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:

• Impact of Baseline Characteristics on GA Progression in the FILLY Trial
• Subthreshold Nanosecond Laser in AMD
• OCT Signs of Early Atrophy in AMD: Inter-reader Agreement
• IAI vs. Sham as Prophylaxis Against Conversion to Exudative AMD in High-risk Eyes
• Recurrent nAMD after Discontinuation of VEGF inhibitors Managed in T&E Regimen
• Role of Intra- and Subretinal Fluid on Outcomes of nAMD Treatment
• Prognostic Significance of Multilayered PED Detachment in AMD
• Relationship Between Multilayered CNV & Choriocapillaris Flow Deficits in AMD
• Response of Retinal NV to Aflibercept or PRP in PDR
• Natural History and Predictors of Vision Loss in Eyes with DME and Good Initial VA
• Ranibizumab and Aflibercept for Macular Edema in BRVO
• Noteworthy

Impact of Baseline Characteristics on GA Progression in the FILLY Trial

Apellis Pharmaceuticals’ investigators evaluated the effect of select baseline characteristics on geographic atrophy progression in eyes receiving intravitreal pegcetacoplan or sham, as part of the company’s Phase II multicenter, randomized, single-masked, sham-controlled trial of the drug.

Patients with GA received 15 mg pegcetacoplan monthly or every other month (EOM), or sham injection monthly or EOM for 12 months. The primary efficacy endpoint was change in GA lesion size (square root) from baseline. Post hoc analysis evaluated the effects of age; gender; lesion size, focality and location (extrafoveal vs. foveal); pseudodrusen status; best-corrected visual acuity; and low luminance deficit (LLD) on GA progression at month 12.

Of 246 randomized patients, 192 with 12-month data were included in this analysis. Here are some of the findings:
• Overall mean (standard deviation) change in lesion size (mm) was +0.26 (+0.17) (p<0.01), in the monthly pegcetacoplan group (n=67); +0.27 (+0.27) (p<0.05) in the EOM pegcetacoplan group (n=58) group; and +0.36 (+0.21) in the sham (n=67) group.
• In univariate analysis, patients with extrafoveal lesions (p<0.001), BCVA ≥20/60 (p=0.001) and larger LLD (p=0.002) had greater mean changes in lesion size.
• Multivariate analysis confirmed significant association of extrafoveal lesions (p=0.001) and larger LLD (p=0.023) with GA progression.
• Monthly and EOM pegcetacoplan significantly reduced progression (p<0.05) when controlling for these risk factors.

Investigators found that extrafoveal lesions and larger LLD were potential risk factors for GA progression. They reported that pegcetacoplan treatment significantly controlled GA progression even after accounting for these risk factors.

Subthreshold Nanosecond Laser in AMD  

Investigators evaluated the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration, as part of an observational extension study to a randomized, sham-controlled trial.

The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in one eye at six-monthly intervals up to 30-months. After the completion of the LEAD study, the two largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study examined all participants from the two sites that were enrolled in the LEAD study at baseline, including the additional observational data. Two-hundred and twelve participants with bilateral large drusen were included.

Main outcome measures included time to develop late AMD defined on multimodal imaging between those randomized to the SNL or sham treatment. Here were some of the findings:

• Overall, no significant differences were found in rate of progression over a 60-month period in those randomized to the SNL compared to sham group (adjusted HR=0.63; CI, 0.36 to 1.09; p=0.098), similar to the findings at 36 months in the LEAD study. However, there continued to be evidence of treatment effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction p=0.007).
• Progression was significantly slowed with SNL treatment for those without coexistent RPD (adjusted HR=0.34; CI, 0.16 to 0.71; p=0.004), but it wasn’t significantly different for those with RPD (adjusted HR=1.81; CI, 0.67 to 4.88; p=0.239).

Investigators wrote that a 24-month observational extension study to the LEAD trial confirmed that SNL treatment didn’t significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, they noted that the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment was encouraging. Investigators suggested that the findings provided further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.

SOURCE: Guymer RH, Chen FK, Hodgson LAB, et al; LEAD Study Group. Subthreshold nanosecond laser in age-related macular degeneration: observational extension study to the lead clinical trial. Ophthalmol Retina. 2021; Mar 1. [Epub ahead of print.]

OCT Signs of Early Atrophy in AMD: Inter-reader Agreement

Researchers analyzed inter-reader agreement for incomplete and complete retinal pigment epithelium and outer retinal atrophy (iRORA and cRORA, respectively), and related features in age-related macular degeneration, as part of an inter-reader agreement study.

After 12 readers from six reading centers received formal training, they qualitatively assessed 60 optical coherence tomography B-scans from 60 eyes with AMD for nine individual features associated with early atrophy. They performed seven different annotations to quantify the spatial extent of OCT features within regions-of-interest. Qualitative and quantitative features were used to derive the presence of iRORA and cRORA as part of an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy.

Main outcome measures included inter-reader agreement based on Gwet’s first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features.

Here were some of the findings:
• Substantial or better inter-reader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1=0.63 to 0.87), except for retinal pigment epithelium attenuation (AC1=0.46) and disruption (AC1=0.26).
• The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (±190.8μm).
• Moderate agreement was found for a three-category classification of no atrophy, iRORA and cRORA (AC1=0.53).
• Exploratory analyses suggested a significantly higher level of agreement for a three-category classification using: no atrophy; presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band as a less severe atrophic grade; and the latter plus an additional requirement of choroidal hypertransmission ≥250μm for a more severe atrophic grade (AC1=0.68; p=0.013).

Researchers reported that assessment of iRORA and cRORA, and most of their associated features, were able to be performed relatively consistently and robustly. They added that a refined combination of features to define early atrophy could further improve inter-reader agreement.

SOURCE: Wu Z, Pfau M Blodi BA, et al. Optical coherence tomography signs of early atrophy in age-related macular degeneration: Inter-reader agreement. CAM Report 6. Ophthalmol Retina 2021; Mar 22. [Epub ahead of print.]

IAI vs. Sham as Prophylaxis Against Conversion to Exudative AMD in High-risk Eyes

Anti-vascular endothelial growth factor agents may provide a prophylactic effect in high-risk eyes with intermediate dry age-related macular degeneration against conversion to exudative AMD (eAMD), lowering the risk of vision loss, and investigators undertook a randomized study to determine if this was, in fact, the case.

This single-masked, sham-controlled, randomized clinical trial performed at four U.S. clinical sites enrolled patients with intermediate AMD in one eye (study eye), defined as: presence of more than 10 medium drusen (≥63 to <125 μm); at least one large druse (≥125 μm) and/or retinal pigmentary changes; and eAMD in the fellow eye. Patients were treated from June 23, 2015 to March 13, 2019.

Patients received intravitreal aflibercept injection (2 mg) or sham quarterly injection for 24 months (1:1 randomization). The primary endpoint was the proportion of patients with conversion to eAMD at month 24 characterized by development of choroidal neovascularization, as assessed by leakage on fluorescein angiography and fluid on spectral-domain optical coherence tomography by an independent masked reading center.

Of 128 patients enrolled, 127 (63 in the IAI group and 64 in the sham group) were included in the primary analysis (68 men [53.5 percent]; mean age, 76.5 ±8.1 years). Baseline demographic and clinical characteristics were balanced between the groups. Here are some of the findings:
• By month 24, six patients (9.5 percent) in the IAI group and seven (10.9 percent) in the sham group developed eAMD (p=0.98).
• Patients with a history of eAMD for longer than two years in their fellow eye at baseline showed a lower rate of conversion to eAMD in the study eye compared with those with a history of eAMD for two years or less in the fellow eye.
• Safety was consistent with previous studies involving intravitreal anti-VEGF injections.

Investigators found that the rates of conversion weren’t lower in the IAI group compared with the sham-treatment group at month 24. They added that understanding the mechanism of conversion to eAMD and therapies that could prevent this event remain an important unmet need.

SOURCE: Heier JS, Brown DM, Shah SP, et al. Intravitreal aflibercept injection vs sham as prophylaxis against conversion to exudative age-related macular degeneration in high-risk eyes: a randomized clinical trial. JAMA Ophthalmol 2021; Mar 18. [Epub ahead of print].

Recurrent nAMD after Discontinuation of VEGF inhibitors Managed in T&E Regimen

Scientists evaluated the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration previously followed in a treat-and-extend regimen in which treatment had been stopped due to disease stability.

This prospective cohort study included 105 patients with nAMD previously followed in a T&E regimen treated with aflibercept injections. All patients with a dry macula on three consecutive visits 12 weeks apart were eligible to participate in the study. Patients were examined at baseline and then monitored for disease recurrence four, six, eight, 10 and 12 months after the last injection.

Main outcome measures included the proportion of patients with recurrent disease within 12 months after the last injection, and changes in BCVA at time of recurrence and after resumed therapy.

Here were some of the findings:

• Evidence of recurrent nAMD was seen in 54/102 patients (52.9 percent) after 12 months of follow-up.
• The mean time to recurrence after the last injection was 6.7 ±2.2 months.
• The best-corrected visual acuity decreased from 71.7 ±10 ETDRS letters at baseline to 68.1 ±11.1 letters at recurrence (p=0.12).
• After treatment was resumed, BCVA increased to 71.4 ±10 letters (p=NS compared to baseline).
• Patients with a pigment epithelial detachment (PED) at baseline had a 74 percent (14/19) recurrence rate compared to 48 percent (40/83) in subjects without a PED (p<0.05).
• Only 22/54 (40.7 percent) of patients with recurrent disease had symptoms of visual loss or metamorphopsia.

Scientists wrote that recurrent nAMD is common in previously stable patients where anti-VEGF injections have been suspended. They added that it is difficult to predict which patients will have a recurrence, and most of these patients don’t have symptoms in the early stages of reactivation. As such, scientists suggested, long-term follow-up is important, and early detection of recurrent disease can improve the chances for maintained visual function.

SOURCE: Aslanis S, Amrén U, Lindberg C, et al. Recurrent neovascular age-related macular degeneration after discontinuation of VEGF inhibitors managed in a treat and extend regimen. Ophthalmol Retina 2021; March 24. [Epub ahead of print].

Role of Intra- and Subretinal Fluid on Outcomes of nAMD Treatment

Investigators assessed the effect of fluid status at baseline and at the end of the loading phase (LP) of three different ranibizumab regimens: treat-and-extend (T&E); fixed bimonthly (FBM) injections; and pro re nata, in patients with neovascular age-related macular degeneration.

In this post hoc analysis of the In-Eye study, patients were randomized 1:1:1 to the three study arms and were treated accordingly. Investigators analyzed the presence and type of fluid, intraretinal fluid (IRF) or subretinal fluid (SRF), and anatomical and visual outcomes.

Main outcome measures included best-corrected visual acuity, the mean change from baseline BCVA, and the proportion of eyes gaining more than 15 letters or losing more than five letters. Morphological characteristics including the subtype of choroidal neovascular membrane and the development of atrophy and fibrosis were also evaluated.

Here were some of the findings:
• Patients with SRF at the loading phase had better visual outcomes than patients with IRF.
• The persistence of SRF didn’t affect the mean change from baseline BCVA among the three treatment regimens; however, in patients with IRF, the mean change from baseline BCVA was significantly lower in the FBM group.
• The presence of IRF at baseline and at the end of the loading phase was associated with the development of fibrosis at the end of the study; this result was contrary to that observed for patients with SRF.

Investigators reported that, while subretinal fluid was compatible with good visual and anatomical outcomes, intraretinal fluid led to worse results in patients with nAMD. They added that their results suggested patients with intraretinal fluid may have better outcomes when individualized treatment regimens are used (PRN or T&E) vs. a fixed bimonthly regimen.

Prognostic Significance of Multilayered PED Detachment in AMD

Researchers investigated the structure of multilayered pigment epithelial detachment (m-PED) in neovascular age-related macular degeneration, and its association with visual prognosis and the progression of fibrotic scars at 12 months.

They retrospectively analyzed 68 eyes of 63 patients with m-PED that included a prechoroidal cleft. The compartments within m-PED were divided into neovascular tissue (layer 1); a hyperreflective band (layer 2); and a prechoroidal cleft (layer 3). Clinical variables were compared between patients presenting with layer 2 and those who didn’t. Multiple regression analyses were used to find the factors related to visual outcome and fibrotic scar formation.

Here are some of the findings:
• Layer 2 was detected in 38 (55.9 percent) of 68 eyes.
• With continuous treatment, those with layer 2 showed gradual visual deterioration (p<0.001 at month 12), while those without layer 2 showed visual improvement (p<0.001 at month 12).
• In the group with layer 2, thickness significantly increased, and in those without layer 2, if it formed, it increased gradually (p=0.004 at month 12).
• In both groups, other layers significantly decreased by month 12.
• The presence of layer 2 at baseline was significantly associated with a poor visual outcome (p=0.009) and fibrotic scar formation (p=0.023).

Researchers found that multilayered pigment epithelial detachment with a hyperreflective band had a higher risk of fibrotic scar formation and was associated with a poor visual prognosis. They added that a hyperreflective band may be an early-stage precursor of a fibrotic scar.

SOURCE: Kim I, Ryu G, Sagong M. Morphological features and prognostic significance of multilayered pigment epithelium detachment in age-related macular degeneration. Br J Ophthalmol 2021; Mar 3.[Epub ahead of print.

Relationship Between Multilayered CNV & Choriocapillaris Flow Deficits in AMD

Researchers used optical coherence tomography angiography to test the hypothesis that more complex, multilayered choroidal neovascular membranes in age-related macular degeneration were associated with worse flow deficits (FD) in the choriocapillaris.

A retrospective, cross-sectional study included 29 eyes of 29 subjects with neovascular AMD. En face choriocapillaris images were compensated for signal attenuation using the structural optical OCT slab and signal normalization based on a cohort of healthy subjects. Researchers binarized the choriocapillaris using local Phansalkar and global MinError(I) methods, FD count/density; and mean FD size in the area outside the CNV, in the 200-µm annulus surrounding the CNV and in the area outside the annulus. They used projection-resolved OCTA to quantify CNV complexity, including highest CNV flow height, number of flow layers and flow layer thickness. Researchers also assessed the relationship between CNV complexity and choriocapillaris FD.

Here are some of the findings:
• The highest CNV flow signal significantly correlated with lower FD count (p<0.01), higher FD density (p<0.05) and higher mean FD size (p<0.05) in the area outside the annulus and the CNV, using Phansalkar and MinError(I).
• Within the annulus, CNV complexity wasn’t consistently correlated with choriocapillaris defects.

Researchers determined that CNV vascular complexity was correlated with choriocapillaris FD outside the CNV area, providing evidence for the importance of choriocapillaris dysfunction in neovascular AMD, as well as the potential role of choroidal ischemia in the pathogenesis of complex CNV membranes.

SOURCE: Nesper PL, Ong JX, Fawzi AA. Exploring the relationship between multilayered choroidal neovascularization and choriocapillaris flow deficits in AMD. Invest Ophthalmol Vis Sci 2021; Mar 1. [Epub ahead of print.]

Response of Retinal NV to Aflibercept or PRP in PDR

Investigators wrote that eyes with proliferative diabetic retinopathy have a variable response to treatment with panretinal photocoagulation or anti-vascular endothelial growth factor agents. The location of neovascularization is associated with outcomes (e.g., patients with disc NV [NVD] have poorer visual prognosis than those with NV elsewhere [NVE]). Investigators researched the distribution of NV in patients with proliferative diabetic retinopathy and the topographical response of NV to treatment with aflibercept or PRP.

This post hoc analysis of the Phase IIb randomized, single-masked, multicenter noninferiority Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial was conducted from November 1, 2019, to September 1, 2020, among 120 treatment-naive patients with proliferative diabetic retinopathy. The aim was to evaluate the topography of NVD and NVE in four quadrants of the retina on color fundus photography at baseline, and at 12 and 52 weeks after treatment.

In the CLARITY trial, patients were randomized to receive intravitreal aflibercept (2 mg/0.05 mL at baseline, four and eight weeks, and as needed from 12 weeks onward) or PRP (completed in initial fractionated sessions and then on an as-needed basis when reviewed every eight weeks). The study included 120 treatment-naive patients (75 men; mean age, 54.8 ±14.6 years) with proliferative diabetic retinopathy.
The main outcomes were per-retinal quadrant frequencies of NV at baseline and frequencies of patterns of regression, recurrence and new occurrence at 12-week and 52-week unmasked follow-up.
Here are some of the findings:
• At baseline:
   o NVD with or without NVE was observed in 42 eyes (35 percent); and
   o NVE-only was found in 78 eyes (65 percent); NVE had a predilection for the nasal quadrant (64 eyes [53.3 percent]).
• Rates of regression with treatment were higher among eyes with NVE (89 of 102 [87.3 percent]) vs. eyes with NVD (23 of 43 [53.5 percent]) by 52 weeks; NVD was more resistant to either treatment, with higher rates of persistence than NVE (20 of 39 [51.3 percent] vs. 29 of 100 [29 percent]).
• With NVE, the regression rate in the temporal quadrant was lowest (32 of 42 [76.2 percent]).
• Eyes treated with aflibercept showed higher rates of regression of NVE compared with those treated with PRP (50 of 52 [96.2 percent] vs. 39 of 50 [78 percent]; difference, 18.2 percent [CI, 5.5 to 30.8 percent]; p=0.01) but no difference was found for NVD (11 of 17 [64.7 percent] vs. 12 of 26 [46.2 percent]; difference, 18.6 percent [CI, -11.2 to 48.3 percent]; p=0.23).

This post hoc analysis found that disc neovascularization was less frequent although associated with more resistance to currently available treatments than neovascularization elsewhere. Investigators reported that aflibercept was superior to PRP for treating NVE, but neither treatment was particularly effective against NVD by 52 weeks. They suggested that future treatments would be needed to better target NVD, which has a poorer visual prognosis.

SOURCE: Halim S, Nugawela M, Chakravarthy U, et al. Topographical response of retinal neovascularization to aflibercept or panretinal photocoagulation in proliferative diabetic retinopathy: Post hoc analysis of the CLARITY Randomized Clinical Trial. JAMA Ophthalmol 2021; Mar 11. [Epub ahead of print].