FLUID Study Rethinks Treat-and-Extend Protocols in Neovascular AMD: Should It Cause You to Do the Same?

Charles C. Wykoff, MD, PhD


June 11, 2019

For patients with neovascular age-related macular degeneration (nAMD), a major cause of visual impairment worldwide,[1] the advent of anti–vascular endothelial growth factor (VEGF) intravitreal injections has been an undeniable breakthrough. Anti-VEGF therapy allows for greater control of the exudative process, which can dramatically improve outcomes compared with observation alone. However, anti-VEGF therapy does not cure nAMD in the substantial majority of patients' eyes and has the associated shortcoming of requiring repeated, regular intraocular injections to optimize long-term visual and anatomic outcomes.[2,3,4,5]

In the face of this long-term treatment burden, treat-and-extend (T&E) protocols were developed to minimize the number of repeated injections while maintaining optimal functional outcomes. T&E protocols have commonly used a zero threshold for fluid approach in which a completely dry retina, without any intraretinal fluid (IRF) or subretinal fluid (SRF), must be achieved before the interval between injections is increased.[6,7,8]

Prospective FLUID Study

Guymer and colleagues[9] published the results of the FLUID study, which nicely challenges an aspect of the T&E clinical approach by hypothesizing that some SRF may be tolerated without compromising visual outcomes.

FLUID was a multicenter randomized, 24-month, phase 4, single-masked clinical trial completed at 16 sites across Australia. Subjects with visual acuity (VA) of 20/320 or better with treatment-naive active subfoveal choroidal neovascularization were randomized to receive ranibizumab, 0.5 mg monthly until either complete resolution of all SRF and IRF (intensive study arm) or resolution of all IRF alone (relaxed study arm). In the relaxed arm, SRF was not tolerated if it was >200 µm at the foveal center. When these thresholds were reached, the interval between treatments was extended similarly between the arms by 2-week increments until the longest tolerated interval between injections was achieved, with a maximum extension interval of 12 weeks. Impressively, a masked reading center was used to assess the presence or absence of IRF and to quantify SRF in order to inform treatment extension decisions.

Among the 349 patients enrolled (174 in the intensive arm and 175 patients in the relaxed arm), 279 (79.9%) completed the primary endpoint at month 24. The mean change in VA was +3.0 letters and +2.6 letters in the intensive and relaxed arms, respectively, with standard deviations of 16.3 letters in each arm, which met the predefined noninferiority margin of five letters. Reassuringly, similar proportions of patients achieved a VA of 20/40 or better and 20/200 or worse in the intensive and relaxed arms (54% vs 57% and 8.7% vs 8.1%, respectively).

Despite intentional tolerance of central SRF up to 200 µm, the relaxed group received just 1.2 fewer mean intravitreal injections than the intensive group through 2 years (15.8 vs 17, respectively), although this was a statistically significant difference (P = .001).

Furthermore, a greater percentage of patients in the intensive group never achieved a treatment interval that extended beyond 4 weeks (13.5% vs 2.8%, P = .003). A greater percentage in the relaxed group extended to the 12-week maximum interval between injections and were able to maintain it (29.6% vs 15.0%, P = .005).

Considerations Before Clinically Applying These Results

When considering applying the FLUID study's findings to clinical practice, there are some key points to consider.

First, all of the patients in FLUID received regular, ongoing anti-VEGF treatment regardless of fluid status. The current protocol did not allow for cessation of therapy under any circumstances. Although many prospective trials have used pro re nata algorithms,[2,5,10] no large prospective trial conducted to date in the anti-VEGF era has intentionally withheld treatment for patients with nAMD with active IRF or SRF.

Second, analyses of prior prospective nAMD data sets have identified baseline SRF as a good prognostic indicator.[11,12,13] The 2-year FLUID study supports the hypothesis that some residual subfoveal SRF may be tolerated when using a T&E management approach, and continued indefinite monthly dosing is not necessarily mandated. Critical to clinical implementation, however, is that even patients' eyes in the relaxed arm of this study were required to demonstrate resolution of IRF before interval extension.

Third, in determining the presence of baseline IRF and SRF, there was 75%-79% agreement between the masked reading center and the treating investigators, meaning that the results from more than 1 out of 5 patients were interpreted differently between the two groups. A similar discrepancy between clinicians and reading centers has been reported in other data sets,[5] and the implications of this are incompletely defined.

Finally, it is worth raising a cautionary note regarding the clinical implementation of a relaxed approach to clinical management of patients with nAMD. The majority of available clinical data indicate that real-world treatment frequencies in the management of patients with nAMD are substantially below those observed in prospective trials. As a result, clinical outcomes in the real world are also substantially lower than those achieved in most prospective trials.[4,14,15] Therefore, achieving and maintaining a dry macula in the ongoing, long-term management of patients with nAMD in order to optimize global outcomes from this blinding disease should remain a priority.

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