JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 4, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2013.0188
Aflibercept in the Treatment of Neovascular Age-Related Macular Degeneration in Previously Treated Patients Laura B. Hall, Nazlee Zebardast, John J. Huang, and Ron A. Adelman
Abstract
Purpose: To study the visual outcomes and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with ranibizumab (Lucentis) and/or bevacizumab (Avastin) and were subsequently switched to aflibercept (VEGF Trap-Eye; Eylea). Methods: Retrospective study of patients who received intravitreal aflibercept from December 2011 to December 2012 and had previous anti-vascular endothelial growth factor treatment for AMD. The main outcome measures were best-corrected visual acuity (BCVA) and CMT as measured by optical coherence tomography. Results: The study population included 30 patients aged 80.4 – 1.45 (mean – SEM) who received 6.27 – 0.37 (range 4–11) aflibercept injections. Eighteen patients had previously received only bevacizumab (12.4 – 2.18 injections), 2 had received only ranibizumab (19 – 6 injections), and 10 had received both ranibizumab and bevacizumab (mean 19.3 injections). BCVA logMAR at the initial visit (aflibercept initiation) was 0.506 – 0.054 (mean VA 20/64), and then, follow ups at 1-month 0.504 – 0.055 (20/64) P = 0.903, 3-months 0.458 – 0.061 (20/57) P = 0.112, 6-months 0.413 – 0.071 (20/52) P = 0.036, and 12-months 0.521 – 0.076 (20/66) P = 0.836. CMT at the initial visit was 261 – 10.9, and then, at 1-month 238 – 12.4 P = 0.021, 3-months 245 – 10.6 P = 0.102, 6-months 245 – 10.4 P = 0.099, and 12-months 237 – 10.2 P = 0.012. Results were similar in a subset of patients (n = 15) with central macular edema or submacular fluid at aflibercept initiation. While on aflibercept, 2 patients developed intraocular pressure increases that required treatment. Conclusions: These findings demonstrate a significant decrease in CMT but no statistically significant improvement in BCVA through the 12-month follow up in patients previously treated who were switched to aflibercept for AMD. Patients may develop ocular hypertension after multiple aflibercept injections.
Introduction
A
ge-related macular degeneration (AMD) is the leading cause of central vision loss in the U. S. elderly population.1,2 Over the past 8 years, there has been widespread acceptance of agents that directly inhibit the action of vascular endothelial growth factor (VEGF) in the retina.3,4 In 2005, bevacizumab was first used off-label and in 2006, ranibizumab came to the market, both of which were used to treat wet (exudative or neovascular) AMD. Until recently, these were the mainstay management for wet AMD. On November 18, 2011, the Food and Drug Administration (FDA) granted regulatory approval to a new agent named aflibercept and within the past 2 years, it has gained popularity. The effect of aflibercept is nested in its molecular structure. While bevacizumab and ranibizumab use an antibodybased binding strategy, aflibercept is a recombinant decoy
fusion protein with 2 binding domains for VEGF receptors 1 and 2, as well as a placental growth factor (another proposed pro-angiogenic factor present in the retina).4 The fusing of these extracellular components enables aflibercept to have a much higher binding capacity than the others, and it is hypothesized to enable a more persistent, longer-lasting VEGF blockade.4–6 Based on clinical trial results [VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW1 and VIEW2)], the FDA approved aflibercept for the treatment of wet AMD.7 For the purpose of this current research study, these clinical trials included 2 interesting details. First, the dosing regimen for aflibercept is 2 mg every 2 months after 3 initial monthly doses. As a result, patients can potentially avoid monthly clinic visits8 and instead go every 2 months, which, respectively, the VIEW 1 and 27 and the CLEAR-IT29 trials showed to be as effective at maintaining vision. Second, the VIEW trials excluded patients
Department of Ophthalmology and Visual Science, Yale School of Medicine, Yale Eye Center, New Haven, Connecticut.
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previously treated with any anti-VEGF modality, specifically bevacizumab or ranibizumab.10 As a result, the utility of aflibercept in patients previously treated with anti-VEGF agents rather than in the treatment of naı¨ve patients remains unclear.
Methods The Yale School of Medicine Institutional Review Board (IRB) approved this single institution retrospective study that adhered to the Declaration of Helsinki. Yale Eye Center billing data identified 64 patients from December 2011 to December 2012 as having received aflibercept (VEGF Trapeye; Eylea, Regeneron, Tarrytown, NY). Efforts were made to have similar inclusion and exclusion criteria set forth in the VIEW trials10 with 3 notable inclusion criteria exceptions. First, for the treatment of wet AMD, patients should have received at least 2 previous intravitreal antiVEGF injections in the study eye, either 1.25 mg of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) and/or 0.5 mg of ranibizumab (Lucentis; Genentech, Inc.) before being transitioned to 2.0 mg intravitreal aflibercept. Second, patients were included despite having bestcorrected visual acuity (BCVA) vision better than 20/40. Third, all patients had to be followed at the Yale Eye Center Retina Clinic for a minimum of 6 months after their first aflibercept injection. This ensured the same team using the same optical coherence tomography (OCT)-guided retreatment strategy managed the patients and that the time between each treatment was not influenced by the use of other therapeutic techniques or other physician opinions. Choroidal neovascularization from wet AMD was diagnosed using both fluorescein angiography (FA) and OCT (CirrusOCT; Zeiss, Jens, Germany). Thirty patients met criteria and were treated with aflibercept in at least 1 eye. If both eyes of a patient matched the inclusion criteria, the right eye was included in the study. Both patients who responded well to previous anti-VEGF therapy and those who were refractory were included in this study. A subgroup analysis identified patients qualitatively and quantitatively by a retina specialist as having central macular edema or submacular fluid on initial OCT defined as intraretinal fluid, or accumulation of fluid under the macula. Two patients with noncentral edema were excluded from this analysis. Data were collected from December 2012 to February 2013. Once aflibercept treatment began, patients did not receive any concurrent AMD treatment such as photodynamic therapy or other anti-VEGF injections. Retina physicians performed all aflibercept injections using a standard, sterile technique. The option to switch was discussed with all active wet AMD patients. Risks, benefits, alternatives, and coverage were discussed with each patient. The general guideline was that since aflibercept’s dosing regimen7 was preferred, all patients with active disease and the desire to change would be transitioned. Since patients were not treatment naı¨ve, physicians used a modified treat and extend11,12 model to determine if and when treatment with aflibercept was needed, unless patients desired not to switch the treatment or there was a contraindication. Specifically, if patients exhibited subretinal fluid on OCT at the time of the switch, they then began aflibercept
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monthly for the first 3 months and then, the treat and extend model was instituted. If OCT exhibited no subretinal fluid at the time of the switch, then the treat and extend model was instituted at the time of the first aflibercept injection.7 At each visit, patients underwent Snellen visual acuity measurements with attempts to obtain Snellen BCVA as well as slit-lamp and biomicroscopic fundus examinations. Snellen BCVA and central macular thickness (CMT) (mm) data were collected at multiple time points: initial visit, defined as the day of the first aflibercept injection, and then, at all subsequent visits between the retina specialist and the patient regardless of whether an injection was administered. Demographic information, the length of time between each visit, the number and timing of each intravitreal injection, and adverse events were also collected. Pretreatment and subsequent FA results were collected but were limited, precluding adequate analysis. FA was not routinely done before the switch. For the purpose of statistical analysis, Snellen visual acuity data was converted to BCVA logarithm of the minimal angle of resolution (logMAR). The primary outcomes collected for this study included (1) visual acuity change from initial (day of aflibercept initiation) to 1-, 3-, 6-, 9-, and 12-month follow ups: improvement in visual acuity (decrease ‡ 0.3 logMAR), decline in visual acuity (increase ‡ 0.3 logMAR) or stability of visual acuity (any change £ 0.3 logMAR), (2) change in CMT (mm) from initial to 1-, 3-, 6-, 9-, and 12-month follow ups, and (3) the number and timing of aflibercept injections. While patients without initial BCVA or CMT measurements or at least 6 months follow up were excluded from all analyses of mean change, other missing data were imputed by the last-observation-carried-forward (LOCF) method. The LOCF was never used as a final observation (the 6-, 9-, or 12-month follow ups) and was never carried forward for more than 1 time point. Visual acuities and CMT were statistically compared between the aflibercept initiation visit and follow ups using P values from paired Student’s t-tests. Statistical significance was defined as P < 0.05. Unless otherwise noted, all data are presented as mean – SEM. Statistical analyses were performed using Microsoft Excel (Microsoft Corporation, Redmond, WA), and paired Student’s t-tests were calculated using GraphPad QuickCalcs Website www.graphpad.com/ quickcalcs/ttest1.cfm (accessed April 2013).
Results Billing records indicated 64 patients had received aflibercept at the Yale Eye Center during the study period. Thirty of these patients received at least 2 previous bevacizumab and/or ranibizumab injections, had at least 6 months of follow up, and fit the inclusion criteria mentioned earlier. A single patient chart was unable to be located during the data collection period. The LOCF was used for 5 patients without a 1-month follow up (BCVA and CMT), for 1 patient without a 1-month CMT, and for 1 patient without a 9-month follow up (BCVA and CMT).
Demographics and clinical characteristics The study population included 8 men (27%) and 22 women (73%) aged 80.4 – 1.45 years with 9 right eyes, 12 left eyes, and 9 with both eyes. Eighteen patients previously
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Table 1.
Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity) and Central Macular Thickness (mm)
Time point 1-month (n = 30) LOCF = 5 3-month (n = 30) 6-month (n = 30) 9-month (n = 27)LOCF = 1 12-month (n = 22)
Initial BCVA 0.506 – 0.054 0.506 – 0.054 0.506 – 0.054 0.518 – 0.059 0.533 – 0.072
(20/64) (20/64) (20/64) (20/66) (20/68)
Follow-up BCVA 0.504 – 0.055 0.458 – 0.061 0.413 – 0.071 0.465 – 0.065 0.521 – 0.076
(20/64) (20/57) (20/52) (20/58) (20/66)
P-value Initial CMT Follow-up CMT P-value 0.903 0.112 0.036 0.210 0.836
261 – 10.9 261 – 10.9 261 – 10.9 262 – 10.7 264 – 12.5
238 – 12.4 245 – 10.6 245 – 10.4 242 – 9.66 237 – 10.2
0.021 0.102 0.099 0.015 0.012
Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point. BCVA, best-corrected visual acuity; CMT, central macular thickness; LOCF, last-observation-carried-forward.
received only bevacizumab (12.4 – 2.18 injections), 2 received only ranibizumab (19 – 6 injections), and 10 received both anti-VEGF agents (mean 19.3 total injections). Overall, the patients received a total of 14.9 – 2.01 (range 2–53) previous injections in the study eye. Patients received 6.27 – 0.37 (range 4–11) aflibercept injections during the study period.
Visual acuity in all patients While there was a modest trend toward improvement within the first 6 months, by 12 months there was no overall change in BCVA (P = 0.84) (Table 1 and Fig. 1). To evaluate the change in the BCVA, we defined 3 categories relative to the initial visit: improvement in visual acuity (decrease ‡ 0.3 logMAR), decline in visual acuity (increase ‡ 0.3 logMAR), and stable (any change £ 0.3 logMAR). In addition, gross changes in vision were defined as follows: any improvement (any decrease in logMAR), any decline (any increase in logMAR), and stayed the same (no change in logMAR). The vast majority (73%–96% of
FIG. 1. Mean change during study period in best-corrected visual acuity (BCVA) logMAR. Values compare mean logMAR BCVA from the follow-up time point to the initial mean BCVA logMAR in each patient subset, where a positive change in logMAR BCVA correlates to a decline (worsening) in vision.
patients) fit into the stable category at all follow ups, similar to clinical studies involving aflibercept (Table 2).7 It should be noted that LOCF was not applied to this analysis, because change is assessed.
CMT in all patients There was a significant initial decrease in CMT after the first month of aflibercept treatment that remained significant at the 12-month follow up for all patients, with initial CMT 264 – 12.5 mm compared with 237 – 10.2 at 12 months (P = 0.012) (Table 1 and Fig. 2).
Visual acuity and CMT in those with initial macular edema In a subgroup analysis, there were 15 patients (50%) who at the time of aflibercept initiation had central macular edema or submacular fluid; essentially, these were patients who had suboptimal response to previous treatment
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Table 2. Change in Vision Relative to Initial Visit, with Number of Patients (%) Experiencing the Column Category of Visual Change at Each Subsequent Time Point (Rows) Time point 1-month (n = 25) 3-month (n = 30) 6-month (n = 30) 9-month (n = 26) 12-month (n = 22)
Improvement in visual acuity 0 3 4 3 2
(10%) (13%) (11%) (9%)
Any improvement 8 14 19 13 10
(32%) (47%) (63%) (50%) (45%)
Decline in visual acuity 1 1 1 2 4
(4%) (3%) (3%) (8%) (18%)
Any decline 5 4 5 7 8
(20%) (13%) (17%) (27%) (36%)
Stable 24 26 25 21 16
(96%) (87%) (83%) (81%) (73%)
Same 12 12 6 6 4
(48%) (40%) (20%) (23%) (18%)
Improvement is a decrease ‡ 0.3 logMAR, any improvement is any decrease in logMAR, decline is an increase ‡ 0.3 logMAR, any decline is any increase in logMAR, stable is any change £ 0.3 logMAR and same is no change in logMAR.
regimens. These patients received 19.1 – 0.06 (range 3–53) previous anti-VEGF injections in the study eye. The subgroup analysis results for BCVA were similar to the allpatients results and did not show a significant improvement after aflibercept initiation (Table 3 and Figure 1). The subgroup analysis results for CMT demonstrated a similar decrease in CMT over most of the 12-month period (Table 3 and Fig. 2).
(341 – 6.30). Six months from the first aflibercept injection, all 30 patients returned to the clinic with an average of 4.50 – 0.11 injections; 9 months from the first injection, 26 patients returned to the clinic with an average of 6.00 – 0.23 injections and 12 months from the first injection, 22 patients returned to the clinic with an average of 7.17 – 0.38 injections. It should be noted that LOCF was not applied to this analysis, because the time between visits and the number of injections within a designated time frame were assessed.
Clinic visit and treatment frequency Data used for the follow-up time points (1, 3-months, etc.) were obtained from visits as close to these time points as possible. We had clinic visit dates for all 30 patients for their initial visit. Follow-up data were collected for 25 patients at 1 month (45.2 – 2.28 days), 30 patients for 3 months (99.1 – 3.02) and 6 months (175 – 4.87), 26 patients for 9 months (265 – 4.98), and 22 patients for 12 months
Intraocular pressure There were 2 instances in which injections were held due to intraocular pressures (IOP) > 25 mmHg. Patients were given IOP-lowering agents and had glaucoma evaluations. In this study, both patients were noted to have elevated IOP at their last follow up study. The injections were held at this visit, but the BCVA and CMT data were still collected.
FIG. 2. Mean change during study period in central macular thickness (CMT) (mm). Values compare mean follow-up time point CMT to mean initial CMT in each indicated patient subset.
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Table 3. Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity) and Central Macular Thickness (mm) in Those with Central Macular Edema or Submacular Fluid at the Time of Aflibercept Initiation Time point 1-month (n = 15) 3-month (n = 15) 6-month (n = 15) 9-month (n = 13) 12-month (n = 11)
Initial BCVA 0.464 – 0.061 0.464 – 0.061 0.464 – 0.061 0.458 – 0.070 0.443 – 0.082
(20/58) (20/58) (20/58) (20/57) (20/55)
Follow-up BCVA 0.469 – 0.059 0.423 – 0.067 0.374 – 0.058 0.472 – 0.092 0.508 – 0.100
(20/59) (20/53) (20/47) (20/59) (20/64)
P-value
Initial CMT
Follow-up CMT
P-value
0.866 0.261 0.014 0.800 0.360
274 – 15.9 274 – 15.9 274 – 15.9 268 – 17.9 275 – 20.7
242 – 17.7 255 – 15.8 241 – 10.2 239 – 12.5 240 – 13.4
0.030 0.207 0.030 0.041 0.078
Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point.
Holding the medication at the 12-month follow up (last study visit) did not affect macular edema or visual outcomes during the study period. After adequate pressure control by a glaucoma specialist, anti-VEGF treatment resumed.
Adverse events No significant sight-threatening complications developed in the study patients during the specified period. There were no other drug- or injection-related adverse events except for mild subconjunctival hemorrhage.
Discussion Aflibercept was approved in 2011 for the treatment of wet AMD based on clinical trial data in the treatment of naı¨ve patients.7 PubMed and Medline searches performed on August 14, 2013 with the search criteria ‘‘aflibercept’’ and ‘‘macular degeneration’’ revealed a handful of papers evaluatingafliberceptinpreviouslytreatedpatients.13–18 Kumar et al. assessed patients with persistent subfoveal fluid resistant to ranibizumab with 6-months’ follow up and found significant improvements in visual acuities and pigment epithelial height and diameter.13 The most comprehensive recent studies by Cho et al.,15 Bakall et al.,16 and Yonekawa et al.17 also only have 6-months’ follow up. All of them reported anatomical improvement in subretinal thickness but no significant change in BCVA by 6 months. This article extends the conclusions to 12 months. Further, only the paper by Yonekawa et al.17 analyzed all patients and not just those who were refractory (defined as persistent exudation despite monthly injections) to treatment. Including the search terms ‘‘switch,’’ ‘‘resistant,’’ and ‘‘previous treatment’’ yielded no further relevant papers. There is not enough generalizable and long-term information in the literature on whether aflibercept is effective in previously treated uncomplicated wet AMD patients.
Visual acuity and CMT This study followed patients with and without initial macular edema for approximately 12 months. Overall, after 12 months of follow up, there was no statistically significant improvement in BCVA and the subgroup analysis of those with initial central macular edema or submacular fluid showed a worsening from baseline. In the literature, there have only been reports with approximately 6 months of aflibercept follow up in previously treated patients.13–18 Similar to those reports, in this study, BCVA showed a trend toward improvement by 6 months of follow up. However, by 12 months, the BCVA was close to or worse than initial values.
Notably, initial BCVA for 9 of the 30 patients (30%) was 20/40 or better. While the VIEW and CLEAR-IT2 trials showed noninferiority in BCVA at all time points, it excluded patients with initial vision better than 20/40.7,9 The present study included patients with any visual acuity. Thus, our patients have a smaller margin for improvement. The CMT in all patients as well as in the subgroup with initial central macular edema or submacular fluid showed a decline throughout the study period, as it also did in the 6-month studies.13–18 The subgroup showed the largest numerical improvement ( - 35 mm) at 12 months, but the small sample size (n = 11) made it difficult to reach statistical significance. Given that aflibercept was introduced later in the treatment course for patients in all of the studies mentioned earlier (particularly in this study after they had received a range of 2 to 53 anti-VEGF injections), some irreversible visual loss and retinal damage may have occurred. These data are representative of the previously treated patients who were switched to aflibercept.
Persistent IOP rise after aflibercept There are reports in the literature on persistent ocular hypertension (OHT) after bevacizumab and ranibizumab19,20 but not with aflibercept treatment in wet AMD. A Pubmed and Medline search on August 14, 2013 with the search terms ‘‘aflibercept’’ and either ‘‘ocular hypertension’’ or ‘‘intraocular pressure’’ revealed studies that report a rise in IOP immediately after aflibercept injection in patients with AMD or diabetic macular edema but not as a specific long-term consequence.7,21,22 In this retrospective study, 2 patients had persistent IOP rises after aflibercept use. The first patient received 14 bevacizumab and 5 ranibizumab and had no history of OHT. Previous pressures were stable in the mid teens and 11 months after switching to aflibercept (9 injections), the IOP increased to 35. The second patient received 13 previous ranibizumab injections and was stable on 1 IOP-lowering agent. Despite being on the same IOP-lowering medication with pressures stable in the mid teens, 11 months after switching to aflibercept (5 injections) the IOP increased to 38. Retina and glaucoma specialists examined both patients and prescribed an IOPlowering regimen.
Clinic visit and treatment frequency Rather than following with monthly injection for 3 times followed by bimonthly treatment regimen for aflibercept,7 since the patients were not treatment naı¨ve, a modified
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‘‘treat and extend’’ model was used.11,12 In this study, patients required fewer clinic visits and received fewer injections over time. These findings suggest that the treat and extend model may be effective with aflibercept treatment. During the study, some macular edema and submacular fluid completely resolved and in these patients, the treatment interval was gradually extended to every 3–4 months. Since most physicians use a treat and extend model when treating wet AMD, this current study is relevant to a large number of practitioners.
8.
Other considerations
9.
This study has several limitations. Primarily, it is retrospective and nonrandomized. It included a small sample size of patients with a relatively short follow-up time of 12 months. However, this study still adds to the growing body of literature on aflibercept’s effectiveness in wet AMD, especially after previous treatments. A larger and longer prospective randomized study is needed to better understand the utility of aflibercept in previously treated AMD patients.
10. 11.
Acknowledgments This research was supported in part by the Richard K. Gershon M.D. Student Research Fellowship (New Haven, CT), Leir Foundation (New York City, NY), Newman’s Own Foundation (Westport, CT), and Research to Prevent Blindness (New York, NY). The sponsors or funding organizations had no role in the design or conduct of this research. The authors would like to thank Victoria Donaldson for technical support.
12.
13.
Author Disclosure Statement The authors have no proprietary interests to disclose.
14.
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20. Abedi, G., Adelman, R.A., and Salim, S. Incidence and management of elevated intraocular pressure with antivascular endothelial growth factor agents. Semin. Ophthalmol. 28:126–130, 2013. 21. Do, D.V., Nguyen, Q.D., Boyer, D., Schmidt-Erfurth, U., Brown, D.M., Vitti, R., Berliner, A.J., Gao, B., Zeitz, O., Ruckert, R., Schmelter, T., Sandbrink, R., Heier, J.S., and da Vinci Study Group. One-year outcomes of the DA VINCI study of VEGF trap-eye in eyes with diabetic macular edema. Ophthalmology. 119:1658–1665, 2012. 22. Ford, J.A., Lois, N., Royle, P., Clar, C., Shyangdan, D., and Waugh, N. Current treatments in diabetic macular oedema: systematic review and meta-analysis. BMJ Open. 3:1–58, 2013.
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Received: September 5, 2013 Accepted: December 10, 2013 Address correspondence to: Dr. Ron A. Adelman Department of Ophthalmology and Visual Science Yale School of Medicine Yale Eye Center 40 Temple Street Suite 3D New Haven, CT 06510 E-mail: [email protected]
Aflibercept in the Treatment of Neovascular Age-Related Macular Degeneration in Previously Treated Patients Laura B. Hall, Nazlee Zebardast, John J. Huang, and Ron A. Adelman
Abstract
Purpose: To study the visual outcomes and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with ranibizumab (Lucentis) and/or bevacizumab (Avastin) and were subsequently switched to aflibercept (VEGF Trap-Eye; Eylea). Methods: Retrospective study of patients who received intravitreal aflibercept from December 2011 to December 2012 and had previous anti-vascular endothelial growth factor treatment for AMD. The main outcome measures were best-corrected visual acuity (BCVA) and CMT as measured by optical coherence tomography. Results: The study population included 30 patients aged 80.4 – 1.45 (mean – SEM) who received 6.27 – 0.37 (range 4–11) aflibercept injections. Eighteen patients had previously received only bevacizumab (12.4 – 2.18 injections), 2 had received only ranibizumab (19 – 6 injections), and 10 had received both ranibizumab and bevacizumab (mean 19.3 injections). BCVA logMAR at the initial visit (aflibercept initiation) was 0.506 – 0.054 (mean VA 20/64), and then, follow ups at 1-month 0.504 – 0.055 (20/64) P = 0.903, 3-months 0.458 – 0.061 (20/57) P = 0.112, 6-months 0.413 – 0.071 (20/52) P = 0.036, and 12-months 0.521 – 0.076 (20/66) P = 0.836. CMT at the initial visit was 261 – 10.9, and then, at 1-month 238 – 12.4 P = 0.021, 3-months 245 – 10.6 P = 0.102, 6-months 245 – 10.4 P = 0.099, and 12-months 237 – 10.2 P = 0.012. Results were similar in a subset of patients (n = 15) with central macular edema or submacular fluid at aflibercept initiation. While on aflibercept, 2 patients developed intraocular pressure increases that required treatment. Conclusions: These findings demonstrate a significant decrease in CMT but no statistically significant improvement in BCVA through the 12-month follow up in patients previously treated who were switched to aflibercept for AMD. Patients may develop ocular hypertension after multiple aflibercept injections.
Introduction
A
ge-related macular degeneration (AMD) is the leading cause of central vision loss in the U. S. elderly population.1,2 Over the past 8 years, there has been widespread acceptance of agents that directly inhibit the action of vascular endothelial growth factor (VEGF) in the retina.3,4 In 2005, bevacizumab was first used off-label and in 2006, ranibizumab came to the market, both of which were used to treat wet (exudative or neovascular) AMD. Until recently, these were the mainstay management for wet AMD. On November 18, 2011, the Food and Drug Administration (FDA) granted regulatory approval to a new agent named aflibercept and within the past 2 years, it has gained popularity. The effect of aflibercept is nested in its molecular structure. While bevacizumab and ranibizumab use an antibodybased binding strategy, aflibercept is a recombinant decoy
fusion protein with 2 binding domains for VEGF receptors 1 and 2, as well as a placental growth factor (another proposed pro-angiogenic factor present in the retina).4 The fusing of these extracellular components enables aflibercept to have a much higher binding capacity than the others, and it is hypothesized to enable a more persistent, longer-lasting VEGF blockade.4–6 Based on clinical trial results [VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW1 and VIEW2)], the FDA approved aflibercept for the treatment of wet AMD.7 For the purpose of this current research study, these clinical trials included 2 interesting details. First, the dosing regimen for aflibercept is 2 mg every 2 months after 3 initial monthly doses. As a result, patients can potentially avoid monthly clinic visits8 and instead go every 2 months, which, respectively, the VIEW 1 and 27 and the CLEAR-IT29 trials showed to be as effective at maintaining vision. Second, the VIEW trials excluded patients
Department of Ophthalmology and Visual Science, Yale School of Medicine, Yale Eye Center, New Haven, Connecticut.
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previously treated with any anti-VEGF modality, specifically bevacizumab or ranibizumab.10 As a result, the utility of aflibercept in patients previously treated with anti-VEGF agents rather than in the treatment of naı¨ve patients remains unclear.
Methods The Yale School of Medicine Institutional Review Board (IRB) approved this single institution retrospective study that adhered to the Declaration of Helsinki. Yale Eye Center billing data identified 64 patients from December 2011 to December 2012 as having received aflibercept (VEGF Trapeye; Eylea, Regeneron, Tarrytown, NY). Efforts were made to have similar inclusion and exclusion criteria set forth in the VIEW trials10 with 3 notable inclusion criteria exceptions. First, for the treatment of wet AMD, patients should have received at least 2 previous intravitreal antiVEGF injections in the study eye, either 1.25 mg of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) and/or 0.5 mg of ranibizumab (Lucentis; Genentech, Inc.) before being transitioned to 2.0 mg intravitreal aflibercept. Second, patients were included despite having bestcorrected visual acuity (BCVA) vision better than 20/40. Third, all patients had to be followed at the Yale Eye Center Retina Clinic for a minimum of 6 months after their first aflibercept injection. This ensured the same team using the same optical coherence tomography (OCT)-guided retreatment strategy managed the patients and that the time between each treatment was not influenced by the use of other therapeutic techniques or other physician opinions. Choroidal neovascularization from wet AMD was diagnosed using both fluorescein angiography (FA) and OCT (CirrusOCT; Zeiss, Jens, Germany). Thirty patients met criteria and were treated with aflibercept in at least 1 eye. If both eyes of a patient matched the inclusion criteria, the right eye was included in the study. Both patients who responded well to previous anti-VEGF therapy and those who were refractory were included in this study. A subgroup analysis identified patients qualitatively and quantitatively by a retina specialist as having central macular edema or submacular fluid on initial OCT defined as intraretinal fluid, or accumulation of fluid under the macula. Two patients with noncentral edema were excluded from this analysis. Data were collected from December 2012 to February 2013. Once aflibercept treatment began, patients did not receive any concurrent AMD treatment such as photodynamic therapy or other anti-VEGF injections. Retina physicians performed all aflibercept injections using a standard, sterile technique. The option to switch was discussed with all active wet AMD patients. Risks, benefits, alternatives, and coverage were discussed with each patient. The general guideline was that since aflibercept’s dosing regimen7 was preferred, all patients with active disease and the desire to change would be transitioned. Since patients were not treatment naı¨ve, physicians used a modified treat and extend11,12 model to determine if and when treatment with aflibercept was needed, unless patients desired not to switch the treatment or there was a contraindication. Specifically, if patients exhibited subretinal fluid on OCT at the time of the switch, they then began aflibercept
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monthly for the first 3 months and then, the treat and extend model was instituted. If OCT exhibited no subretinal fluid at the time of the switch, then the treat and extend model was instituted at the time of the first aflibercept injection.7 At each visit, patients underwent Snellen visual acuity measurements with attempts to obtain Snellen BCVA as well as slit-lamp and biomicroscopic fundus examinations. Snellen BCVA and central macular thickness (CMT) (mm) data were collected at multiple time points: initial visit, defined as the day of the first aflibercept injection, and then, at all subsequent visits between the retina specialist and the patient regardless of whether an injection was administered. Demographic information, the length of time between each visit, the number and timing of each intravitreal injection, and adverse events were also collected. Pretreatment and subsequent FA results were collected but were limited, precluding adequate analysis. FA was not routinely done before the switch. For the purpose of statistical analysis, Snellen visual acuity data was converted to BCVA logarithm of the minimal angle of resolution (logMAR). The primary outcomes collected for this study included (1) visual acuity change from initial (day of aflibercept initiation) to 1-, 3-, 6-, 9-, and 12-month follow ups: improvement in visual acuity (decrease ‡ 0.3 logMAR), decline in visual acuity (increase ‡ 0.3 logMAR) or stability of visual acuity (any change £ 0.3 logMAR), (2) change in CMT (mm) from initial to 1-, 3-, 6-, 9-, and 12-month follow ups, and (3) the number and timing of aflibercept injections. While patients without initial BCVA or CMT measurements or at least 6 months follow up were excluded from all analyses of mean change, other missing data were imputed by the last-observation-carried-forward (LOCF) method. The LOCF was never used as a final observation (the 6-, 9-, or 12-month follow ups) and was never carried forward for more than 1 time point. Visual acuities and CMT were statistically compared between the aflibercept initiation visit and follow ups using P values from paired Student’s t-tests. Statistical significance was defined as P < 0.05. Unless otherwise noted, all data are presented as mean – SEM. Statistical analyses were performed using Microsoft Excel (Microsoft Corporation, Redmond, WA), and paired Student’s t-tests were calculated using GraphPad QuickCalcs Website www.graphpad.com/ quickcalcs/ttest1.cfm (accessed April 2013).
Results Billing records indicated 64 patients had received aflibercept at the Yale Eye Center during the study period. Thirty of these patients received at least 2 previous bevacizumab and/or ranibizumab injections, had at least 6 months of follow up, and fit the inclusion criteria mentioned earlier. A single patient chart was unable to be located during the data collection period. The LOCF was used for 5 patients without a 1-month follow up (BCVA and CMT), for 1 patient without a 1-month CMT, and for 1 patient without a 9-month follow up (BCVA and CMT).
Demographics and clinical characteristics The study population included 8 men (27%) and 22 women (73%) aged 80.4 – 1.45 years with 9 right eyes, 12 left eyes, and 9 with both eyes. Eighteen patients previously
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Table 1.
Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity) and Central Macular Thickness (mm)
Time point 1-month (n = 30) LOCF = 5 3-month (n = 30) 6-month (n = 30) 9-month (n = 27)LOCF = 1 12-month (n = 22)
Initial BCVA 0.506 – 0.054 0.506 – 0.054 0.506 – 0.054 0.518 – 0.059 0.533 – 0.072
(20/64) (20/64) (20/64) (20/66) (20/68)
Follow-up BCVA 0.504 – 0.055 0.458 – 0.061 0.413 – 0.071 0.465 – 0.065 0.521 – 0.076
(20/64) (20/57) (20/52) (20/58) (20/66)
P-value Initial CMT Follow-up CMT P-value 0.903 0.112 0.036 0.210 0.836
261 – 10.9 261 – 10.9 261 – 10.9 262 – 10.7 264 – 12.5
238 – 12.4 245 – 10.6 245 – 10.4 242 – 9.66 237 – 10.2
0.021 0.102 0.099 0.015 0.012
Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point. BCVA, best-corrected visual acuity; CMT, central macular thickness; LOCF, last-observation-carried-forward.
received only bevacizumab (12.4 – 2.18 injections), 2 received only ranibizumab (19 – 6 injections), and 10 received both anti-VEGF agents (mean 19.3 total injections). Overall, the patients received a total of 14.9 – 2.01 (range 2–53) previous injections in the study eye. Patients received 6.27 – 0.37 (range 4–11) aflibercept injections during the study period.
Visual acuity in all patients While there was a modest trend toward improvement within the first 6 months, by 12 months there was no overall change in BCVA (P = 0.84) (Table 1 and Fig. 1). To evaluate the change in the BCVA, we defined 3 categories relative to the initial visit: improvement in visual acuity (decrease ‡ 0.3 logMAR), decline in visual acuity (increase ‡ 0.3 logMAR), and stable (any change £ 0.3 logMAR). In addition, gross changes in vision were defined as follows: any improvement (any decrease in logMAR), any decline (any increase in logMAR), and stayed the same (no change in logMAR). The vast majority (73%–96% of
FIG. 1. Mean change during study period in best-corrected visual acuity (BCVA) logMAR. Values compare mean logMAR BCVA from the follow-up time point to the initial mean BCVA logMAR in each patient subset, where a positive change in logMAR BCVA correlates to a decline (worsening) in vision.
patients) fit into the stable category at all follow ups, similar to clinical studies involving aflibercept (Table 2).7 It should be noted that LOCF was not applied to this analysis, because change is assessed.
CMT in all patients There was a significant initial decrease in CMT after the first month of aflibercept treatment that remained significant at the 12-month follow up for all patients, with initial CMT 264 – 12.5 mm compared with 237 – 10.2 at 12 months (P = 0.012) (Table 1 and Fig. 2).
Visual acuity and CMT in those with initial macular edema In a subgroup analysis, there were 15 patients (50%) who at the time of aflibercept initiation had central macular edema or submacular fluid; essentially, these were patients who had suboptimal response to previous treatment
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Table 2. Change in Vision Relative to Initial Visit, with Number of Patients (%) Experiencing the Column Category of Visual Change at Each Subsequent Time Point (Rows) Time point 1-month (n = 25) 3-month (n = 30) 6-month (n = 30) 9-month (n = 26) 12-month (n = 22)
Improvement in visual acuity 0 3 4 3 2
(10%) (13%) (11%) (9%)
Any improvement 8 14 19 13 10
(32%) (47%) (63%) (50%) (45%)
Decline in visual acuity 1 1 1 2 4
(4%) (3%) (3%) (8%) (18%)
Any decline 5 4 5 7 8
(20%) (13%) (17%) (27%) (36%)
Stable 24 26 25 21 16
(96%) (87%) (83%) (81%) (73%)
Same 12 12 6 6 4
(48%) (40%) (20%) (23%) (18%)
Improvement is a decrease ‡ 0.3 logMAR, any improvement is any decrease in logMAR, decline is an increase ‡ 0.3 logMAR, any decline is any increase in logMAR, stable is any change £ 0.3 logMAR and same is no change in logMAR.
regimens. These patients received 19.1 – 0.06 (range 3–53) previous anti-VEGF injections in the study eye. The subgroup analysis results for BCVA were similar to the allpatients results and did not show a significant improvement after aflibercept initiation (Table 3 and Figure 1). The subgroup analysis results for CMT demonstrated a similar decrease in CMT over most of the 12-month period (Table 3 and Fig. 2).
(341 – 6.30). Six months from the first aflibercept injection, all 30 patients returned to the clinic with an average of 4.50 – 0.11 injections; 9 months from the first injection, 26 patients returned to the clinic with an average of 6.00 – 0.23 injections and 12 months from the first injection, 22 patients returned to the clinic with an average of 7.17 – 0.38 injections. It should be noted that LOCF was not applied to this analysis, because the time between visits and the number of injections within a designated time frame were assessed.
Clinic visit and treatment frequency Data used for the follow-up time points (1, 3-months, etc.) were obtained from visits as close to these time points as possible. We had clinic visit dates for all 30 patients for their initial visit. Follow-up data were collected for 25 patients at 1 month (45.2 – 2.28 days), 30 patients for 3 months (99.1 – 3.02) and 6 months (175 – 4.87), 26 patients for 9 months (265 – 4.98), and 22 patients for 12 months
Intraocular pressure There were 2 instances in which injections were held due to intraocular pressures (IOP) > 25 mmHg. Patients were given IOP-lowering agents and had glaucoma evaluations. In this study, both patients were noted to have elevated IOP at their last follow up study. The injections were held at this visit, but the BCVA and CMT data were still collected.
FIG. 2. Mean change during study period in central macular thickness (CMT) (mm). Values compare mean follow-up time point CMT to mean initial CMT in each indicated patient subset.
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Table 3. Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity) and Central Macular Thickness (mm) in Those with Central Macular Edema or Submacular Fluid at the Time of Aflibercept Initiation Time point 1-month (n = 15) 3-month (n = 15) 6-month (n = 15) 9-month (n = 13) 12-month (n = 11)
Initial BCVA 0.464 – 0.061 0.464 – 0.061 0.464 – 0.061 0.458 – 0.070 0.443 – 0.082
(20/58) (20/58) (20/58) (20/57) (20/55)
Follow-up BCVA 0.469 – 0.059 0.423 – 0.067 0.374 – 0.058 0.472 – 0.092 0.508 – 0.100
(20/59) (20/53) (20/47) (20/59) (20/64)
P-value
Initial CMT
Follow-up CMT
P-value
0.866 0.261 0.014 0.800 0.360
274 – 15.9 274 – 15.9 274 – 15.9 268 – 17.9 275 – 20.7
242 – 17.7 255 – 15.8 241 – 10.2 239 – 12.5 240 – 13.4
0.030 0.207 0.030 0.041 0.078
Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point.
Holding the medication at the 12-month follow up (last study visit) did not affect macular edema or visual outcomes during the study period. After adequate pressure control by a glaucoma specialist, anti-VEGF treatment resumed.
Adverse events No significant sight-threatening complications developed in the study patients during the specified period. There were no other drug- or injection-related adverse events except for mild subconjunctival hemorrhage.
Discussion Aflibercept was approved in 2011 for the treatment of wet AMD based on clinical trial data in the treatment of naı¨ve patients.7 PubMed and Medline searches performed on August 14, 2013 with the search criteria ‘‘aflibercept’’ and ‘‘macular degeneration’’ revealed a handful of papers evaluatingafliberceptinpreviouslytreatedpatients.13–18 Kumar et al. assessed patients with persistent subfoveal fluid resistant to ranibizumab with 6-months’ follow up and found significant improvements in visual acuities and pigment epithelial height and diameter.13 The most comprehensive recent studies by Cho et al.,15 Bakall et al.,16 and Yonekawa et al.17 also only have 6-months’ follow up. All of them reported anatomical improvement in subretinal thickness but no significant change in BCVA by 6 months. This article extends the conclusions to 12 months. Further, only the paper by Yonekawa et al.17 analyzed all patients and not just those who were refractory (defined as persistent exudation despite monthly injections) to treatment. Including the search terms ‘‘switch,’’ ‘‘resistant,’’ and ‘‘previous treatment’’ yielded no further relevant papers. There is not enough generalizable and long-term information in the literature on whether aflibercept is effective in previously treated uncomplicated wet AMD patients.
Visual acuity and CMT This study followed patients with and without initial macular edema for approximately 12 months. Overall, after 12 months of follow up, there was no statistically significant improvement in BCVA and the subgroup analysis of those with initial central macular edema or submacular fluid showed a worsening from baseline. In the literature, there have only been reports with approximately 6 months of aflibercept follow up in previously treated patients.13–18 Similar to those reports, in this study, BCVA showed a trend toward improvement by 6 months of follow up. However, by 12 months, the BCVA was close to or worse than initial values.
Notably, initial BCVA for 9 of the 30 patients (30%) was 20/40 or better. While the VIEW and CLEAR-IT2 trials showed noninferiority in BCVA at all time points, it excluded patients with initial vision better than 20/40.7,9 The present study included patients with any visual acuity. Thus, our patients have a smaller margin for improvement. The CMT in all patients as well as in the subgroup with initial central macular edema or submacular fluid showed a decline throughout the study period, as it also did in the 6-month studies.13–18 The subgroup showed the largest numerical improvement ( - 35 mm) at 12 months, but the small sample size (n = 11) made it difficult to reach statistical significance. Given that aflibercept was introduced later in the treatment course for patients in all of the studies mentioned earlier (particularly in this study after they had received a range of 2 to 53 anti-VEGF injections), some irreversible visual loss and retinal damage may have occurred. These data are representative of the previously treated patients who were switched to aflibercept.
Persistent IOP rise after aflibercept There are reports in the literature on persistent ocular hypertension (OHT) after bevacizumab and ranibizumab19,20 but not with aflibercept treatment in wet AMD. A Pubmed and Medline search on August 14, 2013 with the search terms ‘‘aflibercept’’ and either ‘‘ocular hypertension’’ or ‘‘intraocular pressure’’ revealed studies that report a rise in IOP immediately after aflibercept injection in patients with AMD or diabetic macular edema but not as a specific long-term consequence.7,21,22 In this retrospective study, 2 patients had persistent IOP rises after aflibercept use. The first patient received 14 bevacizumab and 5 ranibizumab and had no history of OHT. Previous pressures were stable in the mid teens and 11 months after switching to aflibercept (9 injections), the IOP increased to 35. The second patient received 13 previous ranibizumab injections and was stable on 1 IOP-lowering agent. Despite being on the same IOP-lowering medication with pressures stable in the mid teens, 11 months after switching to aflibercept (5 injections) the IOP increased to 38. Retina and glaucoma specialists examined both patients and prescribed an IOPlowering regimen.
Clinic visit and treatment frequency Rather than following with monthly injection for 3 times followed by bimonthly treatment regimen for aflibercept,7 since the patients were not treatment naı¨ve, a modified
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‘‘treat and extend’’ model was used.11,12 In this study, patients required fewer clinic visits and received fewer injections over time. These findings suggest that the treat and extend model may be effective with aflibercept treatment. During the study, some macular edema and submacular fluid completely resolved and in these patients, the treatment interval was gradually extended to every 3–4 months. Since most physicians use a treat and extend model when treating wet AMD, this current study is relevant to a large number of practitioners.
8.
Other considerations
9.
This study has several limitations. Primarily, it is retrospective and nonrandomized. It included a small sample size of patients with a relatively short follow-up time of 12 months. However, this study still adds to the growing body of literature on aflibercept’s effectiveness in wet AMD, especially after previous treatments. A larger and longer prospective randomized study is needed to better understand the utility of aflibercept in previously treated AMD patients.
10. 11.
Acknowledgments This research was supported in part by the Richard K. Gershon M.D. Student Research Fellowship (New Haven, CT), Leir Foundation (New York City, NY), Newman’s Own Foundation (Westport, CT), and Research to Prevent Blindness (New York, NY). The sponsors or funding organizations had no role in the design or conduct of this research. The authors would like to thank Victoria Donaldson for technical support.
12.
13.
Author Disclosure Statement The authors have no proprietary interests to disclose.
14.
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Received: September 5, 2013 Accepted: December 10, 2013 Address correspondence to: Dr. Ron A. Adelman Department of Ophthalmology and Visual Science Yale School of Medicine Yale Eye Center 40 Temple Street Suite 3D New Haven, CT 06510 E-mail: [email protected]
