In the present study, at 6 months after switching from aflibercept 2 mg to aflibercept 8 mg, approximately 80% of patients were able to continue aflibercept 8 mg, with anatomical improvement and extension of treatment intervals observed in this group. In the ALTAIR study, which evaluated the 2-year outcomes of aflibercept 2 mg using a treat-and-extend regimen in Japanese patients with nAMD, more than 40% of eyes achieved the maximum treatment interval of 16 weeks, whereas 30–40% of eyes required the minimum treatment interval of 8 weeks, indicating that a certain proportion of cases have difficulty extending treatment intervals [8]. Our findings suggest that aflibercept 8 mg may offer a useful alternative for such cases. On the other hand, about 20% of eyes could not continue aflibercept 8 mg. Compared with those that continued treatment, eyes that discontinued had significantly shorter pre-switch treatment intervals and a higher frequency of prior treatment with other anti-VEGF agents or PDT before receiving aflibercept 2 mg. These results suggest that in more treatment-refractory nAMD cases—characterized by frequent injections and multiple prior therapies—long-term continuation of aflibercept 8 mg may be challenging. Taken together, these findings provide practical information for selecting patients likely to benefit from switching to aflibercept 8 mg.

Among the eyes that discontinued aflibercept 8 mg, 5 cases were unable to continue due to the requirements of drug labeling. In Japan, restrictions in the drug label and health insurance system mandate that after the initial three loading injections, aflibercept 8 mg must be administered at intervals of at least 8 weeks. Although details vary by country, similar system-based restrictions are reported outside of Japan as factors limiting continuation of aflibercept 8 mg [13]. In addition, 4 eyes that discontinued treatment showed worsening of exudative lesions, and in 2 of these, the onset or enlargement of SRH led to visual deterioration. A previous report describes a case in which SRH developed and subsequent visual decline occurred after switching from aflibercept 2 mg to faricimab [14]. These results suggest that there is a risk of exudative worsening when switching anti-VEGF agents. However, in this study, all 4 eyes with worsening had required aflibercept 2 mg every 4 weeks prior to switching and were highly active nAMD cases, suggesting that the risk of exudative worsening may have been present regardless of whether treatment was switched. Therefore, whether exudative worsening reflects the intrinsic severity of these cases or whether switching anti-VEGF agents itself poses a risk of disease progression requires further investigation in future prospective studies.

With respect to safety, no apparent IOI was observed during the 6 months after switching to aflibercept 8 mg in the present study. In the PULSAR trial, no clear difference in the incidence of IOI was demonstrated between the aflibercept 2 mg and aflibercept 8 mg groups; in the HARBOR trial, which investigated a higher dose of ranibizumab, no dose-dependent differences in adverse events are reported [11, 15]. On the other hand, real-world studies report that the incidence of IOI with aflibercept 8 mg may be higher than historically observed with aflibercept 2 mg [16, 17]. The precise mechanisms of IOI remain unclear, and careful monitoring and further research are warranted to clarify the impact of high-dose formulations on the occurrence of IOI.

The present study demonstrates trends similar to those previously reported in nAMD after switching anti-VEGF therapy from aflibercept 2 mg to brolucizumab or faricimab, including anatomical improvement, extension of treatment intervals, and maintenance of visual acuity [14, 18,19,20]. However, differences in patient background, treatment regimens, and outcome measures across studies make direct comparisons of post-switch outcomes among agents difficult. Brolucizumab is characterized by its small molecular size, which enables high molar dosing, and by its strong binding affinity to VEGF, although a relatively higher risk of IOI is reported [21, 22]. Faricimab, in contrast, is a bispecific antibody that simultaneously inhibits VEGF-A and angiopoietin-2 [23, 24]. Given these distinct pharmacologic profiles, future prospective trials, including head-to-head comparisons, will be required to optimize switching strategies among anti-VEGF agents. Meanwhile, this study reveals that cases previously unable to continue brolucizumab and/or faricimab were significantly more common in eyes that discontinued aflibercept 8 mg than in those that continued aflibercept 8 mg. This finding suggests that, in highly active nAMD, a subset of eyes may have difficulty achieving adequate disease control regardless of which anti-VEGF agent is used.

This study has several limitations. The most important is its retrospective design, due to which the timing of switching to aflibercept 8 mg was determined by each treating physician with patient consent. This reflects real-world practice but lacks standardized switching criteria. In addition, although multivariable analysis would be required to accurately identify factors associated with continuation of aflibercept 8 mg, the limited sample size precluded such an analysis in this study.

In conclusion, in patients with nAMD who could not achieve sufficient extension of treatment intervals with aflibercept 2 mg, switching to aflibercept 8 mg resulted in anatomical improvement and extended treatment intervals in approximately 80% of cases at 6 months, suggesting that aflibercept 8 mg may offer a useful alternative to aflibercept 2 mg. However, in patients with more treatment-refractory disease, characterized by frequent injections and multiple prior therapies before switching, continuation after switching may be challenging.