2.1. Study Design and Participants
We retrospectively evaluated Japanese patients aged 50 years or older with newly diagnosed nAMD, including typical AMD, PCV, and type 3 neovascularization at Kawasaki Medical School between May 2016 and January 2021. The study was complied with the principles of the Declaration of Helsinki. The study was performed with the approval of the Institutional Review Board of Kawasaki Medical School Ethics Committee (2543-1) and is registered in the UMIN Clinical Trials Registry (UMIN000023676). The inclusion criteria were the presence of nAMD diagnosed by funduscopic, swept-source optical coherence tomographic (OCT) (DRI OCT-1 Atlantis; Topcon Corporation, Tokyo, Japan), and angiographic findings (HRA-2; Heidelberg Engineering GmbH, Dossenheim, Germany), and a best-corrected visual acuity (BCVA) of 20/400 or better at baseline. Data on cigarette smoking were obtained from hospital records and patient recall. The patients were divided into never-, former-, and current-smoker groups. Former and current smokers were those who smoked at least 1 cigarette per day for more than 1 year in their lifetime. Former smokers were those who did not smoke at baseline and had quit smoking for at least 1 year. The patients were treated with aflibercept (Bayer AG, Leverkusen, Germany) for at least one year. Patients who had received or were receiving other anti-VEGF agents (bevacizumab, pegaptanib, ranibizumab) or had undergone laser photocoagulation, verteporfin photodynamic therapy, or submacular surgery were excluded, as were those with choroidal neovascularization (CNV) as a result of high myopia, angioid streaks, or uveitis. Patients with eye diseases that could potentially influence the clinical features of the studied eyes, such as glaucoma, diabetic retinopathy, or rhegmatogenous retinal detachment, were also excluded.
2.2. Group Classification
We classified drusen subtypes into four groups depending on the condition of the fellow eye as follows: no significant drusen, soft drusen, SDDs, or pachydrusen. The type of drusen was determined using fundus color photographs and swept-source OCT according to the criteria presented in a previous study10. The no significant drusen group included eyes without drusen or eyes with small drusen (size: <63 µm) or few intermediate drusen (number: <20 lesions, size: <125 µm). The soft drusen group included eyes with numerous intermediate drusen (number: ≥20 lesions, size: ≥63 µm and < 125 µm) or one large drusen (size: ≥125 µm) according to the Age-Related Eye Disease Study (AREDS). Eyes with pachydrusen and soft drusen or SDDs were classified into the soft drusen or SDDs group, respectively. Eyes with soft drusen and SDDs were classified into the SDDs group. The subtype of neovascular AMD (typical AMD, PCV, or type 3 neovascularization) was comprehensively diagnosed on the basis of the findings of fundoscopy, angiography, OCT, fluorescein angiography (FA), and indocyanine green angiography (ICGA). The diagnosis of PCV was based on ICGA findings, including polypoidal structures at the borders of the branching choroidal vascular networks. The diagnosis of type 3 neovascularization was based on the characteristic findings of retinal pigment epithelial detachment with overlying cystic retinal edema on OCT images, intraretinal hemorrhage, and intraretinal vascular anastomoses. Typical nAMD was characterized by the presence of exudative changes due to CNV on FA and ICGA.
2.3. Treatment and Assessments
Treatment-naïve nAMD patients received intravitreal aflibercept at Kawasaki Medical School between May 2016 and January 2021. All patients received 3 monthly injections of the anti-VEGF agent initially on a pro re nata basis. If recurrence, including new macular hemorrhage, intraretinal fluid, and subretinal fluid, was observed, anti-VEGF therapy based on a pro re nata or treat-and-extend regimen was resumed. All the included patients were followed for 12 months or longer after the initial intravitreal administration of aflibercept and provided written informed consent for treatment with an anti-VEGF agent and participation in the study. The patients underwent a comprehensive ophthalmological examination, including BCVA measurement, slit-lamp biomicroscopy, indirect fundoscopy, fundus color photography, and swept-source OCT. The treatment outcome measures were the change in BCVA and retinal thickness at baseline and 1 year after the start of anti-VEGF therapy, respectively, as well as the number of injections received, the rate of dry macula after the loading dose, and the retreatment-free period after the loading dose. The BCVA was recorded as decimal values, followed by conversion to the logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. Central retinal thickness (CRT) was defined as the mean retinal thickness measured at the fovea as previously described .
2.4. Statistical Analysis
The results are presented as means and standard deviations. One-way ANOVA followed by Sidak’s test was performed to compare age, BCVA, retinal thickness at the fovea, and the number of injections received among the nAMD-stratified smoking history groups. The chi-square test followed by residual analysis concerning cross-tabulation was used to compare the proportions of sex, drusen subtype, nAMD subtype, and rate of dry macula after the loading dose among the nAMD-stratified smoking history groups. Kaplan-Meier analysis was performed to estimate the incidence of nAMD in the fellow eye and the retreatment-free period after the loading dose. Statistical analyses were performed using Ekuseru-Toukei 2012 (Social Survey Research Information Co., Ltd, Tokyo, Japan). P-values < 0.05 were considered statistically significant in all analyses. * Chi-square test.