This activity will review the latest data on how intraretinal fluid and subretinal fluid in the retinal pigment epithelium affects visual acuity in patients with neovascular macular degeneration.
Retina specialists involved in the treatment and management of patients with retina disorders.
This continuing medical education activity is supported through educational grant from Regeneron Pharmaceuticals, Inc.
Upon completion of this activity, the participant should be able to:
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Credit Designation Statement
Evolve Medical Education LLC designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Aleksandra V. Rachitskaya, MD
Jorge A. Fortun, MD
Associate Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Medical Director, BPEI at Palm Beach Gardens
Mitul Mehta, MD MS
Fellowship Director, Vitreoretinal Surgery
Assistant Clinical Professor
Vitreoretinal Diseases and Surgery
Gavin Herbert Eye Institute
Univ. of California, Irvine
Hemang K. Pandya, MD
Dallas Retina Center
Veeral Sheth, MD, MBA, FACS
Director of Clinical Research
Board Certified Ophthalmologist and Retinal Surgeon
Clinical Assistant Professor
University of Illinois at Chicago
Lejla Vajzovic, MD
Director, Duke Center for Artificial and Regenerative Vision
Co-Director, Duke Pediatric Retina and Optic Nerve Center
Director, Duke Eye Center Continuing Medical Education
Director, Duke fAVS and AVS Courses
Associate Professor of Ophthalmology
Adult and Pediatric Vitreoretinal Surgery and Diseases
Duke University Eye Center
Jeremy Wolfe, MD
Associated Retinal Consultants
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The following fellows/faculty members have the following financial relationships with commercial interests:
Erin K. Fletcher, MIT, director of compliance and education, Evolve, has no financial relationships with commercial interests.
Susan Gallagher-Pecha, director of client services and project management, Evolve, has no financial relationships with commercial interests.
Cassandra Richards, director of education development, Evolve, has no financial relationships with commercial interests.
Nisha Mukherjee, MD, peer reviewer, has no financial relationships with commercial interests.
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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 sub-retinal 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, the following 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
Waldstein et al conducted a study to determine the correlation of 3-dimensionally quantified intraretinal cystoid fluid (IRC) and subretinal fluid (SRF) with best-corrected visual acuity (BCVA) in treatment-naive patients with nAMD and during antiangiogenic therapy.3
The retrospective cohort included 38 patients. The mean [SD] BCVA score at baseline was 54  ETDRS letters (Snellen equivalent approximately 20/160), with a gain to 63  letters (approximately 20/100) at month 12. A total of 19,456 scans underwent complete quantification of IRC and SRF.
VIEW 1 and VIEW 2 were two similarly designed, phase-3 studies that compared monthly and every-2-month dosing of aflibercept with monthly ranibizumab for the treatment of nAMD.4
Similar to the Waldstein study, this post hoc analysis of the VIEW 1 and VIEW 2 studies also showed the presence of retinal fluid impacts BCVA from baseline to week 24 in patients with nAMD. However, looking at patients with persistent IRF versus SRF, there are differences with regard to their final visual outcomes. 5
Eichenbaum et al concluded that eyes with early persistent (ie, residual) IRF were shown to have significantly lower VA gains than those without (P = .0024), whereas no differences in VA were observed between patients with or without early persistent SRF at week 24.5
The 2019 cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (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 geographic atrophy (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.
The HARBOR Trial results revealed that at month 24, mean BCVA improvements were clinically meaningful and similar among the 1,098 patients with treatment-naïve subfoveal wet AMD in who were treated with ranibizumab. The 0.5 mg as-needed group achieved a mean gain of 7.9 letters at month 24 with an average of 13.3 injections (5.6 injections in year 2).6
This post hoc analysis of the HARBOR focused on the mean change in BCVA in eyes with residual or resolved fluid at months 12 and 24 and included pooled results from eyes treated with different doses and regimens of ranibizumab (N=917).7,8
The graph on the left shows a potential benefit by SRF and having a positive visual outcome. The graph on the right shows IRF had a negative visual prognostic outcome.7,8
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. In addition, the eyes considered “dry” had VA similar to eyes with SRF + IRF. And eyes with residual IRF and no SRF had the worst visual outcomes. Therefore, she concluded, in patients treated for nAMD, the treatment improves visual outcomes rather than “drying.”8
The HAWK and HARRIER trials, two similarly designed phase 3 trials, compared brolucizumab with aflibercept to treat nAMD. The primary hypothesis was noninferiority in mean BCVA change from baseline to week 48, and additional key end points included the percentage of patients who maintained every-12-week dosing through week 48 and anatomic outcomes. The study included patients (N = 1,817) with untreated, active choroidal neovascularization (CNV) due to AMD.9
The results revealed that at week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < .001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on every-12-week dosing through week 48 (56% [HAWK] and 51% [HARRIER]).9,10
The BCVA achieved by brolucizumab at week 48 was maintained at Week 96.9
These graphs show the proportion of patients with IRF and/or SRF at weeks 16, 48 and 96.
At week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = .001) and HARRIER (22.7% vs. 32.2%; P = .002). Greater central subfield thickness (CST) reductions from baseline to week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 mm vs. -143.7 mm; P = .001) and HARRIER (LS mean -193.8 mm vs. -143.9 mm; P < .001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept.9,10,11,12,13
Additional analysis of the fluid is needed.
The OSPREY study evaluated at SRF and IRF outcomes over 56 weeks in 89 treatment-naïve participants with active CNV secondary to AMD. This study had similar outcomes to HAWK / HARRIER in that it showed essentially there was no difference in the IRF outcomes, but a better drying effect was seen in SRF with brolucizumab versus aflibercept, therefore not translating to a better VA outcome.
Eligible participants were randomized 1:1 to intravitreal brolucizumab (6 mg/50 μl) or aflibercept (2 mg/50 μl). Both groups received three monthly loading doses and were then treated every 8 weeks (q8) with assessment up to week 40. In the brolucizumab group, the final q8 cycle was extended to enable two cycles of treatment every 12 weeks (q12; to week 56); participants on aflibercept continued on q8. Unscheduled treatments were allowed at the investigator’s discretion.
The mean BCVA change from baseline (letters) with brolucizumab was noninferior to aflibercept at week 12 (5.75 and 6.89, respectively [80% confidence interval for treatment difference, ー4.19 to 1.93]) and week 16 (6.04 and 6.62 [ー3.72 to 2.56]), with no notable differences up to week 40. Outcomes exploring disease activity during the q8 treatment cycles suggest greater stability of the patients who received brolucizumab, supported by receipt of fewer unscheduled treatments versus aflibercept (6 vs.15) and more stable reductions in central subfield thickness. In addition, from post hoc analysis, a greater proportion of brolucizumab-treated eyes had resolved IRF and SRF compared with aflibercept-treated eyes. Approximately 50% of brolucizumab-treated eyes had stable BCVA during the q12 cycles.
The authors concluded that during the matched q8 phase, the BCVA in brolucizumab-treated eyes appeared comparable to aflibercept-treated eyes, with more stable central subfield thickness reductions, receipt of fewer unscheduled treatments, and higher rates of fluid resolution.14
It remains unclear whether complete fluid resolution is required for optimal visual outcomes. Patients with and without residual retinal fluid had improved BCVA in this analysis. Additional studies are needed.