Switching to aflibercept 8 mg in neovascular age-related macular degeneration: real-world outcomes and differential response by switch indication

Switching to aflibercept 8 mg in neovascular age-related macular degeneration: real-world outcomes and differential response by switch indication | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Switching to aflibercept 8 mg in neovascular age-related macular degeneration: real-world outcomes and differential response by switch indication Daniele Veritti, Valentina Sarao, Marco Lupidi, Pasquale Viggiano, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9312361/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To evaluate visual and anatomical outcomes after switching to aflibercept 8 mg in eyes with neovascular age-related macular degeneration (nAMD), and to assess outcomes according to the clinical indication for switching. Methods: Multicentre retrospective observational study including 300 eyes with nAMD previously treated with anti–vascular endothelial growth factor therapy and switched to aflibercept 8 mg for non-response, suboptimal response, or durability-driven reasons. Longitudinal data from the 6 months preceding the switch and post-switch visits at 3 and 6 months were analyzed. The primary outcome was change in best-corrected visual acuity (BCVA, ETDRS letters) from the switch visit to the 3-month post-switch visit. Secondary outcomes included changes in central subfield thickness (CST) and retinal fluid status. Results: During the pre-switch period, mean BCVA declined by −1.9±8.2 letters and CST increased. At 3 months after switching, BCVA improved by +2.0±9.2 letters (95% CI, +0.8 to +3.2; p<0.01), with greater gains in eyes switched for non-response (+2.8±12.6 letters). Mean CST decreased by −45.3±79.8 µm (95% CI, −55.4 to −35.2; p<0.001), with corresponding reductions in retinal fluid. Anatomical improvements were more pronounced in eyes switched for non-response, whereas more modest but consistent changes were observed in suboptimal and durability-driven groups. Visual and anatomical outcomes were maintained at 6 months. Conclusions: In previously treated nAMD eyes, switching to aflibercept 8 mg was associated with reversal of pre-switch anatomical worsening, reduction in retinal fluid, and modest visual gains. Greater responses were observed in eyes with inadequate pre-switch disease control, supporting its role as a treatment escalation strategy in clinical practice. aflibercept 8 mg anti-vascular endothelial growth factor therapy intravitreal injections neovascular age-related macular degeneration real-world study treatment switch Figures Figure 1 Figure 2 Figure 3 Key message What is known: Aflibercept 8 mg has demonstrated non-inferior visual outcomes with extended dosing intervals compared with standard-dose anti-VEGF therapy in randomized clinical trials, suggesting improved treatment durability in neovascular age-related macular degeneration. What is new: In a large multicentre real-world cohort of previously treated nAMD eyes, switching to aflibercept 8 mg was associated with reversal of pre-switch anatomical worsening, significant reduction in retinal fluid, and stable or modestly improved visual acuity up to 6 months. Treatment response varied according to the clinical indication for switching, with greater anatomical improvements observed in eyes with inadequate disease control prior to switch, supporting aflibercept 8 mg as a treatment escalation strategy in routine clinical practice. Introduction Neovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible central vision loss in older adults and represents a major public health burden in aging populations [ 1 ]. The introduction of intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy has fundamentally changed the management of nAMD, allowing stabilization or improvement of visual acuity in a substantial proportion of patients and markedly reducing the risk of severe vision loss [ 2 – 6 ]. However, the long-term effectiveness of anti-VEGF therapy in routine clinical practice is tempered by the need for repeated intravitreal injections and close monitoring over prolonged periods. Even when proactive regimens such as treat-and-extend are adopted, treatment burden remains substantial, and real-world outcomes frequently fall short of those reported in pivotal clinical trials [ 7 , 8 ]. Persistent or recurrent exudative activity, limited interval extension, and progressive anatomical changes continue to be observed in a relevant proportion of treated eyes, underscoring the need for therapeutic strategies with improved durability [ 9 ]. In response to these limitations, longer-acting anti-VEGF approaches have been developed with the aim of sustaining disease control while reducing injection frequency. Aflibercept 8 mg represents a higher-dose formulation delivering a fourfold increase in molar dose compared with the standard 2 mg regimen. This formulation has been associated with prolonged intraocular VEGF suppression and enhanced durability in preclinical and pharmacokinetic evaluations [ 10 , 11 ]. The clinical efficacy and safety of aflibercept 8 mg have been established in randomized controlled trials. The phase 3 PULSAR trial showed that aflibercept 8 mg administered at 12- or 16-week intervals achieved non-inferior visual outcomes relative to aflibercept 2 mg every 8 weeks, while enabling extended dosing intervals in a substantial proportion of patients with nAMD [ 12 , 13 ]. Beyond the controlled setting of clinical trials, early real-world evidence has begun to emerge, suggesting that aflibercept 8 mg may offer anatomical stabilization and extension of treatment intervals in previously treated nAMD populations. Multicentre observational studies and single-centre series have reported stable visual acuity, reduction of retinal fluid, and a favourable short-term safety following transition to aflibercept 8 mg [ 14 – 16 ]. Nevertheless, these reports typically evaluate switched eyes as a single, heterogeneous group and provide limited information on disease behaviour prior to the switch. Detailed characterization of disease activity before switching remains limited in the available literature. Particularly, few studies incorporate longitudinal data from the months preceding the treatment change, a period that is critical for contextualizing anatomical response, treatment burden, and durability under prior anti-VEGF therapy. Moreover, the extent to which different clinical motivations for switching—such as inadequate anatomical response, suboptimal durability, or the pursuit of longer treatment intervals in otherwise controlled eyes—may influence post-switch outcomes remains insufficiently explored. The present multicentre real-world study was designed to address these gaps by focusing exclusively on previously treated nAMD patients switched to aflibercept 8 mg. Detailed longitudinal data from the six months preceding the switch provide the opportunity to interpret post-switch outcomes in relation to different clinical indications for switching. Methods Study Design and Setting This was a multicentre, observational, real-world study conducted across 9 Italian retina centers (University of Udine, Udine; University of Bari "Aldo Moro", Bari; Polytechnic University of Marche, Ancona; University of Rome Tor Vergata, Rome; IRCCS-Fondazione Bietti, Rome; Catholic University "Sacro Cuore", Rome; Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, Bari; University of Turin, Turin; "G. d'Annunzio" University Chieti-Pescara, Chieti). Consecutive patients with nAMD who were switched to intravitreal aflibercept 8 mg as part of routine clinical care between March 2024 and September 2025 were included. Clinical data were collected retrospectively from electronic medical records and standardized data collection forms. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board. Given the retrospective nature of the study, informed consent was obtained or waived according to local regulations governing observational studies based on routinely collected clinical data. 2. Participants Eligible participants were adults with a diagnosis of nAMD who had received prior intravitreal anti-VEGF therapy and were subsequently switched to aflibercept 8 mg. Eyes were included if complete demographic information and longitudinal clinical data were available. Specifically, inclusion required availability of (1) baseline demographic and disease characteristics; (2) longitudinal pre-switch data spanning approximately 6 months before switching, including at least two visits with best-corrected visual acuity (BCVA) and optical coherence tomography (OCT); and (3) clinical data at the switch visit corresponding to the first aflibercept 8 mg injection. A post-switch follow-up visit 3 months after switching was prespecified for outcome analyses. Additional post-switch visits, when available, were used for descriptive or exploratory analyses. When both eyes of a patient met eligibility criteria, only one eye was included to avoid within-patient correlation. In such cases, the eye first switched during the study period was selected. 3. Clinical data and imaging Demographic variables included age and sex. Baseline disease characteristics comprised macular neovascularization (MNV) subtype, eye laterality, disease duration, total number of intravitreal injections before switching, anti-VEGF agent used immediately prior to switching, and the last documented treatment interval. BCVA was recorded at each visit as part of routine clinical assessment. When necessary, BCVA values were converted to approximate ETDRS letter scores using established conversion methods. Spectral-domain or swept-source OCT was performed according to site-specific clinical protocols. Anatomical data were extracted from OCT scans acquired during routine clinical care. Central subfield thickness (CST) values were obtained from automated device measurements, after verification of correct retinal layer segmentation. The presence of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelium detachment (PED) was recorded by the treating physician at each visit and was documented as binary variables (present or absent). The decision to perform a loading phase was left to the treating physician and reflected routine clinical practice. A loading phase was defined as the administration of at least three consecutive intravitreal injections within the first 12 weeks following the switch, corresponding to an initial monthly dosing regimen. 4. Classification of switch indication The clinical indication for switching to aflibercept 8 mg was classified into one of three prespecified categories based on longitudinal clinical and OCT findings during the 3 months preceding the switch, together with the treating physician’s documented rationale. To improve reproducibility, predefined operational criteria were applied: Non-response was defined as persistent/increasing IRF and/or SRF at all available visits during the preceding 3 months, with no meaningful anatomical improvement (defined as a reduction in CST < 10%) and stable or worsening visual acuity (BCVA change ≤ 0 letters), despite ongoing treatment at regular or intensified intervals [ 17 ]. Suboptimal response was defined as partial anatomical response under prior anti-VEGF therapy, characterized by a CST reduction ≥ 10% compared with earlier visits but persistent fluid (IRF, SRF, and/or PED) at one or more visits in the preceding 3 months. These eyes typically showed incomplete disease inactivation or fluctuating exudative activity, with stable or mildly improved BCVA [ 17 ]. Durability-driven switch was defined as a treatment change performed primarily to extend treatment intervals in eyes with controlled or near-controlled disease. These eyes showed absence of IRF/SRF at the last pre-switch visit, stable CST (variation < 10% over the preceding visits), and stable BCVA, but required relatively short treatment intervals (≤ 8 weeks) to maintain disease control [ 18 ]. Although predefined criteria were applied, classification retained a degree of clinical judgment, reflecting real-world decision-making in routine practice. 5. Outcomes and study timepoints The primary outcome was change in BCVA from the switch visit to the 3-month post-switch visit. Secondary outcomes included changes in CST and in the presence of IRF, SRF, and PED. Additional secondary analyses evaluated functional and anatomical outcomes at the 6-month post-switch visit. Descriptive analyses further characterized disease activity during the pre-switch period. To ensure consistent temporal alignment across centres, prespecified time windows were applied. The switch visit was defined as the visit at which the first aflibercept 8 mg injection was administered. The pre-switch period was defined as the 6 months preceding the switch visit. The 3-month post-switch visit was defined as the visit closest to 90 days after the switch (± 15 days). The 6-month post-switch visit was defined as the visit closest to 180 days after the switch (± 30 days). 6. Statistical Analysis Continuous variables were summarized as mean ± standard deviation or median (interquartile range), as appropriate, while categorical variables were reported as counts and percentages. Changes in continuous outcomes, including BCVA and CST, were evaluated using paired comparisons between predefined timepoints (6-month pre-switch visit, switch visit, 3-month post-switch visit, and 6-month post-switch visit). Corresponding mean changes and 95% confidence intervals were calculated. Comparisons between groups were performed using Student’s t-test or Mann–Whitney U test for continuous variables, and one-way ANOVA or Kruskal–Wallis test for comparisons across multiple groups, as appropriate. Categorical variables were compared using chi-square or Fisher’s exact test, while paired categorical comparisons across timepoints were performed using the McNemar test. Normality of data distribution was assessed using the Shapiro–Wilk test. Multivariable regression analyses were performed to identify clinical and anatomical factors associated with functional (BCVA change) and anatomical (CST change) outcomes at the 3-month post-switch visit. Covariates included BCVA or CST at the switch visit, switch indication category, macular neovascularization subtype, presence of IRF, SRF, or PED at the switch visit, subfoveal atrophy, macular fibrosis, prior anti-VEGF agent, and treatment centre. All analyses were considered exploratory in nature, and statistical significance was interpreted cautiously in light of the observational study design. Statistical analyses were performed using IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY, USA). Results 1. Study population and baseline characteristics A total of 300 eyes from 300 patients with nAMD were included in the analysis. All included eyes had complete demographic, functional, and imaging data available for the 6-month pre-switch period, the switch visit, and the 3- and 6-month post-switch visits. During the follow-up period, the mean number of aflibercept 8 mg injections administered was 3.3 ± 1.3. At the 6-month post-switch visit, the mean treatment interval was 9.4 ± 3.7 weeks, with 57.7% of eyes achieving an interval of 12 weeks or longer. Baseline demographic and clinical characteristics at the switch visit are summarized in Table 1 . Type 1 MNV was the most frequent subtype, accounting for 181 eyes (60.3%), followed by Type 2 in 51 eyes (17.0%), polypoidal choroidal vasculopathy in 32 eyes (10.7%), mixed MNV in 20 eyes (6.7%), and Type 3 in 16 eyes (5.3%). Subfoveal retinal pigment epithelium atrophy was present in 78 eyes (26.0%), while subretinal macular fibrosis was observed in 104 eyes (34.7%). The primary indication for switching was suboptimal response in 53% of eyes, non-response in 24.7%, and a durability-driven strategy in 22.3%. A loading phase with aflibercept 8 mg was performed in 156 eyes (52.0%), while 144 eyes (48.0%) did not receive a loading phase. Table 1 Baseline demographic and clinical characteristics at the switch visit Characteristic (mean ± SD; median [IQR] unless otherwise specified) Value Age, years 78.2 ± 7.6; 79 [73–84] Female sex, n (%) 159 (53.0) Disease duration, months 30.1 ± 24.6; 27 [13–48] Total anti-VEGF injections before switch 13.9 ± 8.1; 12 [ 7 – 19 ] Anti-VEGF injections in prior 6 months 3.5 ± 1.1; 3 [ 2 – 6 ] BCVA at switch visit, ETDRS letters 60.1 ± 19.5; 65 [50–75] CST at switch visit, µm 314.1 ± 120.9; 289 [232–370] Intraretinal fluid present, n (%) 150 (50.0) Subretinal fluid present, n (%) 164 (54.7) Pigment epithelium detachment present, n (%) 206 (68.7) Last anti-VEGF agent before switch, n (%) – Aflibercept 2 mg 226 (75.3) – Bevacizumab 47 (15.7) – Faricimab 20 (6.7) – Brolucizumab 5 (1.7) – Ranibizumab 2 (0.7) Last treatment interval before switch, n (%) – q4 weeks 88 (29.3) – q6 weeks 30 (10.0) – q8 weeks 114 (38.0) – q10 weeks 8 (2.7) – q12 weeks 46 (15.3) – q16 weeks 14 (4.7) Switch indication, n (%) – Non-response 74 (24.7) – Suboptimal response 159 (53.0) – Durability-driven switch 67 (22.3) Legend: BCVA: best corrected visual acuity; CST: central subfield thickness; ETDRS: Early Treatment Diabetic Retinopathy Study; IQR: interquartile range; n: number; qX=dosing interval of X weeks; SD: standard deviation; VEGF: vascular endothelial growth factor. 2. Functional outcomes Functional outcomes over time are reported in Table 2 and Fig. 1 . At the 6-month pre-switch visit, mean BCVA was 62.0 ± 19.0 ETDRS letters. From the 6-month pre-switch visit to the switch visit, mean BCVA decreased to 60.1 ± 19.5 letters, corresponding to a mean change of − 1.9 ± 8.2 letters. Table 2 Functional and anatomical parameters over time Outcome Pre-switch (− 6 months) Switch visit (baseline) Change from pre-switch 3-month post-switch Change from switch (3 months) 6-month post-switch Change from switch (6 months) BCVA overall mean ± SD 62.0 ± 19.0 60.1 ± 19.5 −1.9 ± 8.2 62.1 ± 20.1 + 2.0 ± 9.2 62.1 ± 20.2 + 2.0 ± 8.9 Non-response 63.6 ± 16.4 60.0 ± 18.6 −3.6 ± 9.5 62.8 ± 17.9 + 2.8 ± 12.6 63.0 ± 18.0 + 3.0 ± 13.1 Suboptimal response 59.4 ± 21.4 57.7 ± 21.3 −1.6 ± 8.3 59.5 ± 22.1 + 1.8 ± 7.1 59.1 ± 22.4 + 1.4 ± 6.8 Durability-driven switch 66.4 ± 13.9 65.8 ± 14.4 −0.6 ± 6.2 67.4 ± 16.1 + 1.6 ± 9.4 68.0 ± 15.0 + 2.3 ± 7.7 CST overall , mean ± SD 298.1 ± 109.0 314.1 ± 120.9 + 16.0 ± 99.5 268.9 ± 85.0 −45.3 ± 79.8 269.7 ± 89.1 −44.4 ± 87.5 Non-response 341.5 ± 120.9 389.2 ± 154.0 + 47.7 ± 131.7 295.6 ± 105.2 −93.6 ± 104.6 297.1 ± 102.7 −92.1 ± 114.5 Suboptimal response 284.9 ± 104.1 289.7 ± 93.1 + 4.8 ± 93.6 260.2 ± 76.5 −29.5 ± 62.4 261.8 ± 86.5 −27.9 ± 73.1 Durability-driven switch 281.2 ± 94.5 288.7 ± 103.7 + 7.5 ± 56.8 259.6 ± 73.8 −29.1 ± 62.7 257.7 ± 72.8 −31.0 ± 63.5 IRF present, n (%) 138 (46.0) 150 (50.0) + 12 (+ 4.0%) 32 (10.7) −118 (− 39.3%) 76 (25.3) −74 (− 24.7%) SRF present, n (%) 152 (50.7) 164 (54.7) + 12 (+ 4.0%) 62 (20.7) −102 (− 34.0%) 76 (25.3) −88 (− 29.4%) PED present, n (%) 196 (65.3) 206 (68.7) + 10 (+ 3.4%) 170 (56.7) −36 (− 12.0%) 179 (59.7) −27 (− 9.0%) Legend: BCVA: best corrected visual acuity; CST: central subfield thickness; IRF: intraretinal fluid; n:number; PED: pigment epithelium detachment; SD: standard deviation; SRF: subretinal fluid; Δ: change; Changes in fluid presence are expressed as absolute differences in number of eyes and corresponding percentage-point changes. At the 3-month post-switch visit, mean BCVA improved to 62.1 ± 20.1 letters, corresponding to a mean gain of + 2.0 ± 9.2 letters relative to the switch visit (95% CI, + 0.8 to + 3.2; p < 0.01). At the 6-month post-switch visit, mean BCVA was 62.1 ± 20.2 letters, corresponding to a mean change of + 2.0 ± 8.9 letters versus the switch visit (95% CI, + 0.8 to + 3.1; p < 0.01). When stratified by switch indication, eyes switched for non-response exhibited the largest mean BCVA gains, with increases of + 2.8 ± 12.6 letters at the 3-month post-switch visit and + 3.0 ± 13.1 letters at the 6-month post-switch visit. Eyes switched for suboptimal response and those switched for durability-driven reasons showed comparable functional trajectories, characterized by modest but sustained BCVA improvements after switching (+ 1.8 ± 7.1 and + 1.6 ± 9.4 letters at 3 months, respectively; p < 0.01). These gains were maintained at 6 months (+ 1.4 ± 6.8 and + 2.3 ± 7.7 letters, respectively; p < 0.01). When outcomes were analyzed according to loading phase strategy, the distribution of switch indications differed significantly between groups (p < 0.001): eyes receiving a loading phase were more frequently switched for non-response (36.5% vs 11.8%) or suboptimal response (53.8% vs 52.1%), whereas eyes not receiving a loading phase were more often switched for durability-driven reasons (36.1% vs 9.6%). In the overall comparison, eyes treated with a loading phase showed a greater BCVA improvement at the 3-month post-switch visit compared with those without (+ 3.4 ± 9.1 vs + 0.5 ± 9.1 letters; p = 0.006). When stratified by switch indication, the functional benefit associated with the loading phase was most evident in eyes switched for suboptimal response (+ 3.6 ± 6.8 vs − 0.2 ± 6.8 letters; p < 0.001). A similar trend was observed in eyes switched for non-response (+ 4.1 ± 12.4 vs − 1.6 ± 12.4 letters; p = 0.10). In contrast, no significant difference was observed in eyes switched for durability-driven reasons (− 0.5 ± 9.3 vs + 2.2 ± 9.3 letters; p = 0.33). 3. Anatomic outcomes Anatomical outcomes are summarized in Table 2 and Fig. 2 . At the 6-month pre-switch visit, mean CST was 298.1 ± 109.0 µm. From the 6-month pre-switch visit to the switch visit, mean CST increased to 314.1 ± 120.9 µm, corresponding to a mean change of + 16.0 ± 99.5 µm. At the 3-month post-switch visit, mean CST decreased to 268.9 ± 85.0 µm, representing a mean reduction of − 45.3 ± 79.8 µm relative to the switch visit (95% CI, − 55.4 to − 35.2; p < 0.001). At the 6-month post-switch visit, mean CST was 269.7 ± 89.1 µm, corresponding to a mean change of − 44.4 ± 87.5 µm versus the switch visit (95% CI, − 55.6 to − 33.4; p < 0.001). When stratified by switch indication, eyes switched for non-response exhibited the largest anatomical improvements, with mean CST reductions of − 93.6 ± 104.6 µm at the 3-month post-switch visit and − 92.1 ± 114.5 µm at the 6-month post-switch visit. Eyes switched for suboptimal response and those switched for durability-driven reasons showed more modest but consistent CST reductions after switching, with mean changes of − 29.5 ± 62.4 µm and − 29.1 ± 62.7 µm at 3 months, respectively. These reductions were maintained at 6 months (− 27.9 ± 73.1 µm and − 31.0 ± 63.5 µm, respectively), with comparable anatomical trajectories between these two subgroups. The proportion of eyes with IRF and SRF decreased after switching. Detailed changes in individual fluid compartments (IRF, SRF, and PED) across timepoints are reported in Table 2 and illustrated in Fig. 3 . 4. Multivariable analyses After multivariable adjustment, the presence of IRF and SRF at the switch visit were independently associated with a smaller BCVA gain at the 3-month post-switch visit (IRF: β − 2.70 letters, P = 0.017; SRF: β − 3.52 letters, P = 0.006), whereas PED was not. Higher BCVA at the switch visit predicted a smaller subsequent BCVA change (β − 0.084 letters per letter; P = 0.029). Fibrosis, subfoveal atrophy, and MNV subtype were not associated with BCVA change. In the morphological model, CST at the switch visit was the strongest predictor of CST reduction (β − 0.519 µm per µm; p < 0.001), while fluid status at the switch visit, MNV subtype, fibrosis, and subfoveal atrophy were not independently associated with CST change (all p ≥ 0.08). 5. Safety No treatment-related serious adverse events, including intraocular inflammation or endophthalmitis, were recorded during the study period. Discussion In this real-world study, switching to aflibercept 8 mg was associated with meaningful anatomical improvement accompanied by a visual gain in a large, clinically diverse but predominantly treatment-experienced and challenging cohort of eyes with nAMD. Importantly, the observed decline in BCVA and increase in CST during the pre-switch period indicate that a substantial proportion of eyes represented a clinically challenging subgroup with insufficient disease control under prior anti-VEGF therapy. This selection pattern is inherent to switch studies in routine practice and should be considered when interpreting post-switch outcomes. Therefore, the cohort reflects real-world clinical decision-making, where treatment escalation is typically considered in eyes with evidence of disease instability or insufficient response. Within this context, a central finding of this study is the capacity of aflibercept 8 mg to counteract a documented trajectory of anatomical worsening in eyes switched for non-response or suboptimal response. In these subgroups, progressive increases in CST during the months preceding the switch, together with persistent or increasing retinal fluid, indicated insufficient disease control under prior treatment regimens. Following initiation of aflibercept 8 mg, anatomical outcomes improved and were subsequently maintained throughout follow-up, effectively offsetting the pre-switch deterioration. This pattern indicates that the observed post-switch changes reflect not only anatomical improvement, but also a modification of a previously progressive or unstable disease course. These findings are broadly consistent with prior real-world studies of aflibercept 8 mg in switched nAMD populations, which have generally reported anatomical improvement with limited functional gains. 13–16,19 However, most of these reports focused exclusively on post-switch outcomes, without accounting for the disease trajectory preceding treatment escalation. By anchoring post-switch responses to a clearly defined pre-switch course, the present analysis strengthens interpretation of treatment effects, helps contextualize post-switch changes and mitigates the risk of over-attributing regression toward the mean to treatment escalation. At the functional level, visual acuity remained largely stable across the cohort, with modest gains observed during follow-up. This finding is consistent with expectations in switched populations characterized by relatively preserved baseline BCVA and long-standing disease. In such eyes, ceiling effects and irreversible structural damage—including macular fibrosis or atrophy—are likely to limit the potential for substantial visual improvement despite effective anatomical control. Within this context, maintenance of visual acuity, particularly in eyes showing deterioration prior to switching, represents a clinically relevant outcome. Of note, in eyes switched for inadequate response, a complete loading phase was associated with greater BCVA gains, suggesting that treatment intensification may be beneficial when switching is driven by suboptimal disease control. Eyes switched primarily for durability-related reasons represent a distinct clinical phenotype within the cohort. At the time of switching, these eyes were generally under apparent anatomical control, with treatment escalation driven by the goal of extending dosing intervals and reducing treatment burden. Despite relative functional stability at baseline, this subgroup showed a small but consistent improvement in BCVA following the switch. Although modest in magnitude, this finding suggests that functional optimization may still be observed even in eyes considered well controlled. Similar signals have been reported sporadically in smaller real-world series [ 13 , 19 – 21 ], but remain insufficiently explored in larger cohorts. Analysis of individual retinal fluid compartments further clarifies the treatment response. The marked reduction in proportion of patients with IRF and SRF following the switch is consistent with evidence from both pivotal trials and real-world studies of aflibercept 8 mg, supporting its enhanced potency and durability [ 13 , 22 – 25 ]. In contrast, PED followed a more variable and frequently persistent course and was not independently associated with functional outcomes. This differential behaviour is consistent with established pathophysiological models in which IRF and SRF more directly reflect VEGF-driven exudation, whereas PED likely represents more complex or structurally established disease features with limited short-term functional relevance [ 26 ]. Several limitations of this study should be acknowledged. First, the retrospective design and the absence of a control group limit causal inference. Second, treatment regimens were not standardized and reflected routine clinical decision-making. In particular, the classification of switch indication and the decision to perform a loading phase were left to the treating physician, potentially introducing variability across centres. The comparison between eyes receiving a loading phase and those without should therefore be interpreted with caution, as these groups differed in baseline characteristics and switch indications, raising the possibility of selection bias. Third, the relatively short follow-up limits conclusions regarding long-term durability and visual outcomes. Finally, anatomical assessment was based on central subfield thickness and qualitative evaluation of retinal fluid, without quantitative volumetric analysis, and OCT data were derived from routine clinical interpretation rather than centralized reading, which may have introduced additional variability. Nonetheless, the relatively large sample size and inclusion of a broad spectrum of clinical phenotypes support the external validity and real-world relevance of the findings. In conclusion, in a large and heterogeneous real-world cohort of switched nAMD eyes, aflibercept 8 mg was associated with reversal of pre-switch anatomical deterioration, sustained reduction in retinal fluid, and overall visual stability with modest functional gains. The differential responses observed across switch indications highlight the importance of individualized treatment strategies and realistic expectation setting. These findings complement existing trial and real-world evidence and support the role of aflibercept 8 mg as a treatment escalation option in contemporary nAMD management. Declarations Ethics approval: The study adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Boards of the participating centres according to national regulations governing retrospective observational studies based on routinely collected clinical data. Consent to participate: Due to the retrospective nature of the study, informed consent was obtained or waived according to local institutional requirements. Consent for publication: Not applicable. Conflict of interest: Daniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch & Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none Competing Interests Daniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch & Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none Funding information: The research activity conducted at IRCCS-Fondazione Bietti was supported by the Italian Ministry of Health and Fondazione Roma. The funding sources had no role in study design, data collection, data analysis, interpretation of the results, writing of the manuscript, or decision to submit the article for publication. Author Contribution Daniele Veritti, Valentina Sarao, Marco Lupidi and Paolo Lanzetta contributed to the study conception and design. All authors performed material preparation and data collection. Analysis was performed by Daniele Veritti and Valentina Sarao. The first draft of the manuscript was written by Daniele Veritti, and all authors commented on previous versions. All authors read and approved the final manuscript. Data Availability The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. References Wong WL, Su X, Li X et al (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2:e106–e116. https://doi.org/10.1016/S2214-109X(13)70145-1 Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444. https://doi.org/10.1056/NEJMoa062655 Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431. https://doi.org/10.1056/NEJMoa054481 Heier JS, Brown DM, Chong V et al (2012) Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 119:2537–2548. https://doi.org/10.1016/j.ophtha.2012.09.006 Dugel PU, Koh A, Ogura Y et al (2020) HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127:72–84. https://doi.org/10.1016/j.ophtha.2019.04.017 Heier JS, Khanani AM, Quezada Ruiz C et al (2022) Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 399:729–740. https://doi.org/10.1016/S0140-6736(22)00010-1 Ciulla TA, Hussain RM, Pollack JS et al (2020) Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients. Ophthalmol Retina 4:19–30. https://doi.org/10.1016/j.oret.2019.08.010 Veritti D, Sarao V, Soppelsa V et al (2022) Managing neovascular age-related macular degeneration in clinical practice: systematic review, meta-analysis, and meta-regression. J Clin Med 11:325. https://doi.org/10.3390/jcm11020325 Gillies MC, Hunyor AP, Arnold JJ et al (2019) Effect of ranibizumab and aflibercept on best-corrected visual acuity in treat-and-extend for neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol 137:372–379. https://doi.org/10.1001/jamaophthalmol.2018.6796 Korobelnik JF, Lanzetta P, Wykoff CC et al (2024) Sustained disease control with aflibercept 8 mg: a new benchmark in the management of retinal neovascular diseases. Eye (Lond) 38:3218–3221. https://doi.org/10.1038/s41433-024-03055-6 Veritti D, Sarao V, Lanzetta P (2025) Extended duration of VEGF inhibition with aflibercept 8 mg: the role of reduced ocular clearance. Graefes Arch Clin Exp Ophthalmol 263:2985–2987. https://doi.org/10.1007/s00417-025-06877-6 Lanzetta P, Korobelnik JF, Heier JS et al (2024) Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet 403:1141–1152. https://doi.org/10.1016/S0140-6736(23)02724-0 Korobelnik JF, Lanzetta P, Leal S et al (2026) Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration. Ophthalmology 133:39–50. https://doi.org/10.1016/j.ophtha.2025.08.012 Abu Ishkheidem I, Inci E, Breimer M et al (2025) Real-world outcomes of aflibercept 8 mg in patients previously treated for neovascular age-related macular degeneration. Acta Ophthalmol 103:e17590. https://doi.org/10.1111/aos.17590 Bates BA, Mansour HA, Al-khersan H et al (2025) The efficacy and safety of intravitreal aflibercept 8 mg in clinical practice. J Vitreoretin Dis 9:24741264251383384. https://doi.org/10.1177/24741264251383384 Musadiq M, Musadiq M, Latif F et al (2025) Early real-world outcomes of switching to 8 mg aflibercept for neovascular age-related macular degeneration in the United Kingdom. Life (Basel) 15:903. https://doi.org/10.3390/life15060903 Amoaku WM, Chakravarthy U, Gale R et al (2015) Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond) 29:721–731. https://doi.org/10.1038/eye.2015.48 Eckardt F, Hafner M, Lorger A et al (2025) Efficacy of switching treatment to faricimab in recalcitrant neovascular age-related macular degeneration: 6-month results after completion of the loading phase. Graefes Arch Clin Exp Ophthalmol 263:3053–3063. https://doi.org/10.1007/s00417-025-06912-6 Sambhara D, Vakharia P, Eichenbaum DA (2025) Real-world efficacy and safety of 8 mg aflibercept in neovascular AMD: a case series. BMJ Open Ophthalmol 10:e002091. https://doi.org/10.1136/bmjophth-2024-002091 Bala S, Barbosa GCS, Mohan N et al (2025) Initial functional and anatomical outcomes of high-dose aflibercept 8 mg in exudative neovascular age-related macular degeneration. Ophthalmol Retina 9:756–766. https://doi.org/10.1016/j.oret.2025.02.012 Cheng CK, Chen SJ, Chen JT et al (2022) Optimal approaches and criteria to treat-and-extend regimen implementation for neovascular age-related macular degeneration: experts consensus in Taiwan. BMC Ophthalmol 22:25. https://doi.org/10.1186/s12886-022-02297-9 Waldstein SM, Simader C, Staurenghi G et al (2016) Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials. Ophthalmology 123:1521–1529. https://doi.org/10.1016/j.ophtha.2016.03.048 Ohji M, Takahashi K, Okada AA et al (2020) Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: a randomized controlled trial. Adv Ther 37:1173–1187. https://doi.org/10.1007/s12325-020-01263-4 Mitchell P, Holz FG, Hykin P et al (2021) Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: the ARIES study: a randomized clinical trial. Retina 41:1911–1920. https://doi.org/10.1097/IAE.0000000000003146 Patil NS, Mihalache A, Dhoot AS et al (2022) Association between visual acuity and residual retinal fluid following intravitreal anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration: a systematic review and meta-analysis. JAMA Ophthalmol 140:611–619. https://doi.org/10.1001/jamaophthalmol.2022.1104 Guymer RH, Markey CM, McAllister IL et al (2019) Tolerating subretinal fluid in neovascular age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen. Ophthalmology 126:723–734. https://doi.org/10.1016/j.ophtha.2018.11.025 Additional Declarations Competing interest reported. Daniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch & Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9312361","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630574906,"identity":"0d1a6bdc-4983-4b77-9d71-838ef4451818","order_by":0,"name":"Daniele Veritti","email":"","orcid":"","institution":"University of Udine","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Veritti","suffix":""},{"id":630574907,"identity":"cd203499-af19-4a09-b3f9-a90ae84ce1c0","order_by":1,"name":"Valentina Sarao","email":"","orcid":"","institution":"University of Udine","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Sarao","suffix":""},{"id":630574908,"identity":"72a4f6b8-b3e5-4ffc-9aac-d0cc096a36ed","order_by":2,"name":"Marco Lupidi","email":"","orcid":"","institution":"Marche Polytechnic University","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Lupidi","suffix":""},{"id":630574909,"identity":"c43b5d9e-a88e-4897-918b-86baa2881fea","order_by":3,"name":"Pasquale Viggiano","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Pasquale","middleName":"","lastName":"Viggiano","suffix":""},{"id":630574910,"identity":"ef99acc5-ee6d-4e76-bace-7a12399fc2e7","order_by":4,"name":"Marco Lombardo","email":"","orcid":"","institution":"University of Rome Tor Vergata","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Lombardo","suffix":""},{"id":630574911,"identity":"9bf0f8bf-68a7-4f79-b3af-60d9e7a8d59d","order_by":5,"name":"Mariacristina Parravano","email":"","orcid":"","institution":"Fondazione G.B. Bietti","correspondingAuthor":false,"prefix":"","firstName":"Mariacristina","middleName":"","lastName":"Parravano","suffix":""},{"id":630574912,"identity":"d65b2150-5b49-49b2-a0e8-9f41cdfb1e6a","order_by":6,"name":"Maria Cristina Savastano","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Cristina","lastName":"Savastano","suffix":""},{"id":630574913,"identity":"d6d77600-7101-4da0-b26e-5b96fd28f5c7","order_by":7,"name":"Giacomo Boscia","email":"","orcid":"","institution":"Ospedale Generale Regionale Francesco Miulli","correspondingAuthor":false,"prefix":"","firstName":"Giacomo","middleName":"","lastName":"Boscia","suffix":""},{"id":630574914,"identity":"4deeaa84-3ae3-467b-beea-2a98da9106fe","order_by":8,"name":"Enrico Borrelli","email":"","orcid":"","institution":"University of Turin","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"","lastName":"Borrelli","suffix":""},{"id":630574915,"identity":"d8f70565-947e-444c-84d4-a3b90c76782e","order_by":9,"name":"Lisa Toto","email":"","orcid":"","institution":"University of Chieti-Pescara","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Toto","suffix":""},{"id":630574916,"identity":"9b6768a5-5766-44ee-b06c-05a35ecf9854","order_by":10,"name":"Asia Amelia Martin","email":"","orcid":"","institution":"University of Udine","correspondingAuthor":false,"prefix":"","firstName":"Asia","middleName":"Amelia","lastName":"Martin","suffix":""},{"id":630574917,"identity":"4bb9b809-5d87-4cb8-b80b-2bed02c697d3","order_by":11,"name":"Alba Chiara Termite","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Alba","middleName":"Chiara","lastName":"Termite","suffix":""},{"id":630574918,"identity":"7d135bb9-229a-4b1e-adac-234f26db0cc7","order_by":12,"name":"Giulia Ribezzi","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Ribezzi","suffix":""},{"id":630574919,"identity":"641333b3-b35e-4d03-a330-37a4a5d1dbc2","order_by":13,"name":"Enrico Nacciarriti","email":"","orcid":"","institution":"Marche Polytechnic University","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"","lastName":"Nacciarriti","suffix":""},{"id":630574920,"identity":"f7c2acd3-703d-47bd-97e9-badc517c190e","order_by":14,"name":"Claudia Fossataro","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Fossataro","suffix":""},{"id":630574921,"identity":"b52b2f64-41e9-4465-973a-c8ce36745175","order_by":15,"name":"Eleni Nikolopoulou Gisotti","email":"","orcid":"","institution":"Ospedale Generale Regionale Francesco Miulli","correspondingAuthor":false,"prefix":"","firstName":"Eleni","middleName":"Nikolopoulou","lastName":"Gisotti","suffix":""},{"id":630574922,"identity":"cc1df6e5-3acb-4141-bd42-9ebedd58a19a","order_by":16,"name":"Giovanni Neri","email":"","orcid":"","institution":"University of Turin","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Neri","suffix":""},{"id":630574923,"identity":"a8d6a669-dff7-4a61-bb9d-c2156d2d603b","order_by":17,"name":"Cesare Persavalli","email":"","orcid":"","institution":"University of Chieti-Pescara","correspondingAuthor":false,"prefix":"","firstName":"Cesare","middleName":"","lastName":"Persavalli","suffix":""},{"id":630574924,"identity":"a171bedf-230a-4818-b446-5dc604878de0","order_by":18,"name":"Francesco Boscia","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Boscia","suffix":""},{"id":630574925,"identity":"e951795b-8ced-47d7-ba43-27cd8049a96c","order_by":19,"name":"Cesare Mariotti","email":"","orcid":"","institution":"Marche Polytechnic University","correspondingAuthor":false,"prefix":"","firstName":"Cesare","middleName":"","lastName":"Mariotti","suffix":""},{"id":630574926,"identity":"81c7470a-b870-40cd-a72d-48f3e9125556","order_by":20,"name":"Rodolfo Mastropasqua","email":"","orcid":"","institution":"University of Chieti-Pescara","correspondingAuthor":false,"prefix":"","firstName":"Rodolfo","middleName":"","lastName":"Mastropasqua","suffix":""},{"id":630574927,"identity":"1866a0ca-91b7-4c13-a69a-fa2075159600","order_by":21,"name":"Michele Reibaldi","email":"","orcid":"","institution":"University of Turin","correspondingAuthor":false,"prefix":"","firstName":"Michele","middleName":"","lastName":"Reibaldi","suffix":""},{"id":630574929,"identity":"52c7ba99-a828-4e80-b1b9-c5b8dafb8d98","order_by":22,"name":"Federico Ricci","email":"","orcid":"","institution":"University of Rome Tor Vergata","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"","lastName":"Ricci","suffix":""},{"id":630574931,"identity":"75d7fd0d-f6d7-4114-b2d5-09c6c92034e5","order_by":23,"name":"Stanislao Rizzo","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Stanislao","middleName":"","lastName":"Rizzo","suffix":""},{"id":630574932,"identity":"e136da94-c03e-4230-b583-7d663532d5aa","order_by":24,"name":"Alfonso Savastano","email":"","orcid":"","institution":"Ospedale Generale Regionale Francesco Miulli","correspondingAuthor":false,"prefix":"","firstName":"Alfonso","middleName":"","lastName":"Savastano","suffix":""},{"id":630574933,"identity":"cff3989e-8563-413e-9dbc-8219566c3ec9","order_by":25,"name":"Monica Varano","email":"","orcid":"","institution":"Fondazione G.B. Bietti","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"","lastName":"Varano","suffix":""},{"id":630574934,"identity":"5c73f9a0-71d7-4fd9-855e-796b7c201f15","order_by":26,"name":"Paolo Lanzetta","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYHACxgMMDBYwjg0DAzMDgwSDAX49B0BqQHobDjCkwbTg14Os5TBYBMjFrcWc/fCBAx8YJOTN+Q8ff/yh5nzidnYewxsMBX9warHsSUs4OINBwnBnw7HEhgPHbifubOYxtsDnMIMDOQaHeRgkGDcc7DFsOMB2O3HDYR4zvH4xOP8GrMV+w2H+jw0H/p0jQssNiC2JG47xMDYcbDtAWIvljGdAvxhIJG84w2Y442xfsvGGw2zFFgkGxji1mPMnH3zwocLGdsP5w0D6m50skLHxxoc/crgdhkQigQScGvDF2CgYBaNgFIwCGAAATWJY4xGNLQ4AAAAASUVORK5CYII=","orcid":"","institution":"University of Udine","correspondingAuthor":true,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Lanzetta","suffix":""}],"badges":[],"createdAt":"2026-04-03 11:45:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9312361/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9312361/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108234572,"identity":"02fc2d27-c270-42b6-aa65-264cdf638d1b","added_by":"auto","created_at":"2026-04-30 18:24:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73494,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of best-corrected visual acuity (BCVA, ETDRS letters) across study timepoints according to switch indication. Boxplots illustrate BCVA at the pre-switch (−6 months), switch (baseline), 3-month post-switch, and 6-month post-switch visits in the overall cohort and in eyes switched for non-response, suboptimal response, or durability-driven reasons. Boxes represent the interquartile range, whiskers indicate 1.5× the interquartile range, open circles denote outliers, and black dots indicate mean values.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9312361/v1/fe2a023c97f1f1cdcc85c6db.png"},{"id":108234596,"identity":"d617370e-953f-4d8b-a0c5-565313df71ea","added_by":"auto","created_at":"2026-04-30 18:24:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34546,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of central subfield thickness (CST, µm) across study timepoints according to switch indication. Boxplots illustrate CST at the pre-switch (−6 months), switch (baseline), 3-month post-switch, and 6-month post-switch visits in the overall cohort and in eyes switched for non-response, suboptimal response, or durability-driven reasons. Boxes represent the interquartile range, whiskers indicate 1.5× the interquartile range, open circles denote outliers, and black dots indicate mean values.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9312361/v1/a1ad239832e5b99eae018c8f.png"},{"id":108234559,"identity":"0bfac90a-0c8f-43a3-b75b-a5eb98ed45ef","added_by":"auto","created_at":"2026-04-30 18:24:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69758,"visible":true,"origin":"","legend":"\u003cp\u003eTemporal evolution of retinal fluid compartments according to switch indication. Line plots illustrate the percentage of eyes with intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and any fluid (IRF or SRF) at the switch (baseline), 3-month post-switch, and 6-month post-switch visits in the overall cohort and stratified by switch indication (non-response, suboptimal response, and durability-driven). Values represent the proportion of eyes with the specified fluid compartment at each timepoint.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9312361/v1/78a685f7d1e960bbee05663a.png"},{"id":108234602,"identity":"03e7a3f3-4c6e-456a-ada0-41e83f9be3ae","added_by":"auto","created_at":"2026-04-30 18:24:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":450932,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9312361/v1/e963d8f8-bf15-4920-83c5-7f3f374ca2a9.pdf"}],"financialInterests":"Competing interest reported. Daniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch \u0026 Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none","formattedTitle":"\u003cp\u003eSwitching to aflibercept 8 mg in neovascular age-related macular degeneration: real-world outcomes and differential response by switch indication\u003c/p\u003e","fulltext":[{"header":"Key message","content":"\u003cp\u003e\u003cstrong\u003eWhat is known:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAflibercept 8 mg has demonstrated non-inferior visual outcomes with extended dosing intervals compared with standard-dose anti-VEGF therapy in randomized clinical trials, suggesting improved treatment durability in neovascular age-related macular degeneration.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is new:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIn a large multicentre real-world cohort of previously treated nAMD eyes, switching to aflibercept 8 mg was associated with reversal of pre-switch anatomical worsening, significant reduction in retinal fluid, and stable or modestly improved visual acuity up to 6 months.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTreatment response varied according to the clinical indication for switching, with greater anatomical improvements observed in eyes with inadequate disease control prior to switch, supporting aflibercept 8 mg as a treatment escalation strategy in routine clinical practice.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eNeovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible central vision loss in older adults and represents a major public health burden in aging populations [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. The introduction of intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy has fundamentally changed the management of nAMD, allowing stabilization or improvement of visual acuity in a substantial proportion of patients and markedly reducing the risk of severe vision loss [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the long-term effectiveness of anti-VEGF therapy in routine clinical practice is tempered by the need for repeated intravitreal injections and close monitoring over prolonged periods. Even when proactive regimens such as treat-and-extend are adopted, treatment burden remains substantial, and real-world outcomes frequently fall short of those reported in pivotal clinical trials [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Persistent or recurrent exudative activity, limited interval extension, and progressive anatomical changes continue to be observed in a relevant proportion of treated eyes, underscoring the need for therapeutic strategies with improved durability [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn response to these limitations, longer-acting anti-VEGF approaches have been developed with the aim of sustaining disease control while reducing injection frequency. Aflibercept 8 mg represents a higher-dose formulation delivering a fourfold increase in molar dose compared with the standard 2 mg regimen. This formulation has been associated with prolonged intraocular VEGF suppression and enhanced durability in preclinical and pharmacokinetic evaluations [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical efficacy and safety of aflibercept 8 mg have been established in randomized controlled trials. The phase 3 PULSAR trial showed that aflibercept 8 mg administered at 12- or 16-week intervals achieved non-inferior visual outcomes relative to aflibercept 2 mg every 8 weeks, while enabling extended dosing intervals in a substantial proportion of patients with nAMD [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBeyond the controlled setting of clinical trials, early real-world evidence has begun to emerge, suggesting that aflibercept 8 mg may offer anatomical stabilization and extension of treatment intervals in previously treated nAMD populations. Multicentre observational studies and single-centre series have reported stable visual acuity, reduction of retinal fluid, and a favourable short-term safety following transition to aflibercept 8 mg [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, these reports typically evaluate switched eyes as a single, heterogeneous group and provide limited information on disease behaviour prior to the switch. Detailed characterization of disease activity before switching remains limited in the available literature. Particularly, few studies incorporate longitudinal data from the months preceding the treatment change, a period that is critical for contextualizing anatomical response, treatment burden, and durability under prior anti-VEGF therapy. Moreover, the extent to which different clinical motivations for switching—such as inadequate anatomical response, suboptimal durability, or the pursuit of longer treatment intervals in otherwise controlled eyes—may influence post-switch outcomes remains insufficiently explored.\u003c/p\u003e \u003cp\u003eThe present multicentre real-world study was designed to address these gaps by focusing exclusively on previously treated nAMD patients switched to aflibercept 8 mg. Detailed longitudinal data from the six months preceding the switch provide the opportunity to interpret post-switch outcomes in relation to different clinical indications for switching.\u003c/p\u003e "},{"header":"Methods","content":"\u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eStudy Design and Setting\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e\u003cp\u003e This was a multicentre, observational, real-world study conducted across 9 Italian retina centers (University of Udine, Udine; University of Bari \"Aldo Moro\", Bari; Polytechnic University of Marche, Ancona; University of Rome Tor Vergata, Rome; IRCCS-Fondazione Bietti, Rome; Catholic University \"Sacro Cuore\", Rome; Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, Bari; University of Turin, Turin; \"G. d'Annunzio\" University Chieti-Pescara, Chieti). Consecutive patients with nAMD who were switched to intravitreal aflibercept 8 mg as part of routine clinical care between March 2024 and September 2025 were included. Clinical data were collected retrospectively from electronic medical records and standardized data collection forms. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board. Given the retrospective nature of the study, informed consent was obtained or waived according to local regulations governing observational studies based on routinely collected clinical data.\u003c/p\u003e\u003ch3\u003e2. Participants\u003c/h3\u003e\u003cp\u003eEligible participants were adults with a diagnosis of nAMD who had received prior intravitreal anti-VEGF therapy and were subsequently switched to aflibercept 8 mg. Eyes were included if complete demographic information and longitudinal clinical data were available. Specifically, inclusion required availability of (1) baseline demographic and disease characteristics; (2) longitudinal pre-switch data spanning approximately 6 months before switching, including at least two visits with best-corrected visual acuity (BCVA) and optical coherence tomography (OCT); and (3) clinical data at the switch visit corresponding to the first aflibercept 8 mg injection. A post-switch follow-up visit 3 months after switching was prespecified for outcome analyses. Additional post-switch visits, when available, were used for descriptive or exploratory analyses. When both eyes of a patient met eligibility criteria, only one eye was included to avoid within-patient correlation. In such cases, the eye first switched during the study period was selected.\u003c/p\u003e\u003ch3\u003e3. Clinical data and imaging\u003c/h3\u003e\u003cp\u003eDemographic variables included age and sex. Baseline disease characteristics comprised macular neovascularization (MNV) subtype, eye laterality, disease duration, total number of intravitreal injections before switching, anti-VEGF agent used immediately prior to switching, and the last documented treatment interval. BCVA was recorded at each visit as part of routine clinical assessment. When necessary, BCVA values were converted to approximate ETDRS letter scores using established conversion methods. Spectral-domain or swept-source OCT was performed according to site-specific clinical protocols. Anatomical data were extracted from OCT scans acquired during routine clinical care. Central subfield thickness (CST) values were obtained from automated device measurements, after verification of correct retinal layer segmentation. The presence of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelium detachment (PED) was recorded by the treating physician at each visit and was documented as binary variables (present or absent).\u003c/p\u003e\u003cp\u003eThe decision to perform a loading phase was left to the treating physician and reflected routine clinical practice. A loading phase was defined as the administration of at least three consecutive intravitreal injections within the first 12 weeks following the switch, corresponding to an initial monthly dosing regimen.\u003c/p\u003e\u003ch3\u003e4. Classification of switch indication\u003c/h3\u003e\u003cp\u003eThe clinical indication for switching to aflibercept 8 mg was classified into one of three prespecified categories based on longitudinal clinical and OCT findings during the 3 months preceding the switch, together with the treating physician’s documented rationale. To improve reproducibility, predefined operational criteria were applied:\u003c/p\u003e\u003cp\u003eNon-response was defined as persistent/increasing IRF and/or SRF at all available visits during the preceding 3 months, with no meaningful anatomical improvement (defined as a reduction in CST \u0026lt; 10%) and stable or worsening visual acuity (BCVA change ≤ 0 letters), despite ongoing treatment at regular or intensified intervals [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSuboptimal response was defined as partial anatomical response under prior anti-VEGF therapy, characterized by a CST reduction ≥ 10% compared with earlier visits but persistent fluid (IRF, SRF, and/or PED) at one or more visits in the preceding 3 months. These eyes typically showed incomplete disease inactivation or fluctuating exudative activity, with stable or mildly improved BCVA [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDurability-driven switch was defined as a treatment change performed primarily to extend treatment intervals in eyes with controlled or near-controlled disease. These eyes showed absence of IRF/SRF at the last pre-switch visit, stable CST (variation \u0026lt; 10% over the preceding visits), and stable BCVA, but required relatively short treatment intervals (≤ 8 weeks) to maintain disease control [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough predefined criteria were applied, classification retained a degree of clinical judgment, reflecting real-world decision-making in routine practice.\u003c/p\u003e\u003ch3\u003e5. Outcomes and study timepoints\u003c/h3\u003e\u003cp\u003eThe primary outcome was change in BCVA from the switch visit to the 3-month post-switch visit. Secondary outcomes included changes in CST and in the presence of IRF, SRF, and PED. Additional secondary analyses evaluated functional and anatomical outcomes at the 6-month post-switch visit. Descriptive analyses further characterized disease activity during the pre-switch period.\u003c/p\u003e\u003cp\u003eTo ensure consistent temporal alignment across centres, prespecified time windows were applied. The switch visit was defined as the visit at which the first aflibercept 8 mg injection was administered.\u003c/p\u003e\u003cp\u003eThe pre-switch period was defined as the 6 months preceding the switch visit.\u003c/p\u003e\u003cp\u003eThe 3-month post-switch visit was defined as the visit closest to 90 days after the switch (± 15 days).\u003c/p\u003e\u003cp\u003eThe 6-month post-switch visit was defined as the visit closest to 180 days after the switch (± 30 days).\u003c/p\u003e\u003ch3\u003e6. Statistical Analysis\u003c/h3\u003e\u003cp\u003eContinuous variables were summarized as mean ± standard deviation or median (interquartile range), as appropriate, while categorical variables were reported as counts and percentages.\u003c/p\u003e\u003cp\u003eChanges in continuous outcomes, including BCVA and CST, were evaluated using paired comparisons between predefined timepoints (6-month pre-switch visit, switch visit, 3-month post-switch visit, and 6-month post-switch visit). Corresponding mean changes and 95% confidence intervals were calculated. Comparisons between groups were performed using Student’s t-test or Mann–Whitney U test for continuous variables, and one-way ANOVA or Kruskal–Wallis test for comparisons across multiple groups, as appropriate. Categorical variables were compared using chi-square or Fisher’s exact test, while paired categorical comparisons across timepoints were performed using the McNemar test. Normality of data distribution was assessed using the Shapiro–Wilk test. Multivariable regression analyses were performed to identify clinical and anatomical factors associated with functional (BCVA change) and anatomical (CST change) outcomes at the 3-month post-switch visit. Covariates included BCVA or CST at the switch visit, switch indication category, macular neovascularization subtype, presence of IRF, SRF, or PED at the switch visit, subfoveal atrophy, macular fibrosis, prior anti-VEGF agent, and treatment centre. All analyses were considered exploratory in nature, and statistical significance was interpreted cautiously in light of the observational study design. Statistical analyses were performed using IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003e1. Study population and baseline characteristics\u003c/h3\u003e\n\u003cp\u003eA total of 300 eyes from 300 patients with nAMD were included in the analysis. All included eyes had complete demographic, functional, and imaging data available for the 6-month pre-switch period, the switch visit, and the 3- and 6-month post-switch visits. During the follow-up period, the mean number of aflibercept 8 mg injections administered was 3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3. At the 6-month post-switch visit, the mean treatment interval was 9.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 weeks, with 57.7% of eyes achieving an interval of 12 weeks or longer. Baseline demographic and clinical characteristics at the switch visit are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Type 1 MNV was the most frequent subtype, accounting for 181 eyes (60.3%), followed by Type 2 in 51 eyes (17.0%), polypoidal choroidal vasculopathy in 32 eyes (10.7%), mixed MNV in 20 eyes (6.7%), and Type 3 in 16 eyes (5.3%). Subfoveal retinal pigment epithelium atrophy was present in 78 eyes (26.0%), while subretinal macular fibrosis was observed in 104 eyes (34.7%). The primary indication for switching was suboptimal response in 53% of eyes, non-response in 24.7%, and a durability-driven strategy in 22.3%. A loading phase with aflibercept 8 mg was performed in 156 eyes (52.0%), while 144 eyes (48.0%) did not receive a loading phase.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic and clinical characteristics at the switch visit\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003cp\u003e(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; median [IQR] unless otherwise specified)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6; 79 [73\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159 (53.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.1\u0026thinsp;\u0026plusmn;\u0026thinsp;24.6; 27 [13\u0026ndash;48]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal anti-VEGF injections before switch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1; 12 [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-VEGF injections in prior 6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1; 3 [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCVA at switch visit, ETDRS letters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.1\u0026thinsp;\u0026plusmn;\u0026thinsp;19.5; 65 [50\u0026ndash;75]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCST at switch visit, \u0026micro;m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e314.1\u0026thinsp;\u0026plusmn;\u0026thinsp;120.9; 289 [232\u0026ndash;370]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraretinal fluid present, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubretinal fluid present, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164 (54.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePigment epithelium detachment present, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e206 (68.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLast anti-VEGF agent before switch, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Aflibercept 2 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e226 (75.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Bevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (15.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Faricimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Brolucizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Ranibizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLast treatment interval before switch, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q4 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (29.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q6 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q8 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114 (38.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q10 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (2.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q12 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (15.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; q16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSwitch indication, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Non-response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (24.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Suboptimal response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159 (53.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ndash; Durability-driven switch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (22.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eLegend: BCVA: best corrected visual acuity; CST: central subfield thickness; ETDRS: Early Treatment Diabetic Retinopathy Study; IQR: interquartile range; n: number; qX=dosing interval of X weeks; SD: standard deviation; VEGF: vascular endothelial growth factor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e2. Functional outcomes\u003c/h3\u003e\n\u003cp\u003eFunctional outcomes over time are reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At the 6-month pre-switch visit, mean BCVA was 62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0 ETDRS letters. From the 6-month pre-switch visit to the switch visit, mean BCVA decreased to 60.1\u0026thinsp;\u0026plusmn;\u0026thinsp;19.5 letters, corresponding to a mean change of \u0026minus;\u0026thinsp;1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 letters.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFunctional and anatomical parameters over time\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-switch (\u0026minus;\u0026thinsp;6 months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSwitch visit (baseline)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChange from pre-switch\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3-month post-switch\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChange from switch (3 months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6-month post-switch\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eChange from switch\u003c/p\u003e \u003cp\u003e(6 months)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCVA overall\u003c/b\u003e\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.0\u0026thinsp;\u0026plusmn;\u0026thinsp;19.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.1\u0026thinsp;\u0026plusmn;\u0026thinsp;19.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;3.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62.8\u0026thinsp;\u0026plusmn;\u0026thinsp;17.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuboptimal response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.4\u0026thinsp;\u0026plusmn;\u0026thinsp;21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;21.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59.1\u0026thinsp;\u0026plusmn;\u0026thinsp;22.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDurability-driven switch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e67.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68.0\u0026thinsp;\u0026plusmn;\u0026thinsp;15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCST overall\u003c/b\u003e,\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e298.1\u0026thinsp;\u0026plusmn;\u0026thinsp;109.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e314.1\u0026thinsp;\u0026plusmn;\u0026thinsp;120.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;16.0\u0026thinsp;\u0026plusmn;\u0026thinsp;99.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e268.9\u0026thinsp;\u0026plusmn;\u0026thinsp;85.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;45.3\u0026thinsp;\u0026plusmn;\u0026thinsp;79.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e269.7\u0026thinsp;\u0026plusmn;\u0026thinsp;89.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;87.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e341.5\u0026thinsp;\u0026plusmn;\u0026thinsp;120.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e389.2\u0026thinsp;\u0026plusmn;\u0026thinsp;154.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;47.7\u0026thinsp;\u0026plusmn;\u0026thinsp;131.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e295.6\u0026thinsp;\u0026plusmn;\u0026thinsp;105.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;93.6\u0026thinsp;\u0026plusmn;\u0026thinsp;104.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e297.1\u0026thinsp;\u0026plusmn;\u0026thinsp;102.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;92.1\u0026thinsp;\u0026plusmn;\u0026thinsp;114.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuboptimal response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e284.9\u0026thinsp;\u0026plusmn;\u0026thinsp;104.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e289.7\u0026thinsp;\u0026plusmn;\u0026thinsp;93.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;93.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e260.2\u0026thinsp;\u0026plusmn;\u0026thinsp;76.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;62.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e261.8\u0026thinsp;\u0026plusmn;\u0026thinsp;86.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;73.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDurability-driven switch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e281.2\u0026thinsp;\u0026plusmn;\u0026thinsp;94.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e288.7\u0026thinsp;\u0026plusmn;\u0026thinsp;103.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;7.5\u0026thinsp;\u0026plusmn;\u0026thinsp;56.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e259.6\u0026thinsp;\u0026plusmn;\u0026thinsp;73.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;29.1\u0026thinsp;\u0026plusmn;\u0026thinsp;62.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e257.7\u0026thinsp;\u0026plusmn;\u0026thinsp;72.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;31.0\u0026thinsp;\u0026plusmn;\u0026thinsp;63.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIRF present, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138 (46.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;12 (+\u0026thinsp;4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;118 (\u0026minus;\u0026thinsp;39.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;74 (\u0026minus;\u0026thinsp;24.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSRF present, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152 (50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e164 (54.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;12 (+\u0026thinsp;4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62 (20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;102 (\u0026minus;\u0026thinsp;34.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e76 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;88 (\u0026minus;\u0026thinsp;29.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePED present, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196 (65.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e206 (68.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;10 (+\u0026thinsp;3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e170 (56.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026minus;36 (\u0026minus;\u0026thinsp;12.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e179 (59.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026minus;27 (\u0026minus;\u0026thinsp;9.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eLegend: BCVA: best corrected visual acuity; CST: central subfield thickness; IRF: intraretinal fluid; n:number; PED: pigment epithelium detachment; SD: standard deviation; SRF: subretinal fluid; Δ: change; Changes in fluid presence are expressed as absolute differences in number of eyes and corresponding percentage-point changes.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAt the 3-month post-switch visit, mean BCVA improved to 62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20.1 letters, corresponding to a mean gain of +\u0026thinsp;2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 letters relative to the switch visit (95% CI, +\u0026thinsp;0.8 to +\u0026thinsp;3.2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). At the 6-month post-switch visit, mean BCVA was 62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20.2 letters, corresponding to a mean change of +\u0026thinsp;2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9 letters versus the switch visit (95% CI, +\u0026thinsp;0.8 to +\u0026thinsp;3.1; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eWhen stratified by switch indication, eyes switched for non-response exhibited the largest mean BCVA gains, with increases of +\u0026thinsp;2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6 letters at the 3-month post-switch visit and +\u0026thinsp;3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1 letters at the 6-month post-switch visit. Eyes switched for suboptimal response and those switched for durability-driven reasons showed comparable functional trajectories, characterized by modest but sustained BCVA improvements after switching (+\u0026thinsp;1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1 and +\u0026thinsp;1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4 letters at 3 months, respectively; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). These gains were maintained at 6 months (+\u0026thinsp;1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 and +\u0026thinsp;2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 letters, respectively; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eWhen outcomes were analyzed according to loading phase strategy, the distribution of switch indications differed significantly between groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001): eyes receiving a loading phase were more frequently switched for non-response (36.5% vs 11.8%) or suboptimal response (53.8% vs 52.1%), whereas eyes not receiving a loading phase were more often switched for durability-driven reasons (36.1% vs 9.6%). In the overall comparison, eyes treated with a loading phase showed a greater BCVA improvement at the 3-month post-switch visit compared with those without (+\u0026thinsp;3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 vs\u0026thinsp;+\u0026thinsp;0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 letters; p\u0026thinsp;=\u0026thinsp;0.006). When stratified by switch indication, the functional benefit associated with the loading phase was most evident in eyes switched for suboptimal response (+\u0026thinsp;3.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 vs\u0026thinsp;\u0026minus;\u0026thinsp;0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 letters; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A similar trend was observed in eyes switched for non-response (+\u0026thinsp;4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4 vs\u0026thinsp;\u0026minus;\u0026thinsp;1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4 letters; p\u0026thinsp;=\u0026thinsp;0.10). In contrast, no significant difference was observed in eyes switched for durability-driven reasons (\u0026minus;\u0026thinsp;0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 vs\u0026thinsp;+\u0026thinsp;2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 letters; p\u0026thinsp;=\u0026thinsp;0.33).\u003c/p\u003e\n\u003ch3\u003e3. Anatomic outcomes\u003c/h3\u003e\n\u003cp\u003eAnatomical outcomes are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. At the 6-month pre-switch visit, mean CST was 298.1\u0026thinsp;\u0026plusmn;\u0026thinsp;109.0 \u0026micro;m. From the 6-month pre-switch visit to the switch visit, mean CST increased to 314.1\u0026thinsp;\u0026plusmn;\u0026thinsp;120.9 \u0026micro;m, corresponding to a mean change of +\u0026thinsp;16.0\u0026thinsp;\u0026plusmn;\u0026thinsp;99.5 \u0026micro;m. At the 3-month post-switch visit, mean CST decreased to 268.9\u0026thinsp;\u0026plusmn;\u0026thinsp;85.0 \u0026micro;m, representing a mean reduction of \u0026minus;\u0026thinsp;45.3\u0026thinsp;\u0026plusmn;\u0026thinsp;79.8 \u0026micro;m relative to the switch visit (95% CI, \u0026minus;\u0026thinsp;55.4 to \u0026minus;\u0026thinsp;35.2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At the 6-month post-switch visit, mean CST was 269.7\u0026thinsp;\u0026plusmn;\u0026thinsp;89.1 \u0026micro;m, corresponding to a mean change of \u0026minus;\u0026thinsp;44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;87.5 \u0026micro;m versus the switch visit (95% CI, \u0026minus;\u0026thinsp;55.6 to \u0026minus;\u0026thinsp;33.4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). When stratified by switch indication, eyes switched for non-response exhibited the largest anatomical improvements, with mean CST reductions of \u0026minus;\u0026thinsp;93.6\u0026thinsp;\u0026plusmn;\u0026thinsp;104.6 \u0026micro;m at the 3-month post-switch visit and \u0026minus;\u0026thinsp;92.1\u0026thinsp;\u0026plusmn;\u0026thinsp;114.5 \u0026micro;m at the 6-month post-switch visit. Eyes switched for suboptimal response and those switched for durability-driven reasons showed more modest but consistent CST reductions after switching, with mean changes of \u0026minus;\u0026thinsp;29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;62.4 \u0026micro;m and \u0026minus;\u0026thinsp;29.1\u0026thinsp;\u0026plusmn;\u0026thinsp;62.7 \u0026micro;m at 3 months, respectively. These reductions were maintained at 6 months (\u0026minus;\u0026thinsp;27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;73.1 \u0026micro;m and \u0026minus;\u0026thinsp;31.0\u0026thinsp;\u0026plusmn;\u0026thinsp;63.5 \u0026micro;m, respectively), with comparable anatomical trajectories between these two subgroups. The proportion of eyes with IRF and SRF decreased after switching. Detailed changes in individual fluid compartments (IRF, SRF, and PED) across timepoints are reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003e4. Multivariable analyses\u003c/h3\u003e\n\u003cp\u003eAfter multivariable adjustment, the presence of IRF and SRF at the switch visit were independently associated with a smaller BCVA gain at the 3-month post-switch visit (IRF: β\u0026thinsp;\u0026minus;\u0026thinsp;2.70 letters, P\u0026thinsp;=\u0026thinsp;0.017; SRF: β\u0026thinsp;\u0026minus;\u0026thinsp;3.52 letters, P\u0026thinsp;=\u0026thinsp;0.006), whereas PED was not. Higher BCVA at the switch visit predicted a smaller subsequent BCVA change (β\u0026thinsp;\u0026minus;\u0026thinsp;0.084 letters per letter; P\u0026thinsp;=\u0026thinsp;0.029). Fibrosis, subfoveal atrophy, and MNV subtype were not associated with BCVA change. In the morphological model, CST at the switch visit was the strongest predictor of CST reduction (β\u0026thinsp;\u0026minus;\u0026thinsp;0.519 \u0026micro;m per \u0026micro;m; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while fluid status at the switch visit, MNV subtype, fibrosis, and subfoveal atrophy were not independently associated with CST change (all p\u0026thinsp;\u0026ge;\u0026thinsp;0.08).\u003c/p\u003e\n\u003ch3\u003e5. Safety\u003c/h3\u003e\n\u003cp\u003eNo treatment-related serious adverse events, including intraocular inflammation or endophthalmitis, were recorded during the study period.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this real-world study, switching to aflibercept 8 mg was associated with meaningful anatomical improvement accompanied by a visual gain in a large, clinically diverse but predominantly treatment-experienced and challenging cohort of eyes with nAMD. Importantly, the observed decline in BCVA and increase in CST during the pre-switch period indicate that a substantial proportion of eyes represented a clinically challenging subgroup with insufficient disease control under prior anti-VEGF therapy. This selection pattern is inherent to switch studies in routine practice and should be considered when interpreting post-switch outcomes. Therefore, the cohort reflects real-world clinical decision-making, where treatment escalation is typically considered in eyes with evidence of disease instability or insufficient response. Within this context, a central finding of this study is the capacity of aflibercept 8 mg to counteract a documented trajectory of anatomical worsening in eyes switched for non-response or suboptimal response. In these subgroups, progressive increases in CST during the months preceding the switch, together with persistent or increasing retinal fluid, indicated insufficient disease control under prior treatment regimens. Following initiation of aflibercept 8 mg, anatomical outcomes improved and were subsequently maintained throughout follow-up, effectively offsetting the pre-switch deterioration. This pattern indicates that the observed post-switch changes reflect not only anatomical improvement, but also a modification of a previously progressive or unstable disease course.\u003c/p\u003e \u003cp\u003eThese findings are broadly consistent with prior real-world studies of aflibercept 8 mg in switched nAMD populations, which have generally reported anatomical improvement with limited functional gains. \u003csup\u003e13\u0026ndash;16,19\u003c/sup\u003e However, most of these reports focused exclusively on post-switch outcomes, without accounting for the disease trajectory preceding treatment escalation. By anchoring post-switch responses to a clearly defined pre-switch course, the present analysis strengthens interpretation of treatment effects, helps contextualize post-switch changes and mitigates the risk of over-attributing regression toward the mean to treatment escalation.\u003c/p\u003e \u003cp\u003eAt the functional level, visual acuity remained largely stable across the cohort, with modest gains observed during follow-up. This finding is consistent with expectations in switched populations characterized by relatively preserved baseline BCVA and long-standing disease. In such eyes, ceiling effects and irreversible structural damage\u0026mdash;including macular fibrosis or atrophy\u0026mdash;are likely to limit the potential for substantial visual improvement despite effective anatomical control. Within this context, maintenance of visual acuity, particularly in eyes showing deterioration prior to switching, represents a clinically relevant outcome. Of note, in eyes switched for inadequate response, a complete loading phase was associated with greater BCVA gains, suggesting that treatment intensification may be beneficial when switching is driven by suboptimal disease control.\u003c/p\u003e \u003cp\u003eEyes switched primarily for durability-related reasons represent a distinct clinical phenotype within the cohort. At the time of switching, these eyes were generally under apparent anatomical control, with treatment escalation driven by the goal of extending dosing intervals and reducing treatment burden. Despite relative functional stability at baseline, this subgroup showed a small but consistent improvement in BCVA following the switch. Although modest in magnitude, this finding suggests that functional optimization may still be observed even in eyes considered well controlled. Similar signals have been reported sporadically in smaller real-world series [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], but remain insufficiently explored in larger cohorts.\u003c/p\u003e \u003cp\u003eAnalysis of individual retinal fluid compartments further clarifies the treatment response. The marked reduction in proportion of patients with IRF and SRF following the switch is consistent with evidence from both pivotal trials and real-world studies of aflibercept 8 mg, supporting its enhanced potency and durability [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In contrast, PED followed a more variable and frequently persistent course and was not independently associated with functional outcomes. This differential behaviour is consistent with established pathophysiological models in which IRF and SRF more directly reflect VEGF-driven exudation, whereas PED likely represents more complex or structurally established disease features with limited short-term functional relevance [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral limitations of this study should be acknowledged. First, the retrospective design and the absence of a control group limit causal inference. Second, treatment regimens were not standardized and reflected routine clinical decision-making. In particular, the classification of switch indication and the decision to perform a loading phase were left to the treating physician, potentially introducing variability across centres. The comparison between eyes receiving a loading phase and those without should therefore be interpreted with caution, as these groups differed in baseline characteristics and switch indications, raising the possibility of selection bias. Third, the relatively short follow-up limits conclusions regarding long-term durability and visual outcomes. Finally, anatomical assessment was based on central subfield thickness and qualitative evaluation of retinal fluid, without quantitative volumetric analysis, and OCT data were derived from routine clinical interpretation rather than centralized reading, which may have introduced additional variability. Nonetheless, the relatively large sample size and inclusion of a broad spectrum of clinical phenotypes support the external validity and real-world relevance of the findings.\u003c/p\u003e \u003cp\u003eIn conclusion, in a large and heterogeneous real-world cohort of switched nAMD eyes, aflibercept 8 mg was associated with reversal of pre-switch anatomical deterioration, sustained reduction in retinal fluid, and overall visual stability with modest functional gains. The differential responses observed across switch indications highlight the importance of individualized treatment strategies and realistic expectation setting. These findings complement existing trial and real-world evidence and support the role of aflibercept 8 mg as a treatment escalation option in contemporary nAMD management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval:\u003c/h3\u003e\n\u003cp\u003eThe study adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Boards of the participating centres according to national regulations governing retrospective observational studies based on routinely collected clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the retrospective nature of the study, informed consent was obtained or waived according to local institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDaniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch \u0026amp; Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDaniele Veritti: consultant for Bayer, Hofmann La Roche; Valentina Sarao: consultant for Bayer, I-Care, Hofmann La Roche; Pasquale Viggiano: consultant for Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss; Mariacristina Parravano: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Enrico Borrelli: consultant/advisor for Abbvie, Bayer, EyePharma, Hofmann La Roche, Novartis, Zeiss. Francesco Boscia: consultant for Alcon, Abbvie, Bayer, Bausch and Lomb, Hofmann La Roche, Novartis and Zeiss, Michele Reibaldi: consultant for Abbvie, Bayer, Hofmann La Roche, Novartis, Zeiss; Monica Varano: consultant for Abbvie, Bayer, Novartis; Paolo Lanzetta: consultant for Aerie, Allergan, Annexon, Apellis, Bausch \u0026amp; Lomb, Bayer, Biogen, Boehringer Ingelheim, EyeBio, Genentech, I-Care, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Hofmann La Roche. Marco Lupidi, Marco Lombardo, Giacomo Boscia, Lisa Toto, Asia Amelia Martin, Alba Chiara Termite, Giulia Ribezzi, Enrico Nacciarriti, Eleni Nikolopoulou Gisotti, Giovanni Neri, Cesare Persavalli, Claudia Fossataro, Maria Cristina Savastano, Cesare Mariotti, Rodolfo Mastropasqua, Federico Ricci, Alfonso Savastano, Stanislao Rizzo: none\u003c/p\u003e\n\u003ch3\u003eFunding information:\u003c/h3\u003e\n\u003cp\u003eThe research activity conducted at IRCCS-Fondazione Bietti was supported by the Italian Ministry of Health and Fondazione Roma. The funding sources had no role in study design, data collection, data analysis, interpretation of the results, writing of the manuscript, or decision to submit the article for publication.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eDaniele Veritti, Valentina Sarao, Marco Lupidi and Paolo Lanzetta contributed to the study conception and design. All authors performed material preparation and data collection. Analysis was performed by Daniele Veritti and Valentina Sarao. The first draft of the manuscript was written by Daniele Veritti, and all authors commented on previous versions. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWong WL, Su X, Li X et al (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2:e106\u0026ndash;e116. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2214-109X(13)70145-1\u003c/span\u003e\u003cspan address=\"10.1016/S2214-109X(13)70145-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432\u0026ndash;1444. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa062655\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa062655\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419\u0026ndash;1431. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa054481\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa054481\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeier JS, Brown DM, Chong V et al (2012) Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 119:2537\u0026ndash;2548. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ophtha.2012.09.006\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2012.09.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDugel PU, Koh A, Ogura Y et al (2020) HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127:72\u0026ndash;84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ophtha.2019.04.017\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2019.04.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeier JS, Khanani AM, Quezada Ruiz C et al (2022) Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 399:729\u0026ndash;740. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(22)00010-1\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(22)00010-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCiulla TA, Hussain RM, Pollack JS et al (2020) Visual acuity outcomes and anti-vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients. Ophthalmol Retina 4:19\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.oret.2019.08.010\u003c/span\u003e\u003cspan address=\"10.1016/j.oret.2019.08.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeritti D, Sarao V, Soppelsa V et al (2022) Managing neovascular age-related macular degeneration in clinical practice: systematic review, meta-analysis, and meta-regression. J Clin Med 11:325. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm11020325\u003c/span\u003e\u003cspan address=\"10.3390/jcm11020325\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGillies MC, Hunyor AP, Arnold JJ et al (2019) Effect of ranibizumab and aflibercept on best-corrected visual acuity in treat-and-extend for neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol 137:372\u0026ndash;379. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jamaophthalmol.2018.6796\u003c/span\u003e\u003cspan address=\"10.1001/jamaophthalmol.2018.6796\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorobelnik JF, Lanzetta P, Wykoff CC et al (2024) Sustained disease control with aflibercept 8 mg: a new benchmark in the management of retinal neovascular diseases. Eye (Lond) 38:3218\u0026ndash;3221. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41433-024-03055-6\u003c/span\u003e\u003cspan address=\"10.1038/s41433-024-03055-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeritti D, Sarao V, Lanzetta P (2025) Extended duration of VEGF inhibition with aflibercept 8 mg: the role of reduced ocular clearance. Graefes Arch Clin Exp Ophthalmol 263:2985\u0026ndash;2987. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00417-025-06877-6\u003c/span\u003e\u003cspan address=\"10.1007/s00417-025-06877-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanzetta P, Korobelnik JF, Heier JS et al (2024) Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet 403:1141\u0026ndash;1152. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(23)02724-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(23)02724-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorobelnik JF, Lanzetta P, Leal S et al (2026) Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration. Ophthalmology 133:39\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ophtha.2025.08.012\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2025.08.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbu Ishkheidem I, Inci E, Breimer M et al (2025) Real-world outcomes of aflibercept 8 mg in patients previously treated for neovascular age-related macular degeneration. Acta Ophthalmol 103:e17590. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/aos.17590\u003c/span\u003e\u003cspan address=\"10.1111/aos.17590\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBates BA, Mansour HA, Al-khersan H et al (2025) The efficacy and safety of intravitreal aflibercept 8 mg in clinical practice. J Vitreoretin Dis 9:24741264251383384. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/24741264251383384\u003c/span\u003e\u003cspan address=\"10.1177/24741264251383384\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMusadiq M, Musadiq M, Latif F et al (2025) Early real-world outcomes of switching to 8 mg aflibercept for neovascular age-related macular degeneration in the United Kingdom. Life (Basel) 15:903. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/life15060903\u003c/span\u003e\u003cspan address=\"10.3390/life15060903\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmoaku WM, Chakravarthy U, Gale R et al (2015) Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond) 29:721\u0026ndash;731. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/eye.2015.48\u003c/span\u003e\u003cspan address=\"10.1038/eye.2015.48\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEckardt F, Hafner M, Lorger A et al (2025) Efficacy of switching treatment to faricimab in recalcitrant neovascular age-related macular degeneration: 6-month results after completion of the loading phase. Graefes Arch Clin Exp Ophthalmol 263:3053\u0026ndash;3063. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00417-025-06912-6\u003c/span\u003e\u003cspan address=\"10.1007/s00417-025-06912-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSambhara D, Vakharia P, Eichenbaum DA (2025) Real-world efficacy and safety of 8 mg aflibercept in neovascular AMD: a case series. BMJ Open Ophthalmol 10:e002091. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmjophth-2024-002091\u003c/span\u003e\u003cspan address=\"10.1136/bmjophth-2024-002091\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBala S, Barbosa GCS, Mohan N et al (2025) Initial functional and anatomical outcomes of high-dose aflibercept 8 mg in exudative neovascular age-related macular degeneration. Ophthalmol Retina 9:756\u0026ndash;766. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.oret.2025.02.012\u003c/span\u003e\u003cspan address=\"10.1016/j.oret.2025.02.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng CK, Chen SJ, Chen JT et al (2022) Optimal approaches and criteria to treat-and-extend regimen implementation for neovascular age-related macular degeneration: experts consensus in Taiwan. BMC Ophthalmol 22:25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12886-022-02297-9\u003c/span\u003e\u003cspan address=\"10.1186/s12886-022-02297-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWaldstein SM, Simader C, Staurenghi G et al (2016) Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials. Ophthalmology 123:1521\u0026ndash;1529. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ophtha.2016.03.048\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2016.03.048\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhji M, Takahashi K, Okada AA et al (2020) Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: a randomized controlled trial. Adv Ther 37:1173\u0026ndash;1187. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12325-020-01263-4\u003c/span\u003e\u003cspan address=\"10.1007/s12325-020-01263-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell P, Holz FG, Hykin P et al (2021) Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: the ARIES study: a randomized clinical trial. Retina 41:1911\u0026ndash;1920. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/IAE.0000000000003146\u003c/span\u003e\u003cspan address=\"10.1097/IAE.0000000000003146\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatil NS, Mihalache A, Dhoot AS et al (2022) Association between visual acuity and residual retinal fluid following intravitreal anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration: a systematic review and meta-analysis. JAMA Ophthalmol 140:611\u0026ndash;619. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jamaophthalmol.2022.1104\u003c/span\u003e\u003cspan address=\"10.1001/jamaophthalmol.2022.1104\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuymer RH, Markey CM, McAllister IL et al (2019) Tolerating subretinal fluid in neovascular age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen. Ophthalmology 126:723\u0026ndash;734. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ophtha.2018.11.025\u003c/span\u003e\u003cspan address=\"10.1016/j.ophtha.2018.11.025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aflibercept 8 mg, anti-vascular endothelial growth factor therapy, intravitreal injections, neovascular age-related macular degeneration, real-world study, treatment switch","lastPublishedDoi":"10.21203/rs.3.rs-9312361/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9312361/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: To evaluate visual and anatomical outcomes after switching to aflibercept 8 mg in eyes with neovascular age-related macular degeneration (nAMD), and to assess outcomes according to the clinical indication for switching.\u003c/p\u003e\n\u003cp\u003eMethods: Multicentre retrospective observational study including 300 eyes with nAMD previously treated with anti–vascular endothelial growth factor therapy and switched to aflibercept 8 mg for non-response, suboptimal response, or durability-driven reasons. Longitudinal data from the 6 months preceding the switch and post-switch visits at 3 and 6 months were analyzed. The primary outcome was change in best-corrected visual acuity (BCVA, ETDRS letters) from the switch visit to the 3-month post-switch visit. Secondary outcomes included changes in central subfield thickness (CST) and retinal fluid status.\u003c/p\u003e\n\u003cp\u003eResults: During the pre-switch period, mean BCVA declined by −1.9±8.2 letters and CST increased. At 3 months after switching, BCVA improved by +2.0±9.2 letters (95% CI, +0.8 to +3.2; p\u0026lt;0.01), with greater gains in eyes switched for non-response (+2.8±12.6 letters). Mean CST decreased by −45.3±79.8 µm (95% CI, −55.4 to −35.2; p\u0026lt;0.001), with corresponding reductions in retinal fluid. Anatomical improvements were more pronounced in eyes switched for non-response, whereas more modest but consistent changes were observed in suboptimal and durability-driven groups. Visual and anatomical outcomes were maintained at 6 months.\u003c/p\u003e\n\u003cp\u003eConclusions: In previously treated nAMD eyes, switching to aflibercept 8 mg was associated with reversal of pre-switch anatomical worsening, reduction in retinal fluid, and modest visual gains. Greater responses were observed in eyes with inadequate pre-switch disease control, supporting its role as a treatment escalation strategy in clinical practice.\u003c/p\u003e","manuscriptTitle":"Switching to aflibercept 8 mg in neovascular age-related macular degeneration: real-world outcomes and differential response by switch indication","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-30 18:24:02","doi":"10.21203/rs.3.rs-9312361/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3776319c-f944-4e2f-a83d-94db0a2ddda0","owner":[],"postedDate":"April 30th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"298127867770399237754353417427929881983","date":"2026-05-15T14:06:46+00:00","index":21,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-13T02:07:12+00:00","index":18,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T18:24:02+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-30 18:24:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9312361","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9312361","identity":"rs-9312361","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}