Original Paper Ophthalmic Res 2016;55:84–90 DOI: 10.1159/000440886

Received: September 3, 2015 Accepted: September 7, 2015 Published online: December 5, 2015

Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes Andrew A. Chang a–c Geoffrey K. Broadhead a–c Thomas Hong a, b Nichole Joachim a, b Adil Syed a, b Timothy E. Schlub d Levente Toth e Tunde Peto e Meidong Zhu a–c a

Sydney Institute of Vision Science, b Sydney Retina Clinic and Day Surgery, and c Save Sight Institute and d Sydney School of Public Health, University of Sydney, Sydney, N.S.W., Australia; e NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK

Abstract Purpose: To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD). Methods: This prospective, non-randomized clinical trial included 49 patients with treatment-resistant nAMD who received 2 mg intravitreal aflibercept as 3 monthly loading doses, followed by injections every 2 months over 12 months. Inclusion criteria included active nAMD on fluorescein angiography at baseline and persistent intra- or subretinal fluid on optical coherence tomography (OCT) for ≥6 months prior to baseline with a minimum of 4 injections of bevacizumab and/or ranibizumab. Patients were assessed monthly for best-corrected visual acuity (BCVA), central retinal thickness (CRT) measured with OCT and occurrence of adverse events. Retinal pigment epithelium atrophy (RPEA) was assessed at baseline and at 12 months. Results: Mean BCVA improved by 4.7 letters (95% CI: 2.1–7.3, p < 0.001) and CRT decreased by 97.2 μm (95% CI: 54.4–140.1, p < 0.001) at 12 months com-

© 2015 S. Karger AG, Basel 0030–3747/15/0552–0084$39.50/0 E-Mail [email protected] www.karger.com/ore

pared to baseline. Median RPEA area increased by 0.48 mm2 (range = –0.1 to 19.9, p < 0.001). There was 1 arterial thromboembolic event and 2 cases of submacular haemorrhage. Conclusion: In this cohort of treatment-resistant nAMD patients, intravitreal aflibercept was effective in improving vision and reducing exudation. Early visual and anatomic outcomes may predict longer-term response to treatment, but further assessment is required. © 2015 S. Karger AG, Basel


Intravitreal antivascular endothelial growth factor (anti-VEGF) injections represent the current standard of care for neovascular age-related macular degeneration (nAMD). Large clinical trials of anti-VEGF agents for nAMD have consistently shown that up to 30% of treated patients have persistent retinal exudation despite regular, intensive therapy over 12 months [1, 2], potentially limit-

Preliminary data from this work were presented at the EURETINA Congress, September 11–14, 2014, London, UK.

Dr. Andrew A. Chang Sydney Retina Clinic and Day Surgery Level 13, Park House, 187 Macquarie Street Sydney, NSW 2000 (Australia) E-Mail achang @ sydneyretina.com.au

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Key Words Aflibercept · Treatment resistance · Intravitreal injection · Neovascular age-related macular degeneration

Methods Study Design An open-label prospective clinical trial was conducted on 49 patients receiving aflibercept therapy for treatment-resistant nAMD. Treatment resistance was defined as the presence of intraretinal fluid (IRF) or subretinal fluid (SRF) on spectral-domain optical coherence tomography (SD-OCT) despite at least 4 intravitreal injections of an anti-VEGF agent in the preceding 6 months. Full inclusion/exclusion criteria and the study injection procedures have been previously published [5]. The trial was registered on the Australian and New Zealand Clinical Trials Registry (accessible via www.anzctr.org.au, ACTRN 12612000666820). Institutional ethics approval was obtained prior to study commencement, and the study followed the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants prior to enrolment in the study.

ment in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, intraocular pressure (IOP) measurement with Goldmann applanation tonometry, fundus photography (Visucam NM/FA; Zeiss, Dublin, Calif., USA), SD-OCT (Heidelberg Spectralis, Heidelberg, Germany) and adverse event monitoring. Fundus fluorescein angiography (FFA) and indocyanine green angiography were performed at the baseline visit to confirm the presence of AMDrelated choroidal neovascularisation and to exclude lesions such as polypoidal choroidal vasculopathy. Ocular and systemic adverse events were recorded at each visit. Lens opacities were graded according to the Age-Related Eye Diseases Study (AREDS) grading protocol [13]. An increase in lens opacity of ≥2 AREDS levels in nuclear, cortical or posterior subcapsular cataracts, IOP ≥25 mm Hg or an elevation in IOP ≥10 mm Hg compared to baseline were considered an adverse event. The presence and size of retinal pigment epithelium atrophy (RPEA) was graded using colour fundus photography at baseline and at 12 months by two independent graders, with any discrepancies adjudicated by a third independent grader whose decision was taken as final. Central retinal thickness (CRT) was measured from a Heidelberg Spectralis scan (19 lines, 1,028 A-scans per line). In-built Heidelberg licensed software with eye tracking and image recognition (TruTrack and AutoRescan, respectively) was used to ensure continuity of scan location throughout the follow-up period. CRT was defined as the distance between the internal limiting membrane and Bruch’s membrane. Two image graders reviewed the anatomic boundaries on all B-scans to confirm accurate identification of the internal limiting membrane and Bruch’s membrane layers. Where inaccuracies were found, the segmentation lines and central foveal location was manually re-defined. The presence or absence of IRF or SRF was graded at each visit by two independent graders, with discrepancies adjudicated by a third independent grader. A trained and certified grader at Moorfields Eye Hospital Reading Centre assessed characteristics of RPEA on autofluorescence, OCT and FFA images. The presence of RPEA was graded on autofluorescence as areas of contiguous, well-defined hypoautofluorescence which corresponded to window defects on early FFA images and/or to the loss of cellular layers (outer retina, RPE and choriocapillaris) on the accompanying OCTs. Once the area of atrophy was graded, early and late FFA frames were selected to assess the presence of fibrosis. This had features of corresponding initial hypofluorescence with late hyperfluorescence and staining on FFA. The changes were then compared to the equivalent areas on the OCT scans where they appeared as an area of subretinal homogenous hyperdensity if true fibrosis existed. The presence of atrophy and fibrosis was graded as sub- and extrafoveal depending on the localization of the pathology. Available images at baseline and at month 12 were then scrutinized for the change of other lesion and morphology characteristics. The presence of pigment epithelial detachments and SRF and IRF were also graded.

Study Protocol Intravitreal aflibercept (2 mg) was administered as 3 loading doses at month 0, 1 and 2 followed by further injections every 2 months at months 4, 6, 8, 10 and 12. Participants were followed up 1 week after the initial injection, then monthly thereafter for a total of 12 months. A full ophthalmic examination was conducted at each visit including best-corrected visual acuity (BCVA) measure-

Statistics Statistical analyses were performed using R version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Paired t tests were used to compare differences in means for BCVA and CRT between baseline and follow-up examinations as well as between the intervening visits. When a patient did not attend a scheduled visit, the last observation was carried forward for analysis. Non-parametric tests gave similar results.

Aflibercept for Treatment-Resistant nAMD

Ophthalmic Res 2016;55:84–90 DOI: 10.1159/000440886


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ing the visual prognosis in these patients. A limited range of effective strategies exists to overcome this issue, although higher medication dosages, combination therapy and switching of therapeutic agents have been trialled with varying degrees of success [3–7]. Aflibercept (Eylea; Regeneron, Tarrytown, N.J., USA) is an effective therapy for nAMD in treatment-naïve eyes [1]. It can be administered every 2 months following the initial 3 loading doses of monthly injections, potentially reducing injection frequency as well as the burden associated with monthly intravitreal therapy [1]. It has been suggested that the increased duration of action compared to other anti-VEGF agents may be due to a higher binding affinity and a wider range of action against angiogenic growth factors [8]. Aflibercept has also been trialled in patients resistant to treatment with other anti-VEGF agents in order to improve visual and anatomical outcomes, although the reported outcomes associated with this strategy are varied [5, 9–11]. Despite continuing interest in the use of aflibercept for these treatment-resistant and difficult-to-manage patients [12], there is limited prospective evidence for the safety and efficacy of aflibercept therapy in this group of patients. The purpose of this study was to prospectively assess, over a 12-month period, the safety and efficacy of aflibercept in patients deemed non-responders to other antiVEGF therapies.

Table 1. Baseline characteristics of patient cohort

Participants, n Age, years Male, n (%) Right eyes, n (%) BCVA, number of letters CRT, μm Phakic:pseudophakic, % Non-smoker:ex-smoker:current smoker, % Ranibizumab treatment, years Mean previous ranibizumab injections, n Mean ranibizumab injections 6 months before study, n Ranibizumab and bevacizumab 6 months, n (%) Ranibizumab and bevacizumab >6 months and PDT >6 months, n (%)

49 77.8 ± 7.5 21 (42.9) 23 (46.9) 60.5 ± 16.2 448.4 ± 141.2 65.3:34.7 38.8:57.1:4.1 3.4 ± 1.7 34.9 ± 16.1 5.0 ± 0.7 7 (14.3) 1 (2) 1 (2)

BCVA change (ETDRS letters)



8 7 6 5 4 3 2 1 0








6 7 Month



10 11 12


The baseline characteristics of the participants are displayed in table 1. All patients had received at least 4 ranibizumab injections in the 6 months prior to switching to aflibercept, with a mean time between the last ranibizumab injection and first aflibercept injection of 36.0 days. 86

Ophthalmic Res 2016;55:84–90 DOI: 10.1159/000440886

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Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes.

To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD...
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