Purpose
To investigate changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration (AMD).
Design
Retrospective, consecutive, interventional case series.
Methods
This study included 102 eyes of 102 patients with treatment-naïve neovascular AMD. All 102 eyes underwent 3 consecutive monthly 2.0 mg intravitreal aflibercept injections at baseline, 1 month, and 2 months. Choroidal thickness during 3 months were evaluated using either swept-source optical coherence tomography (OCT) or enhanced-depth imaging OCT.
Results
Of the 102 eyes, 46 eyes (45.1%) were diagnosed as typical neovascular AMD and 56 eyes (54.9%) as polypoidal choroidal vasculopathy. After intravitreal aflibercept injections, the mean subfoveal choroidal thickness decreased from 252.0 ± 99.7 μm at baseline to 217.9 ± 95.6 μm at 3 months ( P < .0001; percentage change from baseline, 86.5%). Mean choroidal thickness measured at 3 mm from the foveal center in the superior, inferior, temporal, and nasal directions also decreased significantly from 258.7 ± 85.9 μm to 236.4 ± 84.6 μm, 229.9 ± 93.0 μm to 208.6 ± 86.5 μm, 237.4 ± 86.5 μm to 214.6 ± 79.5 μm, and 183.7 ± 97.0 μm to 162.3 ± 90.6 μm, respectively ( P < .0001 for all directions). Both subtypes of neovascular AMD demonstrated a similar trend toward decreasing choroidal thickness during the follow-up period.
Conclusions
Choroidal thickness significantly decreased not only at the foveal center but also in the entire macula after 3 monthly intravitreal aflibercept injections for neovascular AMD.
Neovascular age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries. To date, various therapies have been attempted to suppress exudation induced by choroidal neovascularization (CNV) associated with neovascular AMD. Ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) is a humanized anti–vascular endothelial growth factor (VEGF) antibody fragment designed to bind all isoforms of VEGF-A. Intravitreal injections of ranibizumab have been widely used for the treatment of neovascular AMD, resulting in significant visual improvement with low risks of systemic and ocular adverse events. Aflibercept (Eylea; Regeneron, Tarrytown, New York, USA, and Bayer HealthCare, Berlin, Germany) is a relatively new anti-VEGF agent, a soluble decoy receptor fusion protein consisting of the binding domains of VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G-1 (IgG-1), allowing it to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor (PlGF). In the VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) 1 and the VIEW 2 trials, intravitreal aflibercept injections dosed monthly or every 2 months after 3 initial monthly doses demonstrated similar efficacy and safety as monthly intravitreal ranibizumab injections.
Recent advances in optical coherence tomography (OCT) such as enhanced-depth imaging OCT (EDI OCT) with conventional spectral-domain OCT or swept-source OCT (SS OCT) with a 1-μm-wavelength light have enabled visualization of cross-sectional images of the choroid. In neovascular AMD, choroidal thickness measurements by these methods appeared to be important not only for adjunctive diagnostic purposes but also for the evaluation of therapeutic intervention.
Recently, we showed that the mean subfoveal choroidal thickness decreased significantly after intravitreal injections of ranibizumab in eyes with neovascular AMD. We concluded that intravitreal injections of ranibizumab might have a pharmacologic effect not only on the neovascular membrane but also on the underlying choroid. On the other hand, other investigators did not find significant changes in subfoveal choroidal thickness after intravitreal injections of ranibizumab for neovascular AMD. It was also reported that the mean subfoveal choroidal thickness transiently increased 2 days after photodynamic therapy (PDT) with verteporfin or combined PDT and ranibizumab therapy in eyes with polypoidal choroidal vasculopathy (PCV); this was then followed by a significant decrease in subfoveal choroidal thickness through 6 months. Although intravitreal aflibercept injections are widely known to be effective for the resolution of exudative changes caused by CNV, information regarding the direct influence of aflibercept on the underlying choroid remains unknown. In this current study, we investigated the changes in choroidal thickness in eyes with neovascular AMD after aflibercept therapy over a 3-month period.
Patients and Methods
This retrospective, interventional study involved 102 eyes of 102 consecutive patients with treatment-naïve neovascular AMD who were seen at the Macula Services of the Tokyo Women’s Medical University, the Fukushima Medical University, or the Kyorin University School of Medicine between December 1, 2012 and June 30, 2013. The study protocol followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of each university hospital. During the period, 2 patients underwent intravitreal aflibercept injections bilaterally, and the eye treated first was included in this study. One patient with retinal angiomatous proliferation was excluded from the study based on its rarity. Diagnosis of the subtype of neovascular AMD (typical neovascular AMD or PCV) was based on funduscopic and angiographic findings. Typical neovascular AMD was characterized by exudative changes attributable to CNV as revealed by fluorescein angiography (FA) and indocyanine green angiography (ICGA). The diagnosis of PCV was based on ICGA findings demonstrating polypoidal structures at the border of branching choroidal vascular networks. In some cases, orange-red protrusions beneath the retinal pigment epithelium (RPE) observed biomicroscopically corresponded to polypoidal lesions revealed by ICGA. Patients were excluded if eyes had CNV secondary to other macular disorders such as angioid streaks. Patients were also excluded if eyes had any of the following criteria: (1) a spherical equivalent of −6 diopters (D) or less and/or chorioretinal atrophic changes secondary to pathologic myopia; (2) a history of intraocular surgery within 6 months; and (3) a history of pars plana vitrectomy. In addition, patients with a systemic contraindication for intravitreal aflibercept injections were excluded.
At baseline, all 102 patients underwent comprehensive ophthalmic examination including refraction, best-corrected visual acuity (BCVA) testing with Landolt C charts, slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, FA and ICGA using confocal scanning laser ophthalmoscopy (HRA-2; Heidelberg Engineering Inc, Heidelberg, Germany), and OCT. At each monthly visit over a 3-month period, all patients underwent BCVA testing, slit-lamp biomicroscopy, color fundus photography, and OCT. All 102 eyes were administered 3 consecutive monthly intravitreal injections of 2.0 mg aflibercept, at baseline, 1 month, and 2 months. Cross-sectional images of the choroid were obtained at baseline, 1 month, 2 months, and 3 months.
In this study, choroidal thickness was measured with either SS OCT (DRI-OCT; Topcon, Tokyo, Japan) at Tokyo Women’s Medical University or EDI OCT (Heidelberg Spectralis; Heidelberg Engineering Inc) at Fukushima Medical University and Kyorin University. A high intersystem correlation between these 2 OCT systems was previously reported, and the same OCT machine was always used for all measurements for each patient. With SS OCT, 12-mm horizontal and vertical scans through the foveal center were obtained from all study eyes. The method used for acquiring the EDI OCT images was the same as reported previously. Briefly, the choroid was imaged by positioning the spectral-domain OCT instrument close enough to the eye to obtain an inverted image. By means of the EDI mode within the OCT, the inverted images automatically appeared on the monitor to match those seen with conventional imaging. All images were obtained using an eye-tracking system, and 100 scans were averaged. With EDI OCT, 9-mm horizontal and vertical scans through the foveal center were obtained from all study eyes. The choroidal thickness was defined as the distance between the hyperreflective line corresponding to the Bruch membrane beneath the RPE and the inner surface of the sclera, and was measured manually using the OCT’s caliper function. All OCT measurements were performed by investigators who were masked to the patients’ information, including the treatment status. At each institute, each measurement was performed by 2 independent investigators, and the averaged value of the measurements was defined as the definite choroidal thickness. The choroidal thickness was measured at the foveal center, and at 3 mm from the foveal center in the superior, inferior, temporal, and nasal directions. A macula was judged to be “dry” when there was complete resolution of subretinal and intraretinal fluid by OCT findings.
The primary outcome was a difference in choroidal thickness between baseline and 3 months at each location in the eyes treated with intravitreal aflibercept injections. The percentage change in choroidal thickness at each time point compared to baseline was also calculated. When no change in choroidal thickness was observed, the percentage change from baseline was 100%.
Data obtained from all patients were analyzed using frequency and descriptive statistics. Mean values were compared by the paired t test and the unpaired t test. BCVA was converted to logarithm of the minimal angle of resolution (logMAR) units prior to calculations. The data was expressed as mean ± standard deviation (SD), and a P value less than .05 was considered to be significant. All statistical analyses were performed with SPSS software version 18.0 (SPSS Inc, Chicago, Illinois, USA).
Results
One hundred and two eyes of 102 patients—21 women (20.6%) and 81 men (79.4%), with a mean age of 74.6 ± 8.3 years (range 50–92 years)—were included in this study. At baseline, neovascular lesions were categorized by FA as predominantly classic (11 eyes, 10.8%), minimally classic (23 eyes, 22.5%), or occult with no classic (68 eyes, 66.7%). With regard to disease subtype, 46 eyes (45.1%) were diagnosed as having typical neovascular AMD and 56 eyes (54.9%) as having PCV. By FA, the CNV lesion was subfoveal in 64 eyes (62.8%), juxtafoveal in 25 eyes (24.5%), extrafoveal in 9 eyes (8.8%), and peripapillary in 4 eyes (3.9%).
There were no missing data with respect to BCVA and choroidal thickness during the study period. Table 1 summarizes the changes in BCVA and the mean choroidal thickness at each location and the percentage change in choroidal thickness from baseline in all 102 eyes. As compared with those at baseline, the mean BCVAs at 3 months were significantly improved ( P < .0001). At all locations, the choroidal thickness at 3 months significantly decreased from baseline ( P < .0001 for all locations). The mean choroidal thickness at the 5 locations demonstrated a similar trend toward decreasing during the 3-month period ( Figure 1 ). Of the 102 eyes, BCVA improved by 0.3 or more logMAR units in 21 eyes (20.6%), was unchanged in 79 eyes (77.5%), and worsened by 0.3 or more logMAR units in 2 eyes (1.9%). In the 21 eyes with improved BCVA and the remaining 81 eyes without improved BCVA, the mean subfoveal choroidal thickness significantly decreased from 262.0 ± 84.5 μm and 249.4 ± 103.6 μm at baseline to 224.4 ± 94.9 μm and 216.2 ± 96.3 μm at 3 months, respectively ( P < .001 and P < .0001). However, the mean change in subfoveal choroidal thickness was not significantly different between the 2 groups (37.6 ± 36.5 μm vs 33.2 ± 36.3 μm, P = .52).
| Baseline | 1 Month | 2 Months | 3 Months | Difference Between Baseline and 3 Months (95% CI) | P Value a | |
|---|---|---|---|---|---|---|
| BCVA (logMAR) ± SD (median) (range) | 0.40 ± 0.37 (0.30) (−0.18 to 1.30) | 0.34 ± 0.33 (0.30) (−0.08 to 1.30) | 0.30 ± 0.32 (0.22) (−0.08 to 1.40) | 0.28 ± 0.33 (0.22) (−0.08 to 1.52) | 0.12 (0.07–0.16) | <.0001 |
| Choroidal thickness (μm) ± SD (median) (range) (percentage change from baseline) | ||||||
| Foveal center | 252.0 ± 99.7 (244) (56–556) (100%) | 230.1 ± 96.9 (217) (55–570) (91.3%) | 226.3 ± 99.2 (218) (57–584) (89.8%) | 217.9 ± 95.6 (204) (57–498) (86.5%) | 34.2 (27.0–41.3) | <.0001 |
| Superior | 258.7 ± 85.9 (251) (90–526) (100%) | 248.4 ± 84.5 (240) (74–498) (96.0%) | 241.2 ± 81.4 (233) (77–464) (93.2%) | 236.4 ± 84.6 (231) (64–526, 91.4%) | 22.3 (13.7–30.1) | <.0001 |
| Inferior | 229.9 ± 93.0 (219) (46–521) (100%) | 212.4 ± 88.7 (191) (56–604) (92.4%) | 211.7 ± 91.9 (195) (43–589) (92.1%) | 208.6 ± 86.5 (197) (53–491) (90.7%) | 21.3 (13.0–29.6) | <.0001 |
| Temporal | 237.4 ± 86.5 (222) (105–564) (100%) | 218.0 ± 85.2 (199) (71–562) (91.8%) | 215.5 ± 81.7 (200) (60–558) (90.8%) | 214.6 ± 79.5 (205) (60–470) (90.4%) | 22.7 (14.6–30.8) | <.0001 |
| Nasal | 183.7 ± 97.0 (163) (52–514) (100%) | 165.5 ± 95.2 (140) (42–483) (90.1%) | 166.6 ± 99.2 (140) (50–578) (90.7%) | 162.3 ± 90.6 (145) (26–457) (88.4%) | 21.4 (15.1–27.7) | <.0001 |
Table 2 summarizes the changes in subfoveal choroidal thickness during the study period in each subtype of neovascular AMD. With regard to the subtypes, the mean subfoveal choroidal thickness at 3 months in eyes with typical neovascular AMD and PCV significantly decreased compared with that at baseline ( P < .0001 for both). Despite the differences in subfoveal choroidal thickness at baseline, both subtypes demonstrated a similar trend toward decreasing choroidal thickness during the 3-month period ( Figure 2 ).
| Baseline | 1 Month | 2 Months | 3 Months | Difference Between Baseline and 3 Months (95% CI) | P Value a | |
|---|---|---|---|---|---|---|
| Choroidal thickness (μm) ± SD (median) (range) (percentage change from baseline) | ||||||
| t-AMD (n = 46) | 242.6 ± 95.6 (243) (83–508) (100%) | 226.7 ± 95.1 (217) (88–427) (93.4%) | 222.3 ± 89.6 (213) (84–410) (91.6%) | 212.9 ± 91.1 (199) (81–431) (87.8%) | 29.7 (17.6–41.7) | <.0001 |
| PCV (n = 56) | 259.8 ± 103.2 (250) (56–556) (100%) | 232.9 ± 99.1 (220) (55–570) (89.6%) | 229.6 ± 107.1 (229) (57–584) (88.4%) | 221.9 ± 99.8 (210) (57–498) (85.4%) | 37.8 (29.2–46.4) | <.0001 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
