Accepted Manuscript

One year result of aflibercept treatment on age-related macular degeneration andpredictive factors for visual outcome

Akio Oishi, Akitaka Tsujikawa, Kenji Yamashiro, Sotaro Ooto, Hiroshi Tamura, HideoNakanishi, Naoko Ueda-Arakawa, Masahiro Miyake, Yumiko Akagi-Kurashige,Masayuki Hata, Munemitsu Yoshikawa, Yoshimasa Kuroda, Ayako Takahashi,Nagahisa Yoshimura

PII: S0002-9394(15)00047-1

DOI: 10.1016/j.ajo.2015.01.018

Reference: AJOPHT 9214

To appear in: American Journal of Ophthalmology

Received Date: 6 September 2014

Revised Date: 17 January 2015

Accepted Date: 19 January 2015

Please cite this article as: Oishi A, Tsujikawa A, Yamashiro K, Ooto S, Tamura H, Nakanishi H, Ueda-Arakawa N, Miyake M, Akagi-Kurashige Y, Hata M, Yoshikawa M, Kuroda Y, Takahashi A, YoshimuraN, One year result of aflibercept treatment on age-related macular degeneration and predictive factorsfor visual outcome, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2015.01.018.

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Abstract Purpose: To investigate the efficacy of periodic injection of aflibercept in each subtype of age-related macular degeneration (AMD) and to explore the predictive factors for visual outcome in clinical settings. Design: Prospective non-randomized interventional case series. Methods: Patients with AMD were recruited and were administered aflibercept injections once a month for 3 months followed by once every 2 months for 8 months. The logarithm of the minimum angle of resolution (logMAR) at 12 months and improvement of vision from baseline were compared among polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. Regression rate of polypoidal lesions was assessed. We also performed regression analysis with logMAR at 12 months as the dependent variable. Results: The study sample consisted of 98 patients: 46 had typical AMD, 42 had PCV, and 10 had RAP. Mean logMAR improved from 0.36 to 0.21 in 12 months. While there was no difference in visual improvement between typical AMD and PCV, final logMAR was better in PCV (0.32 0.09 vs. 0.08 0.04, P = .016). Thirty-nine PCV patients underwent follow-up angiography, and regression of polyps was observed in 27 cases (69.2%). Multiple regression analysis showed that the presence of external limiting membrane (ELM), smaller greatest linear dimension (GLD), and the presence of polypoidal lesion were associated with better visual outcome (R2 = 0.53, P = 2.73 10-14). Conclusions: Periodic injection of aflibercept is effective for PCV as well as for typical AMD. The statuses of ELM, GLD, and polypoidal lesion are predictive for visual outcome.

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Title: One year result of aflibercept treatment on age-related macular degeneration and predictive factors for visual outcome

Short title: Effect of aflibercept on age-related macular degeneration

Akio Oishi, Akitaka Tsujikawa, Kenji Yamashiro, Sotaro Ooto, Hiroshi Tamura, Hideo Nakanishi, Naoko Ueda-Arakawa, Masahiro Miyake, Yumiko Akagi-Kurashige, Masayuki Hata, Munemitsu Yoshikawa, Yoshimasa Kuroda, Ayako Takahashi, Nagahisa Yoshimura

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

Corresponding author: Akio Oishi, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawahara, Shogoin, Sakyo, Kyoto 606-8507, Japan Tel: +81-75-751-3248; Fax: +81-75-752-0933 E-mail: aquio@kuhp.kyoto-u.ac.jp

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Introduction: Age-related macular degeneration (AMD) is a leading cause of visual impairment especially in developed countries. AMD can be divided into dry and wet forms. While the visual impairment progresses gradually in dry AMD, choroidal neovascularization (CNV) develops and hemorrhage or exudative changes deteriorate the vision rapidly.1 The treatment of AMD was unsatisfactory until recently but dramatically changed after two pivotal studies showed the efficacy of anti-vascular endothelial growth factor (VEGF) drug ranibizumab.2, 3 The randomized studies clearly showed that the monthly intravitreal injections of ranibizumab are effective in improving vision.

Aflibercept is another anti-VEGF drug, which has higher affinity to VEGF, longer half life, and capability of inhibiting placental growth factor.4 The VIEW I/II studies were conducted and showed that three monthly injections followed by bimonthly injections are not inferior to monthly injections of ranibizumab in terms of visual gain in 52 or 96 weeks.5, 6

Thus, there is no doubt about the efficacy of anti-VEGF therapy for AMD; however, there are several issues to be addressed when physicians translate the result into clinical practice. First, clinical trials including the ones discussed above have specific inclusion and exclusion criteria as to the baseline visual acuity or the size of the lesions. Information regarding to those who does not met the inclusion criteria, e.g. those with good visual acuity is lacking. Second, subtypes of AMD including polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation (RAP) are not differentiated in the trials. While recent studies reported the favorable result of ranibizumab on PCV,7-9 photodynamic therapy, especially combined with anti-VEGF therapy, is also effective and the optimal treatment of PCV is still controversial.10, 11 RAP was associated with less favorable outcome compared to typical AMD before the era of anti-VEGF therapy and there is still little evidence about the treatment effect of RAP.12 The visual outcome might be different in these subtypes. Third, which kind of patient responds well to the treatment is unclear. Since anti-VEGF therapy for AMD requires frequent and ongoing injections of the drug and accompanies physical, economic, and social burden,13, 14 estimating the chance of visual gain based on baseline characteristics is appreciated for appropriate informed consent.

In the present study, we prospectively recruited consecutive patients with treatment nave AMD and treated them with periodical injections of

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aflibercept. The result would show the real world effect of aflibercept and help predicting the visual outcome in each patient.

Methods: Study design: prospective, non-randomized, interventional study The study design was approved by the Institutional Review Board of Kyoto University Graduate School of Medicine, and all study conduct adhered to the tenets of the Declaration of Helsinki. Each patient gave written informed consent for the participation in the study. Setting: institutional Patients and study population: Participants were recruited at Macular service, Department of Ophthalmology, Kyoto University Hospital from Nov 2012 to December 2013. Inclusion criteria were age older than 50 years, axial length less than 26.5 mm, the presence of neovascular AMD, willing to participate in the study. Only one eye from one patient was included in the study; when a patients second eye developed AMD, they were not included in the study. Exclusion criteria were the any previous treatment to CNV, the presence of other retinal diseases such as angioid streaks, vitelliform macular dystrophy, retinal vein or artery occlusion. Those with chronic course of AMD indicated by disease history and/or massive fibrotic lesions were also excluded. In addition, those who dropped out from the study were excluded from the analysis. Intervention and observation procedure: All the participants underwent 3 times of monthly injections and following bi-monthly injections of aflibercept (2.0 mg). The number of injection should be 3 + 4 in the study period of 12 months. (Figure 1) When there is contraindication such as cerebral infarction or patients do not agree to undergo the treatment, injection was skipped. Alternatively, additional injections were administered or PDT was performed on physicians discretion. Patients underwent comprehensive examinations including visual acuity measurement, axial length measurement (IOL maseter, Carl zeiss Meditec, Dublin, CA), fundus photography, spectral-domain optical coherence tomography (SD-OCT, Spectralis, Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography (FA) and IGA, fundus autofluorescence imaging at baseline (HRA2, Heidelberg Engineering). Fundus photography, SD-OCT, angiography, and fundus autofluorescence imaging were performed under sufficient pupillary dilation.

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Visual acuity measurement and SD-OCT were performed at each visit and the result of 3, 6, 9, and 12 month were analyzed. At 12 month, we also performed FA, IGA, and fundus autofluorescence imaging.

Visual acuity were measured with Landolt C charts (Takagi Seiko, Nakano, Japan) in a standard way.15 SD-OCT images were obtained using Spectralis (Spectralis Family Acquisition Module, version 5.7.5.0) with Heidelberg Eye Explorer (version 1.8.6.0, Heidelberg Engineering). The eye tracking system of the device was used to detect and keep the correct scanning position. Thirty-degree horizontal and vertical scans through the fovea were recorded using normal and enhanced depth imaging mode with averaging 100 scans. 16 Thirteen raster scans covering 20 30 degree oblong rectangle was performed with averaging 50 scans for each scan. We measured the central retinal thickness (CRT), which was defined as the distance between the vitreoretinal surface and the inner surface of retinal pigment epithelium. (Figure 2 top) Choroidal thickness was measured in enhanced depth imaging scans as a length between outer border of Bruchs membrane and chorioscleral interface. (Figure 2 upper middle) CRT and choroidal thickness was measured in horizontal and vertical scans and averaged. PED height was defined as the distance between the outer border of the retinal pigment epithelium and the inner border of Bruchs membrane; maximum PED height in the raster scans were recorded. (Figure 2 lower middle)The presence of foveal external limiting membrane (ELM) and inner segment ellipsoid (ISe) were evaluated in vertical and horizontal scans. The presence of vitreoretinal adhesion was judged in raster scans. (Figure 2 top) Whether the treatment achieved dry macula, defined as the absence of intra- or sub-retinal fluid throughout the raster scans was also judged.

As to the angiography, we measured the greatest linear dimension (GLD) at baseline and 12 M. Although We measured the size of CNV including branching vascular network and polypoidal lesion in PCV, the exact border was unclear in some cases at baseline and/or at 12 M (16/98, 16.3%). Thus, the comparison was made in the rest of patients. We judged the presence of polypoidal lesions in each case. (Figure 2 bottom) The cases with polypoidal lesions were diagnosed as PCV and cases with intraretinal neovascularization were diagnosed as RAP. The other patients were categorized as typical AMD (tAMD). Main outcome measure: Changes in visual acuity.

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Secondary outcome measures: We performed subgroup comparison between patients with or without visual acuity better than 0.5 (20/40) and among subtypes of AMD. In addition, we performed multivariate regression analysis to identify the baseline characteristics predicting visual outcome. Statistics: Statstical analysis was carried out using SPSS version 19 (IBM Japan, Tokyo, Japan). P-value smaller than 0.05 was considered as significant. Visual acuity measured with Landolt C charts was converted to logarithm of minimum angle of resolution (logMAR) to perform statistical analysis. Paired t-test or chi-square test was used to compare baseline and 12 M characteristics. Changes in VA or CRT from baseline were assessed using 1-way repeated-measures analysis of variance (ANOVA) and post-hoc Bonferroni correction. Two-way repeated-measures ANOVA was used to investigate the difference in clinical course of VA or CRT among the groups. Bivariate relationships were examined using Pearsons correlation coefficient for continuous variables and Spearmans correlation coefficient test for binary variables. Step-wise multivariate regression analysis was performed with age, GLD, presence of polypoidal lesion, presence of reticular pseudodrusen, CRT, maximum PED, choroidal thickness, presence or absence of ELM, ISe, and vitreoretinal adhesion as independent factors and visual acuity at 12 M as dependent factor.

Results: The study included 112 patients who met inclusion and exclusion criteria. Fourteen patients dropped out because of gastric cancer, ileus, or unknown reason. Thus, the study sample consisted of 98 patients including 46 patients with tAMD, 42 patients with PCV, and 10 patients with RAP. Mean number of injection was 6.8 0.2 (range: 1 8). One patient developed cerebral infarction after the first injection and was refrained from subsequent treatment. Another 8 patients received less than 6 times of injections due to patients will but continued visiting and were included in the analysis. One patient was refractory to the initial 3-monthly injections and received combination therapy with PDT. As the adverse event, one patient in the study population and another patient who dropped out developed retinal pigment epithelium tear. Baseline and 12 M characteristics of the participants are shown in Table 1. Visual acuity improved by about 1.5 lines in 12 M. CRT, PED, and choroidal thickness decreased significantly. GLD was also decreased primarily by the resolution of hemorrhage and PED. The size of

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the CNV did not change significantly. Vitreoretinal adhesion was noted in 27 patients at baseline and 6 of them developed posterior vitreous detachment during the treatment period.

Clinical course of all the participants is shown in Figure 3 top left. As stated above, the treatment was generally effective. We compared the treatment effect among the subtypes of AMD. (Figure 3 top middle) Patients with each subtype showed similar trend and two-way repeated measures ANOVA showed no significant difference among the subtypes. (P = 0.097) Visual acuity at 12 M was significantly better in PCV patients than tAMD patients. (0.32 0.09 vs 0.08 0.04, P = 0.016) In addition, we compared patients with or without visual acuity better than 0.5 (20/40) (Figure 3 top right) Both groups showed significant improvement from baseline. The visual gain looked better in those with baseline visual acuity < 0.5 but there was no significant difference (1.8 0.4 lines vs 1.2 0.3 line, P=0.171). The clinical courses of CRT are shown in Figure 3 bottom row. Retinal thickness decreased quickly after the treatment with aflibercept and maintained the effect for 12 M in any subtypes (bottom middle) or regardless of the baseline visual acuity (bottom right). Prevalences of dry macula at 3, 6, 9, and 12 M are shown in Table 2. Prevalence of dry macula was significantly lower in tAMD patients compared to PCV patients at 3, 6, and 9 M (P = 0.015, 0.045, and 0.009 respectively).

Among the 42 patients with PCV, one showed urticarial after the baseline angiography and one developed renal dysfunction during the treatment period; these patients were refrained from angiography at 12 M. In addition, a patient who suffered from nausea/vomiting declined to undergo the follow-up examination. In the rest of 39 patients, 27 showed complete regression of polypoidal lesions and 5 showed diminution of the lesion. The polyp regression rate was calculated as 69.2 % (27/39).

We explored the predictive factors for visual outcome. The result of univariate analysis is shown in Table 3. Age, GLD, CRT, presence of polypoidal lesion, presence of foveal ELM and ISe were associated with visual acuity at 12 M. We then performed multiple regression model analysis. The overall regression was significant (P = 2.731 10-14) and R2 was 0.527 meaning that 52.7 % of the visual outcome is explained by the selected factors. The result of multivariate analysis is shown in Table 4. Among the possible predictive factors, the presence of ELM, GLD, and presence of polypoidal lesion were selected as contributing factors for visual acuity at 12 M. The result indicated that if ELM is

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present, GLD is smaller by 1000 m, and polypoidal lesion is present, one can expect the better outcome of logMAR by 0.5, 0.05, and 0.1, respectively.

Discussion: In the present study, we showed that 1) 3 monthly and following bimonthly injections of aflibercept can achieve similar visual gain in each subtypes of AMD 2) visual gain in cases with good baseline visual acuity is as good as in clinical trials, and 3) the presence of ELM, GLD, and the presence of polypoidal lesion can predict visual outcome.

The difference in treatment effect among the AMD subtypes is of clinical interest. While some studies indicate that PCV patients are refractory to anti-VEGF therapy,17, 18 other more recent studies showed satisfactory effect of ranibizumab in PCV patients. 7-9 Concerning RAP, the result is variable and the available data is limited.19 Taken together, the effect of anti-VEGF therapy is not well established in PCV or RAP as in tAMD. The present result adds evidence for the effect of anti-VEGF therapy in these subtypes. Periodical injections or aflibercept achieve visual gain regardless of the subtype of the disease. In addition, the prevalence of dry retina was higher in PCV patients compared to tAMD patients indicating that PCV is not particularily refractory to aflibercept. Although baseline and 12 M visual acuity was not different in RAP patients, it would be the consequence of good baseline visual acuity and relatively small number of patients. The treatment is recommended for any subtypes.

Regression of polypoidal lesions is another controversial issue when considering the treatment of PCV. While PDT resolves polypoidal lesions efficiently (more than 70 %), the polyp closure rate in ranibizumab treatment was up around 25 %. 11 Considering that the persistent polyp might cause recurrent exudation and impair long term visual outcome, current guideline recommend PDT or PDT combined with anti-VEGF agents in the treatment of PCV. 11 In the present study; however, aflibercept monotherapy achieved a favorable rate of polypoidal lesion closure (69 %). Considering that PDT is accompanied by severe complications,20, 21 aflibercept monotherapy would be a better option not only to achieve better visual outcome but also to induce polyp regression than PDT monotherapy.

The clinical trials only deal patients who meet specific inclusion criteria. However, in the clinical practice, we have to treat patients with various characteristics. The present result showed that the visual gain was 1.2 lines in

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those with baseline visual acuity better than 0.5 and was not significantly different from that of those with baseline visual acuity < 0.5 (1.8 lines). Although the vision improving effect of aflibercept might be underestimated in these patients probably due to the ceiling effect, they still get benefit from the treatment. The treatment can be applied to patients regardless of the baseline visual acuity.

We identified some factors predictive for visual outcome. Especially, the presence of ELM was the most significant factor for visual acuity at 12 M. The association of ELM and visual acuity was shown in AMD patients after photodynamic therapy treatment.22 Other studies showed that the status of ELM or ISe can be used as a predictor of visual outcome after the treatment with ranibizumab.23, 24 The present study confirmed that the status of ELM is a prognostic factor also in aflibercept treatment. Small GLD was also associated with good visual outcome as expected from previous studies on patients treated with ranibizumab.25, 26 Interestingly, the presence of polypoidal lesion was associated with good visual outcome. In fact, PCV patients showed good baseline and final visual acuity. The result might be consistent with the association of thick choroid and good visual outcome reported in a previous study27 since PCV patients tend to have thick choroid.28 Predicting visual outcome from baseline retinal status would be helpful in providing patients with appropriate informed consent and individualized treatment.

The present study has several strength and limitations. The strength is that the prospective inclusion of patients, pre-determined treatment protocol and follow-up examinations. Although the treatment is demanding and is associated with relatively high dropout rate in clinical practice,13 most patients in the present study completed the protocol. The treatment protocol is identical to the VIEW I/II studies and the result would be intercomparable. The limitation includes the relatively small number of patients, especially RAP patients. All the patients are recruited in an institution and all of them are Japanese origin. In addition, visual acuity was measured with Landolt chart but not Early Treatment Diabetic Retinopathy Study (ETDRS) chart. That might affect the result especially in patients with poor visual acuity.15 Further studies are needed to confirm the findings in larger population and different ethnicities. Finally, we investigated the effect of aflibercept in AMD. The result showed that the periodical injections of aflibercept can achieve favorable outcome in patients with any subtypes or good visual acuity. The presence of ELM, thicker choroid, and smaller GLD were

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predictive factors for better outcome. The result adds evidence to translate the result of the trials into clinical practice.

Acknowledgement: a. Funding/Support: This research was supported in part by a grant-in-aid for scientific research (No. 24791847) from the Japan Society for the Promotion of Science, Tokyo, Japan and the Innovative Techno-Hub for Integrated Medical Bio-Imaging of the Project for Developing Innovation Systems, from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Tokyo, Japan. b. Financial Disclosures: AO, AT, KY, SO, and NY received lecture fee from several companies including Novartis (Basel, Switzerland) and Bayer (Leverkusen, Germany). Akitaka Tsujikawa received financial support from Pfizer (New York, NY). NY is a consultant of Nidek (Gamagori, Japan) and received financial support from Topcon Corporation (Tokyo, Japan), Nidek, and Canon (Tokyo, Japan). The organizations had no role in the design or conduct of this research. c. Contributions of Authors: Design of the study (AO, AT); Conduct of the study (AO, AT); Analysis and interpretation (AO, AT, KY, SO); Writing the article (AO); Critical revision of the article (AT, HT, MM,MH,NY); Final approval of the article (AO, AT, KY, SO, HT, HN, NUA, MM, YAK, MH, MY, YK, AT, NY); Data collection (AO, MH); Provision of patients (AO, AT, KY, SO, HT, HN, NY); Statistical expertise (AO, MM); Obtaining funding (AO); Literature search (AO, SO, MH); Administrative support (NY). d. Other Acknowledgments: none

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References 1. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet 2012;379(9827):1728-1738. 2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1432-1444. 3. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1419-1431. 4. Stewart MW, Grippon S, Kirkpatrick P. Aflibercept. Nat Rev Drug Discov 2012;11(4):269-270. 5. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119(12):2537-2548. 6. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal Aflibercept Injection for Neovascular Age-Related Macular Degeneration: Ninety-Six-Week Results of the VIEW Studies. Ophthalmology 2013;121(1):193-201. 7. Oishi A, Kojima H, Mandai M, et al. Comparison of the Effect of Ranibizumab and Verteporfin for Polypoidal Choroidal Vasculopathy: 12-Month LAPTOP Study Results. Am J Ophthalmol 2013;156(4):644-651. 8. Oishi A, Miyamoto N, Mandai M, et al. LAPTOP Study: A 24-Month Trial of Verteporfin Versus Ranibizumab for Polypoidal Choroidal Vasculopathy. Ophthalmology 2014;121(5):1151-1152. 9. Hikichi T, Higuchi M, Matsushita T, et al. Results of 2 years of treatment with as-needed ranibizumab reinjection for polypoidal choroidal vasculopathy. Br J Ophthalmol 2013;97(5):617-621. 10. Nowak-Sliwinska P, van den Bergh H, Sickenberg M, Koh AH. Photodynamic therapy for polypoidal choroidal vasculopathy. Prog Retin Eye Res 2013;37:182-199. 11. Koh AH, Chen LJ, Chen SJ, et al. Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment. Retina 2013;33(4):686-716. 12. Gupta B, Jyothi S, Sivaprasad S. Current treatment options for retinal angiomatous proliferans (RAP). Br J Ophthalmol 2010;94(6):672-677. 13. Oishi A, Mandai M, Nishida A, Hata M, Matsuki T, Kurimoto Y. Remission and dropout rate of anti-VEGF therapy for age-related macular degeneration. Eur J Ophthalmol 2011;21(6):777-782.

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14. Haller JA. Current anti-vascular endothelial growth factor dosing regimens: benefits and burden. Ophthalmology 2013;120(5 Suppl):S3-7. 15. Kuo HK, Kuo MT, Tiong IS, Wu PC, Chen YJ, Chen CH. Visual acuity as measured with Landolt C chart and Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Graefes Arch Clin Exp Ophthalmol 2011;249(4):601-605. 16. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146(4):496-500. 17. Cho M, Barbazetto IA, Freund KB. Refractory neovascular age-related macular degeneration secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol 2009;148(1):70-78 e71. 18. Stangos AN, Gandhi JS, Nair-Sahni J, Heimann H, Pournaras CJ, Harding SP. Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab. Am J Ophthalmol 2010;150(5):666-673. 19. Scott AW, Bressler SB. Retinal angiomatous proliferation or retinal anastomosis to the lesion. Eye (Lond) 2010;24(3):491-496. 20. Ojima Y, Tsujikawa A, Otani A, Hirami Y, Aikawa H, Yoshimura N. Recurrent bleeding after photodynamic therapy in polypoidal choroidal vasculopathy. Am J Ophthalmol 2006;141(5):958-960. 21. Hirami Y, Tsujikawa A, Otani A, et al. Hemorrhagic complications after photodynamic therapy for polypoidal choroidal vasculopathy. Retina 2007;27(3):335-341. 22. Oishi A, Hata M, Shimozono M, Mandai M, Nishida A, Kurimoto Y. The significance of external limiting membrane status for visual acuity in age-related macular degeneration. Am J Ophthalmol 2010;150(1):27-32 e21. 23. Akagi-Kurashige Y, Tsujikawa A, Oishi A, et al. Relationship between retinal morphological findings and visual function in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2012;250(8):1129-1136. 24. Mathew R, Richardson M, Sivaprasad S. Predictive value of spectral-domain optical coherence tomography features in assessment of visual prognosis in eyes with neovascular age-related macular degeneration treated with ranibizumab. Am J Ophthalmol 2013;155(4):720-726, 726 e721. 25. Yamashiro K, Tomita K, Tsujikawa A, et al. Factors associated with the response of age-related macular degeneration to intravitreal ranibizumab treatment. Am J Ophthalmol 2012;154(1):125-136.

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26. Kang HM, Koh HJ. Long-term Visual Outcome and Prognostic Factors After Intravitreal Ranibizumab Injections for Polypoidal Choroidal Vasculopathy. Am J Ophthalmol 2013;156(4):652-660. 27. Kang HM, Kwon HJ, Yi JH, Lee CS, Lee SC. Subfoveal choroidal thickness as a potential predictor of visual outcome and treatment response after intravitreal ranibizumab injections for typical exudative age-related macular degeneration. Am J Ophthalmol 2014;157(5):1013-1021. 28. Koizumi H, Yamagishi T, Yamazaki T, Kawasaki R, Kinoshita S. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249(8):1123-1128.

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Figure legends

Figure 1 Intervention schedule for patients with age-related macular degeneration treated with aflibercept. We administered 3 monthly injections and following bi-monthly injections of 2 mg aflibercept and evaluated the efficacy at 12 month. Clinical data were collected at month 3, 6, 9, and 12.

Figure 2 Evaluation of optical coherence tomography (OCT) images (top, upper middle, and lower middle) and indocyanine green angiography (IGA, bottom) of patients with age-related macular degeneration treated with intravitreal aflibercept. We measured central retinal thickness (CRT) in horizontal and vertical scans, choroidal thickness in enhanced depth imaging horizontal and vertical scans, and maximum height of pigment epithelium detachment (PED) in 20 30 degree raster scans. We also investigated the presence of intact external limiting membrane (ELM), inner segment ellipsoid (ISe) at fovea, and vitreoretinal adhesion. For IGA, we evaluated the presence of polypoidal lesion at baseline (bottom left) and at 12 month (bottom right). In this case, the polypoidal lesion regressed during the treatment period.

Figure 3 Visual (top row) and anatomical (bottom row) outcome of age-related macular degeneration (AMD) eyes treated with aflibercept. Left column shows the result of all cases. Central retinal thickness (CRT) improved quickly and gradual improvement of visual acuity followed. Middle column shows the difference among subtypes of AMD. Patients with typical AMD (tAMD) or polypoidal choroidal vasculopathy (PCV) showed significant improvement from baseline. The number of retinal angiomatous (RAP) patients was relatively small and the changes from baseline were not significant. While the difference was not significant at baseline, tAMD patients showed worse final visual acuity than PCV patients. CRT improved in each subtype and there was no difference in the final CRT or improvement of CRT. Right column shows the result of patients with good (better than 0.5 or 20/40) visual acuity (VA ). Treatment with aflibercept was beneficial for both groups. While there was a difference in baseline CRT, final CRT was not different.

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Table 1: Characteristics at baseline and 12 months after the initiation of aflibercept treatment in age-related macular degeneration patients baseline 12 month P value Age (years) 75.7

(74.1 77.3)

Sex (man/woman) 62/36 Subtype (tAMD/PCV/RAP)

46/42/10

logMAR (unit) 0.36 (0.29 0.43)

0.21 (0.12 0.29)

6.356 10-10

GLD (m) 3990.6 (3541.5 4439.7)

3569.0 (3167.9 3970.2)

0.001

lesion size (mm2) 3.77 (3.36 4.18)

3.86 (3.43 4.29)

0.548

CRT (m) 318.3 (289.5 347.1)

176.1 (157.6 194.6)

1.266 10-14

Maximum PED (m) 247.8 (204.9 290.7)

117.9 (94.2 141.6)

1.085 10-9

Choroidal thickness (m)

248.1 (226.9 269.3)

222.5 (202.3 242.5)

3.842 10-12

Intact foveal ELM (+/-)

68/30 72/26 0.421

Intact foveal ISe (+/-)

48/50 57/41 0.193

Vitreoretinal adhesion (+/-)

27/71 21/77 0.311

Continuous values are shown as mean and 95% confidential interval. tAMD: typical age-related macular degeneration; PCV: polypoidal choroidal vasculopathy; RAP: retinal angiomatous proliferation; logMAR: logarithm of minimal angle of resolution; GLD: greatest linear dimension; CRT: central retinal thickness; PED: pigment epithelium detachment; ELM: external limiting membrane; ISe: inner segment ellipsoid

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Table 2: Prevalence of dry macula in age-related macular degeneration (AMD) patients treated with aflibercept

3 month 6 month 9 month 12 month Overall (95 % CI)

0.65 (0.56 - 0.74)

0.66 (0.57 - 0.76)

0.70 (0.61 - 0.79)

0.63 (0.53 - 0.72)

tAMD 0.49 (0.34 - 0.63)

0.43 (0.29 0.58)

0.39 (0.25 0.53)

0.47 (0.32 0.61)

PCV 0.79 ( 0.66- 0.91)

0.81 ( 0.69- 0.93)

0.81 ( 0.69- 0.93)

0.71 (0.58 0.85)

RAP 0.70 (0.41 0.98)

0.50 (0.19 0.80)

0.60 ( 0.29 0.90)

0.60 ( 0.29 0.90)

Visual acuity 0.5 (20/40)

0.68 (0.55 0.80)

0.72 (0.59 0.83)

0.73 (0.61 0.85)

0.71 (0.60 0.83)

CI: confidential interval: tAMD: typical age-related macular degeneration; PCV: polypoidal choroidal vasculopathy; RAP: retinal angiomatous proliferation

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Table 3: The result of univariate analysis between baseline characteristics and visual acuity at 12-month in age-related macular degeneration patients treated with aflibercept. Peasons correlation

coefficient P value

Age 0.213 0.037* GLD 0.371 2.518 10-4* CRT 0.355 3.880 10-4* Spearmans rank correlation

coefficient

Polypoidal lesion -0.348 0.001* ELM -0.607 5.743 10-11* ISe -0.569 1.406 10-9* logMAR: logarithm of minimal angle of resolution; GLD: greatest linear dimension; CRT: central retinal thickness; ELM: external limiting membrane; ISe: inner segment ellipsoid * indicates statistical significance.

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Table 4: Visual outcome prediction model after step-wise selection in age-related macular degeneration patients treated with aflibercept variables Unstandardized

coefficient beta 95 % CI Standardized

coefficient beta P value

Constant 0.390 0.215 0.564 2.578 10-5 ELM -0.482 -0.609 -0.355 -0.581 4.027 10-11 GLD 4.968 10-5 1.869 10-5

8.067 10-5 0.244 0.002

Polypoidal lesion

-0.146 -0.260 -0.031 -0.191 0.013

CI: confidence interval ELM: external limiting membrane; GLD: greatest linear dimension

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BiosketchBiosketchBiosketchBiosketch

Akio Oishi, M.D., Ph.D. is an assistant professor at Department of Ophthalmology and

Visual Sciences, Kyoto University. He received M.D. and Ph.D. at Kyoto University

Graduate School of Medicine. His interest includes imaging and treatment of retinal

diseases.

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