Robyn H. Guymer, MBBS, PhD, Caroline M. Markey, PhD, Ian L. McAllister, MBBS, PhD, Mark C. Gillies, MBBS, PhD, Alex P. Hunyor, MBBS, Jennifer J. Arnold, MBBS, on behalf of the FLUID Investigators. Ophthalmology. Volume 126, Number 5, May 2019
Analysis of the CATT, VIEW, and HARBOR studies has raised the question of the importance of achieving a completely dry retina for optimal vision outcomes. In the CATT study, the number of patients achieving a dry retina in the ranibizumab PRN arm was 22.3% versus 45.5% for patients in the ranibizumab monthly arm. Despite this finding, there was no difference in the proportion of patients who gained 15 letters or more. In the VIEW study, although more patients in the aflibercept arm achieved a dry retina compared with ranibizumab (80.3% versus 60.4%), there was little difference in visual acuity outcomes. In the CATT and HARBOR studies, while intraretinal fluid was associated with more macular atrophy and worse vision outcome, the presence of SRF was associated with better visual acuity outcomes.
The current FLUID study was designed to prospectively evaluate the effect of tolerating SRF in patients with AMD. The study was a multi-center, single blinded trial in which 349 patients with treatment naïve subfoveal CNV were randomized to receive ranibizumab monthly until either complete resolution of SRF and IRF (intensive arm) or until resolution of IRF only while tolerating up to 200 µm of SRF (relaxed arm) before extending treatment intervals. A strong aspect of this study was their use of a masked reading center to grade OCTs.
The primary outcome of this study was mean change in best corrected visual acuity (BCVA), central subfield thickness, and number of injections at 24 months. The change in BCVA was +3.0 letters for the intensive group and +2.6 letters for the relaxed group, meeting their noninferiority endpoint. It is notable that there was a difference of only about 1 injection between the two groups (17 in the intensive group vs 15.8 in the intensive group) over 2 years of follow up. They did note, however, that significantly more patients in the intensive arm were never able to extend beyond the 4 week treatment interval (13.5% intensive vs 2.8% relaxed) and more patients in the relaxed group were able to extend to 12 week intervals (29.6% relaxed vs 15.0% intensive).
Of note, visual acuity gains (+3.0 and +2.6 letters) were lower than other large studies, which the authors explain is likely due to a ceiling effect from better baseline mean visual acuity (63.2 letters) in this study.
One important consideration in interpreting the results from this study is the long-term effect (beyond 2 years) of persistent subretinal fluid. We must consider whether reducing the injection burden by about 1 injection over two years offsets this unknown risk. We must use caution when recommending a more relaxed treatment approach, especially when adherence to injection regimens in clinical practice is not always as ideal as it is in clinical trials. Future studies with longer term follow up and real-world studies will be helpful.
Christopher Aderman, MD