Purpose
To determine the 24-month results of patients who had pro re nata (PRN) aflibercept treatment owing to recurrent or resistant neovascular macular degeneration.
Design
Retrospective, interventional, consecutive case series.
Methods
Eighty-one eyes of 78 patients with resistant or multiple recurrences of intraretinal or subretinal fluid while receiving monthly bevacizumab or ranibizumab injections and were switched to strict, as-needed aflibercept treatment with every-8-weeks spectral-domain optical coherence tomography (SDOCT)-guided monitoring were included. If there was a persistence of fluid despite this treatment, more frequent aflibercept injections were considered. Anatomic outcomes including maximum retinal thickness, central macular thickness, maximum pigment epithelial detachment height, maximum fluid height, and visual acuity (VA) were assessed at given follow-ups.
Results
All anatomic endpoints significantly improved following 3 consecutive aflibercept injections, which were maintained through 24 months ( P < .05 for all endpoints at all visits). Thirty-seven eyes (45.6%) required more frequent injections with monthly SDOCT-guided monitoring at a median of 37 weeks (interquartile range, 30–62 weeks) to adequately treat the retinal fluid. Seventy-one of 81 eyes (87.7%) became completely dry on at least 1 follow-up visit; however, there was no significant improvement in VA during the study period.
Conclusion
Aflibercept injection with an as-needed regimen was effective in many eyes previously treated with monthly bevacizumab or ranibizumab injections that had persistent or recurrent fluid. Despite significant improvement in anatomic outcomes, vision remained stable throughout the 2-year follow-up, likely because this cohort of patients had advanced choroidal neovascular membrane upon enrollment (recurrent or resistant).
Age-related macular degeneration (AMD) is the major cause of vision loss in people over the age of 65 years living in industrialized countries. It is estimated that 1.2 million people in the United States have wet, or exudative, AMD which is characterized by the presence of choroidal neovascularization (CNV), retinal fluid, hemorrhage, and, eventually scarring.
Although anti–vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of wet AMD and is now the standard of care, some patients may have persistence of intraretinal fluid (IRF) or subretinal fluid (SRF). The Comparison of Age-Related Macular Degeneration Treatments Trial (CATT) demonstrated that the proportion of eyes with persistent fluid was 51.5% following monthly ranibizumab injections and 67.4% in eyes treated with monthly bevacizumab injections, after 2 years.
Aflibercept (Eylea; Regeneron, Tarrytown, New York, USA) is a soluble decoy receptor fusion protein that has a high affinity to all VEGF isoforms, as well as to placental growth factor. Theoretical models suggested that aflibercept has a longer duration of action compared with other available anti-VEGF drugs. In the VIEW 1–2 studies, aflibercept intravitreal injections dosed monthly or every other month after 3 initial monthly doses were found to be noninferior to monthly 0.5 mg ranibizumab injections in terms of efficacy and safety outcomes in treatment-naïve wet AMD patients. It has been suggested that aflibercept may have a longer duration of effect, allowing treatment intervals to be extended beyond what may be achieved by bevacizumab or ranibizumab.
In eyes with persistent fluid or multiple recurrences while on bevacizumab or ranibizumab treatment, one strategy often employed is to switch anti-VEGF agents to see if there may be increased efficacy. We previously reported in the same Journal the 6-month and 1-year outcomes of those eyes treated with aflibercept for resistance or recurrence of fluid and/or exudation despite having monthly bevacizumab or ranibizumab injections. In this larger cohort study, we report the 24-month follow-up outcomes of consecutive eyes with multiple recurrences or persistence of fluid/exudation while on monthly bevacizumab or ranibizumab injections that were switched to as-needed intravitreal aflibercept treatment with every-8-weeks spectral-domain optical coherence tomography (SDOCT)-guided monitoring, as well as the initial results of an escalated regimen of aflibercept given to a subgroup of patients with persistent fluid that failed to fully respond to initially given as-needed aflibercept treatment.
Methods
University of California, San Diego Institutional Review Board approval was acquired for the review and analysis of patient data. The study adhered to the tenets of the Declaration of Helsinki for research involving human subjects and complied with Health Insurance Portability and Accountability Act (HIPAA) regulations. Written informed consent was obtained for each patient prior to the intravitreal injections.
We retrospectively reviewed the charts of patients with wet AMD who were treated at the Jacobs Retina Center, Shiley Eye Institute, UCSD between August 23, 2012 and October 25, 2015 with either intravitreal bevacizumab or ranibizumab injections and were switched to aflibercept treatment. Patients who had multiple recurrences or developed resistance while on monthly bevacizumab or ranibizumab injections with monthly monitoring and were switched to aflibercept treatment were included. Multiple recurrences were defined as the reappearance of intraretinal or subretinal fluid with visual disturbances after having been completely dry at 2 or more visits. Resistance was defined as the persistence of fluid and/or exudation for at least 5 months while on monthly intravitreal bevacizumab or ranibuzumab injections.
We employed an as-needed algorithm for the treatment of persistent cases. Aflibercept injections (2 mg/0.05 cc) were given every 8 weeks until complete resolution of fluid (without any loading doses injections). If patients on this aflibercept treatment achieved retinal dryness, an as-needed schedule was followed where patients were monitored with SDOCT every 8 weeks and re-treated if needed. Retreatment criteria included recurrence of IRF and/or SRF, new-onset macular hemorrhage typically accompanied by visual symptoms, or evidence of any vision loss compared to previous visit. If there was persistent fluid despite this treatment, aflibercept injections were escalated to every 4 weeks. If patients receiving more frequent aflibercept injections achieved retinal dryness, an as-needed schedule was then followed where patients were monitored every 4 weeks with SDOCT and re-treated, if needed, at the follow-up visit.
For the bilaterally treated eyes, monitoring was done based on the worse eye (the eye requiring more frequent injections); and if both eyes required treatment, injections were done simultaneously on the same clinic day.
All patients underwent a comprehensive ophthalmic examination including best-corrected visual acuity (BCVA) measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Chart “R”; Precision Vision, La Salle, Illinois, USA), slit-lamp examination, dilated fundus biomicroscopy examination, and applanation tonometry.
SDOCT and fluorescein angiography (FA) were performed in all patients at baseline and after aflibercept injections using the Heidelberg Spectralis (Spectralis HRA-OCT; Heidelberg Engineering, Carlsbad, California, USA). Horizontal and vertical scans cutting through the fovea were acquired, as well as through other areas where the CNV was most pronounced. One experienced retina specialist observer (I.K.M.) masked to visual acuities reviewed all images. All SDOCT measurements were performed manually using the caliper function.
Central macular thickness (CMT) was measured as the distance between internal limiting membrane (ILM) and Bruch membrane in the central fovea. Maximum retinal thickness (MRT) was defined as the maximum vertical distance between the ILM and Bruch membrane within an area 2000 μm from the fovea, where the CNV activity and/or corresponding fibrovascular pigment epithelial detachment (PED) with the greatest amount of overlying IRF or SRF was most pronounced. The maximum height of the PED was measured as the distance between the outer border of the retinal pigment epithelium (RPE) and the inner border of the Bruch membrane in the area of CNV. For the analysis of fluid, the maximum height of the intraretinal or subretinal fluid was measured. In the presence of both IRF and SRF, the one with the greatest dimension was considered for the analysis. If the fluid was located in more than 1 area, the fluid closest to the fovea was selected for the analysis. A disruption in the ELM and ellipsoidal inner segment (ISe) was defined as loss of the back-reflection line. Percentage of disruption of the ELM and ISe was measured in both horizontal and vertical axis and averaged, as in our previous reports, in which “0%” represents no disruption and “100%” represents total loss of the layer.
Intravitreal injections were performed using the same procedure in all eyes, as described in our previous report. Exclusion criteria included use of photodynamic therapy, presence of peripapillary CNV, absence of data on previous injections, and having anti-VEGF treatment other than aflibercept elsewhere during the study period.
The primary outcomes of this study were the mean of parameters including MRT, CMT, maximum PED height, maximum IRF/SRF height, and ETDRS BCVA over the follow-up. Secondary outcomes included number of eyes that were dry at given time points, time to escalation to more frequent injections, and time to recurrence after being completely dry. Outcomes were obtained after first 3 aflibercept injections, at month 12, month 18, and month 24, the percentages of the eyes that were completely dry were assessed at the 4–6 months window, at the 10–14 months window, at the 16–18 months window, and at the 22–24 months window follow-up. In order to be consistent and practical, terms of 5 months, 11 months, 17 months, and 24 months are used through the full text to define those intervals.
The BCVA was converted to logarithm of the minimal angle of resolution (logMAR) units before analysis. The normality was checked using the Kolmogorov-Smirnov test. Wilcoxon signed test was used to compare the difference between baseline and given follow-ups. The Kruskal-Wallis test was performed when comparing visual acuity (VA) improvement (stable, gain, or loss). Fisher exact test or χ 2 test was used for categorical variables. In addition to analysis of all parameters in the entire study group (combined group), a subgroup analysis was done using Mann-Whitney test or Kruskal-Wallis test for the multiple recurrences group and the resistant group for the continuous variables. For the survival analysis, Kaplan-Meier curves were generated and the Cox proportional hazard model was used. All statistical analysis was done using SPSS 23 software (IBM, Chicago, Illinois, USA).
Results
Eighty-one eyes of 78 patients met the inclusion criteria and were included in this study. Patients were followed for a median of 24.12 months (interquartile range [IQR], 18.4–32.4 months). Demographic characteristics of patients at the time of switching to aflibercept treatment are summarized in Table 1 . After initiating treatment with aflibercept, the MRT significantly decreased at all time points compared to baseline in all groups ( P < .05 at all visits). The mean CMT significantly decreased at all follow-up visits compared to baseline in the combined group ( P < .001 at all visits). The decrease in mean CMT was significant at all visits except month 11 ( P = .098) in the multiple recurrence group, whereas the resistant group showed a significant decrease in mean CMT at all visits except month 5 ( P = .085). The mean maximum retinal fluid height significantly decreased compared to baseline at all follow-up visits in all groups ( P < .001 at all visits). The multiple recurrences group showed a larger decrease in fluid height than the resistant group at month 5 (90.5 ± 19.7 μm vs 60 ± 21, P = .03). The mean MRT, CMT, and maximum fluid height over the follow-up are shown in Figure 1 .
| Number of patients (eyes) | 78 (81) |
| Median age, y (IQR) | 80.0 (66–94) |
| Female/male (n) | 43/33 |
| No. of previous injections other than aflibercept in the entire study population, median (IQR) | 14 (7–22) |
| Interval between previous injections and aflibercept, median (IQR), wk | 6 (4–13) |
| Persistent fluid, eyes (n) | 45 (55.5%) |
| Duration of fluid (mo), median (IQR) | 6 (5–9) |
| No. of previous injections other than aflibercept, median (IQR) | 14.4 ± 10 (10–20.2) |
| Multiple recurrences, eyes, n (%) | 36 (45.5%) |
| No of recurrences, median (IQR) | 3 (3–4) |
| No of previous injections other than aflibercept, median (IQR) | 15.3 (10–22.2) |
| Type of fluid, n (%) | |
| SRF | 37 (45.6%) |
| IRF | 36 (44.4%) |
| Both | 8 (9.8%) |
The greatest decrease in maximum PED height was achieved at 17 months and 24 months in the combined group ( P < .001, Figure 2 ). The maximum PED height significantly decreased at all visits in the multiple recurrences group ( P < .05) and the resistant group showed significant improvement in maximum PED height at all visits ( P = .05) except month 24 ( P = .064).
The percentage of eyes that were completely dry during the follow-up is shown in Figure 3 .
There was no significant improvement in vision at any time point in the combined group and in the subgroups ( P > .05, Figure 4 ). In the combined group, the mean BCVA was 0.55 ± 0.44 logMAR at baseline and 0.56 ± 0.45 logMAR at last follow-up, respectively. The mean difference in ETDRS VA compared to baseline was −0.019 logMAR (+1 letter) at last follow-up. At approximately 1 year (11 months), 30.8% of eyes (25 eyes) gained 1 or more line, 34.6% (28 eyes) had stable VA, and 34.6% of eyes lost at least 1 line compared to baseline. At last follow-up, 32% of eyes (26 eyes) gained 1 or more line, 28.5% (23 eyes) had stable vision, and 39.5% (32 eyes) lost at least 1 line. There was no significant association in visual outcomes and age ( P = .2), percent of ELM disruption ( P = .6), and percent of ISe disruption between those who gained and lost vision. Among the eyes that gained VA, 57.6% (15 eyes) had SRF and 42.3% (11 eyes) had IRF. Neither duration of persistence of fluid nor number of previous recurrences was significant between those eyes that gained and lost vision.
Eyes that were maintained on every-8-weeks aflibercept injections received a median of 7 injections (IQR, 4–9 injections) during the follow-up period. At last follow-up, 37 of 81 eyes (45.6%) (16 eyes out of 36 eyes from the multiple recurrences group and 21 eyes out of 45 eyes from the resistant group) required more frequent aflibercept injections owing to persistence of fluid despite a strict regimen. In those eyes, all anatomic parameters significantly improved following 3 consecutive monthly aflibercept injections; however, vision remained stable ( Table 2 ). The median time to switching to escalated regimen (monthly) was 37 weeks (IQR, 30–62 weeks) in the combined group, 48.72 weeks (IQR, 36.5–67.2 weeks) in the multiple recurrences group, and 36 weeks (IQR, 28.4–59 weeks) in the resistant group, respectively; there was no significant difference in switching time to more frequent aflibercept injections between subgroups (log rank, P = .208, Figure 5 ). Among the variables that were studied in univariate analysis including all anatomic parameters, number of previous injections, and duration of previous recurrences, only the number of total aflibercept injections given every 8 weeks was found to be significant for requiring an escalated regimen (hazard ratio: 0.771, 95% CI: 0.664–0.895, P = .001). The mean number of aflibercept injections given every 8 weeks was not statistically different between the subgroups (6.1 vs 6.0, P = .748).
