Accepted Manuscript Short-Term Changes in Choroidal Thickness After Aflibercept Therapy for Neovascular Age-related Macular Degeneration Hideki Koizumi, Mariko Kano, Akiko Yamamoto, Masaaki Saito, Ichiro Maruko, Ryo Kawasaki, Tetsuju Sekiryu, Annabelle A. Okada, Tomohiro Iida PII:
S0002-9394(14)00835-6
DOI:
10.1016/j.ajo.2014.12.025
Reference:
AJOPHT 9194
To appear in:
American Journal of Ophthalmology
Received Date: 14 April 2014 Revised Date:
22 December 2014
Accepted Date: 23 December 2014
Please cite this article as: Koizumi H, Kano M, Yamamoto A, Saito M, Maruko I, Kawasaki R, Sekiryu T, Okada AA, Iida T, Short-Term Changes in Choroidal Thickness After Aflibercept Therapy for Neovascular Age-related Macular Degeneration, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2014.12.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
neovascular age-related macular degeneration (AMD).
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Design: Retrospective, consecutive, interventional case series.
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Purpose: To investigate changes in choroidal thickness after aflibercept therapy for
Methods: This study included 102 eyes of 102 patients with treatment-naïve neovascular
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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
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depth imaging OCT.
Results: Of the 102 eyes, 46 eyes (45.1%) were diagnosed as typical neovascular AMD and
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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
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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).
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All subtypes of neovascular AMD demonstrated a similar trend toward decreasing
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choroidal thickness during the follow-up period. Conclusions: Choroidal thickness significantly decreased not only at the foveal center but
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also in the entire macula after 3 monthly intravitreal aflibercept injections for neovascular
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AMD.
Koizumi H, et al. Choroidal Thickness After Aflibercept for AMD – Page 1
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Short-Term Changes in Choroidal Thickness After Aflibercept Therapy for Neovascular
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Age-related Macular Degeneration
Hideki Koizumi, Mariko Kano, Akiko Yamamoto, Masaaki Saito, Ichiro Maruko, Ryo Kawasaki, Tetsuju Sekiryu, Annabelle A Okada, and Tomohiro Iida
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From the Department of Ophthalmology, Tokyo Women’s Medical University, Tokyo, Japan
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(H.K., I.M., T.I.); the Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan (M.K., M.S., T.S.); the Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan (A.Y., A.A.O.); the Department of Public Health,
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Yamagata University Faculty of Medicine, Yamagata, Japan (R.K.)..
Correspondence: Hideki Koizumi, MD, PhD, Department of Ophthalmology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
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E-mail: [email protected]
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Short Title: Choroidal Thickness After Aflibercept for AMD
Key Words: age-related macular degeneration, aflibercept, choroidal thickness, enhanced depth imaging optical coherence tomography, swept source optical coherence tomography, visual acuity
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Neovascular age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries.1 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.2,3 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.4,5 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).6,7 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.8 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 1µm wavelength light have enabled visualization of cross-sectional images of the choroid.9 10 In neovascular AMD, choroidal thickness measurements by these methods appeared to be important not only for adjunctive diagnostic purposes11-14 but also for the evaluation of therapeutic intervention.15-20 Recently, we showed that the mean subfoveal choroidal thickness decreased significantly after intravitreal injections of ranibizumab in eyes with neovascular AMD.19 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.15,20 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.16 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 2012 and June 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 (RAP)21 was excluded from the study based on its rarity. Diagnosis of the subtype of neovascular AMD (typical neovascular AMD
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or PCV) was based on funduscopic and angiographic findings. Typical neovascular AMD was characterized by exudative changes due 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.22 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.
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At baseline, all 102 patients underwent comprehensive ophthalmic examination including refraction, best-corrected visual acuity (BCVA) testing with Landholt C charts, slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, FA and ICGA using a 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 a 2.0 mg intravitreal aflibercept injections monthly for 3 months; 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., Heidelberg, Germany) at Fukushima Medical University and Kyorin University. A high intersystem correlation between these 2 OCT systems was previously reported,23 and the same OCT machine was always used for all measurement 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.9 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’s 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
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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 minimum 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). The study protocol followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of each university hospital. Results
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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 to 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 regards 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 (62.7%), juxtafoveal in 25 eyes (24.5%), extrafoveal in 9 eyes (8.8%), and peripapillary in 4 eyes (3.9%).24 There were no missing data with respect to BCVA and choroidal thickness during the study period. Table 1 summarized 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 that at baseline, the mean BCVA at 3 months were significantly improved (P < .0001). At the 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 (2.0%). 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 ± 36.5µm vs. 33.2 ± 36.3µm, P = 0.52). Table 2 summarized the changes in subfoveal choroidal thickness during the study period in each subtype of neovascular AMD. With regards 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). At 3 months, a dry macula as assessed by OCT was achieved in 73 of 102 eyes (71.6%). In the 73 eyes with achievement of a dry macula and the 29 eyes without achievement of a dry macula, the mean subfoveal choroidal thickness significantly decreased from 245.4 ± 97.2 µm and 268.8 ± 105.7 µm at baseline to 211.4 ± 94.1 µm and 234.2 ± 99.2 µm at 3 months, respectively (P < .0001 for both). However, the mean change in subfoveal choroidal thickness was not significantly different between the 2 groups (34.0 ± 37.2 µm vs. 37.6 ± 36.5 µm, P = 0.78).
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Of the 102 eyes, a RPE tear developed in 2 eyes during the 3-month period. None of the 102 patients developed systemic complications related to intravitreal aflibercept injections. A representative case is shown in Figure 3. Discussion
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To our knowledge, changes in choroidal thickness after intravitreal aflibercept injections have not been previously reported. In this study, we demonstrated that choroidal thickness decreased in eyes with neovascular AMD treated with aflibercept, not only at the foveal center, but also in the entire macula.
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The mean subfoveal choroidal thickness in all 102 eyes treated with 3 monthly intravitreal aflibercept injections decreased from 252.0 µm at baseline to 217.9 µm at 3 months. The percentage change in subfoveal choroidal thickness over the 3 months was 86.5%. The decrease in subfoveal choroidal thickness after aflibercept therapy was much greater than that reported in normal eyes (1.56 µm /year),25 and thus intravitreal aflibercept injections may be affecting choroidal structures under the neovascular membrane. We and other authors previously reported on the changes in subfoveal choroidal thickness after intravitreal ranibizumab injections in eyes with neovascular AMD. 15,19,20 The percentage change of the mean subfoveal choroidal thickness at 1 month after 3 monthly ranibizumab injections ranged from 92.6% to 98.7%,15,19,20 however, only 1 report19 showed statistical significance. Therefore, there seemed to be no definite consensus on choroidal thickness changes after ranibizumab therapy. Although we should consider the differences in cohorts among the different studies, intravitreal aflibercept injections may be inducing greater choroidal thinning than intravitreal ranibizumab injections. Furthermore, the decreased choroidal thickness with aflibercept therapy was observed not only at the foveal center, but also in the entire macula in the current study. This suggests that decreased choroidal thickness may be a secondary effect following suppression of the neovascularization process, however a direct effect of aflibercept on the underlying choroid is also possible. In addition, as we previously reported with respect to intravitreal injections of ranibizumab,19 intravitreal aflibercept injections also showed a uniform effect on choroidal thickness, regardless of the subtype of neoveascular AMD. Why did aflibercept cause more choroidal thinning than ranibizumab? VEGF-A has numerous pharmacologic actions, including promotion of angiogenesis, increase in vascular permeability, and dilation of vessels.2,3,26,27 In rabbits, after ranibizumab molecules rapidly penetrate through all retinal layers to reach the choroid after intravitreal injection, and thus may have the potential to inhibit the activity of all VEGF-A isoforms in both the retina and the choroid.28 Although the retinal and choroidal pharmacokinetics of aflibercept has yet to be clarified, aflibercept is known to have a much higher affinity to VEGF29,30 and a longer half-life7,31 compared to ranibizumab. In addition to VEGF-A, aflibercept binds to VEGF-B and PlGF, which are not inhibited by ranibizumab.6,7,29 A recent experimental study using monkeys demonstrated that reduction of choriocapillaris endothelium thickness and number of fenestrations were more pronounced after intravitreal aflibercept injections compared to intravitreal ranibizumab injections.32 The reason for the choroidal thinning after intravitreal aflibercept injections may be related, at least in part, to the reduction of choroidal vascular permeability from the fenestrated vascular wall and the narrowing of choroidal vessels due to a more robust blockade of VEGF-A, and/or due to simultaneous inhibition of multiple molecules in the VEGF family.
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It was reported that, with both PDT monotherapy and combined PDT and ranibizumab therapy for PCV, the subfoveal choroidal thickness transiently increased 2 days after PDT, followed by a significant decrease through 6 months.16 Based on the data presented in that report, the change ratio 3 months after PDT was 82.6%, which was even less than that after aflibercept therapy as shown in the current study. Such differences between PDT and anti-VEGF therapy may be accounted for by the different mechanisms of action between those 2 treatments, since PDT causes photothrombotic choroidal vascular occlusion.33,34
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Although the clinical significance of decreased choroidal thickness after intravitreal aflibercept injections remains unclear, several researchers reported that conversion to aflibercept from ranibizumab or bevacizumab was effective for the resolution of persistent retinal fluid and/or pigment epithelial detachment in eyes with neovascular AMD.35-40 The greater impact on choroidal thickness observed after aflibercept therapy may be related to such additive effects to the previous treatments using the other anti-VEGF agents.
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This study has several limitations. While a relatively large number of cases was included, the follow-up period was short. Two different OCT systems were used for the measurement of choroidal thickness. However, the intersystem correlation between those 2 systems was reportedly high,23 and the same OCT machine was always used for all measurement for each patient. The measurements were performed by investigators masked to the patients’ information, but they were carried out manually. Future studies using automated software will be required for a more objective evaluation.
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In conclusion, choroidal thickness appeared to decrease after intravitreal aflibercept injections in eyes with neovascular AMD, not only at the foveal center, but also across the entire macula. The decrease in choroidal thickness was greater than that reported for ranibizumab, but less than that reported for PDT. Further studies with long-term follow-up are needed to confirm the results of the current study.
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Acknowledgements a. Funding/Support: This study was supported in part by Grant No. 25670739 from the Ministry of Education, Culture,
b. Financial Disclosures: The authors have no financial interests.
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c. Contributions to Authors in Each of These Areas:
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Sports, Science and Technology-Japan (H.K.).
Involved in design and conduct of study (H.K., M.K., A.Y., T.S., A.A.O., T.I.); data collection (H.K.,
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M.K., A.Y.); analysis and interpretation of the data (H.K., R.K.); writing (H.K.); critical revision (M.K., A.Y., M.S., I.M., R.K., T.S., A.A.O., T.I.); and approval (H.K., M.K., A.Y., M.S., I.M., R.K., T.S., A.A.O., T.I.) of the manuscript. d. Other Acknowledgments:
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None.
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Figure Captions Figure 1.
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Changes in the mean choroidal thickness at the foveal center and at 3 mm from the foveal center in the superior, inferior, temporal, and nasal directions in 103 eyes with neovascular age-related macular degeneration after intravitreal injections of aflibercept. The mean choroidal thickness significantly decreased at 3 month compared to baseline (P < .0001 for all locations).
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Figure 2. Changes in the mean subfoveal choroidal thickness in eyes with typical neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) after intravitreal injections of aflibercept. The mean subfoveal choroidal thickness in both subtypes was significantly reduced at 3 month compared with that at baseline (P < .0001 for both). The subfoveal choroidal thickness in the both subtypes demonstrated a similar trend toward decreasing during the 3-month period.
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Figure 3. A 54-year-old man with choroidal neovascularization in the juxtafoveal lesion associated with typical neovascular age-related macular degeneration in his right eye. (Top) At baseline, the vertical swept source optical coherence tomography through the foveal center demonstrated subretinal fluid accumulation. (Bottom) One month after the third intravitreal injection of aflibercept, complete resolution of the subretinal fluid was achieved and the choroidal thickness at the foveal center and at 3 mm from the foveal center in the superior and inferior directions decreased.
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Table 1. Changes in Visual Acuity and Choroidal Thickness at Each Location During Intravitreal Aflibercept Injections in All 102 Eyes with Neovascular Age-Related Macular Degeneration
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)
252.0 ± 99.7 (244) (56 to 556) (100%) 258.7 ± 85.9 (251) (90 to 526) (100%) 229.9 ± 93.0 (219) (46 to 521) (100%) 237.4 ± 86.5 (222) (105 to 564) (100%) 183.7 ± 97.0 (163) (52 to 514, (100%)
230.1 ± 96.9 (217) (55 to 570) (91.3%) 248.4 ± 84.5 (240) (74 to 498) (96.0%) 212.4 ± 88.7 (191) (56 to 604) (92.4%) 218.0 ± 85.2 (199) (71 to 562) (91.8%) 165.5 ± 95.2 (140) (42 to 483) (90.1%)
Choroidal thickness (µm) ± SD (median) (range) (percentage change from baseline) Foveal center
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Superior
Nasal
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Temporal
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Inferior
3 Months
P Valuea
0.28 ± 0.33 (0.22) (-0.08 to 1.52)
0.12 (0.07 to 0.16)
< .0001
34.2 (27.0 to 41.3)
< .0001
22.3 (13.7 to 30.1)
< .0001
21.3 (13.0 to 29.6)
< .0001
22.7 (14.6 to 30.8)
< .0001
21.4 (15.1 to 27.7)
< .0001
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1 Month
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BCVA (logMAR) ± SD (median) (range)
Baseline
Difference Between Baseline and 3 Months (95% CI)
226.3 ± 99.2 (218) (57 to 584) (89.8%) 241.2 ± 81.4 (233) (77 to 464) (93.2%) 211.7 ± 91.9 (195) (43 to 589) (92.1%) 215.5 ± 81.7 (200) (60 to 558) (90.8%) 166.6 ± 99.2 (140) (50 to 578) (90.7%)
217.9 ± 95.6 (204) (57 to 498) (86.5%) 236.4 ± 84.6 (231) (64 to 526, 91.4%) 208.6 ± 86.5 (197) (53 to 491) (90.7%) 214.6 ± 79.5 (205) (60 to 470) (90.4%) 162.3 ± 90.6 (145) (26 to 457) (88.4%)
CI = confidence interval; BCVA = best-corrected visual acuity; MAR = minimum angle of resolution; SD = standard deviation. a Difference in values between baseline and 3 months.
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Table 2. Changes in Subfoveal Choroidal Thickness During Intravitreal Aflibercept Injections in Each Subtype of Neovascular Age-related Macular Degeneration
P valuea (95% CI)
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Difference Between Baseline and 3 Months (95% CI)
1 Month
2 Months
t-AMD (n=46)
242.6 ± 95.6 (243) (83 to 508) (100%)
226.7 ± 95.1 (217) (88 to 427) (93.4%)
222.3 ± 89.6 (213) (84 to 410) (91.6%)
212.9 ± 91.1 (199) (81 to 431) (87.8%)
29.7 (17.6 to 41.7)
< .0001
PCV (n=56)
259.8 ± 103.2 (250) (56 to 556) (100%)
232.9 ± 99.1 (220) (55 to 570) (89.6%)
229.6 ± 107.1 (229) (57 to 584) (88.4%)
221.9 ± 99.8 (210) (57 to 498) (85.4%)
37.8 (29.2 to 46.4)
< .0001
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Choroidal thickness (µm) ± SD (median) (range) (percentage change from baseline)
3 Months
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CI = confidence interval; N/A = not applicable; PCV = polypoidal choroidal vasculopathy; SD = standard deviation; t-AMD = typical neovascular age-related macular degeneration.
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a A difference in choroidal thickness between baseline and 3 months.
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260 240
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Foveal center
220
Superior Inferior
200
Temporal
180
Nasal
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Choroidal Thickness (µm)
280
160 140
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1 Month 2 Months 3 Months
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Baseline
280
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260
t-AMD (n=46)
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220
200
1 Month 2 Months 3 Months
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Baseline
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Subfoveal Choroidal Thickness (µm)
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PCV (n=56)
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Biosketch
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Hideki Koizumi received his MD degree from Kyoto Prefectural University of Medicine, Kyoto, Japan in 1998. He was a retinal fellow at the Manhattan Eye, Ear, and Throat Hospital, New York, NY and at the Vitreous-Retina-Macula Consultants of New York from 2006 to 2008. He is currently an assistant professor at Tokyo Women’s Medical University, Tokyo, Japan. His current interests include the diagnosis and treatment of age-related macular degeneration and noninvasive retinal imaging.
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S0002-9394(14)00835-6
DOI:
10.1016/j.ajo.2014.12.025
Reference:
AJOPHT 9194
To appear in:
American Journal of Ophthalmology
Received Date: 14 April 2014 Revised Date:
22 December 2014
Accepted Date: 23 December 2014
Please cite this article as: Koizumi H, Kano M, Yamamoto A, Saito M, Maruko I, Kawasaki R, Sekiryu T, Okada AA, Iida T, Short-Term Changes in Choroidal Thickness After Aflibercept Therapy for Neovascular Age-related Macular Degeneration, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2014.12.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
neovascular age-related macular degeneration (AMD).
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Design: Retrospective, consecutive, interventional case series.
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Purpose: To investigate changes in choroidal thickness after aflibercept therapy for
Methods: This study included 102 eyes of 102 patients with treatment-naïve neovascular
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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
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depth imaging OCT.
Results: Of the 102 eyes, 46 eyes (45.1%) were diagnosed as typical neovascular AMD and
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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
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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).
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All subtypes of neovascular AMD demonstrated a similar trend toward decreasing
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choroidal thickness during the follow-up period. Conclusions: Choroidal thickness significantly decreased not only at the foveal center but
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also in the entire macula after 3 monthly intravitreal aflibercept injections for neovascular
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AMD.
Koizumi H, et al. Choroidal Thickness After Aflibercept for AMD – Page 1
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Short-Term Changes in Choroidal Thickness After Aflibercept Therapy for Neovascular
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Age-related Macular Degeneration
Hideki Koizumi, Mariko Kano, Akiko Yamamoto, Masaaki Saito, Ichiro Maruko, Ryo Kawasaki, Tetsuju Sekiryu, Annabelle A Okada, and Tomohiro Iida
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From the Department of Ophthalmology, Tokyo Women’s Medical University, Tokyo, Japan
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(H.K., I.M., T.I.); the Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan (M.K., M.S., T.S.); the Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan (A.Y., A.A.O.); the Department of Public Health,
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Yamagata University Faculty of Medicine, Yamagata, Japan (R.K.)..
Correspondence: Hideki Koizumi, MD, PhD, Department of Ophthalmology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
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E-mail: [email protected]
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Short Title: Choroidal Thickness After Aflibercept for AMD
Key Words: age-related macular degeneration, aflibercept, choroidal thickness, enhanced depth imaging optical coherence tomography, swept source optical coherence tomography, visual acuity
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Neovascular age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries.1 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.2,3 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.4,5 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).6,7 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.8 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 1µm wavelength light have enabled visualization of cross-sectional images of the choroid.9 10 In neovascular AMD, choroidal thickness measurements by these methods appeared to be important not only for adjunctive diagnostic purposes11-14 but also for the evaluation of therapeutic intervention.15-20 Recently, we showed that the mean subfoveal choroidal thickness decreased significantly after intravitreal injections of ranibizumab in eyes with neovascular AMD.19 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.15,20 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.16 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 2012 and June 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 (RAP)21 was excluded from the study based on its rarity. Diagnosis of the subtype of neovascular AMD (typical neovascular AMD
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or PCV) was based on funduscopic and angiographic findings. Typical neovascular AMD was characterized by exudative changes due 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.22 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.
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At baseline, all 102 patients underwent comprehensive ophthalmic examination including refraction, best-corrected visual acuity (BCVA) testing with Landholt C charts, slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, FA and ICGA using a 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 a 2.0 mg intravitreal aflibercept injections monthly for 3 months; 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., Heidelberg, Germany) at Fukushima Medical University and Kyorin University. A high intersystem correlation between these 2 OCT systems was previously reported,23 and the same OCT machine was always used for all measurement 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.9 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’s 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
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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 minimum 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). The study protocol followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of each university hospital. Results
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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 to 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 regards 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 (62.7%), juxtafoveal in 25 eyes (24.5%), extrafoveal in 9 eyes (8.8%), and peripapillary in 4 eyes (3.9%).24 There were no missing data with respect to BCVA and choroidal thickness during the study period. Table 1 summarized 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 that at baseline, the mean BCVA at 3 months were significantly improved (P < .0001). At the 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 (2.0%). 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 ± 36.5µm vs. 33.2 ± 36.3µm, P = 0.52). Table 2 summarized the changes in subfoveal choroidal thickness during the study period in each subtype of neovascular AMD. With regards 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). At 3 months, a dry macula as assessed by OCT was achieved in 73 of 102 eyes (71.6%). In the 73 eyes with achievement of a dry macula and the 29 eyes without achievement of a dry macula, the mean subfoveal choroidal thickness significantly decreased from 245.4 ± 97.2 µm and 268.8 ± 105.7 µm at baseline to 211.4 ± 94.1 µm and 234.2 ± 99.2 µm at 3 months, respectively (P < .0001 for both). However, the mean change in subfoveal choroidal thickness was not significantly different between the 2 groups (34.0 ± 37.2 µm vs. 37.6 ± 36.5 µm, P = 0.78).
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Of the 102 eyes, a RPE tear developed in 2 eyes during the 3-month period. None of the 102 patients developed systemic complications related to intravitreal aflibercept injections. A representative case is shown in Figure 3. Discussion
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To our knowledge, changes in choroidal thickness after intravitreal aflibercept injections have not been previously reported. In this study, we demonstrated that choroidal thickness decreased in eyes with neovascular AMD treated with aflibercept, not only at the foveal center, but also in the entire macula.
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The mean subfoveal choroidal thickness in all 102 eyes treated with 3 monthly intravitreal aflibercept injections decreased from 252.0 µm at baseline to 217.9 µm at 3 months. The percentage change in subfoveal choroidal thickness over the 3 months was 86.5%. The decrease in subfoveal choroidal thickness after aflibercept therapy was much greater than that reported in normal eyes (1.56 µm /year),25 and thus intravitreal aflibercept injections may be affecting choroidal structures under the neovascular membrane. We and other authors previously reported on the changes in subfoveal choroidal thickness after intravitreal ranibizumab injections in eyes with neovascular AMD. 15,19,20 The percentage change of the mean subfoveal choroidal thickness at 1 month after 3 monthly ranibizumab injections ranged from 92.6% to 98.7%,15,19,20 however, only 1 report19 showed statistical significance. Therefore, there seemed to be no definite consensus on choroidal thickness changes after ranibizumab therapy. Although we should consider the differences in cohorts among the different studies, intravitreal aflibercept injections may be inducing greater choroidal thinning than intravitreal ranibizumab injections. Furthermore, the decreased choroidal thickness with aflibercept therapy was observed not only at the foveal center, but also in the entire macula in the current study. This suggests that decreased choroidal thickness may be a secondary effect following suppression of the neovascularization process, however a direct effect of aflibercept on the underlying choroid is also possible. In addition, as we previously reported with respect to intravitreal injections of ranibizumab,19 intravitreal aflibercept injections also showed a uniform effect on choroidal thickness, regardless of the subtype of neoveascular AMD. Why did aflibercept cause more choroidal thinning than ranibizumab? VEGF-A has numerous pharmacologic actions, including promotion of angiogenesis, increase in vascular permeability, and dilation of vessels.2,3,26,27 In rabbits, after ranibizumab molecules rapidly penetrate through all retinal layers to reach the choroid after intravitreal injection, and thus may have the potential to inhibit the activity of all VEGF-A isoforms in both the retina and the choroid.28 Although the retinal and choroidal pharmacokinetics of aflibercept has yet to be clarified, aflibercept is known to have a much higher affinity to VEGF29,30 and a longer half-life7,31 compared to ranibizumab. In addition to VEGF-A, aflibercept binds to VEGF-B and PlGF, which are not inhibited by ranibizumab.6,7,29 A recent experimental study using monkeys demonstrated that reduction of choriocapillaris endothelium thickness and number of fenestrations were more pronounced after intravitreal aflibercept injections compared to intravitreal ranibizumab injections.32 The reason for the choroidal thinning after intravitreal aflibercept injections may be related, at least in part, to the reduction of choroidal vascular permeability from the fenestrated vascular wall and the narrowing of choroidal vessels due to a more robust blockade of VEGF-A, and/or due to simultaneous inhibition of multiple molecules in the VEGF family.
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It was reported that, with both PDT monotherapy and combined PDT and ranibizumab therapy for PCV, the subfoveal choroidal thickness transiently increased 2 days after PDT, followed by a significant decrease through 6 months.16 Based on the data presented in that report, the change ratio 3 months after PDT was 82.6%, which was even less than that after aflibercept therapy as shown in the current study. Such differences between PDT and anti-VEGF therapy may be accounted for by the different mechanisms of action between those 2 treatments, since PDT causes photothrombotic choroidal vascular occlusion.33,34
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Although the clinical significance of decreased choroidal thickness after intravitreal aflibercept injections remains unclear, several researchers reported that conversion to aflibercept from ranibizumab or bevacizumab was effective for the resolution of persistent retinal fluid and/or pigment epithelial detachment in eyes with neovascular AMD.35-40 The greater impact on choroidal thickness observed after aflibercept therapy may be related to such additive effects to the previous treatments using the other anti-VEGF agents.
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This study has several limitations. While a relatively large number of cases was included, the follow-up period was short. Two different OCT systems were used for the measurement of choroidal thickness. However, the intersystem correlation between those 2 systems was reportedly high,23 and the same OCT machine was always used for all measurement for each patient. The measurements were performed by investigators masked to the patients’ information, but they were carried out manually. Future studies using automated software will be required for a more objective evaluation.
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In conclusion, choroidal thickness appeared to decrease after intravitreal aflibercept injections in eyes with neovascular AMD, not only at the foveal center, but also across the entire macula. The decrease in choroidal thickness was greater than that reported for ranibizumab, but less than that reported for PDT. Further studies with long-term follow-up are needed to confirm the results of the current study.
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Acknowledgements a. Funding/Support: This study was supported in part by Grant No. 25670739 from the Ministry of Education, Culture,
b. Financial Disclosures: The authors have no financial interests.
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c. Contributions to Authors in Each of These Areas:
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Sports, Science and Technology-Japan (H.K.).
Involved in design and conduct of study (H.K., M.K., A.Y., T.S., A.A.O., T.I.); data collection (H.K.,
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M.K., A.Y.); analysis and interpretation of the data (H.K., R.K.); writing (H.K.); critical revision (M.K., A.Y., M.S., I.M., R.K., T.S., A.A.O., T.I.); and approval (H.K., M.K., A.Y., M.S., I.M., R.K., T.S., A.A.O., T.I.) of the manuscript. d. Other Acknowledgments:
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None.
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Figure Captions Figure 1.
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Changes in the mean choroidal thickness at the foveal center and at 3 mm from the foveal center in the superior, inferior, temporal, and nasal directions in 103 eyes with neovascular age-related macular degeneration after intravitreal injections of aflibercept. The mean choroidal thickness significantly decreased at 3 month compared to baseline (P < .0001 for all locations).
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Figure 2. Changes in the mean subfoveal choroidal thickness in eyes with typical neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) after intravitreal injections of aflibercept. The mean subfoveal choroidal thickness in both subtypes was significantly reduced at 3 month compared with that at baseline (P < .0001 for both). The subfoveal choroidal thickness in the both subtypes demonstrated a similar trend toward decreasing during the 3-month period.
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Figure 3. A 54-year-old man with choroidal neovascularization in the juxtafoveal lesion associated with typical neovascular age-related macular degeneration in his right eye. (Top) At baseline, the vertical swept source optical coherence tomography through the foveal center demonstrated subretinal fluid accumulation. (Bottom) One month after the third intravitreal injection of aflibercept, complete resolution of the subretinal fluid was achieved and the choroidal thickness at the foveal center and at 3 mm from the foveal center in the superior and inferior directions decreased.
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Table 1. Changes in Visual Acuity and Choroidal Thickness at Each Location During Intravitreal Aflibercept Injections in All 102 Eyes with Neovascular Age-Related Macular Degeneration
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)
252.0 ± 99.7 (244) (56 to 556) (100%) 258.7 ± 85.9 (251) (90 to 526) (100%) 229.9 ± 93.0 (219) (46 to 521) (100%) 237.4 ± 86.5 (222) (105 to 564) (100%) 183.7 ± 97.0 (163) (52 to 514, (100%)
230.1 ± 96.9 (217) (55 to 570) (91.3%) 248.4 ± 84.5 (240) (74 to 498) (96.0%) 212.4 ± 88.7 (191) (56 to 604) (92.4%) 218.0 ± 85.2 (199) (71 to 562) (91.8%) 165.5 ± 95.2 (140) (42 to 483) (90.1%)
Choroidal thickness (µm) ± SD (median) (range) (percentage change from baseline) Foveal center
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Nasal
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Inferior
3 Months
P Valuea
0.28 ± 0.33 (0.22) (-0.08 to 1.52)
0.12 (0.07 to 0.16)
< .0001
34.2 (27.0 to 41.3)
< .0001
22.3 (13.7 to 30.1)
< .0001
21.3 (13.0 to 29.6)
< .0001
22.7 (14.6 to 30.8)
< .0001
21.4 (15.1 to 27.7)
< .0001
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BCVA (logMAR) ± SD (median) (range)
Baseline
Difference Between Baseline and 3 Months (95% CI)
226.3 ± 99.2 (218) (57 to 584) (89.8%) 241.2 ± 81.4 (233) (77 to 464) (93.2%) 211.7 ± 91.9 (195) (43 to 589) (92.1%) 215.5 ± 81.7 (200) (60 to 558) (90.8%) 166.6 ± 99.2 (140) (50 to 578) (90.7%)
217.9 ± 95.6 (204) (57 to 498) (86.5%) 236.4 ± 84.6 (231) (64 to 526, 91.4%) 208.6 ± 86.5 (197) (53 to 491) (90.7%) 214.6 ± 79.5 (205) (60 to 470) (90.4%) 162.3 ± 90.6 (145) (26 to 457) (88.4%)
CI = confidence interval; BCVA = best-corrected visual acuity; MAR = minimum angle of resolution; SD = standard deviation. a Difference in values between baseline and 3 months.
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Table 2. Changes in Subfoveal Choroidal Thickness During Intravitreal Aflibercept Injections in Each Subtype of Neovascular Age-related Macular Degeneration
P valuea (95% CI)
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Difference Between Baseline and 3 Months (95% CI)
1 Month
2 Months
t-AMD (n=46)
242.6 ± 95.6 (243) (83 to 508) (100%)
226.7 ± 95.1 (217) (88 to 427) (93.4%)
222.3 ± 89.6 (213) (84 to 410) (91.6%)
212.9 ± 91.1 (199) (81 to 431) (87.8%)
29.7 (17.6 to 41.7)
< .0001
PCV (n=56)
259.8 ± 103.2 (250) (56 to 556) (100%)
232.9 ± 99.1 (220) (55 to 570) (89.6%)
229.6 ± 107.1 (229) (57 to 584) (88.4%)
221.9 ± 99.8 (210) (57 to 498) (85.4%)
37.8 (29.2 to 46.4)
< .0001
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Choroidal thickness (µm) ± SD (median) (range) (percentage change from baseline)
3 Months
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Baseline
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CI = confidence interval; N/A = not applicable; PCV = polypoidal choroidal vasculopathy; SD = standard deviation; t-AMD = typical neovascular age-related macular degeneration.
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a A difference in choroidal thickness between baseline and 3 months.
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220
Superior Inferior
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Temporal
180
Nasal
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Choroidal Thickness (µm)
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160 140
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Baseline
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t-AMD (n=46)
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200
1 Month 2 Months 3 Months
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Baseline
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Subfoveal Choroidal Thickness (µm)
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PCV (n=56)
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Biosketch
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Hideki Koizumi received his MD degree from Kyoto Prefectural University of Medicine, Kyoto, Japan in 1998. He was a retinal fellow at the Manhattan Eye, Ear, and Throat Hospital, New York, NY and at the Vitreous-Retina-Macula Consultants of New York from 2006 to 2008. He is currently an assistant professor at Tokyo Women’s Medical University, Tokyo, Japan. His current interests include the diagnosis and treatment of age-related macular degeneration and noninvasive retinal imaging.
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