Purpose
To evaluate 6-month and 1-year outcomes of every-8-weeks (Q8W) aflibercept in patients with resistant neovascular age-related macular degeneration (AMD).
Design
Retrospective, interventional, consecutive case series.
Methods
Retrospective review of patients with resistance (multiple recurrences or persistent exudation) to every-4-weeks (Q4W) ranibizumab or bevacizumab that were switched to Q8W aflibercept.
Results
Sixty-three eyes of 58 patients had a median of 13 (interquartile range [IQR], 7–22) previous anti–vascular endothelial growth factor (anti-VEGF) injections. At 6 months after changing to aflibercept, 60.3% of eyes were completely dry, which was maintained up to 1 year. The median maximum retinal thickness improved from 355 μm to 269 μm at 6 months ( P < .0001) and 248 μm at 1 year ( P < .0001). There was no significant improvement in ETDRS visual acuity at 6 months ( P = .2559) and 1 year follow-up ( P = .1081) compared with baseline. The mean difference in ETDRS visual acuity compared to baseline at 6 months was −0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (-2 letters).
Conclusion
Sixty percent of eyes with resistant AMD while on Q4W ranibizumab or bevacizumab were completely dry after changing to Q8W aflibercept at the 6-month and 1-year follow-ups, but visual acuity did not significantly improve. Only a third of eyes needed to be switched from Q8W to Q4W aflibercept owing to persistence of fluid; Q8W dosing of aflibercept without the initial 3 monthly loading doses may be a good alternative in a select group of patients who may have developed ranibizumab or bevacizumab resistance.
Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in industrialized countries. The most severe vision loss occurs in the neovascular (or wet) form of AMD, involving choroidal neovascularization (CNV) and associated retinal edema. The discovery that vascular endothelial growth factor (VEGF) is the driving force behind the CNV and associated edema seen in AMD led to a paradigm shift in the treatment of AMD with anti-VEGF therapy. Monthly intravitreal injections of 0.5 mg ranibizumab, a humanized monoclonal antibody fragment that blocks VEGF, not only prevent vision loss but also lead to significant visual gain in approximately one third of patients. The risk of rare but serious adverse events resulting from the intravitreal procedure, together with the significant burden of making monthly visits to a retinal specialist, have led to extensive efforts to decrease injection and monitoring frequency. However, fixed quarterly or “as-needed” (pro re nata [PRN]) dosing regimens, without requiring monthly monitoring visits, were not effective at maintaining vision.
Aflibercept (or VEGF Trap-Eye; Regeneron, Tarrytown, New York, USA) is a soluble decoy receptor fusion protein, consisting of portions of VEGF receptors, VEGFR-1 and VEGFR-2, which binds to all isoforms of VEGF-A, as well as placental growth factor, and blocks its activity. One-year follow-up results of 2 large phase 3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) comparing monthly and every-2-months (after 3 initial monthly injections) dosing of intravitreal aflibercept injection with monthly ranibizumab showed that all aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary endpoint of maintenance of vision at 52 weeks compared to baseline (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in best-corrected visual acuity; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.
The binding affinity of intravitreal aflibercept to VEGF is greater than that of bevacizumab or ranibizumab. The greater affinity could translate into a higher efficacy or, as predicted by a mathematical model, into a substantially longer duration of action in the eye, allowing for less frequent dosing, as supported by early clinical trials. Because of the higher potency of aflibercept compared to other anti-VEGF agents, we wanted to test whether this higher potency would translate to better efficacy, seen clinically as improvements in visual and structural outcomes in patients who developed resistance to other anti-VEGF agents (ie, ranibizumab or bevacizumab).
In this current study, we retrospectively evaluated the 6-month and 1-year visual and anatomic outcomes of every-8-weeks intravitreal aflibercept injections in patients with ranibizumab- or bevacizumab-resistant neovascular age-related macular degeneration.
Materials and Methods
Study Design
This was a retrospective review of patients with neovascular AMD who developed resistance to either intravitreal ranibizumab or bevacizumab monotherapy given every 4 weeks, and were subsequently switched to and treated with aflibercept given every 8 weeks (from August 2012 to May 2014) at the Jacobs Retina Center, University of California San Diego (UCSD) Shiley Eye Center. Written informed consent was obtained for each patient prior to the intravitreal injections. UCSD Institutional Review Board approval was acquired for the review and analysis of patient data. All procedures 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.
Study Population
All consecutive eyes that developed resistance to multiple intravitreal ranibizumab or bevacizumab injections every 4 weeks were switched to intravitreal aflibercept injections every 8 weeks. The standard protocol that we employ for the treatment of neovascular AMD is a fixed regimen of strict monthly bevacizumab or ranibizumab intravitreal injections until the eye becomes completely dry, after which we give 1–2 bonus injections before going to an observation or holiday phase. The minimum number of injections we gave per treatment cycle was 3 injections, even if the eyes become dry after a single injection. When there is evidence of a recurrence (anatomic increase in fluid accompanied by visual symptoms and/or loss of visual acuity), we resume the treatment cycle of strict monthly bevacizumab or ranibizumab injections until the eye becomes dry again. When aflibercept became available for use at our institution (August 2012), we started switching patients that were resistant to other anti-VEGF injections. Since these patients were not newly diagnosed cases of neovascular AMD, and because these were not treatment-naïve eyes and have received a median of 13 previous ranibizumab or bevacizumab injections prior to switching to aflibercept, we decided to commence treatment with aflibercept every 8 weeks without the 3 initial monthly injections.
Resistance was defined as having multiple recurrences (minimum of 2 recurrences after the eyes have been completely dry following a series of at least 3 monthly injections per treatment cycle) or persistence of exudation (poor response to monthly ranibizumab or bevacizumab for at least 5 months) as evident on clinical examination and on imaging studies (leakage on fluorescein angiogram [FA], or fibrovascular pigment epithelial detachment [PED] with intraretinal fluid [IRF] or subretinal fluid [SRF] on spectral-domain optical coherence tomography [SD OCT]) while on monthly ranibizumab or bevacizumab monotherapy. Poor compliance was not considered resistance. Recurrence was diagnosed as new or increased IRF or SRF with or without vision changes or symptoms. Eyes were excluded if: (1) they had received aflibercept elsewhere prior to the first aflibercept injection at our institution; and (2) they had other retinal conditions other than typical AMD (macular hole, vitreomacular traction, epiretinal membrane, retinal detachment, polypoidal choroidal vasculopathy, pseudovitelliform macular dystrophy, peripapillary CNV). The collected baseline demographic data included patient age; sex; laterality of the treated eye; phakic status; history of previous vitrectomy; number of previous ranibizumab or bevacizumab injections; duration between the last ranibizumab or bevacizumab injection and the first aflibercept injection; number of recurrences or duration of persistent exudation; percentage disruption of the external limiting membrane (ELM) and photoreceptor inner segment/outer segment (IS/OS) layers; type of fluid; ETDRS visual acuity; and maximum retinal thickness.
Ophthalmologic Examination and Imaging Studies
All patients underwent a thorough ophthalmologic examination at baseline and at every-2-month follow-up visit, including visual acuity (VA) testing using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, mydriatic slit-lamp biomicroscopy, and binocular indirect ophthalmoscopy examinations performed by a retina specialist using either a 78- or a 90-diopter indirect slit-lamp lens and a 20-diopter binocular indirect ophthalmoscopy lens, respectively. ETDRS visual acuities were converted to logarithm of the minimal angle of resolution (logMAR) notation, with 0 being the highest score corresponding to 20/20 visual acuity and a value of 1 corresponding to 20/200 visual acuity.
Imaging studies (FA and SD OCT) using an SD OCT device coupled with a simultaneous scanning laser ophthalmoscope (Spectralis HRA+OCT; Heidelberg Engineering, Carlsbad, California, USA) were performed on all patients at baseline (prior to the first aflibercept) and after each aflibercept injection. The OCT images were reviewed using original software from Spectralis. Multiple SD OCT scans (horizontal and vertical) going through the fovea were obtained, as well as through other areas where the CNV activity was most pronounced. Two experienced observers (C.A. and F.M.) masked to visual acuities measured several variables. First, the maximum retinal thickness was measured using the calipers feature on the SD OCT device in the area where CNV activity was most marked, within an area 2000 μm from the fovea, usually where the fibrovascular PED with the greatest amount of overlying IRF or SRF was located. Retinal thickness was measured manually by placing the digital calipers from the outer border of the retinal pigment epithelium to the internal limiting membrane. Second, the presence of IRF and SRF was noted and compared with the baseline using the progression scans to enable point-to-point correspondence between consecutive follow-up scans. Fluid extent was studied in a minimum of 2 views (horizontal and vertical scans) passing through the fovea. The treatment response was assessed at each of the follow-up visits and graded as being “dry” or not. Eyes were considered “dry” when there was complete resolution of fluid or exudation. Third, the percentage disruption of the ELM and photoreceptor IS/OS junction were evaluated 500 μm in either direction of the fovea at baseline. A disruption in IS/OS or ELM was defined as the loss of the back-reflection line. Analysis of the retinal structures was done as per our previous publications. The percentage disruption was averaged to generate a number between 0% (no disruption) and 100% (total loss of the layer in both horizontal and vertical scans).
Treatment Protocol
Intravitreal injection of aflibercept was carried out under aseptic conditions in the clinic. Preservative-free lidocaine gel was instilled in the eye for at least 3 doses 5 minutes or longer prior to injection. A lid speculum was placed to keep the lids open and 5% povidone-iodine solution was instilled on the conjunctival sac prior to injection. The intravitreal injection was performed using a 30 gauge needle in the superotemporal or superonasal quadrant, 3.5–4.0 mm posterior to the limbus, depending on phakic status. Patients received a dose of 2 mg/0.05 mL intravitreal aflibercept injections. In vitrectomized eyes, we gave a dose of 4 mg/0.1 mL aflibercept. The eyes were thoroughly washed with sterile balanced salt solution after the injection. No topical antibiotic drops were prescribed after the procedure.
Patients were switched from monthly ranibizumab or bevacizumab injections to every-8-weeks aflibercept, without the 3 initial monthly injections. When there was persistent fluid despite strict every-8-weeks injections (after a median of 4), we shifted the regimen to every-4-weeks aflibercept.
Treatment Outcomes
The primary treatment outcomes of this study included change in VA and maximum retinal thickness at 6 months and 1 year compared with baseline. Secondary outcomes included proportion of eyes that were dry at 6 months and 1 year; proportion of eyes that had stable VA, gain of ≥1 line, and loss of ≥1 line of ETDRS VA at 6 months and 1 year; and survival analysis of the time to recurrence after being dry, and time to switching to every-4-weeks aflibercept.
Statistical Analysis
Descriptive statistical analyses using Fisher exact test or χ 2 test was used for categorical variables. For continuous variables, the Kruskal-Wallis test was performed when comparing VA improvement (stable, gain, or loss). Wilcoxon rank sum test was performed when comparing eyes that were dry or not dry at the follow-up time points. Wilcoxon signed test was used to compare the paired difference between baseline and follow-ups. For the survival analysis, Kaplan-Meier curves were generated. The Cox proportional hazard model (using the Breslow method for handling ties) was used, with data for both eyes of the subject included in the model. The method of Lee, Wei, and Amato was used to adjust for the correlation of the 2 eyes from the same subject. Robust sandwich variance estimators were desired. For all hypothesis tests, statistical significance was set at a level of P < .05. Statistical analyses were performed using SAS software version 9.3 (SAS Institute, Cary, North Carolina, USA) and R version 3.0.0 ( http://www.r-project.org/ ).
Results
Sixty-three eyes of 58 patients with neovascular AMD resistant to ranibizumab and/or bevacizumab were switched to every-8-weeks aflibercept during the study period and were included in the review and analysis of data after they had met the inclusion/exclusion criteria. Patient characteristics at the time of aflibercept conversion are summarized in Table 1 . The median age at the time of switching to aflibercept was 81 years (interquartile range [IQR], 76–87). Most of the eyes were pseudophakic (69.8%) and had no history of prior vitrectomy (90.5%). Eyes received a median of 13 (IQR, 7–22) previous bevacizumab and/or ranibizumab injections before being considered resistant and before switching to aflibercept. There were 45 eyes that had multiple recurrences, with a median of 2 recurrences (IQR, 2–3). Thirty-two eyes had poor response with persistent fluid despite strict every-four-weeks ranibizumab or bevacizumab injections, with a median duration of 5 months (IQR, 5–7). The median duration between the last bevacizumab or ranibizumab injection and the first aflibercept injection was 6 weeks (IQR, 4–18). Eyes at baseline had approximately equal distribution of fluid type, with 28 eyes (44.4%) having IRF and 30 eyes (47.6%) with SRF.
| Patients (eyes) | 58 (63) |
| Median age, y (IQR) | 81 (76–87) |
| Female, n (%) | 34 (58.6) |
| Right eye, n (%) | 31 (49.2) |
| Phakic status | |
| Phakic, n (%) | 19 (30.2) |
| Pseudophakic, n (%) | 44 (69.8) |
| History of vitrectomy | |
| Nonvitrectomized, n (%) | 57 (90.5) |
| Vitrectomized, n (%) | 6 (9.5) |
| Multiple recurrences | |
| Eyes, n (%) | 45 (71.4) |
| Number of recurrences, median (IQR) | 2 (2–3) |
| Persistent fluid (in months) | |
| Eyes, n (%) | 32 (50.8) |
| Duration, median (IQR) | 5 (5–7) |
| Previous injections, a median (IQR) | 13 (7–22) |
| Bevacizumab | 13 (7–21) |
| Ranibizumab | 5 (3–8) |
| Duration between last bevacizumab or ranibizumab injection and first aflibercept (in weeks), median (IQR) | 6 (4–18) |
| ELM disruption (%), mean (median; IQR) | 51.7 (50; 0–100) |
| IS/OS disruption (%), mean (median; IQR) | 71.2 (75; 20–90) |
| Type of fluid, n (%) | |
| IRF | 28 (44.4) |
| SRF | 30 (47.6) |
| Both (IRF and SRF) | 5 (7.9) |
The 6-month follow-up visit took place at a median of 24.57 weeks (IQR, 23.71–25.57). Thirty-eight eyes (60.3%) were completely dry at the 6-month follow-up visit, which was maintained up to the 1-year follow-up visit (median of 68.86 weeks, IQR 33.00–80.71). The majority (97.4%) of eyes (37 of 38 eyes) that were dry at the last follow-up had no previous history of vitrectomy ( P = .0323). Neither the number of previous recurrences nor the duration of resistance prior to switching to aflibercept predicted whether or not the eyes were dry at the 6-month and 1-year follow-up visits. Illustrative cases are shown in Figures 1 and 2 .
The median maximum retinal thickness improved from 355 μm to 269 μm at 6 months ( P < .0001) and 248 μm at 1 year ( P < .0001). Despite the good anatomic response, there was no significant improvement in ETDRS visual acuity at 6 months ( P = .2559) and up to the 1-year follow-up ( P = .1081). The mean difference in ETDRS visual acuity compared to baseline at 6 months was −0.05 logMAR (+2.5 letters) and 0.04 logMAR at 1 year (-2 letters). The anatomic and functional outcomes at 6 months and 1 year are summarized in Table 2 .
| Median (IQR) | P Value a | |
|---|---|---|
| Maximum retinal thickness (in μm) | ||
| Baseline | 355 (325–427) | |
| 6 months | 269 (227–325) | <.0001 |
| 1 year | 248 (201–279) | <.0001 |
| ETDRS visual acuity (in logMAR) | ||
| Baseline | 0.40 (0.30–0.70) | |
| 6 months | 0.40 (0.20–0.70) | .2559 |
| 1 year | 0.40 (0.20–0.90) | .1081 |
At 6 months, 24 of 63 eyes (38.1%) had stable VA, 36.5% gained at least 1 line of ETDRS VA, and 23.8% lost at least 1 line. Table 3 summarizes the descriptive characteristics of eyes according to the distribution of visual acuity at 6 months. One hundred percent of gainers at the 6-month follow-up visit were nonvitrectomized eyes. All of the vitrectomized eyes (n = 5) at 6 months had stable VA. Excluding vitrectomized eyes, analysis at 6 months showed a trend toward visual improvement, but it was not significant. Among eyes that gained VA, 52.2% had SRF (12 of 23 eyes) and 39.1% had IRF (9 of 23 eyes). In contrast to this, among eyes that lost at least 1 line, 53.3% had IRF (8 of 15 eyes) and 33.3% had SRF (5 of 15 eyes). Gainers had less ELM disruption (median of 35%, IQR 10–90), compared with eyes that had stable VA (median of 50%, IQR 15–95) and eyes that lost VA (median of 60%, IQR 25–80) ( P = .7960). There was no statistically significant trend in the degree of photoreceptor inner segment/outer segment disruption and visual acuity at the 6-month follow-up.
| Stable VA (n = 24) | Gain ≥1 Line (n = 23) | Loss ≤1 Line (n = 15) | P Value | |
|---|---|---|---|---|
| Age (y), median (IQR) | 79.5 (77–86.5) | 81 (73–85) | 83 (76–89) | .3999 |
| Female sex, n (%) | 5 (20.8) | 12 (52.2) | 6 (40.0) | .0822 |
| Phakic status, n (%) | .5357 | |||
| Phakic | 9 (37.5) | 7 (30.4) | 3 (20.0) | |
| Pseudophakic | 15 (62.5) | 16 (69.6) | 12 (80.0) | |
| History of vitrectomy, n (%) | .0221 | |||
| Vitrectomized | 19 (79.2) | 23 (100.0) | 15 (100.0) | |
| Nonvitrectomized | 5 (20.8) | 0 (0.0) | 0 (0.0) | |
| Number of recurrences, median (IQR) | 2 (2–2.5) | 2 (2–3) | 2 (2–3) | .8392 |
| Duration of persistent fluid (in months), median (IQR) | 5 (5–9) | 5 (5–9) | 5 (5–6) | .8739 |
| Previous injections, a median (IQR) | 12 (7–21) | 13 (10–26) | 12 (8–22) | .7552 |
| Type of fluid, n (%) | .6493 | |||
| IRF | 10 (41.7) | 9 (39.1) | 8 (53.3) | |
| SRF | 13 (54.2) | 12 (52.2) | 5 (33.3) | |
| Both (IRF and SRF) | 1 (4.2) | 2 (8.7) | 2 (13.3) | |
| ELM disruption (%), mean (median; IQR) | 50 (15–95) | 35 (10–90) | 60 (25–80) | .7960 |
| IS/OS disruption (%), mean (median; IQR) | 77.5 (52.5–100) | 75 (70–90) | 70 (50–100) | .9222 |
At the 1-year follow-up, 17 eyes (27.0%) had stable VA, and 25.4% (16 eyes) gained and 44.4% (28 eyes) lost at least 1 line of ETDRS VA. Descriptive characteristics of eyes according to the distribution of visual acuity at 1 year are summarized in Table 4 . Gainers were younger (median age 75 years, IQR 72.5–82) compared with the patients that had stable VA (median age 82 years, IQR 77–87) or lost at least 1 line (median age 83 years, IQR 78–89) ( P = .0113). Similar to the 6-month follow-up, 100% of gainers at the 1-year follow-up visit were nonvitrectomized eyes, and 80.0% of vitrectomized eyes (n = 4) still had stable VA at 1 year. Among eyes that gained VA, 81.3% had SRF (13 of 16 eyes) and 12.5% had IRF (2 of 16 eyes), and among eyes that lost at least 1 line, 53.6% had IRF (15 of 28 eyes) and 35.7% had SRF (10 of 28 eyes). Gainers had significantly less ELM disruption (median of 20%, IQR 10–55), compared with eyes that had stable VA (median of 60%, IQR 20–100) and eyes that lost VA (median of 67.5%, IQR 27.5–95) ( P = .0393). A similar nonsignificant trend in the degree of photoreceptor inner segment/outer segment disruption was noted, with gainers having less IS/OS disruption ( P = .2018).
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