nAMD and Imaging Modalities

Introduction

Intravitreal injections with anti-VEGF medications have been shown to improve vision in patients with neovascular age-related macular degeneration (nAMD) and have become the standard of care. Treatment with anti-VEGF injections has been shown in clinical trials to improve vision by 6 to 10 letters from baseline, but in contrast to pivotal studies, anti-VEGF intravitreal injections may be relegated to as- needed treatment after the initial loading phase. This activity focuses on the recent pivotal trials and reviews the most effective AMD treatment options.

Location, Location, Location

Many retinal conditions involve the presence of fluid. The understanding of the importance of different fluid compartments is critical in clinical decision-making and this idea is evolving. This optical coherence tomography (OCT) scan shows the presence of intraretinal fluid (IRF), subretinal fluid (SRF), and subretinal pigment epithelium (RPE) fluid.

Historically, disease activity in clinical trials has been based on the following parameters: ~ Loss of >5 Early Treatment Diabetic Retinopathy Scale (ETDRS) letters in visual acuity (VA)~ Evidence of new hemorrhage~ Presence of IRF and/or SRF on OCT However, some data suggest that some types of fluid may be tolerated without compromising visual outcomes in patients with neovascular age-related macular degeneration (nAMD).^1,2 For example, the presence of IRF has been associated with lower baseline VA, delayed response and poor VA outcomes, yet the presence of SRF has resulted in a better VA over time, with no effect as a predictor, and the presence of sub-RPE has no impact of VA outcomes yet is a negative predictor in combination with IRF/SRF.^1-5

Multimodal Imaging in AMD

Various imaging modalities are now available and have improved nAMD detection and diagnosis. Some imaging protocols are best suited for certain stages of AMD. A study by Holz et al summarized the results of two consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-nAMD and nAMD in natural history studies and interventional clinical trials. Imaging protocols include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography (OCT) volume scans. These images should be acquired at regular intervals.⁶ The investigators wrote that In studies of non-nAMD (defined as without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions.⁶

For studies in patients with nAMD, increased need for visualization of the vasculature must be considered. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions.⁶ Additional studies have recommended OCT and possibly FA or OCT Angiography be obtained upon the first clinical suspicion of nAMD.^6,7

CATT Post Hoc Analysis

The 2019 cohort study within the CATT studies also evaluated associations of morphologic features with 5-year VA. The results revealed that 60% of eyes had IRF, 38% had SRF, 36% had RPE fluid, and 66% had subretinal hyper-reflective material (SHRM).²

VA and image gradings were available for 523 of 914 participants (57%) 5 years. Mean (standard deviation) foveal center thickness was 148 μm (99) for retina, 5 μm (21) for SRF, 125 μm (107) for subretinal tissue complex, 11 μm (33) for SHRM, and 103 μm (95) for RPE + RPE elevation. The SHRM, thinner retina, greater CNV lesion area, and foveal center pathology (all P < .001) and IRF (P < .05) were independently associated with worse VA. Like the VIEW post hoc analysis, this study demonstrated the same relationship between fluid of any type, not showing any significant difference in the final outcome. However, IRF had a notable difference in the final outcome.²

Adjusted mean VA letters were 62 for no pathology in the foveal center; 61 for CNV, fluid, or hemorrhage; 65 for non-GA; 64 for nonfibrotic scar; 53 for GA; and 56 for fibrotic scar. Incidence or worsening of eight pathologic features (foveal GA, foveal scar, foveal CNV, SHRM, foveal IRF, retinal thinning, CNV lesion area, and GA area) between years 2 and 5 was independently associated with greater loss of VA from years 2 to 5 and VA loss from baseline to year 5.²

The graph on the left shows that relative to the mean VA in eyes with extrafoveal SRF (57 letters), the mean VA was better for eyes with foveal SRF (68 letters, P = .02) and similar to those without SRF (61 letters). A trend toward better VA in eyes with foveal sub-RPE fluid had better mean VA (73 letters) than eyes without sub-RPEF (60 letters; P = .006) or those with extrafoveal sub- RPE fluid (60 letters; P = 0.01), shown in the graph on the right.² The authors concluded that a significant need to develop therapies to address these adverse pathologic features remains.

Mild, Moderate or Severe IRF

Post hoc analysis of the pooled results from eyes treated with PRN or monthly ranibizumab at doses of either 0.5 mg or 2.0 mg (N=917) with 24 months of evaluable OCT data and SRF or IRF at baseline, screening, or week 1. This analysis looked at all the different ways fluid can occur (SRF, resolved SRF and IRF, residual SRF and IRF, and IRF only) and found that the eyes with persistent SRF had the best VA outcomes, according to Holekamp.⁸ In addition, among eyes with IRF, those with more severe IRF tended to have smaller improvements in BCVA.⁹

HARBOR Post Hoc Analysis^9,8

IRF versus SRF

This graph show results from a post hoc analysis of the pooled results from eyes treated with PRN or monthly ranibizumab at doses of either 0.5 mg or 2.0 mg (N=917) with 24 months of evaluable OCT data and SRF or IRF at baseline, screening, or week 1. Eyes with residual SRF had significantly greater improvements in BCVA at months 12 and 24 compared with those with resolved SRF.⁹

HARBOR Post Hoc Analysis⁹

FLUID Study

Guymer and colleagues tested the hypothesis that tolerating some SRF in patients with nAMD treated with treat-and-extend dosing of ranibizumab can achieve similar VA outcomes as treatment aimed at resolving all SRF. The multicenter, randomized, 24-month, phase 4, single-masked, noninferiority clinical trial included 349 participants (intensive arm, n = 174; relaxed arm, n = 175) with treatment-naïve active subfoveal CNV; 279 (79.9%) completed the month 24.¹⁰ Disease activity included: ~ Loss of BCVA ≥5 letters since baseline~ New retinal hemorrhage~ Presence of fluid on OCT When fluid was present, IRF was treated, but SRF was managed either with a zero tolerance (intensive group) or relaxed tolerance (relaxed group).

The two groups in the study included the “zero tolerance/intensive group” in which all OCT-fluid was managed, and the “relaxed group” in which only SRF >200 µm at foveal center was managed. The data suggests BCVA improvements are similar when treating with zero tolerance for all retinal fluid versus tolerating some SRF.¹⁰ Further studies are warranted to explore the role of SRF in nAMD.

Case 1

74-year-old white male referred for reduced vision in November 2017. His right eye was measuring 20/20, and his left eye was measuring 20/80. VA: 20/20 OD, 20/80 OS

Presentation 20/80 OS; 2 different cuts

These images show the patient at one month, December 2017, following anti-VEGF treatment. A key point is that it is often useful to evaluate multiple images cut through the retina to appreciate different regions and features of fluid.²

After 12 monthly anti-VEGF injections, residual SRF is still present and his VA remains 20/25 OS.

These OCT images show the difference between January and February of 2019, following 12 monthly anti-VEGF doses.

Note on these OCT images the difference between January and April 2019, especially when the period between injections extends from 4 weeks to 6 weeks.

This FA taken in June 2019, after 18 months of nearly monthly anti-VEGF injections, shows staining of the fibrotic CNV. The patient’s VA is 20/25 OS.

In June 2019, this OCTA shows flow in the avascular slab and small residual SRF in the patient’s left eye.

Case Summary

Case 2

A pseudophakic 75-year-old woman presented in September 2015 with dry AMD in her right eye and wet AMD in her left eye. She had never been treated for her AMD and her VA was 20/40.

This image shows the patient 12 months later, after receiving monthly anti-VEGF injections. The patient’s VA was 20/40. The top image was taken before the last monthly injection.

These images show 2 weeks after an injection.

These images show the patient’s presentation in January 2017, 2 years after her first treatment. Her VA was 20/40. The top image was taken 6 weeks after her last injection.

At 2 years, in January 2019, the patient’s VA was 20/30. This patient received 41 injections in 41 months. The top image was taken 5 weeks after the last injection.

July 2019, the patient’s VA was 20/40. The top image was taken 6 weeks after her last injection. She received 45 injections in 47 months.

In these FAF images, the image taken in July 2019 shows the change over time.

Conclusion

This activity highlights the significance of retinal fluid, the location of fluid as seen in various imaging modalities, as well as how it can persist despite regular treatment.

References

1. Arnold JJ, Markey CM, Kurstjens NP, et al. The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration - a phase IV randomised clinical trial with ranibizumab: the FLUID study BMC Ophthalmol 2016;16:31.
2. Jaffe GJ, Ying GS, Toth CA, et al; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Macular morphology and visual acuity in year five of the comparison of age-related macular degeneration treatments trials. Ophthalmology 2019;126(2):252–260.
3. Sharma S, Toth CA, Daniel E, et al; for the Comparison of age-related macular degeneration treatments trials research group. Macular morphology and visual acuity in the second year of the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123:865–875.
4. Simader C, Ritter M, Bolz M, et al. Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related macular degeneration. Ophthalmology. 2014;121(6):1237-1245.
5. Wickremasinghe SS, Sandhu SS, Busija L, et al. Predictors of AMD treatment response. Ophthalmology. 2012;119:2413-2414.
6. Holz FG, Sadda SR, Staurenghi G et al. Imaging protocols in clinical studies in advanced age-related macular degeneration - recommendations from classification of atrophy consensus meetings. Ophthalmology. 2017;124:464–478.
7. Garrity ST, et al. In Bandello F, Querques G, Loewenstein A (eds): Medical Retina.Update 2017. ESASO Course Series. Basel, Karger, 2017;9:14–31.
8. Holekamp NM. HARBOR post-hoc analysis: vision outcomes and the presence of fluid. https://eyetube.net/meeting-coverage/chicago-retina-2019-july/harbor-post-hoc-analysis-vision-outcomes-and-the-presence-of-fluid-#. Updated July 2019. Accessed November 14, 2019.
9. Holekamp NM et al. Presentation at the 42nd Macula Society Annual Meeting; Bonita Springs, FL, USA, February 13–16, 2019.
10. Guymer RH, Markey CM, McAllister IL, et al; FLUID Investigators. Tolerating subretinal fluid in neovascular age-related macular degeneration treated with ranibizumab using a treat-and-extend regimen: FLUID Study 24-Month Results. Ophthalmology. 2019;126(5):723-734.