In recent years, medications that inhibit the activity of vascular endothelial growth factor (VEGF) have revolutionized the treatment of exudative age-related macular degeneration (AMD).1–3 Since their introduction, ranibizumab (Lucentis; Genentech, South San Francisco, CA) and bevacizumab (Avastin; Genentech, South San Francisco, CA) have become the standard of care for the management of this disease. In 2011 and again in 2012, the Comparison of AMD Treatments Trials (CATT) research group demonstrated that with respect to visual acuity, bevacizumab was noninferior to ranibizumab in the treatment of exudative AMD.4,10 There was, however, a difference in the two treatment modalities in terms of residual retinal thickening as measured on optical coherence tomography (OCT).4 This finding highlighted a potential difference in the response to these similar pharmacologic agents.
In November 2011, the U.S. Food and Drug Administration (FDA) approved the use of aflibercept (Eylea; Regeneron, Tarrytown, NY) for the treatment of exudative AMD. Aflibercept has a higher binding affinity for the important VEGF subtypes than either ranibizumab or bevacizumab.5 In addition, it is shown to block the isoforms VEGF-A and VEGF-B, as well as placental growth factor (PlGF).6 In phase 3 clinical trials, aflibercept injected every 8 weeks was shown to be noninferior with respect to visual acuity to ranibizumab injected monthly.7 For these reasons, aflibercept has a theoretical benefit in patients who do not respond ideally to primary treatment with bevacizumab or ranibizumab. This study examines the clinical response of patients transitioned to aflibercept due to persistent evidence of exudation on OCT despite regular treatment with bevacizumab and/or ranibizumab.
Patients and Methods
A designated minimal risk institutional review board at the University of Wisconsin granted approval for a retrospective review of clinical records. The medical records of all patients treated with aflibercept for AMD at the University of Wisconsin from August 31, 2012, through March 31, 2013, were reviewed. A total of 111 patients received the medication and were considered for inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with a minimum of three injections of either ranibizumab or bevacizumab. Evidence of persistent exudation was defined as any retinal thickening with signs of active exudation such as cystic spaces, subretinal fluid, or serous pigment epithelial detachment. Eyes with retinal thickening due to subretinal fibrosis with no signs of activity were excluded. A total of 67 eyes of 63 patients were included in the final analysis. Patient data collected included patient age and gender, number and type of anti-VEGF injections prior to transition to aflibercept, duration of treatment prior to change, OCT thickness and morphology before and after transition, Snellen visual acuity before and after transition, total number of aflibercept injections, and treatment interval before and after transition to aflibercept. OCT images were obtained using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) and the Zeiss Cirrus-HD OCT (Carl Zeiss Meditec, Jena, Germany). Retinal thickness data were collected manually for each patient using the manufacturer’s software. Neurosensory retinal thickness, measured from the internal limiting membrane (ILM) to the photoreceptors, as well as the distance from the ILM to Bruch’s membrane, were quantified.
For statistical analysis, Snellen visual acuity values were converted to logarithm of the minimum angle of resolution (logMAR) values. The average log-MAR visual acuity measurements were then converted back to Snellen acuities. The comparison of retinal thickness measurements before and after transition to aflibercept was performed using a Student’s t test.
For the 68 eyes that met the inclusion criteria, the average patient age was 79.9 years; 68% (43 patients) were women and 32% (20 patients) were men. The number of injections prior to the transition to aflibercept ranged from three to 38 injections. Patients were treated with either bevacizumab and/or ranibizumab for an average of 36.3 months prior to transition to aflibercept (range: 3 to 73 months). Six of the patients included in the series participated in the CATT, and the total number of injections prior to transition was unavailable. All of these patients had been continually treated monthly or PRN for the 2 years of the trial and on an ongoing basis prior to the change to aflibercept. Patients in the present series were treated primarily with a treat-and-extend approach, although many were treated every 4 weeks due to persistent exudation. The treatment interval prior to transition varied from 4 to 10 weeks (average: 5.88 weeks), and the treatment interval once started on aflibercept ranged from 4 to 8 weeks (average: 6.47 weeks). The total number of aflibercept injections ranged from two to 11 (average: 5.53 injections).
The retinal morphology as demonstrated by OCT scan was documented at the time of transition and compared with scans taken at the last follow-up appointment after aflibercept injection. Twenty-four of 67 eyes (34%) showed complete resolution of exudation by last follow-up examination. Seventeen of 67 eyes (25%) showed clear improvement in the amount or severity of exudation without complete resolution. Clear improvement was defined as a substantial decrease in the amount of retinal thickening, sub-RPE fluid, and/or subretinal fluid on OCT as interpreted by the authors. Twenty-three of 67 eyes (34%) showed no improvement, and four of 67 (6%) demonstrated worsening of exudation. There was no obvious trend that suggested improvement was more common with PEDs versus subretinal fluid versus cystic retinal thickening. Snellen visual acuity at the time of transition versus last follow-up appointment after aflibercept injection did not appreciably change (logMAR 0.494–0.505, Snellen equivalent 20/62–20/64; P = .84). The mean center point neurosensory retinal thickness decreased from 228.6 to 176.9 µm (P = .001). Similarly, the mean distance from the ILM to Bruch’s membrane at the center point, which takes into account pigment epithelial detachment size as well as neurosensory retinal thickness, decreased from 425.1 to 324.7 µm (P = .0012) (Figure).
Graph of retinal thicknesses before and after transition to aflibercept.
The recent FDA approval of aflibercept provides practitioners with an additional tool for the treatment of exudative AMD. The results of the 2012 American Society of Retina Specialists Preferences and Trends Survey show that retina practitioners are primarily using this medication as rescue therapy for patients who demonstrate a suboptimal response to ranibizumab or bevacizumab. Only 3.6% of practitioners from the U.S. and Canada reported using aflibercept for all new patients with choroidal neovascularization secondary to AMD. However, 80% of the practitioners surveyed responded that they would recommend a switch to aflibercept in patients with some combination of persistent subretinal fluid, pigment epithelial detachment, or retinal cysts despite multiple injections of ranibizumab or bevacizumab.8 This trend is reflected in the patients that met selection criteria for this study.
The results of this retrospective review suggest that aflibercept decreases the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity. These results are consistent with those recently published in two similar retrospective case series.9,11 Both of these series also showed anatomical improvement in retinal morphology on OCT without an improvement in visual acuity. Bakall et al showed an average decrease in central macular thickness of 64 µm after three injections in 31 patients transitioned to aflibercept. Similarly, Cho et al found a 21-µm decrease in central subfoveal thickness at 6 months in 28 patients transitioned to aflibercept. The current study adds to these findings with a larger number of patients.
As with any retrospective series, there are significant limitations to this study. Visual acuity data were collected from patient charts and were not recorded in ETDRS letters. Although visual acuity measurements were taken with current spectacle correction, there was no standardized refraction for these patients. The treatment interval prior to and after transition to aflibercept was not standardized. Decisions regarding frequency of treatment for patients on treat-and- extend and as-needed protocols who were treated less than every 4 weeks despite the presence of exudation were made by the individual physicians in conjunction with their patients. Many patients who had stable anatomy and vision, albeit with persistent edema on OCT, were eventually extended, with careful attention paid to the stability of their vision prior to switching to aflibercept. In each case, the authors had to balance the treatment burden to the patient with the potential for visual decline. Patients were treated with a variable number of injections prior to transition to aflibercept. For several patients, the total number of injections prior to aflibercept could not be accurately calculated. Reasons include practitioner masking in CATT patients, patients whose care was split with another practitioner due to seasonal travel, and patients who transitioned their care from another institution or practitioner. For this reason, the amount of treatment prior to transition was quantified in average months of ongoing treatment, which could be accurately obtained, rather than average total number of injections prior to transition to aflibercept. Five patients were treated with photodynamic therapy several years prior to their transition to aflibercept, and one was treated with a triamcinolone injection in 2009.
Despite the limitations of this study, this series is the largest of its kind to date. It provides supporting evidence for the use of aflibercept in patients with persistent exudation due to AMD despite regular injections of bevacizumab or ranibizumab. Although there was no significant change in visual acuity after transition from bevacizumab or ranibizumab to aflibercept, there was a robust and statistically significant improvement in retinal anatomy after the transition to aflibercept. The broader mechanism of action of aflibercept, with added effects on VEGF-B and PlGF, may be clinically evidenced as changes in retinal anatomy that are apparent on OCT imaging. This may translate to reduced activity and greater regression of choroidal neovascularization. The lack of effect on visual acuity may be due to the relative chronicity of the disease for many of these patients, who were treated for a mean of 36.29 months with bevacizumab and/or ranibizumab prior to being transitioned to aflibercept. A prospective study with larger numbers of participants, earlier transition to aflibercept, and standardization of procedures would be required to definitively assess the effects of aflibercept on eyes with persistent exudation after repeated injections of bevacizumab and/or ranibizumab.
- Rosenfeld P, Brown D, Heier J, et al. Ranubizumab for neovascular age-related macular degeneration. N Eng J Med. 2006;355(14):1419–1431. doi:10.1056/NEJMoa054481 [CrossRef]
- Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A Phase IIb study to evaluate the safety of ranubizumab in subjects with neovascular age-related macular degeneration. Ophthalmology. 2009;116(9):1731–1739. doi:10.1016/j.ophtha.2009.05.024 [CrossRef]
- Brown DM, Kaiser PK, Michels M, et al. Ranubizumab versus verte-porforin photodynamic therapy for neovascular age-related macular degeneration. Twp year results from the ANCHOR study. Ophthalmology. 2009;116(1):57–65e5. doi:10.1016/j.ophtha.2008.10.018 [CrossRef]
- Martin D, Maguire M, Fine S, et al. Ranibizumab and Bevacizumab for treatment of Neovascular Age-related Macular Degeneration Two Year Results. Ophthalmology. 2012;119(7):1388–1398. doi:10.1016/j.ophtha.2012.03.053 [CrossRef]
- Papadopoulos N, Martin J, Run Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–185. doi:10.1007/s10456-011-9249-6 [CrossRef]
- Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci. U S A. 2002;99(17):11393–11398. doi:10.1073/pnas.172398299 [CrossRef]
- Heier J, Brown D, Chong V, et al. Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-Related Macular Degeneration. Ophthalmology. 2013;120(1):209–210.
- ASRS PAT Survey 2012. http://www.asrs.org/asrs-community/pat-survey
- Cho H, Shah C, Weber M, Heier J. Aflibercept for exudative AMD with persistent fluid on ranubizumab and/or bevaczumab. Br J Ophthalmol. 2013;97(8):1032–1035. doi:10.1136/bjophthalmol-2013-303344 [CrossRef]
- Martin D, Maguire M, Ying G, et al. Ranubizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–1908. doi:10.1056/NEJMoa1102673 [CrossRef]
- Bakall B, Folk J, Boldt H, et al. Aflibercept Therapy for Exudative Age-related Macular Degeneration Resistant to Bevacizumab and Ranubizumab. Am J Ophthalmol. 2013;156(1):15–22. doi:10.1016/j.ajo.2013.02.017 [CrossRef]