Retinal fluid may persist even long after anti-VEGF Tx for nAMD

A systematic review and meta-analysis show persistence of retinal fluid (RF) up to 2 years after anti-VEGF treatment for neovascular age-related macular degeneration (nAMD).

“[O]ur analysis estimates that nearly half of all treated patients have persistent RF after initiating treatment, and a substantial 18 percent may never attain complete fluid resolution despite continuous therapy,” said the researchers. The analysis also shows correlations between sub-RF (SRF) and better visual outcomes, and intra-RF (IRF) and worse visual outcomes.

Fifty trials (n=21,333) were included. Only treatment arms evaluating US FDA-approved intravitreal anti-VEGF agents (aflibercept, aflibercept 8 mg, bevacizumab, brolucizumab, faricimab, ranibizumab, ranibizumab-nuna, and ranibizumab-eqrn) were analysed. [Ophthalmol Retina 2025;9:603-617]

In fixed-dosing studies, 41.4 percent of patients exhibited some form of RF (SRF ± IRF) by month 12 despite the initial sharp decline from baseline. This rose to 47.4 percent after 12 more months.

This trend was similarly observed in non-fixed-dosing studies (43.2 percent and 41.4 percent at 12 and 24 months, respectively).

These findings suggest that there is significant room for efficacy improvement in terms of achieving better drying, the researchers noted. “This is particularly important for IRF, which was associated with worse BCVA outcomes.”

Despite the paucity of studies with longer follow-ups, the incidence of RF persistence was also high at 60 months, based on pooled analyses of data from two studies with initial fixed dosing (~62.4 percent) and two non-fixed dosing studies (58.6 percent).

The pooled median time-to-first fluid resolution was 10.2 weeks. By week 96, 83 percent of patients achieved a fluid-free finding. Based on cure modelling analysis, about 17.6 percent of eyes may never achieve complete fluid resolution at least once. According to the investigators, these are patients who may have persistent fluid throughout their entire treatment.

“This may be because some patients may have disease driven by pathways apart from VEGF, or have disease driven by [retinal pigment epithelium] pump dysfunction. These findings provide impetus for developing therapies targeting additional pathways, such as those targeting VEGF-C/D,” they explained.

“It would also be prudent to consider that these patients might … be short-term responders … [T]he true proportion of patients who may never achieve a fluid-free finding may be lower than the results from our exploratory finding, assuming there is optimal timing of assessment,” the researchers added.

Fluid status, visual outcomes

Eyes with SRF had significantly higher best-corrected visual acuity (BCVA) than eyes without SRF at all prespecified follow-up timepoints: weighted mean differences (WMDs), 2.84, 2.39, 4.30, and 7.69 letters at baseline, 12, 24, and >60 months, respectively (p<0.05 for all).

“It may be attractive to consider tolerating SRF, as this may reduce treatment burden. Some studies have also suggested that SRF might be beneficial or protective. However, none can prove causality over association, and several key confounders exist. The association between SRF and better visual outcomes might reflect the natural history of certain subtypes of macular neovascularization,” the researchers explained.

Conversely, eyes with IRF had significantly poorer BCVA than eyes without IRF at baseline (WMD, -7.66 letters; p<0.05), 12 months (WMD, -5.38 letters; p<0.05), and >60 months (WMD, -16.23 letters; p=0.03).

There was no significant difference in BCVA between eyes with and without any RF at 12 (WMD, -3.23 letters; p=0.06), 24 (WMD, -2.62 letters; p=0.11), and >60 months (WMD, -2.19 letters; p=0.38).

‘Suboptimal response’

“Patients who receive a course of anti-VEGF injections without complete fluid resolution are sometimes labelled as having ‘suboptimal response’. However, the relationship between fluid resolution and VA gain is unclear,” the investigators noted.

“Our study provides clinicians with key information for patient counselling and suggests there continues to be a significant clinical need for improvement in nAMD management,” they concluded.