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The Relationship Between Fluid and BCVA

By: Aleksandra V. Rachitskaya, MD; Jorge A. Fortun, MD; Mitul Mehta, MD MS; Hemang K. Pandya, MD; Veeral Sheth, MD, MBA, FACS; Lejla Vajzovic, MD; Jeremy Wolfe, MD

Webinar Credits: .5

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.

PRIMARY AUDIENCE:
Retina specialists involved in the treatment and management of patients with retina disorders.


Expiration Date: Friday, April 30, 2021
Release Date: April 2020

Learning Objectives

Upon completion of this activity, the participant should be able to:

  • Summarize how treatment paradigms have evolved over time and how they relate to current treatment options.
  • Identify the relationships between disease characteristics, drug, treatment frequency, visual and anatomic outcomes.

Accreditation and Designation Statement

Accreditation Statement

Evolve Medical Education LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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.

This educational activity is provided by Evolve Medical Education

 

Faculty and Disclosures

Faculty 

Aleksandra V. Rachitskaya, MD

Cleveland Clinic

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

Vitreoretinal Specialist
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

 

Disclosures

It is the policy of Evolve that faculty and other individuals who are in the position to control the content of this activity disclose any real or apparent conflict of interests relating to the topics of this educational activity. Evolve has full policies in place that will identify and resolve all conflicts of interest prior to this educational activity.

The following fellows/faculty members have the following financial relationships with commercial interests:

Aleksandra V. Rachitskaya, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Alcon, Allergan, & Carl Zeiss Meditec.
Jorge A. Fortun, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Allergan, Carl Zeiss, & Novartis; Grant/Research: Allergan, & Novartis.
Mitul Mehta, MD, MS, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Novartis; Speaker: Novartis; Shareholder: Eyedaptic.
Hemang K. Pandya, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Speaker: Novartis.
Veeral S. Sheth, MD, MBA, FACS, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Speaker: Genentech, Alimera, Novartis, EyePoint; Grant/Research: Allergan, Alimera, Genentech, Regeneron, Novartis.
Lejla Vajzovic, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Aerie, Alcon, Allergan, Alimera, B&L, DORC, Guidepoint, Orbit Biomedical Inc.; Grant/Research: Heidelberg Engineering, Orbit Biomedical Inc., Second Sight.
Jeremy Wolfe, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Speaker: Allergan, Genentech, Novartis, Regeneron; Grant/Research: Genentech, Novartis.

Editorial Support

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.

 

Disclaimer

OFF-LABEL STATEMENT
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER
The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Evolve,  or Regeneron Pharmaceuticals.

Pretest

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Introduction

Retinal disorders, including age-related macular degeneration (AMD), diabetic eye disease, and retinal vein occlusion (RVO) can result in vision loss if not treated early and continuously. This activity will focus on treatment and the presence of fluid in patients with neovascular age-related macular degeneration (nAMD).

Fluid

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.

Figure

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

IRC and SRF Related to Baseline BCVA

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 [16] ETDRS letters (Snellen equivalent approximately 20/160), with a gain to 63 [19] letters (approximately 20/100) at month 12.  A total of 19,456 scans underwent complete quantification of IRC and SRF.

Figure

These graphs show some of the work that’s being done to understand the differences in fluid compartments seen in the previous image. The graphs on the left show that both IRC presence and volume affect the actual visual outcome in patients with nAMD in the end of the study. The graphs to the right show how SRF has no relationship with both the volume and presence with the final visual outcome.

The results of this proof-of-principle study indicated that IRC-derived morphometric variables correlated well with treatment-naive BCVA and BCVA outcomes in antiangiogenic therapy. While IRC reduction was associated with BCVA gains, some IRC-mediated neurosensory damage remained permanent.3

VIEW Post Hoc Analysis

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

Figure

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

CATT Post Hoc Analysis

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

Figure

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; = .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.

Figure

HARBOR Trial Post Hoc Analysis

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

Figure

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

HAWK and HARRIER Trials

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

Figure

These graphs show the proportion of patients with IRF and/or SRF at weeks 16, 48 and 96.

Figure

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.

OSPREY

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.

 

Figure

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

Conclusion

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.

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. Waldstein S, Philip AM, Leitner R, et al. Correlation of 3-Dimensionally Quantified Intraretinal and Subretinal Fluid With Visual Acuity in Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2016;134(2) 182–90.
  4. Nguyen QD, Heier J, Brown D, et al. Randomized, double-masked, active-controlled phase 3 trial of the efficacy and safety of intravitreal VEGF trap-eye in wet AMD: one-year results of the View-1 study Invest Ophthalmol Vis Sci. 2011;52:E-Abstract 3073.
  5. Eichenbaum D et al. Poster at the Association for Research in Vision and Ophthalmology (ARVO) 2019 Annual Meeting; Vancouver, Canada, April 28 – May 2, 2019.
  6. Ho AC, Busbee BG, Regillo CD, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014; 121(11):2181-2192.
  7. Holekamp NM et al. Presentation at the 42nd Macula Society Annual Meeting; Bonita Springs, FL, USA, February 13–16, 2019.
  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. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2019:1e13.
  10. Dugel PU et al. Presented at: The Annual Meeting of the American Academy of Ophthalmology 2018; Chicago, IL; October 27-30, 2018.
  11. Dugel PU. Presentation at the American Academy of Ophthalmology (AAO) Annual Congress 2017; New Orleans, Louisiana; 11–14 November, 2017.
  12. Dugel PU et al. Poster presented at the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting; Honolulu, HI, USA, April 29–May 3.
  13. Hamilton R. Presentation at the Royal College of Ophthalmologists (RCOphth) Annual Congress 2018; Liverpool, UK, May 21–24 2018.
  14. Dugel PU, Jaffe GJ, Sallstig P, et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial. Ophthalmology. 2017;124(9):1296-1304.

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    Summarize how treatment paradigms have evolved over time and how they relate to current treatment options.
    Identify the relationships between disease characteristics, drug, treatment frequency, visual and anatomic outcomes.
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