Rod McNeil

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This article was reviewed by Prof. Martin S. Zinkernagel

Anti-vascular endothelial growth factor (VEGF) treatment regimens for neovascular age-related macular degeneration (nAMD) generally aim to dry the neovascular lesion, but evidence suggests that not all retinal fluid is the same. When fluid is present, intraretinal fluid (IRF) is associated with poorer vision.

However, some fluid, particularly subretinal fluid (SRF), may be tolerated.

Admittedly, questions about the impact of refractory SRF on visual outcomes, such as threshold values and duration, continue to be raised. Practitioners nonetheless agree that persistent (i.e., residual) IRF is bad for vision and requires aggressive treatment to maintain sight. At multiple international congress debates in recent months, advocates for and against the need for complete fluid resolution when treating nAMD have presented cogent arguments, shared below.

Based on current clinical data and clinical practicability, outcomes are best if all fluid is treated rigorously when using protocols other than a fixed dosing regimen, argued Prof. Martin Zinkernagel of the University of Bern, Switzerland, at the 19th European Society of Retina Specialists (EURETINA) Congress in 2019 in Paris, France. He pointed to multiple studies which show that improvement of vision correlates with a dry macula and that IRF correlates with poorer final vision.

A zero-tolerance approach to the presence of fluid in nAMD is encouraged, since patients who avoid fluctuations in fluid in the macula may have better visual outcomes. Higher central subfield thickness (CST) variability was associated with lower best-corrected visual acuity (BCVA) gains up until 96 weeks, according to pooled treatment and study data from an analysis of the Phase 3 HAWK and HARRIER nAMD registration studies.

 Although the amplitude of the BCVA gain is individual, more stable CST was associated with both better visual outcomes and a fluid-free retina.

Dr David Brown, Retina Consultants of Houston, United States, who spoke at the American Academy of Ophthalmology (AAO) 2019 Retina Subspecialty Day in October 2019 in San Francisco, US, also cautioned that visual outcomes in nAMD are poorer when fluid is tolerated. In the FLUID study of ranibizumab treat-and-extend for nAMD, up to 40% of patients had refractory IRF and the mean improvement in BCVA overall was no more than 3 letters at 24 months.

 Substantially better visual outcomes have been reported in other proactive anti-VEGF treat-and-extend studies.

Practitioner experience confirms that nAMD patients can tolerate a small amount of SRF with no detrimental effects on visual outcome and it may be helpful in some patients, observed Dr Ramin Tadayoni, Hopitaux de Paris, France, speaking at the 19th EURETINA Congress. Both baseline and persistent intraretinal cystoid fluid have a negative impact on visual acuity despite treatment, while SRF is associated with better outcomes and a lower rate of progression to geographic atrophy.

Eyes with SRF present at baseline had a higher visual acuity improvement than eyes without baseline SRF up to 96 weeks in the Phase 3 VIEW trials of aflibercept (Eylea, Bayer/Regeneron) for nAMD.

 Irrespective of treatment frequency, presence of SRF shows a stable association with better visual outcomes in nAMD.

Further supporting evidence comes from theComparison of Age-related Macular Degeneration Treatments Trials (CATT) study, which showed that foveal IRF is associated with worse visual acuity at year 5 and eyes with foveal SRF had better visual acuity at this time point than eyes that did not.

In the FLUID study, vision outcomes with ‘intensive’ treatment aiming for complete fluid resolution were not significantly better than those seen with a ‘relaxed’ regimen that tolerated some SRF (≤200 µm only at the foveal centre).

Not all retinal fluid is the same, argued Dr Joan Miller, Harvard Medical School, United States, who spoke at the AAO 2019 Retina Subspecialty Day. While some SRF may be tolerated with ongoing treatment, IRF indicates CNV activity and needs to be treated more assertively, she said.

Anatomic improvements (in particular, resolution of IRF) are closely associated with better visual outcomes in nAMD. Clinical studies show that stable subfoveal SRF may be associated with better visual outcomes than persistent IRF.

Recent evaluations from the HARBOR study showed that those patients with residual SRF have the best vision outcomes, suggesting that a dry retina does not necessarily correlate with the best vision gains.17 In a post-hoc analysis of the VIEW trials, eyes with early, persistent IRF were shown to have significantly poorer visual acuity gains than those without residual IRF (Figure 1).

 Furthermore, IRF but not SRF was found to have a detrimental impact on visual acuity over 52 weeks.

In the HAWK and HARRIER studies, superior anatomic efficacy outcomes seen for brolucizumab (Beovu, Novartis) with respect to retinal thickness and fluid did not translate to superior vision gains over standard-of-care aflibercept.

Recommendations on the use of fluid status to guide treat-and-extend regimen decisions with anti-VEGF therapy for nAMD, from a global collaboration of expert ophthalmologists and retinal specialists who presented at the Europe Controversies in Ophthalmology 2020 Virtual Conference (COPHy) in March 2020, are summarised in Table 1. Whilst IRF can be considered a biomarker of disease activity, some persistent SRF may be tolerated. Moreover, improving IRF and/or stable SRF can be managed using maintained or extended treatment intervals.

Treat-and-extend retreatment/extension decisions should differentiate between IRF and SRF to improve patient outcomes, as a zero-tolerance approach to SRF may not be required for optimal outcomes, considered Dr Paolo Lanzetta, University of Udine, Italy, at the 2020 COPHy. Moreover, maintaining or extending injection intervals in the presence of residual SRF can decrease overall patient burden by minimising treatment exposure, he added.

Real-world data suggests that some fluid, particularly SRF, may be tolerated without compromising visual outcomes with maintained retreatment in patients with treatment-naïve nAMD (Figure 2).

  If SRF persists but is stable despite intensive therapy and follow-up, only an increase in SRF may be clinically relevant.

Prof. Zinkernagel is a retina specialist based at the Department of ophthalmology at Bern University Hospital, Bern, Switzerland. He has no financial interest in the subject matter.

Wickremasinghe SS, Janakan V, Sandhu SS, et al. Implication of recurrent or retained fluid on optical coherence tomography for visual acuity during active treatment of neovascular age-related macular degeneration with a treat and extend protocol. 

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Recent international ophthalmic congresses have featured advocates for and against the need for complete fluid resolution when treating nAMD, with some ophthalmologists arguing for a zero-tolerance approach to the presence of fluid, and others claiming some residual fluid can be tolerated and may be helpful in some patients. 

Author | Rod McNeil

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