduction of 139 µm in the integrated analysis of the VIEW 1 and VIEW 2 studies at 52 weeks and 133 µm in 96 weeks. In our study, macular fluid was
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absent in 59.3% and 72.7% of eyes at year 1 and year 2 respectively. Based on the VIEW
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studies the equivalent figures were 67.7% and 50.1% of eyes at year 1 and year 2 respectively. Our data relating to morphological outcomes relates favourably when compared to the VIEW clinical trials. It is difficult to explain why we report a higher proportion of eyes which are fluid free after 2 years of aflibercept treatment in a clinical setting when compared to VIEW and this may be a chance finding in our cohort. Alternatively, this difference may in part be accounted for by the more exacting standards applied in a reading center when ruling out the presence of macular fluid.
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ACCEPTED MANUSCRIPT Interestingly, when we divided out cohort into eyes with or without macular fluid on SD-OCT at 2 years, we found no significant difference in vision gain suggesting that presence of macular fluid at 2 years does not in itself compromise outcomes of treatment. However, this finding should be treated with caution given the small number in each subgroup though the CATT investigators3 reported also this negative finding in their analysis
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or retinal morphology.
In our study the mean number of injections per eye was 11.4, which is again
consistent with the VIEW studies where the average number was 11.2 injections over two
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years of follow up. In the report from the United Kingdom Aflibercept Users Group detailing one year outcomes of aflibercept treatment in 16 centers across the UK10 there were a
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median of 8 injections after 1 year of follow-up with 33.5% of eyes achieving a VA of 70 ETDRS letters or more after one year of treatment. In our study 29.1% and 29.8% of eyes achieved a VA of 73 letters or more (20/40 or better) after 1 and 2 years of treatment respectively. The results we present may be better than other real-world reports because more injections were given to patients than in other real-world studies. This is a
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consequence of using a treatment paradigm based on the EMA product label for aflibercept in year one followed by a treat and extend based retreatment approach in year 2, rather than using a pro re nata based approach to retreatment.
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The real-world nature of this study meant that there was variability in treatment
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between clinicians and the sub-analysis of VA outcomes in eyes treated as per VIEW with fixed dosing in year 1 had better 2 year outcomes in our study compared to the eyes receiving more or less intensive treatment in year 1. However, this finding must be interpreted with caution as the poorer outcomes seen in the latter group may have been more to do with factors intrinsic to the nAMD lesion rather than the treatment paradigm used. Clinical trials are by their very nature carried out in a restricted study population and despite this, results of such trials are widely assumed to reflect outcomes which may be hoped to be achieved in future clinical practice. Furthermore, cost-effectiveness evaluation 12
ACCEPTED MANUSCRIPT of therapies are also made on the basis of clinical trial data but real-world cost-effectiveness can vary significantly. It is therefore crucial to have outcome data from a clinical setting study, to allow a fair assessment of how good and cost-effective a treatment in clinical practice and this may indeed from clinic to clinic or country to country. To our knowledge, this is the first study evaluating long-term VA and OCT based
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retinal morphology outcomes of aflibercept treatment for nAMD in a clinical setting in eyes with no previous treatment. Overall the findings from this study compare well with clinical trial results. The strengths of the study include an attempt to minimise bias by reporting data on
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consecutively treated patients and collecting data on SDOCT outcomes relating to macular morphology and thickness. This approach contrasts with retrospective reports from real-
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world, big-data set reports10,14 which tend to be limited by significant loss to follow-up of patients over time (potentially introducing bias) and which focus on VA without reporting any variables relating to OCT imaging. A further strength of this report is the sub-analysis of eyes treated as per the VIEW studies in year 1 and looking at the influence of macular fluid at 2 years on treatment outcomes. The limitations include its retrospective nature, the limited
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sample size compared to reports of outcomes from "big data" sets and indeed potential variability regarding treatment paradigms between clinicians despite setting up a Moorfields aflibercept nAMD treatment protocol. A further limitation of our study is the use of habitual
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refractive correction based visual acuity measurements rather than refracted visual acuity.
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This can lead to less precise measurements, though reflects the method of visual acuity recording used widely in NHS clinical settings. In conclusion, we present 2 year clinical setting outcomes of intravitreal aflibercept, in
treatment naïve eyes with nAMD. Implementing aflibercept treatment with fixed dosing in year 1 as per the European Medicines Agency product label, followed by a treat and extend treatment paradigm as standard care in clinical practice results in excellent visual acuity and retinal morphological outcomes over 2 years.
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Figure legends Figure 1. Consolidated Standards of reporting Trials-style diagram showing the patients and
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eyes included in the analysis.
Figure 2. Moorfields protocol for aflibercept treatment for wet age-related macular
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degeneration (treatment naive eyes).
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Figure 3. Change in mean visual acuity over time : baseline, year 1 and year 2.
Figure 4: Percentage of patients with visual acuity of 73 letters (20/40) or better over time
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Figure 5 Change in mean visual acuity over time stratified by median starting visual acuity. Visual acuity of 58 letters (20/63) was used as a cut off to divide the group into
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two subgroups.
Figure 6: Waterfall plots showing the change in visual acuity for each treated eye over
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different follow-up intervals
a) Top left, waterfall plot for change in visual acuity between baseline and year 1. b) Top right, waterfall plot for change in visual acuity between baseline and year 2. c) Bottom left, waterfall plot for change in visual acuity between year 1 and year 2.
Figure 7: Change in mean central macular thickness over time: baseline, year 1 and year 2.
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ACCEPTED MANUSCRIPT Figure 8: Bar graph showing the number of patients with macular fluid including subretinal (SRF) , intraretinal (IRF), both (IRF+SRF) or a dry macula (no macular fluid) at different time points.
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Aknowledgements/Disclosures
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A. Funding/Support: Drs Eleftheriadou, Vazquez-Alfageme, Crosby-Nwaobi, Sivaprasad, Hykin, Hamilton and Patel have received a proportion of their funding from the Department of Health’s NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health.
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B.Financial disclosure: Drs Praveen Patel, Sobha Sivaprasad, Philip Hykin have received research grants, travel grants and attended advisory board meetings of Novartis, Bayer, Allergan and Roche. Dr Patel has received travel-funds assistance from SalutarisMD. Dr Hamilton has received research grants, travel grants and attended advisory board meetings of Novartis, Bayer, Allergan and Ellex. The rest of the co-authors have no financial disclosures.
References:
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C.Other Acknowledgements: Not applicaple.
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1.Brown DM, Kaiser PK, Michels M, et el; Ranibizumab versus verteporfin for neovascular
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age related macular degeration. N Engl J Med 2006;355(14):1432-1444 2.Rosenfild PJ, Brown DM, Heier JS, et al; Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419-1431 3. CATT Research Group,Martin DF, Maguire MG, et al;. Ranibizumab and Bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364(20):1897-1908 4.Holtz FG, Tadayoni R, Beatty S, et al. Multi-country real life experience of antivascular endothelial growth factor therapy for wet age related macular degeneration. Br J Ophthalmology 2015;99(2):220-226 15
ACCEPTED MANUSCRIPT 5.Gillies MC, Walton RJ, Arnold JJ, et al. Comparison of outcomes from a phase 3 study of age related macular degeneration with a matched, observational cohort. Ophthalmology 2014;121(3):676-681 6. Pushpoth S, Sykakis E, Merchant K, Browning AC, Gupta R, Talks SJ. Measuring the
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benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Br J Ophthalmol 2012;96(12):1469-1473.
7. Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and
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bevacizumab for neovascular age-related macular degeneration according to LUCAS treatand-extend protocol. Ophthalmology. 2015 Jan;122(1):146-152.
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8. Heier JS, Brown DM, Chong V, et al. Intravitreal ablibercept (VEGF trap-eye) in wet age related macular degeneration. Ophthalmlology 2012;119(12):2537-2548 9.Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascualr age related macular degeneration:ninety six week results of the VIEW studies.
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Ophthalmology 2014;121(1):193-201
10. Talks JS, Lotery AJ, Ghanci F et al. First year visual acuity outcomes in the United Kingdom of providing Aflibercept according to the VIEW study protocol for age-related
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macular degeneration. Ophthalmology 2015;123(2):337-343
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11. Kim LN, Mehta H, Barthelmes D, Nguyen V, Gillies MC. Metaanalysis of real-world outcomes of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration. Retina 2016;36(8):1418-1431 12. Arnold JJ, Campain A, Barthelmes D, et al. Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration. Ophthalmology 2015;122(6):1212-1219
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ACCEPTED MANUSCRIPT 13.Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976
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ranibizumab injections:report 1: visual acuity. Ophthalmology 2014;121(5):1092-1101.
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ACCEPTED MANUSCRIPT Table 1. Aflibercept for Neovascular Age-related Macular Degeneration 2 year outcomes in comparison with the results from the integrated analysis of the VIEW 1 and VIEW 2.
Aflibercept for Neovascular Age-related Macular Degeneration 2 year outcomes Present Study – 2 years follow up
10%
94 eyes 10%
Not given
21.3%
27.3%
14.3%
Not given
22.3%
24.2%
17.8%
53.6
55.9
54.9 ± 15.6
55.3 ± 14.4
7.6
5.72
7 ± 15.3
3.1 ± 13.4
-79.5
-77.1 ± 96.3
-94.9 ± 129.6
11.39
13.5 ± 2.5
6.8 ± 2.4
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Eyes which lost fewer than 15 letters (%) Eyes which improved by 15 letters or more (%) Eyes with baseline VA ≥ 20/40 (%) Baseline mean VA (ETDRS letter score) Mean Gain in VA (ETDRS letter score) Change in central subfield OCT macular thickness (microns) Number of injections
Treated as per VIEW protocol (96 week extension) 66 eyes 10%
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104 week extension phase of VIEW studies
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Month 24 (n=66) 62 ±16.8
n/a
7.3 ±15.7
7.1 ±15.4
13.6%
33.3%
31.8%
309.2 ± 90
235.2 ± 42.6
232.2 ± 53.3
n/a
8 ± 1.1
11.4 ± 3.9
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Month12 (n=66) 62.2 ± 16.9
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Mean VA (ETDRS letters) Mean Gain in VA (ETDRS letters) Eyes with baseline VA ≥ 20/40 (%) Mean central subfield OCT macular thickness (microns) Number of injections
Baseline (n=66) 54.9 ±15.6
ACCEPTED MANUSCRIPT Table 3. Comparison of outcomes for eyes with residual fluid at year 1 and year 2 with eyes with no macular fluid after treatment.
Year 1 (n=91)
Baseline VA
54.6±14.8
54.5±14.9
54.6±14.8
54.5±14.9
Baseline OCT thickness
311.2±93
311.6±93.4
311.2±93
311.3±93.6
VA change
5.3±14.7
5.2±14.9
5.9±14.9
5.6±15.2
OCT reduction
85.6±97.4
83.8±96.4
77.7±102.7
75.9±102.2
Number of injections
7.3±1.7
7.3±1.7
11.4±3.9
11.6±4
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P value> 0.05
77.6±7.6
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Age (mean±SD)
P value > 0.05
No fluid (n=62)
77.7±7.6
Residual fluid (n=39) 77.6±7.6
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OCT findings
Year 2 (n=88)
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S0002-9394(16)30501-3
DOI:
10.1016/j.ajo.2016.09.038
Reference:
AJOPHT 9920
To appear in:
American Journal of Ophthalmology
Received Date: 23 June 2016 Revised Date:
26 September 2016
Accepted Date: 28 September 2016
Please cite this article as: Eleftheriadou M, Vazquez-Alfageme C, Citu CM, Crosby-Nwaobi R, Sivaprasad S, Hykin P, Hamilton RD, Patel PJ, Long-term outcomes of aflibercept treatment for neovascular age-related macular degeneration in a clinical setting, American Journal of Ophthalmology (2016), doi: 10.1016/j.ajo.2016.09.038. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract:
Purpose: To report 2 year treatment outcomes with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) in routine clinical practice.
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Design: Retrospective, non-randomized, interventional case series.
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Methods: Retrospective analysis of electronic medical record (EMR) notes (OpenEyes), paper case notes and review of spectral-domain optical coherence tomography (SD-OCT) imaging of patients with consecutively treated eyes with previously untreated nAMD. Patients were commenced on aflibercept injections in one or both eyes from 1st October 2013 to 31st December 2013. Data including age, gender, visual acuity (VA) measured on Early Treatment of Diabetic Retinopathy Study charts, injection episodes and complications were recorded. Additionally SDOCT data including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1 and 2, were also recorded.
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Results: Of the 109 eyes of 102 patients treated, data from 94 eyes of 88 patients were available at 2 year follow-up (86% of patients). In the analysis of 2 year outcomes, there were 58 women (60%), the mean (± standard deviation) age was 77.5 ± 8 years. Over the 2 years, these eyes received a median of 12 (mean, 11.4 ± 4) injections at a median of 100 (mean, 99.3 ± 5.3) weeks of follow-up. The mean VA changed from 55.9 ± 15 letters at baseline to 61.3 ± 16.9 letters (VA gain 5.4 letters gain) at 1 year and to 61 ± 17.1 letters (VA gain 5.1 ± 14.9 gain) at 2 years. The reduction in CSMT was 79.5 µm with absence of macular fluid in 70.4% of the 88 eyes with SD-OCT data available at 2 year follow-up.
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Conclusions and relevance: The VA and SD-OCT results compare favourably with outcomes seen in randomized controlled trials. The results suggest that good longterm outcomes can be achieved using aflibercept for nAMD in clinical settings.
ACCEPTED MANUSCRIPT Long-term outcomes of aflibercept treatment for neovascular age-
related macular degeneration in a clinical setting.
Maria Eleftheriadou MBBS MSc1, Clara Vazquez-Alfageme MBBS1, Cristina Maria Citu
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BSc1, Roxanne Crosby-Nwaobi PHD1, Sobha Sivaprasad FRCOphth1, Philip Hykin
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FRCOphth1, Robin D. Hamilton FRCOphth1, Praveen J Patel FRCOphth MD(Res)1
NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and
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1 UCL Institute of Ophthalmology, London, United Kingdom
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Word count: 4521
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Short title : Aflibercept for neovascular age-related macular degeneration (AMD).
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Praveen J. Patel, Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, United Kingdom. Email: [email protected] Tel:
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Abbreviations: AMD – age-related macular degeneration CNV – choroidal neovascularisation
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ETDRS – Early Treatment Diabetic Retinopathy Study nAMD – neovascular age-related macular degeneration
CSMT – central subfield macular thickness
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EMR – electronic medical record
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SD-OCT – spectral-domain optical coherence tomography SD – standard deviation SE – standard error
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VA – visual acuity
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Introduction
The prognosis for patients with neovascular age-related macular degeneration (nAMD) has been transformed by agents which block the action of vascular endothelial
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growth factor (VEGF). The first effective, licensed anti-VEGF agent, ranibizumab (Lucentis; Genentech USA Inc, San Francisco, CA, USA) was introduced into clinical practice on the basis of compelling clinical trial data supporting improvement in vision with this agent for 2
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years post initiation of therapy1-3. However, emerging real world data show that outcomes in clinical practice differ from clinical trials with patients receiving fewer treatments in real world
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clinics and achieving less impressive long-term outcomes4-6. Other data suggest that better outcomes may be achieved using a different treat and extend paradigm7 in which the interval between successive treatments is increased when there are no signs of nAMD disease acitvity.
More recently a new agent, aflibercept (Eylea; Regeneron Pharmaceutical Inc,
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Tarrytown, NY, USA and Bayer Healthcare, Berlin, Germany) has been licensed for the treatment of nAMD. This agent has additional activity in blocking the action of placental growth factor in addition to all isoforms of VEGF. In the VEGF Trap-Eye: Investigation of
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Efficacy and Safety in Wet AMD (VIEW protocol8,9) aflibercept was administrated every 8 weeks, after a loading phase of 3 injections given at 4-weeks intervals for the first year of
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treatment. In the second year of treatment the dosing schedule was changed to a capped pro re nata (PRN) paradigm with monthly examination guided injections where indicated and with mandatory quarterly dosing. . Early short term data from the UK show good outcomes of treatment in clinical
practice10 however at the time of writing there are no data reporting longer term visual acuity(VA) and spectral-domain optical coherence tomography (SD-OCT) based outcomes of aflibercept therapy in eyes without previous treatment.
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ACCEPTED MANUSCRIPT The aim of this retrospective study was to report long-term VA and SD-OCT based outcomes of aflibercept treatment in eyes with no previous treatment for nAMD at a large
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teaching hospital in London, UK (Moorfields Eye Hospital NHS Foundation Trust).
Materials and methods
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This was an electronic case note review using Open Eyes supported by review of SD-OCT data and paper case notes. The study was approved by Moorfields IRB (Research
the Declaration of Helsinki.
Study population
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and Development Department ROAD number 15/059) and adhered to the tenets set forth in
Consecutive patients were identified from the electronic record of Eylea National
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Health Service (NHS) funding approvals for the treatment of nAMD at Moorfields Eye Hospital, London, United Kingdom. Eyes receiving their first aflibercept treatment between 1st October 2013 and 31st December 2013 were included in this analysis. Consecutively
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treated eyes were included in the analysis and any exclusions were recorded using a Consolidated Standards of Reporting Trials - like approach (Figure 1) to minimise bias. NHS
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funding of Eylea is approved when National Institute of Health and Care Excellence (NICE) criteria are met including evidence of subfoveal CNV secondary to nAMD with a VA between 20/40 and 20/400 and no evidence of permanent structural damage at the fovea (atrophy or fibrosis) at the time of the funding application. Visual acuity and OCT based outcomes are reported for 1 and 2 years of follow-up.
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ACCEPTED MANUSCRIPT Treatment paradigm The Moorfields Eylea wet AMD treatment protocol (Figure 2) recommends that clinicians follow the VIEW study in year one and then recommends using a treat and extend approach in year 2 with a maximum extension of treatment interval of 3 months. However
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practice varied as Eylea had only just been introduced into clinical practice at the time of initiation of treatment for this cohort and also partly because of the large number of clinicians (consultants, medical retina service fellows and other health care professionals) involved in assessing patients with nAMD at Moorfields Eye Hospital. Given this variability in treatment
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pattern, a secondary analysis of outcomes for the sub-group of eyes which had received treatment as per the VIEW trial treatment paradigm for year 1 followed by a treat and extend
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approach to treatment in year 2, was also performed. Note that in this analysis, no additional exclusion criteria were applied other than the pattern of the treatment over 2 years. This was to make the results as generalizable as possible to the real-world where a wider range of eyes (for example with poorer vision or different CNV morphology) can be
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treated when compared to clinical trials. We also included eyes in which an intensification of treatment was performed in year 2.
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Outcome measures
VA data were analysed at 0, 1 and 2 years for the eyes included in the analysis. VA
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measurement in clinic is carried out using an Early Treatment of Diabetic Retinopathy (ETDRS) chart at a starting distance of 4 m with the patients habitual correction where available (supplemented with pin-hole correction). In a further analysis we divided the patients into two subgroups using the median baseline VA as a cut-off and compared the two groups. In all patients with loss of 15 letters or more, an analysis of fundus photographs, OCT imaging, fluorescein angiography and review of medical notes or combination was performed. Topcon 3DOCT-2000 (Topcon Inc) SD-OCT imaging data were used to determine macular morphology and central subfield macular thickness (CST). Macular 5
ACCEPTED MANUSCRIPT morphology was assessed by a single observer (M.E.) noting the presence or absence of intra and subretinal fluid on SD-OCT imaging at 0, 1 and 2 years. Macular thickness was extracted from the automated values generated by the Topcon Fast Map automated
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software algorithm.
Statistical analyses
Descriptive statistics were calculated including mean and standard deviation (SD) for VA and SD-OCT macular thickness data using Excel (Microsoft Excel for Mac 2011).
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Waterfall plots and other graphical means were used to show changes at both a per patient and cohort level to best present the data in an informative format. The t-tests, Chi-squared or
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Fisher exact test was used for categorical variables. Subanalyses of VA outcomes based on presenting VA, presence of absence of macular fluid and eyes treated as per the Moorfields nAMD treatment protocol (as per VIEW in year 1 and treat and extend in year 2) were also
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Results
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performed.
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Subject characteristics
In total, 109 eyes of 102 patients were treated with a first Eylea injection between 1st
October 2013 and 31st December 2013 at Moorfields Eye Hospital (including at 4 other satellite sites). In the analysis of 1 year treatment outcomes, 103 eyes of 96 patients were suitable for inclusion in the analysis. The reasons for exclusion are shown in Figure 1 with loss to follow-up being the main reason for exclusion (5 eyes) in this first year of treatment. In year 2, a total of 94 eyes of 88 patients were included in the analysis (data from a further 9 eyes of 8 patients were not available between year 1 and 2 as they were lost to follow-up). 6
ACCEPTED MANUSCRIPT In total, data from 15 eyes of 14 patients were excluded or not available for the 2 year analysis (13.7% of eyes and 13.7% of patients). The eyes for which OCT data were missing were not different in the baseline characteristics from those that were included in the analysis (age, sex, CNV type p>0.05). There were 58 (60%) female patients included in the analysis of 2 year follow-up
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outcomes and the mean (± SD) age of patients was 77.5 (± 8.0) years (range 60-93 years). There were 52 right eyes and 42 left eyes included in the 2 year follow up analysis (of these data from both eyes included from 6 patients). CNV morphology included a classic
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component in 25 (27.4%) of cases and purely occult in 66 (72.5%) eyes.
The mean number of Eylea injections was 11.4 ± 4.0 per eye throughout the 2 years
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follow up period (99.3 (± 5.3) weeks), with a minimum of 3 and a maximum of 20 injections and a median of 12 injections. For the patients completing 2 years of follow-up, in year 1 the mean number of treatments was 7.3 ± 1.8 injections and 4.2 ± 2.7 injections in the second
Visual acuity data
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year of treatment.
VA data were available for 103 eyes of 96 patients who completed the first year follow-
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up and for 94 eyes of 88 patients who completed 2 year follow-up. The pre-treatment, baseline VA ranged from 30 to 84 ETDRS letters (mean ± SD, 55.9 ± 15.0 letters) with
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a range of final VA of 26 to 90 ETDRS letters (mean ± SD, 61.0 ± 17.1 letters). After 2 years, the mean gain in vision was 5.1 letters (SD 14.9 letters) as shown in Figure 3 (p value<0.001). Of the 94 eyes included in the analysis of 2 year treatment outcomes, 9 (9.6%) lost more than 15 letters with 21 (22.3%) gaining 15 letters or more. Baseline VA was 73 ETDRS letters (20/40) or better in 15 (14.6%) eyes, with 30 (29.1%) eyes at 1 year and 28 (29.8%) eyes at 2 years with vision of 73 ETDRS letters or greater (Figure 4). Table 1 compares these results to the VIEW study. In 9 eyes (9.6%) which lost 15 letters or more, an analysis of fundus photographs, OCT imaging, 7
ACCEPTED MANUSCRIPT fluorescein angiography, and review of medical notes or combination thereof enabled us to attribute the visual loss to the presence of foveal atrophy in 5 eyes, subretinal fibrosis in 3 eyes, and a retinal pigment epithelial tear in 1 eye. In our group of patients, the median baseline VA was 58 ETDRS letters. Therefore, using starting VA of 58 ETDRS letters (20/63) as a cutoff, we divided the patients into
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two subgroups. 51 eyes had starting vision of less than 58 ETDRS letters (median ±
SD, 45 ±8.7, range of 30 to 57 ETDRS letters) and 52 eyes had equal or better than 58 EDTRS letters (69 ± 7, range of 58 to 84 ETDRS letters). The largest VA gains
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were observed in eyes that started treatment with the worst vision, as shown in Figure 5 (p value <0.001). The median gain in VA for the first group was 9 and 10.5 letters at
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the end of the 1st and 2nd year of treatment respectively. On the other hand, the median gain in vision in the group with better baseline VA was 2 EDTRS letters at year 1 and 2.5 ETDRS letters median gain at year 2 (p value <0.001). Figure 6 is composite figure with waterfall plots of the change in vision for each treated eye over different
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follow-up intervals.
SD-OCT Data Analysis
Baseline and 2 year SD-OCT data were available for 88 eyes of the 82 patients who
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completed 2 year follow-up (85.44% of the included eyes). The baseline central subfield macular thickness (CSMT) ranged from 152 µm to 605 µm (mean ± SD, 311 ±
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92 µm) with a range of CSMT of 119 µm to 390 µm (mean ± SD, 228 ± 46 µm) after 1 year and a range of 108 µm to 475 µm (mean ± SD, 232 ± 52 µm) after 2 years (Figure 7).Analysis of retinal morphology on SDOCT showed that macular fluid (intraretinal fluid, subretinal fluid or both) was present in 100% of eyes at baseline, 42.9% at year one and 29.6 % at year 2 (Figure 8). Note that the eyes with missing OCT data at 2 years were not significantly different with respect to baseline characteristics to the group with available OCT data (baseline VA, 53.6±18 letters and CSMT 318±90
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Sub-group Analyses Table 2 summarises the VA and OCT outcomes for the subgroup of eyes and
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patients who had fixed dosing of Eylea in year 1 as per the VIEW study. There were 66 eyes of 62 patients in this subgroup with a mean (± SD) baseline VA of 54.9 (± 15.6) letters with a mean gain of 7.3 (± 15.7) letters (p value <0.001) at 1 year and 7.1 (± 15.4) letter gain from baseline at 2 years follow-up (p value <0.001). There were a
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mean (± SD) number of Eylea injections over 2 years of 13.5 (± 2.4) with a median of 13 injections over 2 years.
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Sub-analysis of VA and correlation to residual fluid on OCT
Table 3 compares the VA and SD-OCT outcomes between eyes with residual fluid versus no fluid, at the end of 12 and 24 months. The number of eyes with residual macular fluid (n=26) at 24 months was less than in the group with dry macula (n=62).
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The baseline VA and SD-OCT thickness was similar in both groups (p>0.05). The mean gain in VA was 5.9 (±14.9) for eyes with no macular fluid and 5.6 (±15.2) for eyes with residual fluid. None of the comparisons between the two groups were found
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to be statistically significant (p>0.05).
Discussion
The results of this study show that excellent long-term morphological and functional treatment outcomes can be achieved when treating nAMD eyes with intravitreous aflibercept in a clinical setting. We found that in this cohort of patients treated at Moorfields Eye Hospital, 95% of patients achieved maintenance of vision (loss of less than 15 ETDRS
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aflibercept in the UK according the VIEW Study Protocol, found that the mean gain of vision at the end of follow up was ± 5.1 ETDRS letters which is in agreement with the outcomes found for the first year in our study as well. Recent reports of long-term clinical outcomes of
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nAMD treatment using ranibizumab and a treat and extend paradigm show good outcomes can be achieved in the real world. Kim et al11 recently published a meta-analysis of real-
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world outcomes of ranibizumab for wet AMD including 26,360 patients. The mean change in VA for patients receiving a treat and extend regimen was +8.8 ETDRS letters at year 1 (n=1539) and +6.7 ETDRS letters at year 2 (n=2521). In the treat and extend arm of the meta-analysis, patients received 6.9 mean injections in year 1 vs 4.7 in the PRN group and 4.9 in year 2 vs 3.7 in PRN group. The 2 years results from this meta-analysis using
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ranibizumab in a treat and extend regimen in real life are similar to ours using aflibercept in a fixed 2 monthly dosing in year 1 and treat and extent in year 2 (Fig 1). The results from our study are also in line with those from Arnold JJ el al12 who published the two-year outcomes
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of treat and extend treatment regimen using three drugs: bevacizumab, ranibizumab and
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aflibercept. Arnold et al12 reported a mean gain of 5.3 ETDRS letters at year 2 in comparison to 5.1 letters gain in our study, with a mean number of 7.5 and 5.5 injections in the first and second year respectively whereas in our study the reported mean number of injections were 7.3 injection in year 1 and slightly less , 4.2 injections in year 2. The CATT3 ( Comparison of Age-related macular degeneration Treatment Trials)
compared ranibizumab and bevacizumab given monthly or PRN with monthly monitoring. Both groups achieved significant VA gains over a 2-year period, 8.8 ETDRS letters and 7.8 ETDRS letters in monthly ranibizumab and bevacizumab respectively but these were 10
ACCEPTED MANUSCRIPT marginally yet statistically significantly less in the PRN group, 6.7 ETDRS letters in ranibizumab and 5 letters in Bevacizumab. The mean number of injections over the first 24 months in the PRN treatment groups were 12.6 and 14.1 for ranibizumab and bevacizumab respectively. However, the 5 year outcomes of CATT13 showed that the vision gains were not maintained. One important underlying reason for the erosion of VA gains after 2 years
schedule after the end of the 2 year study protocol.
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was that very few patients continued to be reviewed or treated as per the CATT dosing
In order to draw meaningful conclusions regarding the mean gain in vision it is important to
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know the starting vision in each study. In the VIEW studies8,9, the mean baseline vision was 53.6 letters giving a gain of 7.6 letters at year 2, whereas in our group the starting vision was
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higher at 55.9 ± 15 letters at baseline improving by 5.4 letters at year 1. This higher average baseline vision in our cohort may partly explain why treated eyes in our study did not gain as much vision as in the pivotal VIEW studies though other factors including the wider-range of lesion subtypes and clinician driven variability in treatment will also have contributed to this difference
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Anatomically, the mean reduction of CMT was 82.9 µm at 12 months and 79.5 µm at 2 years, compared to a mean reduction of 139 µm in the integrated analysis of the VIEW 1 and VIEW 2 studies at 52 weeks and 133 µm in 96 weeks. In our study, macular fluid was
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absent in 59.3% and 72.7% of eyes at year 1 and year 2 respectively. Based on the VIEW
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studies the equivalent figures were 67.7% and 50.1% of eyes at year 1 and year 2 respectively. Our data relating to morphological outcomes relates favourably when compared to the VIEW clinical trials. It is difficult to explain why we report a higher proportion of eyes which are fluid free after 2 years of aflibercept treatment in a clinical setting when compared to VIEW and this may be a chance finding in our cohort. Alternatively, this difference may in part be accounted for by the more exacting standards applied in a reading center when ruling out the presence of macular fluid.
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ACCEPTED MANUSCRIPT Interestingly, when we divided out cohort into eyes with or without macular fluid on SD-OCT at 2 years, we found no significant difference in vision gain suggesting that presence of macular fluid at 2 years does not in itself compromise outcomes of treatment. However, this finding should be treated with caution given the small number in each subgroup though the CATT investigators3 reported also this negative finding in their analysis
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or retinal morphology.
In our study the mean number of injections per eye was 11.4, which is again
consistent with the VIEW studies where the average number was 11.2 injections over two
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years of follow up. In the report from the United Kingdom Aflibercept Users Group detailing one year outcomes of aflibercept treatment in 16 centers across the UK10 there were a
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median of 8 injections after 1 year of follow-up with 33.5% of eyes achieving a VA of 70 ETDRS letters or more after one year of treatment. In our study 29.1% and 29.8% of eyes achieved a VA of 73 letters or more (20/40 or better) after 1 and 2 years of treatment respectively. The results we present may be better than other real-world reports because more injections were given to patients than in other real-world studies. This is a
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consequence of using a treatment paradigm based on the EMA product label for aflibercept in year one followed by a treat and extend based retreatment approach in year 2, rather than using a pro re nata based approach to retreatment.
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between clinicians and the sub-analysis of VA outcomes in eyes treated as per VIEW with fixed dosing in year 1 had better 2 year outcomes in our study compared to the eyes receiving more or less intensive treatment in year 1. However, this finding must be interpreted with caution as the poorer outcomes seen in the latter group may have been more to do with factors intrinsic to the nAMD lesion rather than the treatment paradigm used. Clinical trials are by their very nature carried out in a restricted study population and despite this, results of such trials are widely assumed to reflect outcomes which may be hoped to be achieved in future clinical practice. Furthermore, cost-effectiveness evaluation 12
ACCEPTED MANUSCRIPT of therapies are also made on the basis of clinical trial data but real-world cost-effectiveness can vary significantly. It is therefore crucial to have outcome data from a clinical setting study, to allow a fair assessment of how good and cost-effective a treatment in clinical practice and this may indeed from clinic to clinic or country to country. To our knowledge, this is the first study evaluating long-term VA and OCT based
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retinal morphology outcomes of aflibercept treatment for nAMD in a clinical setting in eyes with no previous treatment. Overall the findings from this study compare well with clinical trial results. The strengths of the study include an attempt to minimise bias by reporting data on
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consecutively treated patients and collecting data on SDOCT outcomes relating to macular morphology and thickness. This approach contrasts with retrospective reports from real-
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world, big-data set reports10,14 which tend to be limited by significant loss to follow-up of patients over time (potentially introducing bias) and which focus on VA without reporting any variables relating to OCT imaging. A further strength of this report is the sub-analysis of eyes treated as per the VIEW studies in year 1 and looking at the influence of macular fluid at 2 years on treatment outcomes. The limitations include its retrospective nature, the limited
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sample size compared to reports of outcomes from "big data" sets and indeed potential variability regarding treatment paradigms between clinicians despite setting up a Moorfields aflibercept nAMD treatment protocol. A further limitation of our study is the use of habitual
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refractive correction based visual acuity measurements rather than refracted visual acuity.
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This can lead to less precise measurements, though reflects the method of visual acuity recording used widely in NHS clinical settings. In conclusion, we present 2 year clinical setting outcomes of intravitreal aflibercept, in
treatment naïve eyes with nAMD. Implementing aflibercept treatment with fixed dosing in year 1 as per the European Medicines Agency product label, followed by a treat and extend treatment paradigm as standard care in clinical practice results in excellent visual acuity and retinal morphological outcomes over 2 years.
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Figure legends Figure 1. Consolidated Standards of reporting Trials-style diagram showing the patients and
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eyes included in the analysis.
Figure 2. Moorfields protocol for aflibercept treatment for wet age-related macular
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degeneration (treatment naive eyes).
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Figure 3. Change in mean visual acuity over time : baseline, year 1 and year 2.
Figure 4: Percentage of patients with visual acuity of 73 letters (20/40) or better over time
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Figure 5 Change in mean visual acuity over time stratified by median starting visual acuity. Visual acuity of 58 letters (20/63) was used as a cut off to divide the group into
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Figure 6: Waterfall plots showing the change in visual acuity for each treated eye over
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different follow-up intervals
a) Top left, waterfall plot for change in visual acuity between baseline and year 1. b) Top right, waterfall plot for change in visual acuity between baseline and year 2. c) Bottom left, waterfall plot for change in visual acuity between year 1 and year 2.
Figure 7: Change in mean central macular thickness over time: baseline, year 1 and year 2.
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Aknowledgements/Disclosures
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A. Funding/Support: Drs Eleftheriadou, Vazquez-Alfageme, Crosby-Nwaobi, Sivaprasad, Hykin, Hamilton and Patel have received a proportion of their funding from the Department of Health’s NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health.
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B.Financial disclosure: Drs Praveen Patel, Sobha Sivaprasad, Philip Hykin have received research grants, travel grants and attended advisory board meetings of Novartis, Bayer, Allergan and Roche. Dr Patel has received travel-funds assistance from SalutarisMD. Dr Hamilton has received research grants, travel grants and attended advisory board meetings of Novartis, Bayer, Allergan and Ellex. The rest of the co-authors have no financial disclosures.
References:
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C.Other Acknowledgements: Not applicaple.
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1.Brown DM, Kaiser PK, Michels M, et el; Ranibizumab versus verteporfin for neovascular
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age related macular degeration. N Engl J Med 2006;355(14):1432-1444 2.Rosenfild PJ, Brown DM, Heier JS, et al; Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419-1431 3. CATT Research Group,Martin DF, Maguire MG, et al;. Ranibizumab and Bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364(20):1897-1908 4.Holtz FG, Tadayoni R, Beatty S, et al. Multi-country real life experience of antivascular endothelial growth factor therapy for wet age related macular degeneration. Br J Ophthalmology 2015;99(2):220-226 15
ACCEPTED MANUSCRIPT 5.Gillies MC, Walton RJ, Arnold JJ, et al. Comparison of outcomes from a phase 3 study of age related macular degeneration with a matched, observational cohort. Ophthalmology 2014;121(3):676-681 6. Pushpoth S, Sykakis E, Merchant K, Browning AC, Gupta R, Talks SJ. Measuring the
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benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Br J Ophthalmol 2012;96(12):1469-1473.
7. Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and
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bevacizumab for neovascular age-related macular degeneration according to LUCAS treatand-extend protocol. Ophthalmology. 2015 Jan;122(1):146-152.
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8. Heier JS, Brown DM, Chong V, et al. Intravitreal ablibercept (VEGF trap-eye) in wet age related macular degeneration. Ophthalmlology 2012;119(12):2537-2548 9.Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascualr age related macular degeneration:ninety six week results of the VIEW studies.
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Ophthalmology 2014;121(1):193-201
10. Talks JS, Lotery AJ, Ghanci F et al. First year visual acuity outcomes in the United Kingdom of providing Aflibercept according to the VIEW study protocol for age-related
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macular degeneration. Ophthalmology 2015;123(2):337-343
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11. Kim LN, Mehta H, Barthelmes D, Nguyen V, Gillies MC. Metaanalysis of real-world outcomes of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration. Retina 2016;36(8):1418-1431 12. Arnold JJ, Campain A, Barthelmes D, et al. Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration. Ophthalmology 2015;122(6):1212-1219
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ACCEPTED MANUSCRIPT 13.Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976
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ranibizumab injections:report 1: visual acuity. Ophthalmology 2014;121(5):1092-1101.
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ACCEPTED MANUSCRIPT Table 1. Aflibercept for Neovascular Age-related Macular Degeneration 2 year outcomes in comparison with the results from the integrated analysis of the VIEW 1 and VIEW 2.
Aflibercept for Neovascular Age-related Macular Degeneration 2 year outcomes Present Study – 2 years follow up
10%
94 eyes 10%
Not given
21.3%
27.3%
14.3%
Not given
22.3%
24.2%
17.8%
53.6
55.9
54.9 ± 15.6
55.3 ± 14.4
7.6
5.72
7 ± 15.3
3.1 ± 13.4
-79.5
-77.1 ± 96.3
-94.9 ± 129.6
11.39
13.5 ± 2.5
6.8 ± 2.4
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-133
11.2
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Treated PRN
28 eyes 10.7%
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Eyes which lost fewer than 15 letters (%) Eyes which improved by 15 letters or more (%) Eyes with baseline VA ≥ 20/40 (%) Baseline mean VA (ETDRS letter score) Mean Gain in VA (ETDRS letter score) Change in central subfield OCT macular thickness (microns) Number of injections
Treated as per VIEW protocol (96 week extension) 66 eyes 10%
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Total
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104 week extension phase of VIEW studies
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Month 24 (n=66) 62 ±16.8
n/a
7.3 ±15.7
7.1 ±15.4
13.6%
33.3%
31.8%
309.2 ± 90
235.2 ± 42.6
232.2 ± 53.3
n/a
8 ± 1.1
11.4 ± 3.9
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Month12 (n=66) 62.2 ± 16.9
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Mean VA (ETDRS letters) Mean Gain in VA (ETDRS letters) Eyes with baseline VA ≥ 20/40 (%) Mean central subfield OCT macular thickness (microns) Number of injections
Baseline (n=66) 54.9 ±15.6
ACCEPTED MANUSCRIPT Table 3. Comparison of outcomes for eyes with residual fluid at year 1 and year 2 with eyes with no macular fluid after treatment.
Year 1 (n=91)
Baseline VA
54.6±14.8
54.5±14.9
54.6±14.8
54.5±14.9
Baseline OCT thickness
311.2±93
311.6±93.4
311.2±93
311.3±93.6
VA change
5.3±14.7
5.2±14.9
5.9±14.9
5.6±15.2
OCT reduction
85.6±97.4
83.8±96.4
77.7±102.7
75.9±102.2
Number of injections
7.3±1.7
7.3±1.7
11.4±3.9
11.6±4
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Residual fluid (n=26)
P value> 0.05
77.6±7.6
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Age (mean±SD)
P value > 0.05
No fluid (n=62)
77.7±7.6
Residual fluid (n=39) 77.6±7.6
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No fluid (n=54)
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OCT findings
Year 2 (n=88)
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