THE LATEST PUBLISHED RESEARCH

WELCOME to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• Early Experience with Brolucizumab Treatment of nAMD
• The Effectiveness of Intravitreal Aflibercept in nAMD
• Biomarkers for Predicting Anti-VEGF’s Effect
• Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material and Sub-RPE Disease in nAMD
• Evaluating Treatment Response of Aflibercept in Wet AMD Using OCTA
• Characteristics of Treatment-naïve Quiescent CNV Detected by OCTA in AMD
• Risk factors for Fellow Eye Treatment in Protocol T
• Widefield SS-OCTA Metrics Associated with Development of Diabetic Vitreous Hemorrhage
• pRNFL and Microvasculature in Prolonged Type 2 Diabetes Patients
• VA Outcomes Following Anti-VEGF Treatment for Macular Edema Secondary to CRVO
• A Novel Method to Detect & Monitor Retinal Vasculitis Using SS-OCTA
• Noteworthy

Early Experience with Brolucizumab Treatment of nAMD

Investigators wrote that since outcome data is limited regarding early experience with brolucizumab, the most recently approved anti-vascular endothelial growth factor agent for the treatment of neovascular age-related macular degeneration, they thought it would be helpful to report clinical outcomes after intravitreous injection (IVI) of brolucizumab 6 mg for nAMD.

This retrospective case series conducted at 15 U.S. private or academic ophthalmological centers included consecutive patients with eyes treated with brolucizumab by six retina specialists between October 17, 2019, and April 1, 2020.

Main outcomes included change in mean visual acuity and optical coherence tomography parameters, including mean central subfield thickness, and presence or absence of subretinal and/or intraretinal fluid. Secondary outcomes included ocular and systemic safety.

A total of 172 eyes from 152 patients (87 women [57.2 percent]; mean age, 80 ±8 years) were included. Here were some of the findings:
• Most eyes (166 [96.5 percent]) had been treated before, and 65.7 percent (109 of 166) were switched from the prior anti-VEGF agent because of persistent fluid detected on optical coherence tomography scans.
• Study eyes received a mean of 1.46 ±0.62 brolucizumab IVIs.
• The mean VA prior to starting brolucizumab was a 64.1 ±15.9 Early Treatment Diabetic Retinopathy Study letter score (Snellen equivalent, 20/50) and a 63.3 (17.2) ETDRS letter score (Snellen equivalent, 20/63) at the last study evaluation (mean difference, 0.8; CI, -2.7 to 4.3; p=0.65).
• No difference was found in mean VA prior to starting brolucizumab compared with VA after brolucizumab IVIs or at the final study evaluation.
• The mean central subfield thickness in eyes prior to starting brolucizumab was 296.7 ±88 μm and at the last study exam was 269.8 ±66.5 μm (mean difference, 26.9 µm; CI, 9 to 44.7 µm; p=0.003).
• Intraocular inflammation was reported in 14 eyes (8.1 percent), was self-limited and resolved without treatment in almost half those eyes (n=6).
• One previously reported eye (0.6 percent) had occlusive retinal vasculitis and severe loss of vision.

Investigators found that brolucizumab IVI for nAMD yielded stable VA with a reduction in central subfield thickness. They added that intraocular inflammation events ranged from mild with spontaneous resolution, to severe occlusive retinal vasculitis in one eye.

SOURCE: Enríquez AB, Baumal CR, Crane AM, et al. Early experience with brolucizumab treatment of neovascular age-related macular degeneration. JAMA Ophthalmol 2021; Feb 25. [Epub ahead of print].

The Effectiveness of Intravitreal Aflibercept in nAMD  

Researchers assessed the real-world effectiveness of intravitreal aflibercept injections in Germany in patients with neovascular age-related macular degeneration over 24 months, as part of the PERSEUS prospective, non-interventional cohort study.

The primary endpoint was the mean change in visual acuity from baseline. Secondary endpoints included the proportion of patients with a VA gain or loss of ≥15 letters, and the frequency of injections and exams. Patients with regular (bimonthly after three monthly injections during year one and ≥four injections in year two) and irregular (any other) treatments were analyzed. The last observation carried forward (LOCF) and the observed cases (OC) approach was applied for primary endpoint analysis to account for missing data.

A total of 803 patients were considered for effectiveness analysis. At month 24, only 38 percent of patients were still under observation. The LOCF population included 727, and the OC population included 279 patients. Here were some of the findings:
• Treatment-naïve patients improved by 6.3 letters (LOCF)/8.1 (OC) with regular treatments over 24 months, but only by 3.3 letters (LOCF)/3.1 (OC) with irregular treatment.
• The proportion of treatment-naïve patients achieving a VA improvement of ≥15 letters was similar between regularly and irregularly treated cohorts.
• More patients experienced a VA worsening of ≥15 letters in the irregular cohorts ([LOCF] 18.7 percent) vs. the regular cohorts ([LOCF] 7.4 percent).

Researchers determined that regular intravitreal injections of aflibercept treatment resulted in better VA outcomes than irregular treatment at month 24, although only a minority of patients received regular treatment over a two-year period.

SOURCE: Eter N, Hasanbasic Z, Keramas G, et al; PERSEUS Study Group. PERSEUS 24-month analysis: A prospective non-interventional study to assess the effectiveness of intravitreal aflibercept in routine clinical practice in Germany in patients with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021; Feb 6. [Epub ahead of print].

Biomarkers for Predicting Anti-VEGF’s Effect

Researchers sought to determine structural predictors of treatment response in neovascular age related macular degeneration by analyzing optical coherence tomography-related biomarkers.

A retrospective review of patients undergoing treatment for nAMD at a tertiary institute were reviewed at presentation. A high-intensity regimen included eyes on long-term anti-vascular endothelial growth factor treatment unable to extend beyond a month without a relapse and needing double the dose of medication (n=25). A low-intensity regimen included eyes that went into long-term remission after at least three injections and remained dry for more than a year until the last visit (n=20). Multimodal imaging such as fluorescein angiogram, optical coherence tomography and comprehensive ocular evaluation was used. Choroidal vascularity index, total choroidal area, luminal area, subfoveal choroidal thickness, choriocapillaris thickness, and Haller’s and Sattler’s layer thickness were analyzed for statistical significance.

Researchers found the groups had no significant difference at baseline in age, gender, incidence of reticular pseudodrusen, polypoidal choroidal vasculopathy features on OCT, type of choroidal neovascular membrane or geographic atrophy. Multinomial logistic regression revealed that thicker SFCT and larger total choroidal area were the significant predictors of poor response to anti-VEGF treatment (E=0.02, p=0.02; E=1.82, p=0.0075).

Researchers concluded that greater subfoveal choroidal thickness and larger total choroidal area were useful variables to predict a poor treatment response.

SOURCE: Jhingan M, Cavichini M, Amador M, et al. Choroidal imaging biomarkers to predict highly responsive and resistant cases treated with standardized anti-vascular endothelial growth factor regimen in neovascular age related macular degeneration. Retina 2021; Feb 24. [Epub ahead of print.]

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material and Sub-RPE Disease in nAMD

In a study funded by Novartis, researchers longitudinally assessed the effect of anti-vascular endothelial growth factor treatment on ellipsoid zone (EZ) integrity, subretinal hyperreflective material (SHRM), and the subretinal pigment epithelium compartment in eyes with neovascular age-related macular degeneration.

This study was a post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, Phase II study comparing brolucizumab 6 mg with aflibercept 2 mg over 56 weeks. Participants with treatment-naïve nAMD at the initiation of the trial were included in the analysis.

Eyes were evaluated with spectral-domain optical coherence tomography at four-week intervals in the OSPREY trial (n=81). SD-OCT scans collected from each visit were automatically segmented using a proprietary machine-learning-enabled higher-order feature-extraction platform for the retinal layer, SHRM and sub-RPE boundary lines, which were evaluated and corrected as needed by masked trained graders. The current analysis focused only on subjects evaluated with Cirrus (Zeiss) platform, n=28).

Outcome measures included change from baseline in EZ-RPE volume, EZ-RPE central subfield thickness (CST), total EZ attenuation, SHRM volume, SHRM CST and total sub-RPE volume. The correlation between each of these measures and best-corrected visual acuity at each visit was evaluated.

Here were some of the findings:

• EZ-RPE volume and EZ-RPE CST showed significant increases.
• Total EZ attenuation, SHRM volume, SHRM CST and total sub-RPE volume showed significant decreases from baseline at each visit from week four to 56 (p<0.05 at each visit).
• EZ integrity measures and SHRM volume significantly correlated with BCVA at most visits (p<0.05).
• No significant correlation was found between total sub-RPE volume and BCVA.

Researchers determined that EZ integrity, SHRM and sub-RPE disease features in eyes with nAMD showed improvement as early as week four of anti-VEGF treatment. They found that EZ integrity measures and SHRM volume were predictors of visual acuity over the first year of treatment.

SOURCE: Ehlers JP, Zahid R, Kaiser PK, et al. Longitudinal assessment of ellipsoid zone integrity, subretinal hyperreflective material, and sub-RPE disease in neovascular AMD. Ophthalmol Retina. 2021 Feb 25. [Epub ahead of print].

Evaluating Treatment Response of Aflibercept in Wet AMD Using OCTA

Researchers used optical coherence tomography angiography to measure the change in size (mm²) and density (flow index) of choroidal neovascular membranes from baseline to week 52 of treatment-naïve wet age-related macular degeneration patients receiving intravitreal aflibercept injections (IAI).

Patients were treated with IAI at baseline, months one and two, and then every other month for a total of 12 months. Along with clinical exam and best-corrected visual acuity, OCTA 6- and 3-mm scans were acquired at every visit between May 2017 and January 2019. Data from baseline, week 12 and week 52 were analyzed prospectively and included in the final analysis.

Twenty-five eyes from 23 patients were included in the study. Here were some of the findings:
• The mean BCVA at baseline and week 52 increased from 20/125 to 20/80, respectively (p<0.001).
• The mean central subfield thickness at baseline and week 52 decreased from 330.48 to 222.40 μm, respectively (p<0.001).
• Seventeen patients (18 eyes) completed all protocol-based 6 × 6 mm and 3 × 3 mm OCTA scans. In this subgroup:
   o 6-mm OCTA scans revealed that the mean size of choroidal neovascular membranes before and after IAI was 1.21 mm² and 0.56 mm², respectively (p<0.001);
   o 3-mm OCTA scans at baseline and week 52 demonstrated a decrease in mean size of the choroidal neovascular membranes from 0.89 to 0.37 mm², respectively (p<0.001).
• The 6-mm perfusion density map revealed no difference at either time point.

Researchers found that OCTA provided a useful approach for monitoring and evaluating the treatment of intravitreal aflibercept for choroidal neovascular membranes. They added that mean size of choroidal neovascular membranes could be identified by 3- or 6-mm scans, but without machine learning, it required extensive segmentation. While reproducibility and clear delineation of choroidal neovascular membranes in wet AMD using OCTA was challenging, OCTA offered the ability to monitor choroidal neovascular membrane size changes during treatment, and may offer another biomarker to assist in assessing treatment response.

Characteristics of Treatment-naïve Quiescent CNV Detected by OCTA in AMD

Scientists aimed to determine the characteristics of eyes with treatment-naïve quiescent choroidal neovascularization detected by optical coherence tomography angiography.

Thirty-eight eyes of 37 treatment-naïve consecutive patients (30 men, 7 women, average 69.8 years) were studied. Quiescent CNVs were detected by OCTA (RTVue XR Avanti, Optovue) in all eyes. Swept-source OCT (SS-OCT; DRI-OCT, Topcon) confirmed the absence of exudation. The symptoms, visual acuity, CNV size and status of the fellow eye were evaluated. Patients were followed longitudinally, and the length of follow-up period and development of exudation were recorded for each patient. Scientists also investigated patients' medical records from referral hospitals in search of prior exudation.

Here were some of the findings:

• All eyes with quiescent CNV were diagnosed at the initial visit with subretinal pigment epithelium CNVs, i.e., type 1 CNV, from the OCT and OCTA images.
• Prior exudation was confirmed in 15 eyes (39.5 percent) from their medical records of the referral hospitals.
• Symptoms were present in 18 eyes (47.3 percent).
• An exudative CNV was present in 12 of the fellow eyes. Exudation developed in 12 eyes (31.6 percent) during an average follow-up period of 25.1 months.
• One-half of the eyes had prior exudation.
• The CNV at baseline in eyes that developed exudation during the follow-up period was larger than eyes without exudation; however, the difference wasn’t significant (0.59 ±0.47 vs 0.48 ±0.32 mm², p=0.50).

Scientists reported that quiescent CNVs developed exudation in approximately 30 percent of eyes during a mean two-year follow-up period. They suggested that these findings should be remembered when investigating quiescent CNVs that can’t be distinguished from eyes with formerly active CNV and naturally deactivated CNV.

Risk factors for Fellow Eye Treatment in Protocol T

Investigators identified risk factors for fellow-eye treatment of diabetic retinopathy with vascular endothelial growth factor injections from the Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol T trial, as part of a post hoc analysis of randomized clinical trial data.

Cox regression analysis was performed at 52 and 104 weeks to determine risk factors for treatment in 360 fellow eyes. Survival analysis was performed to determine mean time to treatment based upon medication used.

Here were some of the findings:
• Of 360 fellow eyes, 142 (39.4 percent) required treatment between weeks four and 104.
• Risk factors predicting a lower likelihood of year-one treatment included older subject age (HR=0.98; CI, 0.96 to 0.99; p=0.02) and higher baseline study eye ETDRS score (HR=0.98; CI, 0.97 to 0.99; p=0.04).
• Center-involving DME at baseline in the fellow eye was predictive of a higher treatment need at 52 weeks (HR=1.89; CI, 1.42 to 2.51, p<0.0001) and 104 weeks (HR=2.68; CI, 1.75 to 4.11, p<0.0001).
• Subjects treated in the study eye with aflibercept (HR=0.574; CI, 0.371 to 0.887, p=0.013) and ranibizumab (HR=0.58; CI, 0.36 to 0.94, p=0.03) were less likely to require first-year fellow-eye injection than subjects treated with bevacizumab, although this difference was no longer statistically significant at week 104 (aflibercept HR=0.77; CI, 0.52 to 1.16; p=0.21; ranibizumab HR=0.66; CI, 0.43 to 1.00, p=0.05).
• Mean time to treatment was significantly shorter in the bevacizumab group (bevacizumab 25.83 weeks, aflibercept 38.75 weeks, ranibizumab 34.70 weeks (p=0.012)).

Investigators reported that bilateral treatment with intravitreal anti-VEGF injections was common during the DRCR.net Protocol T. They added that medication choice may impact on the risk of fellow-eye treatment.

SOURCE: Ness S, Green M, Loporchio D, et al. Risk factors for fellow eye treatment in protocol T. Graefes Arch Clin Exp Ophthalmol 2021; Feb 10. [Epub ahead of print].

Widefield SS-OCTA Metrics Associated with Development of Diabetic Vitreous Hemorrhage

Investigators assessed the association among widefield swept-source optical coherence tomography angiography (WF SS-OCTA) metrics and systemic parameters, and the occurrence of vitreous hemorrhage (VH) in eyes with proliferative diabetic retinopathy, as part of a prospective, observational study. Two of the authors have consulted for, or received honoraria from, OCTA-maker Heidelberg Engineering.

Fifty-five eyes from 45 adults with PDR, with no history of VH, followed for at least three months were included.

All patients were imaged with WF SS-OCTA (Montage 15×15 mm and HD-51 Line scan). Images were independently evaluated by two graders for quantitative and qualitative WF SS-OCTA metrics defined a priori. Systemic and ocular parameters and WF SS-OCTA metrics were screened using Least Absolute Shrinkage and Selection Operator (LASSO) and logistic/Cox regression for variable selection. Firth's Bias-Reduced logistic regression models (outcome: occurrence of VH) and Cox regression models (outcome: time to occurrence of VH) were used to identify parameters associated with the occurrence of VH. The main outcome measure was occurrence of VH.

Here were some of the findings:

• Over a median follow-up of 363 days (range, 28 to 710 days), 13 of 55 (24 percent) PDR eyes developed VH during the follow-up period.
• Presence of extensive neovascularizations (NVs)(OR=8.05; CI,1.43-58.56; p=0.02), defined as NVs with total area greater than four disc diameters, and forward NVs (OR=5.42; CI, 1.26 to 35.16; p=0.02) that traversed the posterior hyaloid face into the vitreous were associated with the occurrence of VH.
• The presence of flat NVs (OR=0.25; CI, 0.04 to 1.01; p=0.05) confined to the posterior hyaloid face was associated with a lower risk of VH with borderline significance.
• Similarly, presence of extensive NVs (HR=18.24; CI, 3.51 to 119.47, p<0.001) and forward NVs (HR=9.50; CI, 2.07 to 68.08, p=0.002) were significantly associated with time to development of VH.

Investigators concluded that WF SS-OCTA was useful to evaluate NVs and their relationship with the vitreous; the presence of forward NVs and extensive NVs were associated with the occurrence of VH in patients with PDR. Investigators suggested that larger samples and longer follow-up would be needed to verify the risk factors and imaging biomarkers for diabetic VH.

pRNFL and Microvasculature in Prolonged Type 2 Diabetes Patients

Investigators aimed to identify the effects of prolonged type 2 diabetes (T2DM) on the peripapillary retinal nerve fiber layer (pRNFL) and peripapillary microvasculature in patients with prolonged T2DM without clinical diabetic retinopathy.

Subjects were divided into three groups: controls (153 eyes); patients with T2DM <10 years (DM group 1; 136 eyes); and patients with T2DM ≥10 years (DM group 2; 74 eyes). Investigators compared the pRNFL thickness and peripapillary superficial vessel density. They performed linear regression analyses to identify factors associated with peripapillary vessel density in patients with T2DM.

Here were some of the findings:
• The mean pRNFL thicknesses for the following groups were: controls: 96 ±7.9; DM group 1: 94.5 ±0.9; and DM group 2: 92.2 ±8.2 µm (p<0.001).
• The VDs for the following groups were: controls: 18.24 ±0.62; DM group 1: 17.60 ±1.47; and DM group 2: 17.15 ±1.38 mm−1 (p<0.001).
• In multivariate linear regression analyses, significant factors affecting the peripapillary vessel density in patients with T2DM were: visual acuity (B=-2.460, p=0.001); axial length (B=-0.169, p=0.008); T2DM duration (B=-0.056, p<0.001); and pRNFL (B=0.024, p=0.001).

Investigators wrote that patients with T2DM without clinical DR showed thinner pRNFL, and lower peripapillary vessel density and perfusion density (PD) compared with normal controls. They added that this damage was more severe in patients with T2DM ≥10 years. Furthermore, investigators found peripapillary vessel density was significantly associated with best-corrected visual acuity, axial length, T2DM duration and pRNFL thickness in patients with T2DM.

SOURCE: Lee M-W, Lee W-H, Ryu C-K, et al. Peripapillary retinal nerve fiber layer and microvasculature in prolonged type 2 diabetes patients without clinical diabetic retinopathy. Invest Ophthalmol Vis Sci 2021;62:2:9.